Sixty-second annual scientific meeting June 17–22, 2000, San Juan, Puerto Rico

ELSEVIER

DRUGand AlCDHOl@ LRENDEE Drug and Alcohol Dependence 60 Suppl. 1 (2000) Sl-S246 www.elsevier.com/locate/drugalcdep

Supplement

Sixty-Second Annual Scientific Meeting June 17-22, 2000, San Juan, Puerto Rico ACKNOWLEDGEMENT:

1

ADOLESCENT SERVICE UTILIZATION TO SEVERITYOFSUBSTANCEINVOLVEMENT

IN RELATION

MH 55282 and NIAAA 2

THE

COMPUTERIZED

Supported by NIMH grant UOl grant ROl AA 07033 ABUSE

MODULE

G.A. Aarons, S.A. Brown, R.L. Hough, and P.A. Wood, Child and Adolescent Services Research Center, San Diego, CA

A.B. Abdallah and L.B. Cottler, Washington sity School of Medicine, St. Louis, MO

Univer-

This study examines service utilization patterns for adolescents with substance involvement, abuse, or dependence sampled from a large public service system. Participants included 1036 adolescents ages 13 - 18 (M= 15.9; SD = 1.5). Two-thirds were male, 31% were Caucasian, 26% Latino, 18% African-American, 8% Asian-Pacific Islander. Youth report of substance involvement and was obtained using the Composite International Diagnostic Interview-Substance Abuse Module (CIDI-SAM-IV) to assess use, abuse, and dependence of alcohol, cannabis, amphetamines, hallucinogens, cocaine, and opioids. We obtained caregiver report of service utilization using the Services Assessment for Children and Adolescents (SACA). Youth were categorized into four substance use groups: (1) low use; (2) moderate use with no diagnosis; (3) abuse; and (4) dependence. As substance involvement increased, youth were more likely to receive services in the juvenile justice (JJ) and alcohol/drug (AD) sectors (P’s < O.OOl), however, the pattern was more systematic for JJ involvement. As substance involvement became more serious JJ involvement increased in a stepwise fashion. For AD services the pattern was less systematic. Logistic regressions demonstrated that severity of substance involvement was related to increased service involvement for JJ and AD services but this varied by age, gender, ethnicity, and functional impairment. It is likely that comorbid disorders (e.g. Conduct Disorder) are also related to these service use patterns. These findings may reflect a paucity of available and accessible alcohol/drug services for youth with SUDS. However, problems associated with alcohol and drug involvement increased the likelihood of services for secondary problems rather than attention to SUDS.

This hands-on poster session will demonstrate the newly-released NIDAjWHO funded Computerized Substance Abuse Module, an expanded and more detailed version of the substance use sections of the Composite International Diagnostic Interview (CIDI). The SAM can be administered by both non-clinicians and clinicians after appropriate training. The interview questions serve the diagnostic criteria of DSM-III, DSM-III-R, DSM-IV and ICD-10 psychoactive substance use disorders. In addition to alcohol and tobacco (all forms including chew), the SAM includes amphetamines and other stimulants, cannabinoids, cocaine, PCP and other hallucinogens, inhalants, heroin and other opiates, barbiturates and other sedatives and tranquilizers. Recent additions include club drugs and caffeine. The SAM covers onset and recency of specific symptoms, specific withdrawal symptoms and physical, social, and psychological consequences for each category of substances. Information is also obtained on the severity and course of each disorder, including the quantity and frequency of both the heaviest use and use in the past 12 months, age at first and last use, age at first and most recent symptoms, age when criteria were first and most recently met, and age at remission. Impairment and treatment seeking are also elicited. Finally, because of the significant associations between disorder and demographic characteristics, the SAM also elicits critical information about parental absence during childhood, marital status, parenthood, educational achievement, and employment, in addition to general demographic items. The new computerized interview is valuable to investigators because of its userfriendly approach and menu-driven format - one is allowed to choose the substances, as well as the diag-

0376~8716100/$ - see front matter 0 2000 Elsevier Science Ireland Ltd. All rights reserved PII: SO376-8716(00)00212-X

SUBSTANCE

s2

Abstracts

nostic systems - and because it cuts down on training and administration time. 3 GAMMA-HYDROXYBUTYRATE ABATES ABSTINENCE SIGNSIN MORPHINE-DEPENDENTRHESUSMONKEYS M.D. Aceto and E.R. Bowman, Virginia Commonwealth University, School of Medicine, Richmond, VA GHB, an endogenous metabolite of gamma-aminobutyric acid, has been used medically as a hypnotic and general anesthetic and, in the treatment of narcolepsy and drug abuse. It is also used recreationally, predominantly by adolescents and young adults. Our laboratory reported that GHB, which has little, if any, antinociceptive activity in the mouse tail-flick assay, potentiated morphine’s action in this test. It also partially inverted antinociceptive tolerance to morphine. Tolerance reversal was antagonized by naloxone (NIDA Monograph 179, 1998). To further characterize its interaction with the opioid system, single doses of 7.5, 30, 60, 120, and 240 mg/kg, S.C.were substituted for morphine in physically dependent rhesus monkeys in spontaneous withdrawal. GHB produced an inverse dose-response attenuation of withdrawal signs. Onset of action was prompt and duration of action was at least 2.5 h. At the doses tested, no overt behavioral signs attributable to GHB were noted. In a double-blind clinical study Gallimberti and his coworkers (1994) reported that a subanesthetic dose of GHB given every 4-6 h for 8-9 days suppressed most abstinence signs in heroin addicts. Whether or not all of these results are GHB-receptor related and/or due to its interaction with the opioid and/or other systems remains to be ascertained. Therapeutic applications for the treatment of pain and opioid drug abuse suggest themselves. Supported by NIDA Contract DA 5-8059. 4 SMOKING OUTPATIENTS

AND DEPRESSION

AMONG

PSYCHIATRIC

G.S. Acton, J.J. Prochaska, A.S. Kaplan, and S.M. Hall, University of California, San Francisco, CA University of California, San Diego, CA, San Diego State University, San Diego, CA, and University of Hawaii, Honolulu, HI The relations between psychopathology and cognitive and motivational aspects of smoking were examined in a convenience sample of 205 psychiatric outpatients (68% female, mean age 41). Participants completed measures of psychopathology (PRIME-MD and BDIII), readiness to quit smoking, and attitudes toward abstinence. The stages of change distribution approximated that of the general U.S. population. As hypothesized, patients who had never smoked showed lower

rates of Major Depressive Disorder (MDD) than those who had ever smoked. Patients in early stages of change did not show more depressive symptoms or MDD but, as hypothesized, showed less self-efficacy for abstinence. Therapeutic applications are discussed. This research was supported by NIDA grants P50DA09253, ROl-DA02538, and T32-DA07250, and by NC1 grant ROl-CA71378. 5 THE DEVELOPMENT PHENETHYLPHENYLMORPHAN COTIC ANTAGONISTS

OF

ANALOGUES OF NAS POTENTIAL NAR-

S.A. Adah, R.B. Rothman, C.M. Dersch, R. Horel, A.E. Jacobson, and K.C. Rice, NIDDK, NIH and IRP, NIDA, NIH, Bethesda, MD It has recently been reported that (-)-Nphenethylphenylmorphan: (1) was found to act as a narcotic antagonist. We posed the question of whether the N-phenethyl substitution was the only N-substituent which could convert phenylmorphan from a narcotic agonist to a narcotic antagonist in the absence of Carroll’s 9-P-methyl moiety. We have, thus, synthesized other N-substituted phenylmorphan analogues as potential opiate receptor antagonists with a focus on phenyl ring substitution; (2) Synthetic and biological data to date will be presented. 6 DIFFERENTIAL EFFECTS OF DOPAMINE ANTAGONISTS ON LOCOMOTOR ACTIVITY, CONDITIONED ACTIVITYANDCONDITIONEDPLACEPREFERENCEINDUCEDBY COCAINEINRATS J.U. Adams, J.M. Careri, T.R. Efferen, and J. Rotrosen, New York Harbor VA and New York University Medical Centers, New York, NY The acute stimulant and reinforcing effects of cocaine are largely attributed to its action as an indirect dopamine agonist in brain. However, neuronal substrates that mediate the conditioned effects of cocaine are not well characterized. To examine dopaminergic mechanisms, we tested three antagonists, haloperidol (HAL), raclopride (RAC) and SCH23390 (SCH), for their capacity to inhibit both the conditioned stimulation of locomotor activity (CLA) and conditioned place preference (CPP). Antagonist activity was also assessed against acute cocaine-stimulated locomotor activity for comparison. Male, S-D rats were injected with escalating doses of cocaine (5540 mg/kg) after 20 min pretreatment with antagonist (0.03-0.1 mg/kg) or vehicle. For CLA, six conditioning sessions were conducted over a lo-day period. Paired rats received 10 mg/kg cocaine prior to activity sessions and saline after; unpaired controls received saline prior and cocaine after.

Abstracts

In an unbiased CPP design, eight conditioning sessions were conducted over a 13-day period; rats received 10 mg/kg cocaine while restricted to one of two distinct chambers and, on alternate days, they received saline in the other. Antagonists (0.03-0.1 mg/kg) were given only on test days for conditioned effects (CLA and CPP). All three antagonists significantly and dose-dependently attenuated the acute stimulation of locomotor activity by cocaine. Of the three drugs, only the Dl-selective antagonist SCH blocked the expression of CLA, and only the D2 antagonist HAL blocked the expression of CPP. Thus, conditioned stimulant and reinforcing effects of cocaine were shown to be differentially sensitive to dopamine receptor blockade. Further, conditioned effects differed from acute effects in this regard. Funded by a VA Merit Review grant. 7

ANATOMICAL

TIDES BRAIN:

IN THE

CHARACTERIZATION NUCLEUS

FUNCTIONAL

ACCUMBENS

OF AND

CART

VENTRAL

PEPMID-

IMPLICATIONS

S. DallVechia Adams, Y. Smith, and M.J. Kuhar, Yerkes Regional Primate Research Center, Emory University, Atlanta, GA The circuitry of the nucleus accumbens (Act) and the modulation of midbrain dopamine (DA) neurons are strongly implicated in the mechanism of action of psychomotor stimulants. CART peptides are a novel family of neuropeptide transmitters first identified as upregulated by cocaine and amphetamine in the striaturn, specifically, CART peptides are abundant in the Act region of the striatum. In addition, CART peptideimmunoreactive (CARTir) terminals innervate the ventral tegmental area (VTA), and intra-VTA injection of CART peptides produces psychostimulant-like effects. The goal of the present study is to further characterize the anatomical circuits of CART peptides in these brain areas. One aim has been to utilize selective excitotoxic lesions of the Act core and shell regions to identify the efferent projections of the CARTir neurons. Kainic acid-induced lesions of the Act core result in a dramatic loss of CARTir terminals in the substantia nigra (SN). Currently, experiments are examining the effects of ibotenic acid-induced lesions of the Act shell, which contains remarkably high levels of CART peptide and mRNA. Possible projections of the CARTir neurons of the Act shell include the VTA, ventral pallidum and lateral hypothalamus. Further studies involve analysis of the ultrastructural features of CARTir terminals in the VTA. Intra-VTA injections of CART peptides produce increases in locomotor activity and conditioned place preference. These effects are very likely mediated by dopaminergic neurons in the VTA. If synaptic contact exists between CARTir terminals and DA neurons

s3

in the VTA, this would provide an anatomical basis for the behavioral effects. Preliminary data have already demonstrated that CARTir terminals form synaptic contact with DA neurons in the SN. 8 COME

EFFECT

OF

COCAINE

ABUSE

ON

IN METHADONE-MAINTAINED

TREATMENT

OUT-

PATIENTS

E. Akerele, P. Lazaridis, R. Brady, E. Nunes, and F. Levin, Division of Substance Abuse, New York State Psychiatric Institute, and Columbia University, New York, NY While the use of methadone has been successful for the treatment of the majority of heroin dependent patients, success continues to elude a substantial percentage. One such group are those that continue to abuse cocaine. It is our hypothesis that cocaine abuse has a negative impact on treatment outcome. This retrospective study determined effect of cocaine abuse on treatment outcome in methadone patients. The following groups of patients were assessed: (1) Cocaine abstainers; (2) Moderate cocaine abusers; and (3) Heavy cocaine abusers. The pattern of opiate and cocaine use was then assessed over a period of 6 months, excluding the first month in the program. Preliminary data suggest that patients who did not use cocaine showed a decrease in opiate use during the 6 month assessment. Both the moderate and heavy cocaine users had an initial decrease in opiate use, however, after 3 months opiate use increased and continued to do so up to the sixth month. Data collection is underway and will be completed prior to this presentation. The results of this study will be useful in patient education and the development of a comprehensive treatment that takes into account the interaction between cocaine and methadone in the delivery of care. 9 TYPE

ANANDAMIDE AMPA

SENSITIVITY

OF

MUTANT

AND

WILD-

RECEPTORS

B.E. Akinshola, H. Wang, R.E. Taylor, and E.S. Onaivi, Howard University College of Medicine, Washington, DC, and Vanderbilt University School of Medicine and NRI, Nashville, TN Anandamide is known to endogenously modulate AMPA (a-amino-3-hydroxy-5-methyl4-isoxazole propionic acid) glutamate receptor function in a presynaptic fashion. Similarly, we have previously shown Anandamide inhibition of recombinant AMPA receptor subunit currents in Xenopus oocytes. In order to probe the molecular basis of Anandamide inhibition of AMPA receptor function, we used voltage clamp electrophysiology and oocyte expression system to study mutant and wild type AMPA receptor currents in vitro.

s4

Abstracts

The three mutant receptors studied (EG19, T840A and S831A) were constructed from a single hydrophobic amino acid substitution of Alanine for a previously hydrophilic amino acid on the wild type GluRl receptor subunit. The mutations targeted both the extracellular splice variable region (EG19) and the C terminal intracellular domain (T840A, S831A) of the receptor. Our results indicate that the mutant receptors were less sensitive to Anandamide inhibition than the wild type GluRl subunit receptor. However, the similarity in the Anandamide sensitivity of the EG19 mutant to the wild type receptor may indicate an extracellular site of receptor inhibition by Anandamide. Supported by NIAAA grant # l-U-24AA11898 and NHLBI grant # HL03319*. 10 TERNS

A

DESCRIPTIVE AMONG

EXAMINATION TWO

RACIAL

OF GROUPS

SMOKING OF

PAT-

PREGNANT

ADOLESCENTS

S.A. Albrecht, M.V. Taylor, B.J. Braxter, M.D. Reynolds, M.D. Cornelius, and J.R. Cornelius, School of Nursing and School of Medicine, University of Pittsburgh, Pittsburgh, PA This analysis was an examination of smoking patterns and level of nicotine dependence of two racial groups of pregnant adolescent smokers. Data for these analyses were drawn from baseline information collected from 60 Caucasian and 63 African-American pregnant adolescents who participated in an ongoing smoking cessation intervention study. Self-report questionnaires obtained demographic data and tobacco use data including: number of cigarettes smoked per day; amount of the cigarette smoked (measured in increments of 0.25), and milligrams of nicotine in the preferred brand. The adolescent version of the Fagerstrom Tolerance Questionnaire (FTQ) was used to measure perceived levels of nicotine dependence. Results indicated that there were smoking pattern differences for these two groups. In addition, levels of nicotine dependence differed (t = 3.98; P < 0.00) significantly between Caucasian and African-American girls. The mean FTQ scores were 5.40, with 56% scoring 6 or higher, and 4.08, with only 14% scoring 6 or higher, for the Caucasian and African-American girls, respectively. Caucasian girls had a significantly higher (t = 2.78; P = 0.006) mean level of daily nicotine intake (7.44) than African-Americans (4.85). These racial differences in smoking behaviors support the need for tailoring smoking cessation interventions to address the unique smoking patterns of these two groups of pregnant adolescents, specifically, the heavier tobacco use and greater nicotine dependence that occurs among Caucasian as compared to African-American teenagers.

11

DIFFERENTIAL

SYSTEMS

TO

RESPONSES LOW

AND

BY

MET-ENKEPHALIN

HIGH

DOSES

OF

METHAMPHETAMINE

M.E. Alburges, L. Bush, and G.R. Hanson, University of Utah, Salt Lake City, UT Administration of methamphetamine (METH) alters neurotensin, dynorphin and substance P systems associated with the striatonigral pathway. Met-enkephalin (met-ENK) is a neuropeptide primarily associated with afferent striatal-pallidal projections. The present study was designed to investigate the effect of a single administration of low and high doses of METH on the levels of this peptide in basal ganglia regions and to test the effects of selective dopamine antagonists on METH-induced changes in met-ENK. Sprague-Dawley rats received a single injection of METH (0.5 or 10.0 mg/kg, s.c.) in the presence or absence of a selective dopamine receptor antagonist (Dl; SCH 23390 or D2; eticlopride) and were sacrificed 12 or 24 h after drug treatment. The low dose of METH significantly decreased the content of met-ENK in caudate and pallidal tissues. In contrast, the high dose of METH increased met-ENK concentration in these caudate and pallidal structures. The caudate and pallidal met-ENK changes induced by low or high doses of METH were prevented by pretreatment with either dopamine Dl or D2 receptor antagonists. These data demonstrate opposite responses of the striatopallidal met-ENK systems to low and high dose of METH and suggest that a combination of dopamine Dl and D2 receptors activity surprisingly contribute to both effects. Supported by a NlDA grant DA09407 and DA00378. 12 NOVEL

INDIVIDUAL ENVIRONMENT

DIFFERENCES IN

IN

PREDICTING

REACTIVITY EFFECTS

TO

A

OF

D-

AMPHETAMINE

SM. Alessi, M.K. Greenwald, Wayne State University, Detroit,

and C.E. Johanson, MI

Individual differences in the reinforcing and behaviorally activating effects of D-amphetamine (AMPH) have been predicted in animals based on locomotor responding in a novel environment. In an analogous assessment we used an automated measure of motor activity to classify healthy adults as High Responders (HR) (n = 18) and Low Responders (LR) (n = 6) to a novel environment. Group differences in motor activity, acoustic startle reflex, subjective effects, reinforcing effects of AMPH (indirect measure), personality measures and salivary cortisol levels were then assessed following oral administration of AMPH (0, 5, 10, and 20 mg). Motor activity was significantly greater in HR compared to LR regardless of AMPH dose. Startle

S5

Abstracts

eyeblink magnitude on probe-alone trials (105 dB) and across prepulse conditions (0, 50, 100,200 ms) was significantly greater in HR compared to LR following placebo; reflex activity increased in LR following 20 mg AMPH and was comparable to that exhibited by HR. LR reported significantly greater levels of negative affect compared to HR although a dose-dependent increase in the reinforcing effects of AMPH was similarly evident in HR and LR and was not related to cortisol levels contrary to predictions by the animal model. Finally, sensation-seeking was negatively correlated with percent prepulse inhibition. Results are discussed in terms of individual differences in behavioral arousal in the absence of AMPH and how such differences may be useful in predicting sensitivity to several effects of AMPH. ACKNOWLEDGEMENTS: Supported by NIDA grant # DA 10239-03. 13

COMPARISON

ANAESTHETIC TION

PRIOR

SIX-MONTH

OF WITH

TO

OPIOID

STANDARD

NALTREXONE

DETOXIFICATION INPATIENT MAINTENANCE

UNDER DETOXIFICATHERAPY:

FOLLOW-UP

R. Ali, C. McGregor, J.M. White, P. Thomas, J. Myburgh, and L. Gowing, Drug and Alcohol Services Council, University of Adelaide, and Royal Adelaide Hospital, South Australia Rapid opioid detoxification under anaesthetic (RODA) is being widely used for induction onto naltrexone maintenance. However, to date no studies have compared anaesthetic-based detoxification with standard inpatient withdrawal methods to assess medium or long-term relapse to opioid use. A randomised controlled trial was conducted using 101 heroin users who met the DSM-IV criteria for substance dependence. Mean age was 31 years, 59% were male, and mean frequency of heroin use was 3 times per day. Naloxone was used to induce withdrawal under anaesthetic in half of the sample; the other half withdrew from heroin by means of a 5--7 day inpatient treatment regime using clonidine plus symptomatic medication. Both groups were offered 9 months of naltrexone maintenance therapy. Outcome measures included rates of induction onto naltrexone and duration of naltrexone maintenance therapy. Significantly more subjects randomised to the RODA group presented for detoxification and were subsequently inducted onto naltrexone. A preliminary intention to treat analysis of the whole sample showed that 19% were maintained on naltrexone therapy for one month; 10% for two; 9% for three and 3% for 6 months. Significantly more subjects from the RODA group were retained for follow-up for the initial 3 months after which numbers were too low to conduct statistical tests. Preliminary analyses of 6 month follow-

up data on 73 subjects showed that 4% were still in naltrexone maintenance therapy (all from the RODA group); 10% were in prison; 20% were receiving methadone treatment; 8% were not taking naltrexone and had ceased heroin use; 36% were using heroin sporadically and 22% were using heroin daily. Rates of self-reported substance use will be confirmed by hair analysis. 14

METHAMPHETAMINE-INDUCED

NEUROTOXICITY OXYNITRITE:

SOD

CAUSED

DOPAMINERGIC BY THE

ATTENUATION

OVEREXPRESSED

GENERATION

OF

OF THE

TOXICITY

NNOS

KNOCKOUT

AND

IN

PER-

CU-&I-

MICE

SF. Ali, S.Z. Imam, J.L. Cadet, G.D. Newport, F. Islam, W. Slikker, Jr., and Y. Itzhak, NCTR/FDA, Jefferson, AR, NIDA/NIH, Baltimore, MD, Jamia Hamdard, New Delhi, India, and University of Miami, Miami, FL Methamphetamine (METH)-induced dopaminergic neurotoxicity is produced by oxidative stress and free radical generation and might be the result of programmed cell death of dopaminergic neurons via apoptosis. To study the role of METH-induced peroxynitrite generation in dopaminergic cell-death pathway, the production of 3-nitrotyrosine (3-NT) in the mouse striatum and its correlation with changes in the expression of two major proteins (~53 and bcl-2) involved in the cell to cell signaling controlling cell death were investigated. The levels of 3-NT were significantly higher in the striatum of wild type mice treated with multiple doses of METH (4 x 10 mg/kg, 2 h interval) as compared to the respective controls. However, no significant production of 3-NT was observed in the striata of neuronal nitric oxide synthase knockout mice (nNOS-/-) or copper-zinc superoxide dismutase overexpressed transgenic mice (SOD-Tg) after multiple doses of METH. Moreover, METH treatment up-regulated the expression of ~53 and down-regulated the expression of bcl-2 in the striatum of wild type mice whereas no significant alterations were observed in the expression of these proteins in the nNOS -/- or SOD-Tg mice. These data suggest that METH causes damage to the dopaminergic system by producing peroxynitrite resulting in altered gene expression and proteins production leading to dopaminergic cell apoptosis. 15

DEXTROMETHORPHAN

NOCICEPTIVE AGONIST

EFFECTS

SNCSO

POTENTIATES OF MORPHINE

IN A PRIMATE

AND

THE THE

SHOCK-TITRATION

ANTI-

A-OPIOID PRO-

CEDURE

R.M. Allen, A.L. Granger, and L.A. Dykstra, University of North Carolina at Chapel Hill, Chapel Hill, NC

S6

Abstracts

Dextromethorphan (DXM) is a non-competitive NMethyl-D-Aspartate (NMDA) receptor antagonist shown to prevent the development of tolerance to the antinociceptive effects of morphine in rodents. Under some conditions, DXM alone can produce antinociception and can potentiate the antinociceptive effects of morphine. This study was designed to determine whether DXM would potentiate the acute antinociceptive effects of morphine as well as those of the A-opioid agonist SNC80. A squirrel monkey shock titration procedure was used in which shock (delivered to the tail) increased in intensity every 15 s (0.01-2.0 mA) in 30 increments. Five lever presses during any given 15 s shock period produced a 15 s shock free period after which shock resumed at the next lower intensity. This assay provides a measure of antinociception that can be separated from non-specific motor effects (response rate, RR). Morphine (0.3-3.0 mg/kg, im.), but not SNC80 (0.1 - 10 mg/kg, i.m.) or DXM (1.0-10 mg/kg, i.m.) dose- and time-dependently increased the intensity below which monkeys (n = 4) maintained shock 50% of the time (medial shock level, MSL). Doses of morphine and SNC80 that alone did not increase MSL were dose-dependently potentiated by DXM. Importantly, these combinations did not significantly alter RR. These data suggest that DXM can potentiate both uand A-opioid antinociception independently of non-specific motor effects. Supported by USPHS grants DA02749 and DA05803. 16 CHANGEINNEUROPSYCHOLOGICALFUNCTIONING WITH LONG-TERM ABSTINENCE FROM CRACK COCAINE

K. Alper, L.S. Prichep, M. Tom, H. Merkin, B. Howard, S. Kowalik, and M.S. Rosenthal, New York University School of Medicine, New York, NY Neuropsychological testing was performed on 59 subjects in residential treatment for crack cocaine dependence at a mean of 10.2 days after their last use of cocaine, and after 1, 6, and 9 months of continuous, rigorously supervised drug-free residential treatment. These subjects were 22 females and 37 males with a mean age of 33.9 years, and 11.3 years of cocaine use, and no history of IVDA or head injury or neurological disease. Overall IQ estimates were found to be average, although, digit symbol substitution (DSS) and digit span (DS), were borderline. The baseline Buschke Selective Retention Test (BSRT), Paced Auditory Serial Addition Test (PASAT), Benton Visual Recall Test (BVRT), Trails B and Stroop Test all fell below expected normal values (Prichep et al., 2000). Significant improvement over time was seen in subjects relative to their own baseline scores on the BSRT, PASAT, DSS, Trails B, Stroop but not the DS or BVRT. Attention is a dimension that appears to be involved in the neu-

ropsychological domains in which improvement was most evident. The greater apparent within subject improvement in the domains of verbal memory and attention versus non-verbal memory is generally similar to patterns of neuropsychological change reported with recovery from a variety of diffuse brain insults. The interpretation of baseline abnormality is limited by the need for normative data that takes into account possible sociodemographic and psychiatric comorbidity effects. The conceptualization of cocaine exposure as a diffuse brain insult that is partially ameliorated with abstinence is consistent with evidence we have previously presented showing a relative normalization of some quantitative EEG measures during extended abstinence from cocaine. This work was supported by NIDA Grant number ROl DA # -07707. 17 ABUSE LIABILITY OF IV BUPRENORPHINE-NALOXONE, BUPRENORPHINE AND HYDROMORPHONE IN BUPRENORPHINE-NALOXONE MAINTAINED VOLUNTEERS

L. Amass, J.B. Kamien, C. Reiber, and S.A. Branstetter, University of Colorado School of Medicine, Denver, CO, Friends Research Institute, and UCLA Integrated Substance Abuse Program, Los Angeles, CA A combination buprenorphine-naloxone tablet (BNX) designed to mitigate diversion and abuse of buprenorphine (BUP) is pending approval by the FDA for opioid dependence treatment. However, a direct assessment of BNX reinforcement has not been reported. This study compared the subjective, physiological and reinforcing effects of BNX to BUP and hydromorphone (HYD) in seven opioid-dependent male outpatients maintained on the SL 8:2 mg BNX tablet. Subjects had to be abstinent from illicit drugs to participate and receive compensation. During 7 sets of 4 daily laboratory sessions, placebo and either BNX (4: 1, 8:2 mg), BUP (4, 8 mg) or HYD (9, 18 mg) were identified by letter code and administered IV in a double-blind, mixed order. Forced exposure sessions comprised the first 3 days of each set and subjective and physiological data were collected before and for 3 h following drug administration. On the 4th day, the reinforcing effects of the drugs given on the past 3 days were assessed in a multiple-choice session in which subjects chose one of the three letter-coded drugs or increasing amounts of money. One of these choices was randomly selected and implemented that day. BNX, BUP and HYD produced dose-related increases in observer- and subject-rated agonist effects during the forced-exposure sessions. However, subjects did not consistently identify these drugs as opiates. During multiple-choice sessions, 5 of 7

Abstracts

subjects chose money exclusively over all drugs, reporting a desire to avoid drugs entirely. The drug-drug choices revealed no clear preferences, except that all subjects chose 9 mg HYD and 8 mg BNX over saline. Thus, despite the presence of dose-related agonist effects, the almost universal preference for money over drug suggests a low abuse liability for BNX, as well as for BUP and HYD, in abstinent BNX-maintained outpatients. Supported by NIDA grant DA1 1160. 18 DOESSTAGEOFCHANGEPREDICTTREATMENTRETENTIONANDIMPROVEMENTINPERINATALSUBSTANCE ABUSERS?

A. Amponsah, D. Miles, K.E. Bott, and D.L. Haller, Medical College of Virginia of Virginia Commonwealth University, Richmond, VA Background: Prochaska and DiClemente’s Transtheoretical Model of Stages of Change has been found in various clinical studies to predict substance abuse treatment outcomes although, to our knowledge, this has not been looked at in the perinatal population. This study will retrospectively examine the relationship between pre-treatment University of Rhode Island Change Assessment (URICA) scores and Addiction Severity Index (ASI) change scores (Intake to 6 months). Additionally, length of stay (LOS) will be examined as a function of baseline URICA scores. Subjects: 111 substance abusing pregnant women were recruited through a residential treatment program in Richmond, VA. Most were never married (68%), African Americans (81%) with a mean age of 26 years. Two-thirds had completed high school, although only 3% were employed. Primary substances of abuse were cocaine/crack (87%) and heroin (8%); secondary substances of abuse were alcohol (43%), and cannabis (33%); 86% were also nicotine dependent. Procedure: Subjects underwent extensive baseline evaluation including medical, psychosocial and drug use assessment prior to treatment initiation. Each subject’s highest URICA score was used to determine her stage of change. Due to small cell size for Precontemplation, subjects in this group were combined with those in the Contemplation group to form three groups (Pre/Con N = 54; Action N = 96; and Maintenance N = 23). ANOVA was used to evaluate change on the AS1 by URICA group and survival analyses (Kaplan-Meier) were conducted to determine whether there were differences in retention for the three groups. We predict that women in the Action and Maintenance Stages will have longer LOS and will evidence more improvement on the ASI for Alcohol, Drug, and Psychiatric severity than will those in the Precontemplation/ Contemplation

Sl

group. This work was supported by Grant # : This work was supported by Grant # HS4 T100555. 19 THE REINFORCING AND DISCRIMINATIVE LUS EFFECTS OF RTI 111, A PHENYLTROPANE, ANDINCOMBINATIONWITHMETHAMPHETAMINE

STIMUALONE

K.G. Anderson, R. Ranaldi, F.I. Carroll, and W.L. Woolverton, University of Mississippi Medical Center, Jackson, MS, and Research Triangle Institute, Research Triangle Park, NC One of the neuronal actions of methamphetamine (MA) is to increase extracellular levels of dopamine (DA) presumably via reverse transport involving the dopamine transporter (DAT). This action is thought to play an important role in the behavioral effects of MA. In the present experiment, it was hypothesized that a DAT ligand would block the behavioral effects of MA. Accordingly, RTI 111, a newly synthesized phenyltropane with high affinity for the DAT, was evaluated alone and in combination with MA for its ability to block the reinforcing and discriminative stimulus effects of MA in rhesus monkeys. When RTI 111 (0.0003-0.03 mg/kg, i.v.) was made available for self-administration under a fixed-ratio 25 schedule it functioned as a positive reinforcer in all four monkeys tested. When RTI 111 (0.01-0.1 mg/kg, i.m.) was given as a pretreatment (15 min prior) to MA self-administration under a progressive-ratio schedule, the MA dose-response function shifted to the left. When RTI 111 (0.001-0.1 mg/kg, i.m.) or MA (0.01-1.0 mg/kg, i.m.) was given to monkeys (n = 4) trained to discriminate D-amphetamine (AMPH) from saline, full AMPH-like responding was observed for both drugs. Given in combination, RTI 111 shifted the MA dose-response function to the left. These data suggest that RTI 111 is behaviorally similar to traditional psychomotor stimulants that act at the DA transporter and enhances, rather than blocks, the effects of MA when given in combination. Supported by NIDA grants DA-10352, DA-09139, and DA-00161 (WLW). 20 LONG-TERM DICTION:FINDINGS

CONSEQUENCES OF NARCOTICS ADFROM A 33-YEAR FOLLOW-UP STUDY

M.D. Anglin, Y.I. Hser, C.E. Grella, and V. Hoffman, University of California, La Jolla, CA Objective: This study examined longitudinal patterns of narcotics use, other substance use, health, mental health, employment, criminal involvement, and mortality among narcotics addicts. Procedures: This study collected data in 1996-97 to update information previously obtained from records and face-to-face interviews

S8

Abstracts

conducted in 1974-75 and 1985-86. The study cohort included 581 narcotics addicts admitted to the California Civil Addict Program from 1962 to 1964; 284 were dead and 242 were interviewed in this latest follow-up. Results: In 1996-97, 48.9% of the sample had died and 23.2% tested negative for heroin. Age, disability, and heavy alcohol use were among the strongest correlates of mortality. Among the survivors (mean age = 57.4 years) 66.9% reported tobacco use, 22.1% reported daily alcohol use, 35.5% reported marijuana use, and 19.4% reported crack use. There were also high rates of health problems, mental health problems, and criminal justice system involvement. Abstinence was associated with less criminality, morbidity, psychological distress, and higher employment. Conclusions: While the cohort’s mortality increased steadily over time, narcotics use patterns were remarkably stable, particularly among those addicts who had not ceased use by their late 30s. The study underscores the importance of intervening early in an individual’s addiction career. 21 LAAM AND METHADONE MENT: RETENTION, DRUG BEHAVIORS

MAINTENANCE TREATUSE AND HIV RISK

J. Annon, D. Longshore, R. Rawson, and M.D. Anglin, Drug Abuse Research Center, Los Angeles, CA This is a report on preliminary, 3rd year findings of a 4 year study comparing the differential effects of methadone and levo-alpha-acetyl methadol (LAAM) on retention in treatment, drug use and HIV risk behaviors among heroin addicts. This study recruited 315 addicts in the Los Angeles area and randomly assigned by a 2~1 ratio to either methadone or LAAM maintenance. The study sample is 18% white, 40% African American and 37% Latino. Women comprise 29% of the sample. Three-hundred and three clients have reached their 1 year anniversary date. Fourty-five percent of the MM subjects completed treatment, compared to 56% of the LAAM maintenance subjects (P = NS). Incarceration continues to be the primary reason for discharge. There was less heroin use at 6 month follow-up by the LAAM clients (87 vs. 72%, P = 0.004) though equivalent crack cocaine use (39 vs. 40%, P = NS). With regard to HIV risk behaviors, there was less drug injection for the LAAM clients (70 vs. 85%, P = 0.004), though equivalent use of bleach to clean needles. Condom use and number of sex partners were similar across groups. Urine analysis data will be available for comparison in June. Supported by NIDA grant R01 DA10422.

22

GENDER

DIFFERENCES

IN TREATMENT

ADMISSION

C. Arfken, N. Borisova, C. Klein, S. di Menza, and C.R. Schuster, Research Division on Substance Abuse, Wayne State University, Detroit, MI We have previously shown that women have lower retention rates in substance abuse treatment than men. For this study, we examined if women were also more likely to drop out during the interval between intake and admission. Of the 5004 people seeking publicly funded substance abuse treatment in Detroit for 1997, 50.3% actually entered treatment. Women (31% of the clients) had a lower rate of admission (45% vs. 53% of men; OR = 1.34; P < 0.0001). Even after controlling for known risk factors, women had a lower rate of admission (OR = 1.34; P < 0.0001). Women who were given priority for admission (pregnant, had children or injected drugs) had a higher rate of admission than other women (73% vs. 39%; P < O.OOOl),but only 18% of the women fell into the high priority groups. Men who were injecting (another priority group) also had a higher rate of admission than other men (83% vs. 49%; P < 0.0001). In multivariate analysis controlling for high priority groups, know risk factors and referred treatment setting, women were less likely to be admitted (OR = 1.41, P < 0.0001). Establishing priorities improves the rate of admission for those groups but more still needs to be done to eliminate the gender difference in rate of treatment admission. 23 A LITERATUREREVIEWOFPOPULATIONSTUDIESOF SUBSTANCE USE AND PSYCHIATRIC COMORBIDITY ADOLESCENT FEMALES T.D. Armstrong and E.J. Costello, Medical Center, Durham, NC

IN

Duke University

Many clinicians who treat a greater proportion of male adolescent substance abusers compared to females may assume that gender differences in treatment rates reflect the gender distribution of substance abuse in the population. However, general population studies have shown that females are as likely or more likely to develop substance abuse and comorbid psychiatric disorder. A review of the literature on adolescent substance use and psychiatric comorbidity in representative, non-clinical samples was conducted with particular focus on female pre-adolescents and adolescents. From a review of 141 published studies, 21 community studies were included in the meta-analysis of youth ranging from 9 to 19 years of age. Substance-abusing females were at greater risk of comorbidity than substance-abusing males for oppositional defiant disorder and attention-deficit/hyperactivity disorder, and significantly so for conduct disorder and anxiety disorders. A similar pattern of gender differences was noted for substance use. These findings suggest that

Abstracts

substance-abusing females with comorbid psychiatric disorder are undertreated and comprise a target population for more intensive mental health and substance abuse interventions. ACKNOWLEDGEMENTS: Supported by NIDA Grant DA-l-33. 24

EFFECT

TION

OF CODEINE

OF

PIGMENTATION INTO

HUMAN

ON

THE

INCORPORA-

HAIR

M. Augsburger, D.G. Wilkins, M.H. Slawson, C.L. O’Neal, A. Mizuno, C.R. Borges, and D.E. Rollins, Center for Human Toxicology, University of Utah, Salt Lake City, UT Hair analysis has been proposed as a complement to urine and/or blood analysis. To evaluate the role of pigmentation in the incorporation of drug in human hair, codeine was administered to healthy volunteers. Subjects that were African American (n = 3), Asian American (n = 6) Hispanic (n = 2) or Caucasian (n = 6) with black hair or Caucasians with brown (n = 12) blond (n = 8) or red hair (n = 6) received oral doses of codeine, 30 mg, three times daily for 5 days. Hair samples were cut before (control) and 4, 5,6, 7 weeks after drug administration. Hair specimens were analyzed by LC-MS (API-ES). At week 4, codeine concentrations (mean pg/mg f SD) were: black hair (1612 f 1085); brown hair (243 f 46); blond hair (120 + 25); and red hair (69 &- 14). A similar pattern of codeine disposition was observed for the entire study period. Data obtained with this controlled clinical study show that hair pigmentation plays a crucial role during the incorporation of codeine into human hair. 25 LAPSE TING:

NALTREXONE TO

ALCOHOL

A DOUBLE-BLIND,

IS IN

INEFFECTIVE

TO

A REALISTIC

OUT-PATIENT

1 YEAR

CONTROLLED

PREVENT

RESET-

STUDY

M. Auriacombe, M. Robinson, D. Grabot, and J. Tignol, Universite Victor Segalen Bordeaux, Bordeaux, France Naltrexone treatment has been shown in several high quality double-blind placebo controlled studies to be effective in reducing relapse to alcohol. However these results were found in treatment settings that had a high intensity of psychotherapy (daily to weekly) that was over short periods of time (12 weeks). This is not the level of psychotherapy that most alcohol patients receive. The present double-blind placebo controlled study was designed to determine if naltrexone treatment reduces relapse (Volpicelli’s criteria) to alcoholic drinking, in a realistic therapeutic environment, that is similar in intensity to the one that most alcohol dependent out-patients receive (monthly to less then weekly visits).

s9

One-hundred and nine subjects were included. A survival analysis was completed examining the time to first meeting predefined relapse criteria. Compliance with medication was not measured. The differences among the groups were not statistically significant by log rank (x2 = 0.2742, df = 1, P > 0.6006). When considering 3 months as the endpoint there was still no difference (log rank x2 = 0.6948 P = 0.4045). The results did not differ either when considering only those who sampled alcohol before meeting relapse criteria. Thus in a treatment setting involving monthly visits, naltrexone was not found to be effective. 26

THE

AND

PTSD

PENDENT

LINK

BETWEEN

SYMPTOMATOLOCY

HIV

HIGH-RISK AMONG

BEHAVIORS COCAINE-DE-

INDIVIDUALS

S. Back, K.T. Brady, B.S. Dansky, H. Resnick, J. Monnier, and T. Timmons, Medical University of South Carolina, Charleston, SC The association between cocaine dependence and HIV high-risk behaviors has been well documented. This relationship, however, is not well understood among individuals with comorbid PTSD. Given the high rates of PTSD among cocaine-dependent samples (e.g. 43%; Back et al., in press), this is an important area for further investigation. The present study examined the relationship between HIV high-risk behaviors (i.e. condom use with main partner and with casual partners in last 6 months) and current PTSD symptomatology. Participants were treatment seeking, cocaine-dependent individuals (N= 39) with comorbid PTSD. The Structured Clinical Interview for the DSM-IV was used to assess cocaine and other Axis I diagnoses. The Stages of Change Condom Use Questionnaire assessed HIV high-risk sexual behaviors. The Addiction Severity Index assessed substance use severity. PTSD symptoms were assessed using the Clinician Administered PTSD Scale and the Mississippi Scale for PTSD. Results revealed that condom use with casual partners was inversely related to PTSD symptomatology. That is, the more severe the PTSD symptoms, the less likely the person was to use a condom when engaging in sex with a casual partner. Significant correlations were demonstrated between condom use with casual partners and the MISS total score (r = 0.42, P < 0.05) and all PTSD symptom cluster frequency and severity ratings on the CAPS [intrusion frequency (Y= 0.66, P < 0.001) and severity (Y = 0.64, P < 0.01); avoidance frequency (r = 0.53, P < 0.01) and severity (r = 0.48, P < 0.05); hyperarousal frequency (r = 0.44, P < 0.05) and severity (r = 0.45, P
Abstructs

SlO

some HIV high-risk sexual behaviors and PTSD symptomatology among cocaine-dependent individuals. Further investigation of this relationship is warranted and may ultimately serve to enhance prevention and treatment efforts. A

27 AND

NOVEL

ANTI-COCAINE

CAINE

(mAb 15AlO)

ANTIBODY

(BChE)

BUTYRYL-CHOLINESTERASE SELF-ADMINISTRATION

IN

ALTER

CO-

RATS

T.J. Baird, D.W. Landry, G. Winger, and J.H. Woods, Columbia University, New York, NY Thirty male Sprague-Dawley rats were trained in daily 8 h sessions to self-administer intravenous (i.v.) cocaine. A within-session multiple-dose protocol was employed wherein a given subject was allowed access to one of seven unit doses of cocaine (0 [Sal], 0.015,0.03,0.06,0 [Sal], 0.125,0.25, and 0.5 mg/kg/inf) per h, in the order listed. After demonstrating stable dose-response curves over three consecutive days, rats were administered 30 min iv. pretreatments of saline, and either BChE (3000,lO 000, or 30000 U/kg, iz = 5) or mAb 15AlO (10, 30, 100 mg/kg, n = 5) before being placed in operant chambers for their usual, daily cocaine self-administration session. Both mAb 15AlO and BChE, but not saline pretreatments significantly altered dose-response curves for cocaine self-administration in a dose- and time-dependent manner, resulting in a downward and rightward shift in rates-of-responding across the dose range. These effects were not due to general behavioral suppression, and were specific to cocaine. The present data extend prior work (Mets et al., 1998, PNAS 95:10176- 10181) suggesting that cocaine antibodies, as well as the naturally-occurring endogenous enzyme, BChE, may be of worth in the search for clinically effective cocaine antagonists. 28

UTILIZING

THE

EFFECTS

TION: IN

HIV

A OF

EVIDENCE

MOUSE

DRUGS

OF

FOR

REPLICATION

G.C. Baldwin, Divisions of and Critical Medicine, Los

SCID

MODEL ABUSE

TO DETERMINE ON

A COCAINE-MEDIATED IN

HIV

REPLICAINCREASE

VIVO

R. Choi, J. Zack, and D.P. Tashkin, Hematology-Oncology and Pulmonary Care Medicine, UCLA School of Angeles, CA

Active crack cocaine use has been linked to progression of disease in HIV-infected individuals. However, there are inherent difficulties in analyzing the in vivo effects of inhaled drugs of abuse on HIV replication in infected persons. Moreover, while in vitro studies can directly assess the impact of drugs of abuse on the biology of HIV, they cannot control for the complex interactions that occur when an individual is repeatedly

exposed to a drug over time. To define the effects of cocaine on HIV replication, we have established a murine model utilizing the human lymphocyte/SCID (huPBL/SCID) mouse. Briefly, we have found that following peritoneal implantation of human cells in SCID mice and in vivo HIV infection (18 days post implantation), 49.33 + 14.2% of harvested peritoneal lavage cells are HIV-infected in cocaine-treated animals (5 mg cocaine/kg, qd for 10 days at 4 days post infection) versus 22.1 + 6.9% HIV + in untreated control animals (saline injections qd for 10 days at 4 days post infection). Additionally, the percent of total CD4 + target cells recovered from the lavage of cocaine treated/HIV-infected animals is 2.43 + 0.7 vs. 15.1 + 4.6% for untreated HIV-infected control animals. Since we have shown that exposure to cocaine in the absence of HIV infection does not affect the implantation and/or function of human cells or the distribution of T cell subsets, these results suggest that the profound decrease in CD4 + cells in HIV-infected animals is most likely due to the cocaine-mediated increase in HIV infectivity and commensurate CD4 -t- target cell lysis. This is the first report indicating that cocaine can directly affect HIV replication in vivo. Our results also suggest that the huPBL/SCID model has the potential to define how other drugs of abuse, alone or in combination, affect HIV pathobiology in vivo. Supported by NIDA/NIH grant DA08254. 29

CRACK

EPIDEMIOLOGIC

AND

LUNG

EMPHYSEMA:

A RETROSPECTIVE

STUDY

N. Ballon, D. Soffer, and A. Charles-Nicolas, University Hospital, Fort de France, French West Indies Introduction due to cultural, economical and geographical reasons, drug addiction to crack in the Caribbean is neither associated with consumption of opiates nor of psychotropics drugs and is exclusively consumed by inhalation. Its allows us to study specifically this toxic drug and its pulmonary complications. Hypothesis following the observation of a patient of 28 years, crack addict and clinically presenting a centro lobular emphysema whereas this pathology usually occurs among patients of more than 40 years with chronic nicotinism. We searched if this association were fortuitous. Method: We have studied cases of patients hospitalised for lung emphysema in Fort-de-France University hospital for these last 2 years and searched if they were crack abuser. Result: In 15 cases recorded, only two patients presented with this pathology before age 40. These two patients turned out to be crack addicts. This association crack-pulmonary emphysema, has not been described so far, and is compatible with the result of other survey.

Abstracts

30

THE

ROLE

PERACTIVITY

OF INDUCED

5-HT2B/2C RECEPTORS BY ( + )-MDMA

M.G. Bankson and K.A. Cunningham, Texas Medical Branch, Galveston, TX

IN THE

HY-

University

The locomotor stimulant effects of ( + )-MDMA appear to be mediated through activation of 5-HTlB receptors following 5-HT release from terminals. We have previously shown that the 5-HTlB/lD antagonist GR 127935 blocks the locomotor stimulant effects of ( + )-MDMA; however, the non-selective 5-HT antagonist methysergide has been shown to potentiate the locomotor stimulant effects of ( + )-MDMA (Gold and Koob, 1988). The goal of the present experiment was to further define the 5-HT receptors which may be involved in the hyperactivity caused by ( + )-MDMA, and address the paradoxical finding that GR 127935 blocks, while methysergide potentiates, ( + )-MDMAinduced hyperactivity. In the present study, activity monitors which measure central, peripheral, and rearing activity were used to investigate the ability of the selective 5-HT2B/2C antagonist SB 206553 (0.5-4.0 mg/kg ip) to alter the locomotor stimulant effects of an acute ( + )-MDMA injection (3.0 mg/kg SC) in rats (n = 8 per group). The hyperactivity evoked by ( + )MDMA was dose-dependantly increased by up to 240% in the presence of SB 206553, which had no effect on basal locomotor activity when administered alone. Furthermore, the administration of GR 127935 (2.5 mg/kg SC)only partially attenuated the SB 206553 potentiation of ( + )-MDMA-evoked activity. Also, SB 206553 did not potentiate the hyperactivity induced by the 5HTlA/lB agonist RU 24969, the 5-HT2 agonist DOI, or the indirect 5-HT agonist fenfluramine. These data support the hypothesis that hyperactivity evoked by ( + )-MDMA-induced 5-HT and DA release is limited by activation of 5-HT2B or 5-HT2C receptors, which partially counteract the hyperactivity caused by the interaction of these neurotransmitters. Supported by NIDA DA 00260, DA 06511 and DA 07287. 31 TANCE SITY

ANTINOCICEPTIVE OF AND

EFFECTS

GENOTYPE, ACTIVITY

AT

OF OPIOIDS

NOCICEPTIVE

STIMULUS

THE

RECEPTOR

K OPIOID

II:

IMPORINTEN-

A.C. Barrett, C.D. Cook, E.L. Roach, and M.J. Picker, University of North Carolina, Chapel Hill, NC The influence of sex and nociceptive stimulus intensity on kappa opioid-induced antinociception was examined in male and female rats of the F344 and Lewis strains using a warm-water tail-withdrawal procedure (all drugs tested at 50, 52 and 55’C). Spiradoline was maximally effective at water temperatures of 50, 52 and

Sll

55°C in both sexes and strains; there were no sex or strain differences in its antinociceptive potency. In both sexes and strains, LJ50,488 produced maximal antinociception at 50°C and submaximal antinociception at 55°C. At 55°C U50,488 was slightly more effective in F344 rats. Enadoline was more potent at 50°C and more potent and effective at 52°C in F344 males than females, whereas there were no differences in its potency or effectiveness in Lewis rats. Bremazocine produced intermediate to high levels of antinociception at 50 and 52°C in F344 and Lewis males, and only low to intermediate levels in their female counterparts. Nalorphine produced intermediate to high levels of antinociception in F344 males at 50 and 52°C respectively. In contrast, in F344 females, Lewis males and Lewis females nalorphine produced intermediate levels of antinociception at 50°C and low levels at 52°C. Under conditions in which bremazocine and nalorphine produced near maximal effects in F344 males and submaximal effects in F344 females, these opioids antagonized the effects of spiradoline. A similar pattern of results was obtained with bremazocine in Lewis males and females. These antagonism data suggest that bremazocine and nalorphine function as lower efficacy kappa opioids in female rats. The present findings further suggest that in both sexes and strains, the rank order of antinociceptive effectiveness was spiradoline > U50,488 > enadoline > bremazocine > nalorphine and that sex is an important determinant of sensitivity to the antinociceptive effects of kappa opioids. ACKNOWLEDGEMENTS: Supported by PHS grants DA10277, DA05888 and MH0743 1. 32

CHARACTERISTICS

OF

HISTORIES

WHO

ABUSE

WOMEN ENTER

WITH

SEXUAL

METHADONE

TREATMENT

N.G. Bartholomew, G.A. Rowan-Szal, and L.R. Chatham, Institute of Behavioral Research, Texas Christian University, Fort Worth, TX Women who enter substance abuse treatment with a history of sexual abuse often report greater indicators of psychopathology (e.g. depression, anxiety, PTSD) that hold implications for treatment providers. This study investigates admission differences between female clients with and without a history of sexual abuse who entered an outpatient methadone treatment in Texas between 1995 and 1998. In a sample of 137 women, 39% (N= 53) reported a history of sexual abuse, based on screening questions contained in the intake interview. Analysis of variance (ANOVA) and x2 tests were used to examine primary areas of interest such a sociodemographics, family relations, substance abuse, psychological functioning, and health. Sexual abuse clients were more likely to have experienced physical

s12

Abstracts

and emotional abuse and to report more negative familyof-origin relationships (e.g. conflict, parental criminality). Sexual abuse clients also self-reported more drug-related problems and more frequent use of marijuana, nonprescribed tranquilizers, and other opiates in the 6 months before intake. Compared to those with no sexual abuse history, sexual abuse clients reported more depression, anxiety, more thoughts of suicide, and more trouble concentrating and controlling violent behavior. Results support the importance of screening for sexual abuse history during intake in order to assure adequate treatment planning. 33

DOES

ENCE LOGICAL

PSYCHOPATHOLOGY

OF SUBSTANCE

USE

MODERATE INTENSITY

THE

INFLU-

ON NEUROPSYCHO-

FUNCTIONING?

M.E. Bates, G.T. Voelbel, E.W. Labouvie, and C. Desai, Center of Alcohol Studies, Rutgers University, Piscataway, NJ Although neuropsychological impairment is evidenced by many alcohol, cocaine, and other drug use disordered persons, there is inconsistent evidence for direct use quantity or frequency effects on severity of neuropsychological impairment. We hypothesized that a dose-response relationship between use intensity and nemopsychological functioning may be found in persons who have enhanced vulnerability due to co-occurring psychopathology. Participants were 169 men and women with alcohol and/or other drug use disorders. Cognitive flexibility, information processing speed, memory, and verbal ability were assessed. The effects of age, gender, education, medical disorders, familial alcoholism history, and personality disorders were controlled. Preliminary analyses indicated that the co-occurrence of one or more Axis I psychiatric disorders moderated the association of: (a) drug use frequency with cognitive flexibility; and (b) alcohol quantity with verbal ability. Persons with current psychopathology showed decreased neuropsychological performance with increasing use intensity, while those with no current disorder showed no or inconsistent relations. The moderation model accounted for 5.3% more of the variance in drug use frequency (Total R’ = 0.422) and 7.3% more in alcohol quantity (Total R2 = 0.420) than simple main effects models. We are now replicating analyses using structural equation path models to determine the stability of effects. Supported by NIAAA Grants AA08747 and AA1 1594. 34

METHAMPHETAMINE

CENTRATION AS AN OUTCOME PHARMACOTHERAPY TRIALS:

QUANTITATIVE MEASURE VALIDITY

URINE

CON-

IN OUTPATIENT AND UTILITY

S.L. Batki, J. Moon, K. Delucchi, T. Panganiban, M. Bradley, D. Hersh, S. Smolar, M. Mengis, D. Sexe, E.

Lefkowitz, L. Morello, T. Everhart, R.T. Jones, and P. Jacob III, SUNY Upstate Medical University, Syracuse, NY, and UCSF, San Francisco, CA Objective: To determine the usefulness of quantitative urine methamphetamine (MA) concentration as a primary outcome measure in outpatient pharmacotherapy trials for MA dependence. Method: Urine was collected twice weekly and quantitative MA concentration [MA] was determined by gas chromatography in a randomized trial of fluoxetine 40 mg/da or placebo. All 64 subjects (Ss) had DSM-IV primary MA dependence and used MA an average of 7.4 years. Mean age was 35, 72% were male, and 73% were white. Results: At intake, mean MA use was 2.6 days per week; 7.3 times per week; and 0.83 grams per week. Mean intake urine [MA] was 17 898 rig/ml (SD + 43 024) (range O-279 512 rig/ml). During the study, mean urine [MA] for all Ss at each assessment ranged 9 121-26 430 rig/ml; individual samples ranged O-482 230 rig/ml. Urine quantitative [MA] correlated significantly with reports of MA use. Over the course of the trial, Kendall’s taus averaged mean 0.53 for the correlations between urine [MA] and concurrently reported days, grams, and dollars of MA use. Furthermore, intake urine [MA] predicted outcome, and correlated significantly with final measures of MA use and final urine [MA] (P < 0.01). MA levels from weeks 3 and 4 correlated negatively with study retention (P = 0.02). Conclusion: Quantitative urine [MA] ranged widely, correlated well with self-reports of MA use, and was predictive of final MA use. These data from an outpatient trial support the validity and utility of quantitative urine MA concentration as an outcome measure in pharmacotherapy studies for MA dependence. Supported by NIDA: P50 DA09253, P50 DAO1696, and ROl DAl1397. 35

CSD/BEM

ADOLESCENTS TEX

DYSFUNCTION

LOCALIZATION ‘AT-RISK’: IN

EVIDENCE CONDUCT

OF

P300 OF

SOURCES

FRONTAL

IN COR-

DISORDER

L.O. Bauer and V.M. Hesselbrock, University of Connecticut School of Medicine, Farmington, CT Childhood conduct problems (CP) and a family history (FH) of substance dependence are significant risk factors for substance dependence and other forms of adult psychopathology. The present study attempted to identify neurophysiological differences that might underly these risk factors. The study examined 158 boys and girls, aged 15-20 years. The subjects were assigned to one of six groups formed by the crossing of two factors: Conduct Problems (low/high) and type of paternal sub-

s13

Abstracts

stance dependence (none/alcohol/drug). Event-related EEG potentials were recorded while subjects performed a varied-set version of Sternberg’s (1966) memory scanning task. Each of the 120 trials of the task consisted of a brief presentation of 2 or 4 consonant letters, which the subject was instructed to commit to memory. Two seconds later, a single letter was briefly presented and the subject was asked to press one of two response keys to indicate if this probe letter was or was not a member of the memorized set. P300 ERPs elicited by the memory probe and performance data were sorted by memory set size and member/nonmember conditions, and subject group. As in numerous previous studies, no significant effects of FH were found. However, CP + subjects exhibited significantly slower reaction times than their CP-counterparts. In addition, the interactive effects of CP group and probe membership on RT approached significance (P = 0.07). Analyses of P300 amplitude revealed a significant (P < 0.05) interaction between CP group and probe membership: the P300 difference between matching and mismatching probe stimulus ERPs was significantly greater in the control, CP-, group than in the affected, CP + , group. Current source density analyses of the group-averaged, matchminus-mismatch difference waveforms revealed that CP-subjects exhibited a robust activation of the left frontal cortex on matching versus mismatching trials. Among CP + subjects, the degree of frontal cortex activation was not significant. 36 DISSOCIATION OF DRUG-INDUCED FROMTOXIC 5-HT DEPLETIONS

5-HT RELEASE

M.H. Baumann, T.S. Benaderet, M.A. Ayestas, and R.B. Rothman, IRP, NIDA, NIH, Baltimore, MD Amphetamine analogs such as methamphetamine and fenfluramine (FEN) are known to cause long-term depletion of forebrain 5-HT in animals. While the mechanism underlying this depletion is unknown, there is speculation that drug-induced 5-HT release might be involved. In the present study, we sought to examine the relationship between drug-induced 5-HT release and long-term 5-HT depletion. To achieve this aim, we performed in vivo microdialysis in the nucleus accumbens of rats during treatment with a neurotoxic regimen of FEN and its isomer dFEN (20 pmol/kg, ip, every 2 h x 4). We tested the non-amphetamine 5-HT releasers m-chlorophenylpiperazine (mCPP) and m-trifluoromethylphenylpiperazine (TFMPP) under identical conditions. Levels of dialysate 5-HT and DA were determined by HPLC-EC. All drugs caused large ( > IO-fold) elevations in dialysate 5-HT, but not DA, after the first dose. Upon subsequent administrations of FEN, dFEN and

mCPP, levels of 5-HT did not increase further but reached a plateau at 5- to IO-fold above baseline. In contrast, TFMPP caused elevations in dialysate 5-HT that continued to rise during dosing and 5-HT levels reached 30-fold above baseline. Two weeks after repeated dosing, rats exposed to FEN and dFEN displayed marked postmortem depletions of forebrain 5-HT whereas mCPP and TFMPP rats did not. In conclusion, 5-HT release may not mediate the 5-HT depletion associated with amphetamines and being a substrate of the 5-HT transporter is necessary, but not sufficient, to induce long-lasting 5-HT depletion. 37 EFFECTS OF SELEGILINE ON HEROIN-AND MAINTAINEDPERFORMANCESINRHESUSMONKEYS

FOOD-

P.M. Beardsley and LX Harris, Medical College of Virginia, Richmond, VA and NIDA, Rockville, MD Selegiline(R-(-)-N,a-Dimethyl-N-[2-propnyl]phenethylamine; R(-)-deprenyl) is a selective MAO-B inhibitor which has been reported to attenuate the subjective effects of cocaine in human subjects, as well as cocaine self-administration in rhesus monkeys. In order to determine if selegiline could also reduce levels of heroin self-administration it was tested in rhesus monkeys trained to self-administer heroin. Four, male adult rhesus monkeys were prepared with chronically indwelling venous catheters and trained to press one of two levers in an operant chamber for 30 yg/kg heroin infusion according to fixed ratio 30 (FR30) reinforcement schedules during 1 h experimental sessions beginning at 1400 h daily. Additionally, they were trained to press the opposite lever for 1 g food pellet delivery according to FR50 schedules during 1 h experimental sessions beginning at 900 h daily. When food- and heroin-maintained behavior had stabilized they were chronically infused (except during food and heroin sessions) with 0 (vehicle), 75, 133, 233, and 0 (vehicle) pg/kg/h of selegiline. Selegiline or vehicle was infused for at least 4 days and until behavior had either stabilized for three consecutive sessions or until either the food- or the heroin-maintained baseline had been reduced to nearzero levels. Selegiline reduced heroin self-administration in all monkeys. The selectivity of effect of selegiline, i.e. whether the food- or the heroin-maintained baseline was suppressed the greater, depended on the subject tested. Following termination of selegiline administration, food- and heroin-maintained response rates initially increased, and then decreased, before fully recovering to baseline levels. Supported by NIDA contracts DA 5-8059 and DA 5-8088.

s14

38 NEURAL RESPONSES ASSOCIATED WITH CUEEVOKED EMOTIONAL STATES AND HEROIN IN OPIATE ADDICTS J. Bearn, L. Sell, J. Morris, R. Frackowiak, K. Friston and R. Dolan, National Addiction Centre, Institute of Psychiatry, and Institute of Neurology, London, UK We have tested the hypothesis that cue evoked craving in heroin addicts correlates with changes in regional cerebral blood flow (rCBF) in cortical target regions of the mesolimbic dopamine system subserving conditioning and reward, by studying 10 male opiate addicts undergoing PET scanning of the distribution of H2 1.5 0 during exposure to a sequence of six alternating drug related and neutral video cues, on two occasions. After the second scan each subject received 20 mg of diamorphine or placebo using a randomised single-blind procedure, allowing the investigation of patterns of brain activity during a range of self-reported cue evoked emotional states both in the presence and absence of heroin. ‘Urge to use’ was significantly correlated with changes in rCBF in inferior frontal cortex bilaterally (right z = 4.12, P < 0.001; left z = 3.14, P < 0.001) and right orbitofrontal cortex (z = 4.06, P < 0.001). Unpredicted findings were a strong positive correlation with right pre-cuneus (; = 4.65, P < 0.05) an area associated with episodic memory retrieval, and with the left insula (z = 4.60, P < O.OOl), implicated in the processing of the emotional components of stimuli. Self-reports of feeling ‘high’ correlated with rCBF activation in the hippocampus (left, z = 4.14, P < 0.001; right, z = 3.30; P < O.OOl.), an area relevant to the acquisition of stimulus-associated reinforcement. 39 RAPID OPIATE DETOXIFICATION CLONIDINE:A PILOT STUDY

WITH LAAM

AND

A.B. Becker, R.E. Johnson, H.E. Jones, E.C. Strain and G.E. Bigelow, Johns Hopkins University School of Medicine, Baltimore, MD LAAM has not been approved for opioid detoxification, but may be an effective rapid detoxification agent, given the long half-lives of its metabolites (i.e. kinetic detoxification). Purpose: To compare the relative efficacies of LAAM and clonidine in mitigating the signs and symptoms of acute opioid withdrawal during rapid detoxification. Methods: Heroin-dependent inpatients were randomly assigned to either LAAM or clonidine treatment for 18 days. Drug administrations were doubleblind and double-dummy. LAAM doses of 0.4, 0.5, and 0.6 mg/kg were administered at 0, 36, and 72 h, respectively. Clonidine was administered every 6 h; total daily doses for days l-5 were 0.9,0.8,0.6,0.4, and 0.2 mg, respectively. Placebo dosing continued through day 18.

Primary outcome measures were physiological signs and subjective reports of opiate withdrawal. Results: Eighty percent of LAAM subjects (n = 4) and 40% of clonidine subjects (n = 2) completed. AUC scores plotted for each completer across study days showed that clonidine lowered blood pressure and LAAM constricted pupils, as expected. Both medications appeared to suppress withdrawal, LAAM less so than clonidine particularly over the first 3 days. Conclusions: Combining LAAM and clonidine during the first 72 h of detoxification may be a useful approach to overcome the delayed onset of LAAM. Comparison of completers vs. non-completers on level of pre-treatment heroin use suggests subjects should be stratified on this variable in a larger-scale study. Supported by grants T32-DA07209, P50-DA05273, K02DA00332, and K05-DA00050. 40

EFFECTSOFREINFORCEMENTMAGNITUDEONDATA ENTRY PRODUCTIVITY OF CHRONICALLY UNEMPLOYED METHADONE PATIENTSIN A THERAPEUTIC WORKPLACE

G. Bedient, J. Dallery, E. Robles, D. Svikis and K. Silverman, Johns Hopkins University School of Medicine, Baltimore, MD, University of Arkansas for Medical Sciences, Little Rock, AR, and Virginia Commonwealth University, Richmond VA The Therapeutic Workplace shows promise as an effective drug abuse treatment. This treatment integrates abstinence reinforcement into a work setting, using salary that drug abusers earn for work to reinforce abstinence. In this treatment, patients are hired and paid to work in a job. To link salary to abstinence, patients are required to provide drug-free urines to gain access to the workplace each day. Businesses that use these procedures may be ideal vehicles for the treatment of drug abuse. However, for such an intervention to be cost-effective, the labor of each employee must yield business income equal to the cost of the employee’s wages. The treatment’s cost-effectiveness will depend on employee productivity. We studied productivity of six unemployed methadone patients in a model Therapeutic Workplace. During 1 h of each daily 3 h work shift, participants entered printed data into spreadsheets. The data were grouped into batches, each containing 4300 characters on 25 sheets of paper. Patients earned $1 .OOin vouchers per batch minus $0.02 per error. All participants maintained low error rates (f 1% errors), but correct response rates varied across participants from 33 to 140 characters per min. A within-subject reversal design was used to see if response rates could be increased by increasing reinforcement magnitude to $10.00 per batch minus $0.08 per error. Repeated measures ANOVA and Tukey’s post hoc tests showed that the high magnitude significantly (p f 0.01) increased correct responding (mean 105 characters

s15

Abstracts

per min) relative the low magnitude conditions that preceded and followed the high condition (means of 72 and 79 per min, respectively). Two of the six participants had the lowest response rates and did not respond to the magnitude manipulation. The results suggest that reinforcement magnitude can be used to improve productivity in Therapeutic Workplace participants, but other procedures must be developed to promote optimal performance in all participants. Supported by NIDA grants ROl DA09426, ROI DA12564, ROl DA13107, and T32 DA07209. 41 NIST, RATS

CTAP, ASELECTIVEII-OPIOIDRECEPTORANTAGOATTENUATES

LIPOPOLYSACCHARIDE

FEVER

IN

K. Benamar, L. Xin, E.B. Geller, and M.W. Adler, Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA The endogenous opioid system has been found to be involved in fever caused by pyrogens. In the present study, we have investigated the role of the u-opioid receptor in the brain in fever induced by lipopolysaccharide (LPS). Male SpragueeDawley rats (ZivicMiller) weighing 250-300 g were used in this study. A sterilized stainless-steel 21 -gauge cannula guide was implanted stereotaxically just above the right or left preoptic anterior hypothalamus (POAH). Following post-operative recovery, body temperature (Tb) of each rat was read from a digital thermometer. Intraperitoneal (i.p.) injection of 50 yg/kg of LPS (E. coli, 0111: B4), produced a significant elevation in Tb (1.43 + 0.1 “C), which peaked at 300 min. Rats were microinjetted with 1 ug of the selective u-opioid receptor antagonist, CTAP, into the (POAH). Thirty min later, LPS (50 ug/kg) was injected intraperitoneally (ip.). The prior injection of CTAP significantly reduced the LPS fever. However, CTAP did not affect LPS fever when it was given 3 h after LPS. These data indicate that u-opioid receptors within the POAH mediate the initiation of LPS fever and suggest that the opioid system is involved in the pathogenesis of fever in rats. Supported by Grant DA 00376 from NIDA. 42 RELATIONSHIP BETWEEN ABUSE ANDPSYCHOPATHOLOGY DENTWOMENOFCHILDBEARING

REPORTED HISTORY OF INSUBSTANCE-DEPENAGE

S.M. Benedict, J.L. Kulstad, D. Svikis N. Haug, D.L. Haller, and M.E. McCaul, Medical College of Virginia of Virginia Commonwealth University, Richmond, VA, and Johns Hopkins University School of Medicine, Baltimore, MD

Childhood abuse is a risk factor for subsequent development of substance abuse and psychopathology in women. Much less is known about the complex interaction between pregnancy, drug addiction, abuse and psychopathology. The purpose of this study was to examine the impact of abuse on psychopathology in pregnant opiate and/or cocaine dependent women. All participants (N = 170), were enrolled in a comprehensive treatment program, after consenting to participate in a larger behavioral treatment program. The sample was primarily young (M = 29 years.), African American (79”/), and unemployed (95%). On admission, participants completed an assessment battery that included the Minnesota Multiphasic Personality Inventory B Revised (MMP12) and the Addiction Severity Index (ASI). Women were classified into one of three groups: no abuse, physical and/or emotional abuse and sexual abuse. Demographic and abuse variables were compared using t-tests and x2 analyses; MANCOVA was used to examine effects of abuse on T-scores for MMPI-2 Clinical Scales with age and race as covariates. Results indicated that 60% of participants reported a history of lifetime abuse. For the entire sample, 9 out of 10 mean Clinical Scale T-scores were within normal limits with one elevation on Scale 4 (Pd). The majority (91%) of individual patient profiles, however, yielded elevations on 2 or more Clinical Scales with one-fourth of individual profiles producing elevations on 7710 Clinical Scales. The patterns of psychopathology differed across abuse groups, although there were no group differences on demographic or substance use variables. There was a significant main effect for abuse group with univariate ANCOVAS yielding significant differences (P < 0.05) on Clinical Scales 2, 3,4, 5, 7, and 8. Women reporting sexual abuse had higher mean T-scores across Clinical Scales, with the exception of Scale 4 (Pd), than those reporting physical and/or emotional abuse. History of abuse, particularly sexual abuse, appears to be a significant risk factor for psychopathology in these women, highlighting the need for intervention programs designed to address the complex, interrelated issues presented by pregnant substance abusers. This research was supported by Grant # DA 12403. 43

DECREASED SELF-CONTROLCHOICEOF RATSFOLLOWING ADMINISTRATION OF COCAINE AND ETHANOL IN A DISCRETE-TRIAL CHOICE TASK

S.M. Bennett, S.C. Haworth, and F. van Haaren, University of Florida, Gainesville, FL The current study examined the effects of acute administration of two drugs of abuse, ethanol and cocaine, on established self-control choice behavior. The study was designed to investigate the extent to which drugs typi-

S16

Abstracts

tally associated with impulsive behavior will in fact result in impulsive behaviors in subjects with a history of self-control choice patterns. Six, male Sprague-Dawley rats, were presented with a choice between 1 pellet (45 mg) of food following a O.l-second delay and 3 pellets following a 6-second delay. During the baseline condition, subjects showed high proportions of self-control with exclusive preference for the larger, delayed alternative. Acute administration of cocaine hydrochloride, l-30 mg/kg, resulted in dose-dependent decreases in self-control choice proportions at doses higher 5.6 mg/ kg. Acute ethanol administration, 0.25-3 g/kg, also resulted in dose-dependent decreases in self-control choice for three of the five subjects. Two of the subjects showed minimal changes in self-control choice until doses higher than 2 g/kg. The current findings suggest that ethanol and cocaine administration will result in impulsive choice but the behavioral effects are only seen when the drug is active. 44 A NIDA-SPONSORED COCAINE RAPID EFFICACY SCREENING TRIAL OF GABAPENTIN, LAMOTRIGINE AND RESERPINE

S.P. Berger, D. Leiderman, M. Majewska, P. Bridge, A. Montgomery, T. Winhusen, J. Goldsmith, J. Harrer, A. Stein, J. Mezinskis, and E. Somoza, Cincinnati VA/UC/ NIDA MDRU: VA Medical Center, Cincinnati, OH Considerable progress in preclinical research has provided a basis for hypothesis driven clinical trials in cocaine dependence. A greater mechanistic understanding of both cocaine and many clinically approved medications has led to the identification of many promising medications for the treatment of cocaine dependence. For this reason NIDA has developed a CREST (Clinical Rapid Evaluation Screening Trial) protocol to provide a needed incremental medication screening step between preclinical research and full blown expensive Phase III pivotal trials. While patients receive manual based psychotherapy, three medications are screened compared to unmatched placebo in an S-week, 60-subject, four cell design trial. Another important features of the CREST protocol involve collecting baseline measurements over a 2-week period. The three medications being evaluated in this trial include reserpine, gabapentin and lamotrigine. Reserpine is being screened because of its wellknown preclinical ability to functionally antagonize cocaine (by depleting neurochemicals elevated by cocaine). Gabapentin and lamotrigine are hypothesized to interfere with glutamatergic cocaine sensitizationkindling mechanisms relevant to addiction. Although we are still analyzing the data our preliminary impression is that reserpine is the only promising medication of the three. Statistical approaches to highly variable urine benzoylecgonine data will be discussed.

Supported by NIDA under agreement # YOI DA 5003% 00. 45

PHARMACODYNAMICCOMPARISONOFNASALAND ORALEPHEDRINE

I. Berlin, D. Warot, G. Aymard, E. Acquaviva, B. Diquet, and P. Lechat, Pitie-Salpetriere University Hospital, Paris, France Ephedrine, (E) a b-hydroxy analog of metamphetamine, and its stereo-isomers are used by sportmen to increase performance, are constituents of various, cough remedies, herbal products as appetite suppressants or ‘alternative psychoactives’. As a nasal decongestant, they are frequently used for months or years. Animals can be trained to discriminate E and this discrimination is generalized to ( + )amphetamine (A). In humans E is less reinforcing than A. We tested the pharmacodynamic effects (blood pressure [BP], heart rate, drug liking, subjective drug effects, response on the ARC1 and POMS, visual analogue scales, VAS) of intranasally administered single dose E 5, 10 mg, and compared to 50 mg oral route and Placebo (PI) in a double blind, double dummy, crossover study in healthy subjects (no history of drug/alcohol/nicotine abuse or dependence). When compared to PI, E increased supine diastolic BP (P < 0.003) systolic blood pressure (P < 0.0001) (maximal increase [mean f SD]: 10 mg: 5.6 &- 7.4, P < 0.05; 50 mg: 13.4 k 10.6 mmHg), induced orthostatic hypotension (P < 0.02) (maximal systolic BP drop: 50 mg: 14 f 9.9, PcO.03; 10 mg: 10.7 + 5.6, P=O.ll). On the 49 items ARCI, E modified significantly only LSD subscale (P = 0.04). E, decreased depression factor of POMS (P = 0.09) decreased tiredness (PI: - 2 f 39, 5 mg: -17+39, 10 mg: -3Ok42, 50 mg: -24+36 mmxh, P = 0.04) and showed a tendency for drug liking (P = 0.09). On the ‘Any Drug Effect’ questionnaire subjects could identify drug effect (P = 0.007). Conclusion: E even at low dose and by nasal route can decrease tiredness in healthy subject; this is accompanied by substantial increase in BP and orthostatic hypotension exposing the subjects in case of intensive physical exercise to cardiovascular risks. 46 CHANGES IN THE EEG OF CHRONIC ABUSERS OVERAMONTHOFABSTINENCE

MARIJUANA

W.E. Better, R.I. Herning, K. Tate, and J.L. Cadet, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD Marijuana has witnessed a recent increase in use among young individuals. Research suggests that the EEG of chronic marijuana abusers has elevated abundance of

s17

Abstracts

alpha power at frontal locations (Struve et al., 1999). We thus recorded the resting eyes-closed EEG from 16 electrode sites (Fpl, F7, F3, C3, T3, TS, P3, 01, Fp2, F8, F4, C4, T4, T6, P4, and 02) in marijuana abusers (n = 19) and control subjects (n = 13) to access the EEG changes over the first month of monitored abstinence. The EEG was recorded within 3 days of admission to the inpatient research unit in order to evaluate the subacute effects of the drug. The measurements were retaken after about 28 days after being on the inpatient research ward in order to ascertain if there were any changes during monitored abstinence. Absolute and relative power (FFT) were determined for A, 4, c~i, CI~, p, and p2 bands. The marijuana abusers had significantly more absolute CI~at frontal sites early during abstinence than the control subjects. Absolute 4 and CI, significantly increased over the month of abstinence for the marijuana abusers. Thus, chronic marijuana abusers have increased alpha power early during abstinence and CIpower continues to increase during the first month of abstinence. These EEG data are discussed in view of the findings that chronic abuse of marijuana results in cognitive deficits. 47 TORS

INVOLVEMENT IN COCAINE-INDUCED

OF

CORTICAL

DOPAMINE

RECEP-

SENSITIZATION

C.E. Beyer and J.D. Steketee, Louisiana State University Health Sciences Center, Shreveport, LA Behavioral sensitization to cocaine (and other psychomotor stimulants) is characterized by an augmented locomotor response following repeated, intermittent administration of the drug. This behavioral phenomenon is postulated to be intimately associated with human behaviors including drug dependence and psychosis. Recently, considerable evidence has emerged to suggest an integral role for dopamine (DA) transmission in the medial prefrontal cortex (mPFC) in the development of cocaine-induced behavioral sensitization. For example, DA depletion in the mPFC has been demonstrated to produce a sensitized-like behavioral response to an acute injection of cocaine. Attention has now begun to focus on the involvement of DA receptor subtypes in the mPFC that mediate the effects of cocaine-induced DA transmission in this region. Thus, we have recently shown that intra-mPFC injection of quinpirole (5 nmol/ side), a DA D2-like agonist, effectively blocks the development of behavioral neurochemical and sensitization to cocaine. Similar studies designed to examine the potential involvement of cortical DA Dl receptors in the development of sensitization to cocaine are in progress. To do this, male Sprague-Dawley rats will receive bilateral intra-mPFC injections of saline or the selective Dl agonist SKF 81297 (0.3 nmol/side) approximately 5 min before systemic saline or cocaine

(15 mg/kg IP) administration. Initially, the effect of intracortical SKF 81297 administration on the acute motor-stimulant response to cocaine will be analyzed and ultimately, studies determining the effect of this DA Dl agonist on the development of behavioral sensitization to cocaine will be performed. The results of these studies should further enlighten the specific type of DA receptors in the mPFC that participate in the locomotor activating effects of cocaine and may support evidence for the purported modulatory role of DA transmission in the mPFC. Supported by NIDA grant DA08079. 48

COMPARISON

OF

AMINO-CYCLAZOCINE ARYLACETAMIDES

THE

EFFICACY

DERIVATIVES FOR

STIMULATING

OF WITH

GTP

NOVEL

II-

K-SELECTIVE BINDING

J.M. Bidlack, G.P. Richardson, C. Cioffi, and M.P. Wentland, University of Rochester, Rochester, and Rensselaer Polytechnic Institute, Troy, NY Opioid stimulation of [35S]GTPyS binding to G proteins is a biochemical measure of opioid efficacy. Recently, we reported the synthesis and opioid binding properties of a novel series of cyclazocine analogues where the 8-OH was replaced by amino and substituted-amino groups (Bioorgan. Med. Chem. Lett. 9: 1833 187, 2000). 8-Phenylamino-cyclazocine and its 4methyl and 4-methoxy derivatives bound with high affinity to the K opioid receptor, having Ki values of 0.6 nM or less. The current study compared the stimulation of [35S]GTPyS binding by 8-phenylamino-cyclazocine and its analogues, with other benzomorphans and K--selective arylacetamides. R 1EGO cell membranes, which express only the K-type opioid receptor, were used in the assays. X-Phenylamino-cyclazocine and its analogues stimulated GTP binding by 40-70%, while ethylketocyclazocine and the arylacetamides produced a 110 and 130- 150%, respectively, increase in GTP binding. This study demonstrated that different classes of K agonists produced varying degrees of maximal stimulation of GTP binding. Benzomorphans produce less dysphoria than the arylacetamides, probably due to their lower efficacy. Supported by NIDA grants K05-DA00360, DA03742 and DAl2180. 49

SYSTEMICALLY

BASED EFFECTS

ADMINISTERED

GLYCOPEPTIDES PRODUCE POTENT WITH REDUCED PHYSICAL

ENKEPHALINANALGESIC DEPENDENCE

LIABILITY

E.J. Bilsky, N.O. Elmagbari, H. Jones, W.R. Schmid, M.M. Palian, S.A. Mitchell, F. Porreca, and R. Polt, University of Northern Colorado, Greeley, CO, and University of Arizona, Tucson, AZ

Sl8

Abstracts

Development of opioid peptides as therapeutic agents has been limited by their poor CNS bioavailability following systemic routes of administration. We have synthesized a series of enkephalin-based (Tyr-D-ThrGly-Phe-Leu-Ser) glycopeptides (B-glucose, a-mannose and B-galactose) in an effort to improve stability, antinociceptive activity and blood-brain barrier permeability of the parent peptides. Using male ICR mice and the 55°C warm-water tail-flick test, we have pharmacologically characterized the antinociceptive actions of these compounds. All of the compounds tested produced potent antinociceptive effects following i.c.v. administration with calculated A50 values in the 20-60 pmol range. Glycosylation with B-glucose increased the i.c.v. potency of the parent peptides by approximately 2-3-fold. Systemic administration of the compounds by the i.v. or S.C. route resulted in full antinociceptive effects with the glycosolated peptides being 4-5-fold more potent than the parent unglycosolated peptides. The glycopeptide L-Ser-beta-glucose was more potent than morphine following S.C. administration (A50 = 7.2 vs 13.2 ymol/kg). The potency of this glycopeptide, and the ability to synthesize gram quantities, allowed us to assess the physical dependence liability of the compound using an acute mouse model. A single S.C. injection of morphine or the glycopeptide (20 x A50 values) was followed 4 h later by an injection of naloxone (10 mg/kg, i.p.). The number of vertical jumps was recorded for 15 min following administration. Glycopeptide injected mice jumped significantly fewer times than morphine injected mice (P < 0.05, Student’s ttest). These results suggest that opioid glycopeptidebased pharmaceuticals can be developed as analgesics with fewer side-effects than currently available nonpeptidic opioid analgesics. 50

SEX

DIFFERENCES

IN PATHOLOGICAL

GAMBLING

C. Blanco, J. Saiz-Ruiz, and A. Ibafiez, Hospital Raman y Cajal/Universidad de Alcala, Madrid, Spain

and more dependent traits in the 16-PF questionnaire. Males had more frequent history of substance abuse/ dependence, earlier onset (generally triggered by winning streaks) and more psychopathic traits in the 16-PF questionnaire (all P < 0.05). Conclusion: The clinical characteristics of male and female pathological gamblers are substantially different. These results are consistent with previous findings from our group suggesting that the genetic contribution to PG and treatment response of this disorder to fluvoxamine may be gender-related. 51

MACROCYCLIC

WIN

THE

CONNECTION

BETWEEN

ING

DOMAINS

THE

THE

ESTER

ANALOGS:

EXPLORING

TRANSPORTER AND

BIND-

PHENYL

RING

B.E. Blough, H.A. Navarro, and F.I. Carroll, Research Triangle Institute, Research Triangle Park, NC Early studies on WIN 35 065-2 analogs indicated that a large, open domain exists on the DAT binding site beyond the ester group. These analogs were made as part of our research into the reinforcing and behavioral effects of cocaine, which are thought to be modulated by binding to the dopamine, serotonin, and norepinephrine transporters (DAT, 5-HTT, and NET). More recent evidence shows a large, open domain beyond the phenyl group. Similar, much smaller domains are evident on the 5-HTT binding site, but no such areas are evident on the NET. These results loosely suggest that the domains in each case may be connected. A series of macrocyclic WIN 35 065-2 analogs were then synthesized and studied which connect the C2 ester to the C3 phenyl ring in order to study the relationship between these binding domains. Their synthesis was accomplished by utilizing an olefin metathesis ring closure reaction. Both the synthesis and binding studies will be described. Work supported under NIDA grant number DA05477. 52

Pathological gambling (PG) is a highly prevalent disorder with high substance abuse comorbidity that is increasingly gaining attention from clinicians and policy-makers. However, there is little research on gender differences between male and female pathological gamblers. We compared the clinical characteristics of males and females seeking treatment for PG. Method: Sixty-eight (46 males and 22 females) consecutive patients with DSM-IV PG disorder admitted to a specialized outpatient treatment program were compared regarding their clinical characteristics. Results: Women had more frequent history of trauma, current or past affective disorders, and a history of psychiatric treatment. They also had a later onset of gambling problems (usually triggered by loneliness and boredom) Objective:

BEYOND

35065-2

UNDER YEAR

FACTORS

ASSOCIATED

CONDITIONS FOLLOW-UP

OF

WITH TREATMENT

TREATMENT ON

ENTRY DEMAND:

l-

DATA

R.N. Bluthenthal, L. Gee, A. Gleghorn, M.Y. Iguchi, and B.R. Edlin, RAND, Santa Monica, CA, Charles R. Drew University, Urban Health Study, UCSF, and CSAS, San Francisco, CA To determine factors associated with drug treatment entry among injection drug users (IDUs) in San Francisco, CA, a community sample of IDUs was recruited beginning in April 1998 (n = 601). Using Community Substance Abuse Services (CSAS) system treatment data, community sample members were tracked to determine who entered drug treatment in the subsequent

s19

Abstructs

year. Between April 1998 and June 1999,48% (286/601) of IDUs had entered drug treatment according to CSAS data. Of those entering drug treatment, 39% entered methadone maintenance, 23% entered methadone detoxification, 19% entered outpatient treatment, and 16% entered residential treatment or detoxification. In multivariate analysis, white IDUs (Adjusted Odds Ratio [AOR] 0.34; 95% confidence interval [CI] 0.12,0.96) and speed users (AOR = 0.68; 95% CI = 0.46,0.99) were less likely to enter drug treatment, while IDUs with any drug treatment experience (AOR = 1.69; 95% CI = 1.06,2.72) and those who had recently tried, but failed to enter drug treatment (AOR = 1.62; 95% CI = 1.05,2.50) were more likely to have entered drug treatment. The Treatment on Demand Initiative in San Francisco appears to be attracting long-term IDUs into drug treatment. Expansion of drug treatment options to better serve users of drugs other than heroin and cocaine is warranted. 53 UNITED

CLUSTERS

OF

HALLUCINOGEN

DRUG

USE

IN

THE

STATES

G.V. Bobashev and J.C. Anthony, Research Triangle Institute, Research Triangle Park, NC, Johns Hopkins University, Baltimore, MD The purposes of this study are estimate the clustering of hallucinogen use within United States neighborhoods and to illustrate how such estimates can depend on definition of cluster structure, sampling design and prevalence of the outcome. We use the data from annual nationally representative household sample surveys on drug abuse (NHSDA) conducted during the period 1990- 1995 (n = 88 902). Six large metropolitan areas were oversampled in 1991- 1993 with additional oversampling of households with tobacco users in 1993. Pair-Wise Cross Product Ratios (PWCPR)s, a measure of clustering is estimated via Alternating Logistic Regression (ALR) method. The resulting estimates of Pair-Wise Odds Ratios (PWOR) ranged from 1.3 (95% confidence interval, CI, 1.12-1.47) for the lifetime history of hallucinogen use to 2.85 (95% CI, 1.6-5.01). The order of magnitude of these estimates is comparable to previously reported results for other drugs such as marijuana and inhalants. In accord with previous studies we observe a slight decrease of clustering effects after adjustment for individual-level covariates: age, sex, race, education, annual family income, and history of tobacco use. Alternating logistic regression could be used to study more detailed clustering structure such as clustering within age or sex subgroups within neighborhoods. However, when the prevalence of the outcome is reduced below 0.8% the estimation procedure becomes very unstable and estimates unreliable.

54 DRUG

A

TEST

OF

THE

TEMPORAL

CONDITIONING

DYNAMIC MORPHINE

ON

MODEL

OF SELF-

ADMINISTRATION

J.C. Bombace, P.S. Vosler, J.I. Hrabosky, and T.A. Kosten, Quinnipiac College, Hamden, and Yale University School of Medicine, New Haven, CT Previous research suggests that morphine’s biphasic (immediate hypoactivity and delayed hyperactivity) effects might reflect underlying motivational states. The Temporal Dynamics Model has as a centerpiece the assumption that the motivation to self-administer drugs is elicited by the conditioned elements. These elements reflect the differing temporal emotive states (produced by the drug stimuli) that modulate responding. We tested this model using IV morphine self-administration in rats. After lever-press training for food reward, four groups of rats are primed with either morphine (10 mg/kg SC) or physiological saline and allowed to selfadminister morphine (1 mg/kg/infusion) during daily 6 h sessions under an fixed-ratio one schedule of reinforcement for 14 days. One of each group receives injections immediately (15 min) and the other after a delay (2.5 h post injection). Data are collected on the acquisition of morphine self-administration and on the temporal pattern of lever-press behavior and compared across groups. The effects on the temporal pattern of behavior after placement in the morphine lever-press context in extinction will be examined. Support: NIDA ROl-09994. 55 VALUE

GENDER

DIFFERENCES

OF DELAYED

IN

DISCOUNTING

THE

REWARDS

D.E. Booth, K. Krajnak, H. de Wit, and J.B. Richards, West Virginia University, Morgantown, WV and University of Chicago, IL In this study we investigated gender differences in the discounting of delayed rewards in rats. The degree to which an individual discounts the value of delayed consequences (rewards) may be an indicator of impulsivity. Human males have been found to be more impulsive on both delay discounting tasks and paper pencil tests of impulsivity. We also determined if discounting varied across the 4-5 day estrous cycle in female rats. Twelve female and 12 male rats were trained to choose between a large delayed water reward or a smaller amount of immediate water. The amount of the immediate water reward was adjusted until each rat chose the immediate reward and the delayed large reward with equal frequency (i.e. indifference point). Indifference points for five delays of the large water reward (0,2,4, 8, and 16 s) were determined. During the first 30 training sessions males valued the large

Abstracts

s20

delayed alternative less than females indicating that they were more impulsive. With continued training this difference became smaller so that by days 61-90 there was no significant difference. Even after 90 sessions, however, the discount curves of the male rats fit a hyperbolic discount function better than the discount curves of female rats suggesting long term gender differences in discounting. There was no effect of estrous cycle on discounting. These results indicate that gender differences may exist in delay discounting in rats as well as humans. Supported by DA10588. 56 HAVE MONTH

THE

USE

NOT

OF LAAM

ACHIEVED

IN METHADONE HEROIN

ABSTINENCE:

PATIENTS 12- AND

WHO 30-

FOLLOW-UP

L. Borg, A. Ho, A.Wells, H. Joseph, P. Appel, and M.J. Kreek, The Rockefeller University, New York, NY, Weill Medical College of Cornell University, New York, NY, and Office of Substance Abuse Services, New York, NY LAAM (levo-alpha-acetyl-methadol) is an opioid agonist oral therapy and long-acting congener of methadone usually administered 3 x per week (M-W-F). We previously reported an g-week study then in progress (CPDD 1998) on 12 subjects (9M, 3F: mean age 39.9 f 1.6 years) transferred to LAAM due to continued illicit opioid use after 2 11 months on methadone maintenance (MM) despite adequate doses ( 2 60 mg) at the Adult Services Clinic (AC) of the New York Presbyterian Hospital. Five subjects did not complete the 8week study due to nonadherence or by their request, and were returned to MM (4) or continued LAAM (1). Some subjects reported sedation (4/7) or insomnia (5/7) on LAAM. By the end of the g-week study, urine toxicology (EMITa, Syva Co., Palo Alto, CA) showed that subjects were using illicit opioids (2/7), non-prescribed methadone (l/7) or both (2/7). Twelve month follow-up showed that 517 subjects who completed the protocol were still receiving LAAM treatment (217 returned to MM), with the average M-W = 88 mg (range 50-135) and the mean 72 h dose at 1.27 the M-W dose. Urine toxicology revealed 4/5 subjects had stopped heroin, but of these 3/4 tested positive for non-prescribed methadone. At 30 month follow-up lo/ 12 original LAAM protocol subjects were still in treatment at the AC: l/12 was deceased possibly due to polydrug overdose, l/l2 had left the AC due to lack of cooperation in obtaining a source for payment; 2/12 remained on LAAM and 8/12 transferred back to MM. It will be important to determine whether the previously-reported absence of steady-state in such subjects,

i.e. MM patients transferred to LAAM due to continued illicit opioid use, is persistent. Neuroendocrine testing could be of value in making this assessment. ACKNOWLEDGEMENTS: Supported in part by NIH grants: NIDA DA-P50-05130, NIDA DA00049 and NCRR MOI-RR00102: OASAS-NYS. 57

AN EPIDEMIOLOGICAL

MENT

AND

TEMPTS AND

AT

MIDDLE

OTHER SELF-HARM SCHOOL

STUDY

SUSPECTED IN

RISK A SAMPLE

OF

DRUG

FACTORS OF

INVOLVEFOR

AT-

ELEMENTARY

CHILDREN

G. Borges, A.M. Arria, and J.C. Anthony, Instituto Mexican0 de Psiquiatria, Mexico City, Mexico, and Johns Hopkins University School of Hygiene and Public Health, Baltimore, MD This nested case-control study estimates the strength of the association between very early youthful drug involvement and the occurrence of attempts at self-harm. The main suspected risk factors (i.e. drug use and levels of depression) first were assessed in 1989 as part of a prospective study on etiology of drug-taking within an epidemiological sample of youths growing up and going to school in an urban area within the mid-Atlantic region of the United States. In 1993, a total of 1500 of these youths were located within the same public school system and were re-assessed using a standardized interview schedule that included four items on suicide-related behavior and self-harm. In this assessment, 90 cases of attempted self-harm were found. The main finding of the study is that the risk for suicide attempt was observed to be greater for drug-involved youths even after alternative suspected risk factors were held constant. Compared to youths with no drug use in 1991, those who had taken one drug were an estimated 2.54 times more likely to report a subsequent suicide attempt in 1993 (95% confidence interval, CT = 1.524.25) and youths who had taken two or more drugs were an estimated 4.95 times more likely to report a later suicide attempt (95% CI = 2.87-8.54). Based on sub-analyses, we found that this association is not likely to be attributable to a previous depressed mood or suicidal ideation, and the association retained strength when other potential explanations were taken into account, including possibilities that self-harm might lead to drug involvement and that the observed association might be due to selective attrition from the sample between 1989 and 1993. One of the most important future studies might be a follow-up of youths who have participated in drug prevention field trials, in order to see whether reduced drug use might yield later reduced incidence of suicide ideation, suicide attempt, or suicide.

Abstracts

58 PARTNERSUPPORTANDLEVELOFTOBACCO DENCEIN PREGNANT WOMEN

DEPEN-

K.E. Bott, J. Kulstad, S. Benedict, H. Jones, R. Mejia, and D. Svikis, Medical College of Virginia Commonwealth University, Richmond, VA, and Johns Hopkins University School of Medicine, Baltimore, MD Background: Partner support has been identified as an important factor in tobacco cessation efforts. Few studies have examined factors such as pregnancy that might influence partner support. The present study compared levels of partner support in pregnant women with different levels of tobacco use severity. Subjects: Participants were pregnant smokers attending a hospital-based prenatal care clinic. To date, 44 women provided informed consent. Demographically, they were primarily Caucasian (66.7%); single/never married (75%) and unemployed (50%). Procedure: Subjects completed a comprehensive assessment that included the Fagerstrom and Partner Support questionnaires. Degree of partner support was compared for women categorized as high or low tobacco use severity using the Fagerstrom item. ‘How soon after you woke up would you smoke your first cigarette?’ Results: High and low tobacco severity participants differed on several measures of partner support. Partners of high tobacco use severity women were significantly less likely than those of low tobacco use severity women to try and talk them out of smoking ((. = 8.45, P < O.Ol), less likely to compliment them on not smoking (c = 6.62, P < O.OS),less likely to tell them to stick with it (c = 6.73, P < 0.05) and less likely to calm them when they are stressed or upset (trend; c = 3.59, P < 0.08). Low tobacco severity women were more likely to have tried quitting in the past 6 months (c = 5.87, P < 0.05) and to picture themselves to never smoking again (c = 4.7. P < 0.05). Study findings suggest that partner support was related to tobacco severity, and tobacco severity was related to motivation to quit smoking. These findings may have implications for partner involvement in tobacco use interventions for pregnant women. This research was support by ROlAA 11802. 59 THE PREDICTIONOFCRIMEBYANTISOCIALBEHAVIOR AND PSYCHOPATHY: A LONGITUDINAL STUDY METHADONEMAINTENANCEPATIENTS

OF

G.B. Bovasso, A.I. Alterman, and J.S. Cacciola, University of Pennsylvania, Philadelphia, PA The participants were 254 subjects sampled from a methadone maintenance population. Factor analysis of baseline measures resulted in five factors measuring hostility, insecure attachment, impaired reality testing, antisociality and empathy. These factors were used in

s21

logistic regression analysis to predict charges for violent and non-violent crimes over a 2-year period following treatment entry. Individuals with high scores on the antisociality factor had an increased risk of both violent and non-violent criminal charges. In addition, individuals with low scores on the empathy factor were at high risk for violent crimes. Measures of the antisocial traits, asocialization and psychopathy were better predictors of criminal charges than measures of prior antisocial behavior. 60 THE EFFECTS OFF-OPIOIDRECEPTORLIGANDS ANTERIORPITUITARYHORMONESINMALERHESUSMONKEYS:USEOFCUMULATIVEDOSING PROCEDURES

ON

CA. Bowen, S.S. Negus, M. Kelly, and N.K. Mello, Alcohol and Drug Abuse Research Center, McLean Hospital-Harvard Medical School, Belmont, MA There is considerable evidence that u-opioid receptors are involved in the regulation of anterior pituitary function. For example, in nonhuman primates and humans, high efficacy u-agonists generally decrease luteinizing hormone (LH) and increase prolactin (PRL) levels. In contrast, u-antagonists increase LH and have inconsistent effects on PRL levels. The goal of this study was to assess the potential utility of cumulative dosing procedures for the evaluation of the endocrine effects of opioids with different efficacies at the u-opioid receptor. The effects of acute and cumulative doses of the high efficacy agonist heroin and the antagonist quadazocine, alone and in combination, on plasma LH and PRL levels were examined in four male rhesus monkeys. Cumulative dose-response curves were determined by infusing increasing drug doses at 60 min intervals over 290 min. Blood samples for LH and PRL analysis were collected at 25 and 50 min after opioid infusions. Heroin (O.Ol0.32 mg/kg, i.v.) administration produced dose-dependent increases in PRL levels without affecting LH levels. Heroin-induced PRL secretion was equivalent after acute and cumulative dosing. Quadazocine (0.032- 1 .O mg/kg, i.m.) administration did not alter LH or PRL levels significantly under acute or cumulative dosing conditions. Quadazocine (0.1 mg/kg) antagonized the acute and cumulative heroin-stimulated increases in PRL levels. These data suggest that a cumulative dosing procedure similar to that used in behavioral pharmacology studies may be useful to study the endocrine pharmacology of u-opioids in rhesus monkeys. 61 FURTHER CHARACTERIZATION TION TO OPIOID ANTAGONISTS

OF THE SENSITIZA-

S.E. Bowen, A. Weber, C.L. Steinmiller, and A.M. Young, Wayne State University, Detroit, MI We have previously reported that CTAP (D-Phe-CysTyr-D-Trp-Arg-Thr-Pen-Thr-Nh2), a somatostatin

Abstracts

s22

derivative, was able to antagonize the antinociceptive effects of u-opioids while not producing a precipitated withdrawal in animals made acutely dependent to morphine (MS). The present experiments further compared the ability of several antagonists with activity at the u-opioid receptor to precipitate withdrawal during acute and/or chronic treatment with MS. Lever pressing by rats was reinforced under a FR30 schedule of food delivery in sessions comprised of several 5-min trials, each preceded by a 10 min time-out. Cumulative dose tests examined the potency and maximal rate-decreasing effects of compounds following acute administration of MS and before, during, and after chronic infusion of lo-40 mg/kg per day MS. Single and cumulative doses of naltrexone (NTX) and naloxone methiodide (M-NLX) dose-dependently decreased response rates in rats pretreated (- 4 h) with either saline, 5.6 or 10 mg/kg MS (SC). Acute MS pretreatment enhanced sensitivity to NTX given by either the SC or icv route. Acute MS pretreatment did not, however, alter the potency of either icv M-NLX or CTAP. Chronic administration of 10 mg/kg per day MS produced sensitization to NTX (SC and icv) and M-NLX (icv) but did not change the potency of CTAP. Increasing the chronic dose of MS to 20 or 40 mg/kg/day produced further sensitization to NTX (SCand icv) and M-NLX (icv). In contrast, MS doses of 10 or 20 mg/kg per day did not change the potency or maximal effect of CTAP (icv) and an increase to 40 mg/kg per day MS produced a slight sensitization to CTAP (icv). Taken together, these results suggest that acute or chronic treatment with MS greatly enhances sensitivity to NTX and M-NLX (SC and icv) with no change in sensitivity to CTAP. The inability of CTAP to precipitate withdrawal did not appear to arise solely from its limited distribution, inasmuch as M-NLX produced behavioral evidence of withdrawal by both the SC and icv routes. Supported by NIDA grants DA 03796 and K02 DAO0132.

62 EFFECT OF MOBILE METHADONE CRlMEINBALTIMORENEIGHBORHOODS

TREATMENT

ON

S. Boyd, J. Schroeder, and B. Crape, NIDA/IRP, and Johns Hopkins University School of Public Health, Baltimore, MD Although methadone treatment programs (MTPs) have been shown effective in reducing crime among their patients, their impact on neighborhood crime rates has not been studied. Alternate theories have been proposed: the presence of a MTP in a community could increase crime rates by attracting drug-using individuals, or reduce crime rates by treating opiate abusers who are neighborhood residents. The present study is an ecological analysis of the impact of a mobile metha-

done treatment program (MMTP) on neighborhood crime. We examined arrest statistics from May 1994 to April 1996 in four Baltimore neighborhoods with MMTPs. (Neighborhoods were defined geographically as clusters of census block groups contiguous to the MMTPs.) In April 1995, the MMTPs in two of the neighborhoods were discontinued. Generalized estimating equations (GEE) were used to determine whether arrest rates changed during the second year (April 19955April 1996) in the two neighborhoods where the MMTP left (MMTP-1) compared to the two neighborhoods where the MMTP remained (MMTP-r) and to the rest of Baltimore (BALT), after adjusting for baseline arrest rates and a socioeconomic index (derived by factor analysis of 1990 census data for all Baltimore block groups). No significant changes in arrest rates occurred in the MMTP-1 neighborhoods. However, in the MMTP-r neighborhoods, the following percent decreases in arrests were observed: all arrests 4.1% (P < 0.05), drug related 5.0% (P < 0.05), heroin related 3.8% (P < 0.05), and cocaine related 6.4% (P < 0.05). Also in the MMTP-r neighborhoods, violent crimes tended to decrease (1.7%, P < 0.10); changes in rates of “crimes to obtain money for drugs” and “nuisance crimes” were not statistically significant. While this model indicated decreases in all categories of arrests for BALT, regression models comparing the MMTP-r neighborhoods to BALT revealed a significant negative interaction term for time*MMTP presence, indicating that MMTP-r neighborhoods experienced greater decreases in arrests than the remainder of the city. Thus, in this study of four Baltimore neighborhoods, MMTPs were associated with decreases in crime. 63 GENETIC Loci RELATED ~0 STRESS AND COCAINEINDUCED ACTIVATION IN RECOMBINANT INBRED AND CONGENICSTRAINSOFMICE

A. Boyle and K. Gill, Montreal General Hospital Research Institute and McGill University, Montreal, Quebec, Canada These studies were conducted in order to map genes for cocaine- and stress-induced activational responses in strains of recombinant inbred (RI) and recombinant congenic (RC) mice developed from the A/J and C57BL/6J progenitors. The AcB/BcA RC strains represent a novel genetic approach that has not been previously applied to behavioural genetics. Cocaine-induced activity was measured in a computerized open-field apparatus under stressful (novel) and habituated conditions following IP saline or cocaine (0, 5, 10, 20, or 40 mg/kg). The C57BL/6J was the most activated strain at 20 and 40 mg/kg cocaine ( - 500% above saline controls). Significant interstrain differences were observed across a wide range of‘ phenotypes including habitua-

Abstracts

tion, as well as stress- and cocaine-induced activation. Quantitative trait loci (QTL) were identified using simple and composite interval mapping. QTL for cocaine activation accounting for 86% of the genetic variance were mapped to chromosomes 12 (23cM, LOD 5.71) 15 (46.8cM, LOD 4.38) and 17 (4.IcM, LOD 3.19). The markers on chr 12 and chr 15 map to regions containing the somatostatin receptor 1 (smstrl at 23cM), and receptor 3 (smstr3 at 46.3cM) genes, respectively. Research suggests that somatostatin may influence locomotor activation through an interaction.

64 COMPARATIVEPROFILESOFCOCAINE-DEPENDENT AND ALCOHOL-DEPENDENTWOMENWITH PTSD K.T. Brady, S. Back, S. Sonne, B.S. Dansky, and C. Diaz-Zuniga, Center for Drug and Alcohol Programs, Medical University of South Carolina, Charleston, SC The current study compared psychosocial and psychiatric correlates of women with PTSD and comorbid cocaine (N = 32) or alcohol dependence (N = 42) who were enrolled in outpatient psychotherapy trials. The Structured Clinical Interview for the DSM-III-R was used to assess substance use and other Axis I diagnoses. Substance use severity was evaluated using the Addiction Severity Index. The National Women’s Survey was employed to assess trauma history and generate diagnosis of PTSD. Frequency and severity of PTSD symptoms and levels of functioning were measured using the Clinician Administered PTSD Scale. In comparison to alcohol-dependent women, cocaine-dependent women evidenced greater employment problems (AS1 employment composite score: 0.75 vs 0.43, P < 0.001; CAPS occupational functioning extremely impacted by substance: 23.5 vs 2.7O/o, P < 0.001; years of longest full time job: 3.1 vs 5.3, P < 0.01; monthly net income: $258 vs 536, P < 0.05) legal problems (e.g. greater number of arrests for shoplifting, prostitution, parole violation; greater number of months incarcerated), and social impairment (CAPS social functioning extremely impacted by substance: 38.2 vs 2.6%, P < 0.001; fewer number of close friends: 1.28 vs 2.93%, P < 0.001). Significantly higher rates of social phobia and major depression were evidenced among alcohol-dependent, as compared to cocaine-dependent women (22.5 vs 6.3%, P < 0.05: 25.0 vs 3.1%, P < 0.01). Examination of trauma history revealed no significant differences in total number of traumas, but alcohol-dependent women had higher rates of serious accidents (67.5 vs 40.6%, P < 0.05) other situations involving serious injury (35.0 vs 12.5%, P < 0. 05) and other stressful life events (65.0 vs 37.5%, P < 0.05). The observed differences enhance awareness of the specific needs of women with PTSD and comorbid substance use disorders, which may have implications for prevention and treatment intervention.

S23

65 METHADONE FOR THE TREATMENT OF DEPRESSIVE SYMPTOMS IN OPIOID-DEPENDENT ADULTS S.A. Branstetter, J.B. Kamien, and L. Amass, The Efficacy of Buprenorphine-Naloxone and University of Colorado School of Medicine, Denver, CO Psychiatric comorbidity is common among opioid-dependent adults with rates of depression as high as 50%. Depression in this population is associated with a poorer treatment prognosis. While some reduction in depressive symptoms has been noted during the first few months of methadone (METH) treatment, METH as a pharmacological agent appears to have minimal antidepressant effects. Recent trials of standard antidepressant medications (e.g. Prozac) among methadonemaintained populations have also yielded little success. Buprenorphine, a partial u-opoid agonist pending FDA approval, has been successful in treating depression among opioid-dependent adults and non-dependent populations with refractory depression. A combination formulation of buprenorphine containing buprenorphine and naloxone in a 4:l ratio is planned for use in the United States. The current study compared buprenorphine-naloxone (BNX) versus METH for the reduction of depressive symptoms among treatment seeking opioid-dependent adults. Subjects were 38 adults participating in a controlled, randomized trial of BNX and METH who presented with moderate to severe depression at intake as measured by the Beck Depression Inventory (BDI; X = 22 + 1.4). Subjects experienced an equal amount of cognitive and somatic symptoms of depression at intake. BDI’s collected at intake and within one month of initiation of treatment were compared. All subjects experienced a significant reduction in depressive symptoms within one month of intake (t(37) = 5.10, P < 0.001). There were no significant differences in depressive symptoms as a function of drug and dose. These results suggest that decreases in overall depressive symptomology among opioid-dependent adults receiving treatment do not differ as a function of BNX or METH therapy, but that entering treatment has a positive impact on depressive symptoms. Supported by NIDA grant DA1 1160.

66 METHAMPHETAMINEANDVIOLENCEZPREDICTORS AND RELATIONSHIPTO TREATMENT OUTCOMES M.-L. Brecht, C.L. von Mayrhauser, and M.D. Anglin, UCLA Drug Abuse Research Center, Los Angeles, CA Violent behavior is often cited as a consequence of chronic amphetamine/methamphetamine (A/M) abuse. With increasing prevalence of (A/M) abuse and its spread to previously low prevalence areas, there is a

s24

Abstructs

commensurate increase in concern about the impact of its consequences, such as violent behavior, in the drug use prevention/treatment and criminal justice systems. This study describes correlates of reported A/M-related violent behavior and the relationship of such behavior to treatment outcomes. Data for this analysis are from the first 250 interviews in a study of the natural history and treatment outcomes of A/M users; subjects were randomly sampled from A/M users admitted to publicly funded treatment in Los Angeles in 1996 and interviewed in 1999-2000. The analysis sample was approximately 42% female, 58% male; 21% AfricanAmerican, 25% Hispanic, 44% non-Hispanic White. Preliminary analyses show 53% reporting A/M use-related violent behavior. Logistic regression identified characteristics associated with violent behavior: early risk profiles (physical abuse before age 15) A/M use behaviors (younger ages of initiation and regular use, injection use, selling and/or making A/M), other A/M consequences (weight loss, sleeplessness, skin problems, paranoia, hallucinations, financial, work, and legal problems), psychological vulnerability (attempted suicide, higher depression scores), and more arrests. Treatment histories were not related. Survival analysis showed no significant relationship of violent behavior with time to relapse after treatment. Results support the importance of early prevention programs and the need for treatment and health services to address syndromes of drug-related physical and psychological consequences. 67

RECOVERY

TIME

COURSE

DROME TOR

AND LEVELS

FROM OF THE RETURN AND

CANNABINOID PRECIPITATED OF

BRAIN

SR141716A immediately after the THC infusion. In the present study, all brain regions examined from THCtreated rats (basal ganglia, cerebellum, frontal cortex, and hippocampus) showed 30&70% decreases in 3HWIN55212-2 B,,, values (with little change in KD) versus vehicle-treated. Only hippocampus showed a decrease in WIN55212-2-stimulated [35S]GTPgS binding B,,, values (50% decrease), but increases in KD values in cerebellum and basal ganglia were indicated. In contrast, THC stimulation of [35S]GTPgS binding was decreased by 50-80% in basal ganglia, hippocampus and cerebellum. SR 141716A challenge 24 h after cessation of drug/vehicle infusion resulted in withdrawal signs similar to previously reported, and brain receptor changes similar to those observed at the 1 h time point. A notable exception was an apparent recovery of WIN55212-2-stimulated [35S]GTPgS binding B maxvalues from 50 to 70% of control in hippocampus. Subsequent experiments will investigate the duration of withdrawal and down-regulation, anticipating that all or most parameters will return to control values. Supported by NIDA training grant DA 07027 and DA 03672. 68

TEACHING

REDUCTION

COLLEGE VIA

INTERNATIONAL

STUDENTS

DRUG

USE

HARM

TRAVEL

M. Bronson, R. Stohler, and G. Schippers, Midwestern University, Glendale, AZ Psychiatrische Universitatsklinik, Zurich, Switzerland, and Amsterdam Institute of Addiction Research, The Netherlands

DEPENDENCE: WITHDRAWAL

CANNABINOID

SYNRECEP-

ACTIVITY

C.S. Breivogel, 1.0. Beletskaya, SM. States, M.D. Aceto, and B.R. Martin, Virginia Commonwealth University, Richmond, VA Chronic administration of D9-tetrahydrocannabinol (THC) to rats results in decreases in brain cannabinoid receptor levels and activity as determined by ex-vivo binding. Administration of the CBl antagonist, SR141716A, to THC-tolerant rats results in a dependence syndrome. In the current study, we hypothesized that the disappearance of the withdrawal syndrome over time would correlate with recovery of CBl receptors or CBl receptor activation of G-proteins. Groups of six male Sprague-Dawley rats were infused i.p. with vehicle or THC beginning at 12.5 mg/kg/day and doubling the dose each day. On day 4, the infusion solution was replaced with water for 24 h before challenge with 10 mg/kg SR141716A. In a previous study, THC- (but not vehicle-) treated rats showed dramatic increases in the number of wet dog shakes precipitated by

We hypothesized that pharmacy students would be more open to the concept of harm reduction as it relates to drug use if they visited countries where harm reduction is practiced. An elective course was designed to familiarize students with the basic concepts of harm reduction, and then to let them compare drug abuse policies in the United States and Europe by visiting Amsterdam, The Netherlands and Basel, Switzerland. The first day of class, students watched ABC News America’s War on Drugs (4/6/95) and then wrote a short paper on their opinion of harm reduction as defined in this program. In subsequent classes, students presented papers on various aspects of harm reduction as it relates to alcohol and drug use, followed by a trip to Europe. In Amsterdam, students visited the Municipal Health Department where a senior administrator explained the history of drug policy in the Netherlands and provided statistics on crime and disease since implementation of the policy. They then visited a heroin maintenance clinic where a three-armed clinical trial is taking place. The final visit was to a ‘coffee shop’, where the owner explained the history and future of marijuana policy in The Netherlands. In Basel, students visited a university-run residential drug detoxification

Abstracts

center and a government-funded injection center where intravenous drug users receive sterile needles and syringes and can inject their drugs in a clean, controlled environment. Students kept daily journals, and upon return to the United States wrote research papers on one aspect of harm reduction and whether they felt it would be beneficial in the United States. In comparison to their initial mostly negative reaction to harm reduction as viewed in ‘America’s War on Drugs’, after the trip to Europe, all students felt that some aspects of harm reduction were viable options for the United States. Based on verbal feedback and the students’ written reports, the course was determined to be a good exercise in global awareness and critical thinking. 69 COGNITIVE FUNCTIONING IN METHADONE TIENTS:THE EFFECTS OF COCAINE AND ADHD

PA-

D.J. Brooks, F.R. Levin, S.M. Evans, E. Nunes, and A. Sia, Columbia University and New York State Psychiatric Institute, New York, NY Cocaine abuse is a substantial problem among methadone maintained patients that is often ignored. Recent trends for treating cocaine abuse have focused on treating dually diagnosed sub-populations of abusers, specifically those diagnosed with Adult Attention Deficit Hyperactivity Disorder (ADHD). Diagnostic services capable of identifying cognitive deficits among these patients with ADHD and/or cocaine abuse are needed in order to track the efficacy of novel therapeutic approaches. Although cognitive deficits found in cocaine abusers and in children with ADHD are represented in recent research, few studies address cognitive deficits in adults with ADHD, let alone substance abusers with ADHD. Of interest is the varying degree of attentional deficits as evidenced in patients with cocaine abuse and those with adult ADHD; specifically under investigation is the possible cumulative effect of these two diagnoses. The California Computerized Assessment Package (Calcap) allows us to perform standardized assessments on cognitive functions requiring focused and sustained attention. Using the structured clinical interview for DSM-IV Axis-1 Disorders (SCID) and a SCID like module for Adult ADHD, individuals are placed into one of four diagnostic categories: (1) current cocaine dependence alone; (2) Adult ADHD with current cocaine dependence; (3) Adult ADHD alone; and (4) a control group. All individuals are currently maintained on methadone with doses ranging from 40 to 200 mg/day. To date 30 people have participated. Twenty-two have been male (73%): 21 (70%) have been Caucasian, 3 (10%) have been African American and 6 (20”/0) have been Hispanic. Comparisons between groups will be carried out by examining the percentages of true and false positive responses and the

mean reaction and sequential attention. The level will also

s25

times on tasks examining simple, choice reaction time, as well as visual selective effects of age, education and methadone be investigated.

70 HEPATITIS c VIRUS QUALITATIVE POLYMER CHAIN REACTION PREVALENCE AMONG OPIOD-DEPENDENT PATIENTS

L.S. Brown, M.M. Chu, S. Dabo, J. Rawls, and B.J. Primm, Addiction Research and Treatment Corporation, Brooklyn, NY Introduction: Previously, we and other investigators have reported the significant prevalence of hepatitis C virus (HCV) infection among substance abusers as determined by serum assessments of the HCV antibody positivity rate. However, HCV antibody positive (HCV Ab) status may only be an indicator of past HCV infection and not current infection. Objective: This study was designed to determine the prevalence of current HCV infection among patients who tested positive for HCV Ab. Methods: Patients admitted to methadone treatment clinics in New York City were screened for HCV Ab. Demographic, behavioral, and clinical information was obtained through chart abstraction. For patients who tested positive for HCV antibody, their samples were further assayed for HCV polymerase chain reaction (PCR) using a qualitative assay (Roche). Results: Nearly 61% (972 of 1595) of the patients were HCV Ab positive. Males and older patients were more likely to be HCV Ab positive. Abnormal liver function tests occurred in nearly one-third of the HCV Ab positive patients. Eighty-eight percent (425 of 486) of the HCV Ab samples were found to be positive for HCV PCR with nearly 40% of these patients demonstrating abnormal liver function. Conclusion: Consistent with other researchers, the overwhelming majority of HCV Ab positive patients have current HCV infection. However, a substantial percent of those who are HCV Ab positive have cleared their infection. Unfortunately, HCV PCR determinations are not universally available to all. This has significant implications for health care for HCV infection and disease among the poor. 71 DISTRESS TOLERANCE AND SMOKING CESSATION ATTEMPTS

DURATION

OF PAST

R.A. Brown, C.W. Lejuez, C.W. Kahler, and D.R. Strong, Brown University School of Medicine and Butler Hospital, Providence, RI Evidence suggests that a large percentage of individuals attempting smoking cessation lapse to smoking within a matter of days, and few recover to achieve and maintain smoking abstinence. Results of studies relating

S26

Abstracts

severity of nicotine withdrawal symptoms to short-term smoking cessation outcomes have been equivocal. Based on a small body of laboratory work in this area, we hypothesized that one’s inability to tolerate psychological and physical discomfort might be associated with early lapse to smoking. To examine this hypothesis, the present study studied 32 current cigarette smokers: one group of 16 individuals who have previously been unable to quit smoking for more than 24 h (immediate relapsers) and a second group of 16 individuals who had previously quit for more than 3 months (delayed relapsers). Specifically, subjects were exposed to a psychological stressor (mental arithmetic) and a physical stressor (inhalations of carbon dioxide-enriched air) both on a day in which the subject was smoking ad libidum up until the session and on a second day in which the subject abstained from smoking for 12 h prior to the session. Regardless of which day of participation, immediate relapsers were less able to endure these stressors (i.e. shorter escape latencies) and reported greater self-reported effects (e.g. increased anxiety, craving for a cigarette). These results suggest that individual differences in a smoker’s ability to tolerate discomfort during nicotine withdrawal may be related to smoking cessation outcomes. 72

DEPRESSIVE

PHYSIOLOGICAL

SYMPTOMS RESPONSE

PREDICT TO

COCAINE

SUBJECTIVE

AND

IN HUMANS

S. Brown, M. Sofuoglu, and D.K. Hatsukami, sity of Minnesota, Minneapolis, MN

Univer-

Recently, in cocaine dependent men, subjective response to IV cocaine was reported to be significantly correlated to Beck Depression Inventory (BDI) scores. Similarly, in a recent study, we found BDI scores to be predictive of the subjective response to smoked-cocaine. To examine further the relationship between BDI scores and response to cocaine, data from 75 male and female cocaine users were analyzed. Non-treatment seeking cocaine users who participated in various inpatient studies received a single 0.4 mg/kg smoked cocaine on the adaptation day. BDI was given in the beginning of the sessions. Similar trends in various measures were found when the relationship between the BDI scores and subjective and physiological (heart rate, blood pressure) response to cocaine was examined. Low BDI scores (O-7) were associated with a smaller physiological and subjective cocaine response. Medium (8-13) BDI scores were associated with increasing cocaine response which plateaued or declined in the high ( > 14) BDI groups. Analysis with ANOVA showed significant (P < 0.05) group differences for subjective ratings (feel high, stimulated, desire cocaine, feel the effect of last dose) and physiological response (change in heart rate and change in diastolic blood pressure) to cocaine.

Altogether, these results suggest that presence of depressive symptoms are associated with increased physiological and subjective response to smoked cocaine administration. The implication of these results is that the presence of depressive symptoms may increase cocaine use behavior partly by increasing the cocaine effects. Supported by NIH grants P-50 DA09259 and MOlRR00400. 73

POLYDRUC

HIGH

ETHANOL

ABUSE:

SELF-ADMINISTRATION

CONCENTRATIONS

AND

OF

METHADONE

V.L. Brown, N.S. Wang, and R.A. Meisch, University of Texas Health Science Center at Houston, Houston, TX Although ethanol use among methadone maintenance patients is a serious problem, there have been few preclinical studies of methadone-ethanol combinations. One study, using 1% (w/v) ethanol and 0.2 mg/ml methadone, reported that this combination was an effective oral reinforcer in monkeys. Arguably, the behavior maintained by this combination was due to the sweet taste of the low ethanol concentration. This report is an attempt to address that issue. In the current study ethanol concentrations, 16, 22.6, and 32% (w/v), that are not readily self-administered by naive rhesus monkeys were utilized in combination with 0.4 mg/ml methadone. Deliveries were obtained under concurrent nonindependent fixed-ratio fixed-ratio or variable-ratio variable-ratio reinforcement schedules. Responses on one spout counted toward completion of the ratio requirements for both spouts. Since the number of responses on a spout could vary, the response per delivery ratio was calculated as an additional dependent variable. The results show that methadone and each ethanol concentration functioned as oral reinforcers in five rhesus monkeys. Further, when methadone-ethanol combinations and methadone were concurrently available all of the monkeys preferred the methadone plus the high ethanol combinations to methadone alone. Thus ruling out the interpretation that methadone--ethanol combinations maintain behavior because of the sweet taste of ethanol. Further, this study supports the validity of nonindependent ratio schedules in creating an additional dependent variable useful for determining the relative preference of one reinforcer over another. 74

CONSISTENCY

MEASURED ON-SITE

BY TESTING

AND

VALIDITY

SELF-REPORT, AND

LABORATORY

OF

MARIJUANA

COLLATERAL

USE

REPORTS,

TESTING

B.J. Buchan, F. Tims, and M.L. Dennis, Operation PAR. St. Petersburg, FL, Chestnut Health Systems

s21

Abstracts

Bloomington, phia, PA

IL, and Children’s Hospital

of Philadel-

Researchers and therapists alike seek confidence in self-reported substance use from adjunct ‘on-site’ and/ or laboratory based urine tests. Adolescent marijuana use from self-report and ‘on-site’ urine testing is compared to the ‘gold standard’ laboratory test. Data (n = 248) are from adolescents recruited at four sites under a cooperative agreement; the Cannabis Youth Treatment (CYT) study. Interviews were conducted using the Global Appraisal of Individual Needs (GAIN) at intake and 3 and 6 months post baseline. Urine specimens were collected at the same points, tested with an ‘onsite’ kit and quantitatively confirmed by laboratory based Gas Chromatography/Mass Spectrometry (GC/ MS). At intake, use of marijuana in the past 30 days was self-reported by 82% of clients which compared with a positive lab confirmation rate of 52% at a cutoff level of 41 rig/ml for D9-THC (the major marijuana metabolite) (95% sensitivity, 31% specificity) and 70%) at a cutoff level of 5 rig/ml D9-THC (93% sensitivity, 45% specificity). Self-reported use is for ‘the past 30 days’ whereas the window of detection of the analyte in urine averages 3-10 days but could be up to 30 days for a chronic user. The ‘on-site’ kit produced a positive test result for 77% of the adolescents at intake. This ‘on-site’ kit detects an average of 41 rig/ml D9-THC but because it is an immunoassay procedure it actually detects multiple marijuana metabolites and therefore may appear a more sensitive test (10% false positive rate at intake but 91% sensitivity and 79% specificity overall). This may be problematic if used by a clinician or as a measure of change over time for treatment of known drug users unless the clinician has a clear understanding of the pharmacokinetics of marijuana. On-site kit testing is a reliable way of providing rapid presumptive screening results which can be used to influence clinical care. 75 SIGNS

A

CONTROLLED, AND

SYMPTOMS

OUTPATIENT OF MARIJUANA

STUDY

OF

THE

WITHDRAWAL

A.J. Budney, P.L. Novy, J.R. Hughes, and M. Allen, University of Vermont, Burlington, VT Inpatient studies indicate that withdrawal symptoms can occur following discontinuation of marijuana smoking. However, the clinical relevance of marijuana withdrawal has not been established. This outpatient study examined the signs and symptoms of marijuana abstinence that occur when heavy marijuana users stop using marijuana while remaining in their natural living environments. Twelve heavy marijuana smokers participated in a 16-day, ABAB study. During Condition A subjects ‘smoked-as-usual’. During Condition B they

abstained from smoking marijuana. Between-condition comparisons showed significant decreased heart rate, weight loss, decreased appetite, increased aggression, sleep difficulty, and increased craving during the abstinence condition. Additional analyses showed a wide range of individual differences regarding the number and severity of abstinence symptoms. This paper will also provide preliminary data from a second outpatient study in which abstinence effects were systematically reported by outpatients during the first three weeks of treatment for marijuana dependence. The marijuana withdrawal syndrome appears to consist of affective and behavioral symptoms commonly experienced during withdrawal from most drugs of abuse. The relevance of the marijuana withdrawal syndrome to the development of dependence and its effect on cessation attempts will require additional investigation. Supported by NIDA grant DA12471. 76

COGNITIVE

TION

THERAPY

INTERIM

BEHAVIORAL FOR

ADOLESCENT

TREATMENT

VERSUS

PSYCHOEDUCA-

SUBSTANCE

ABUSERS:

OUTCOME

J.A. Burleson and Y. Kaminer, University of Connecticut Health Center, Farmington, CT O&ctive: To compare the efficacy of Cognitive Behavioral (CBT) versus Psychoeducation Therapy (PET) in the treatment of adolescent substance abusers. Hypothesi,s:Youth assigned to CBT condition will show better outcomes than those assigned to PET condition. Method: Ninety consecutively admitted adolescents were randomized to one of two conditions, each comprised of eight weekly outpatient psychothearpy group sessions. Subjective and objective outcome measures were collected at 3- and 9-month follow-up. Results: Eighty-four percent (76/90) completed treatment. Independent of completion, 74% (61/82) of those eligible completed 3-month follow-up; 90% (55/61) of those were available to provide urine samples. CBT subjects had a significantly lower rate of positive urines (1 l/36; 31%) than did PET subjects (12/19; 63%) at 3-month follow-up, x2 = 5.43, P = 0.02. Abuse diagnosed subjects had a significantly lower rate of positive urines (4/l& 22%) than did dependence diagnosed subjects (17/33; 52%) x2 = 4.13, P = 0.042. Gender and age were not significant predictors. Conclusion: CBT appears to be superior to PET for the treatment of adolescent substance abusers. Complete results, including 9-month follow-up, will be reported subsequently. 77

OPIOID

USE

FOR

CHRONIC

PAIN

IN

CANADA

U.E. Busto, J. Thomas, M.K. Romach, and E.M. Sellers, Centre for Addiction and Mental Health, University of Toronto, Canada

S28

Abstracts

Several opioid analgesics are used for the treatment of chronic pain. Restrictions to analgesic opioid use have been introduced because of concerns about abuse. Yet at the same time pain management seems inadequate. National and regional opioid use (1994-1997) was calculated from sales data using defined daily doses (DDD). Overall use of codeine in Canada was stable at around 14 DDD/lOOO inhab per day accounting for 80% of total opioid use, while use of other opioids increased (e.g. hydromorphone: 0.7-1.6 DDD/lOOO inhab per day; oxycodone: 0.4-0.7 DDD/lOOO inhab). Codeine was 97% used as combination product rather than as single entity. General practioners accounted for 64% of all codeine prescription. Wide regional disparities were observed, e.g. British Columbia used 14.9 DDD/lOOO inhab per day ( + 45% over the national average and Quebec 3.5 DDD/lOOO inhab per day ( - 70% national average). Quebec had the lowest rate of codeine use and the greatest prevalence of chronic pain, while British Columbia was the opposite. Differential provincial narcotic regulations did not account for this finding. Differences in socioeconomic factors, access to care, and physician practices are likely explanations. These data suggest that pain management may be inadequate in some parts of the country but overuse is more common in others. 78 K-OPIOID AGONIST-INDUCED PROLACTIN RELEASE IN RHESUS MONKEYS IS PREVENTED BY A DOPAMINERGIC DZ-LIKE AGONIST E.R. Butelman, C.S. Lawinski, A.W. Lin, P. Thagirisa, and M.J. Kreek, The Rockefeller University, New York, NY k--opioid agonists may have pharmacotherapeutic potential in the management of psychostimulant abuse, as suggested by their ability to modulate dopaminergic systems that may be involved in drug reinforcement (e.g. the mesolimbic system). K-agonists also modulate other dopaminergic systems, such as the hypothalamic tuberoinfundibular system. The dopaminergic tuberoinfundibular system has inhibitory control over the release of the anterior pituitary hormone, prolactin. Prolactin levels may therefore be a neuroendocrine marker for the ability of K-agonists to modulate a dopaminergic system in vivo in primates. The effectiveness of a D2-like dopaminergic agonist (quinpirole, 0.01-O. 1 mg/kg, s.c.) in preventing U69 593 (a selective K-agonist; 0.01 mg/kg, i.v.) - induced prolactin release was studied in intact female rhesus monkeys (n = 4). This U69 593 dose produced a more than lo-fold increase in prolactin levels, relative to baseline, from 5 min after administration. Quinpirole caused dose-dependent, complete suppression of U69 593-induced prolactin release, under the present conditions. This

confirms that the prolactin-releasing effect of a selective K-agonist is due (directly or indirectly) to modulation of a dopaminergic system. This suggests that prolactin release is a valid quantitative marker for the ability of K-opioid agonists to modulate dopaminergic function in vivo in primates. Supported by NIH-NIDA grants DA 11113 (ERB), DA 00049 and DA 05130 (MJK). 79 VARIABLESTHATIMPACTRELIABILITYOFPERSONALITY DISORDER DIAGNOSES IN OPIATE DEPENDENT CLIENTS J.S. Cacciola, A.I. Alterman, M.J. Rutherford, and G.B. Bovasso, University of Pennsylvania/VA Medical Center, Center for Studies of Addiction, Philadelphia, PA, and Alcohol and Drug Abuse Institute, University of Washington, Seattle, WA As with general psychiatric patients, longer term testretest reliability of personality disorder (PD) diagnoses in substance abusing clients has been poor to fair. Reasons for this finding have rarely been empirically examined. The present study examined factors that may enhance or diminish the test-retest reliability of DSMIII-R PD diagnoses in a sample of 235 opiate dependent clients assessed with the Structured Interview for DSM-III-R Personality (SIDP-R) 2 months following admission to methadone maintenance treatment (Tl) and again 2 years later (T2). Analyses examined the relationships of a number of client, treatment status (in or out of treatment) and interviewer (Ph.D. or non Ph.D.) variables to diagnostic concordance. Client variables included drug use, depression, psychiatric severity and functional status in a number of other domains at each time point. Although client state, treatment status, and interviewer variables did impact on diagnostic concordance, the relationship between these variables and concordance was not straightforward and varied according to different PDs and different variables. Change in depression and psychiatric severity was most consistently and inversely related to diagnostic concordance. 80 PERSISTENTCEREBROVASCULARDEFICITSINMARIJUANA ABUSERS L. Cadet, W.E. Better, K. Tate, and RI. Herning, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD Marijuana has witnessed a recent surge among young individuals. Research suggests that the cerebrovascular perfusion of chronic marijuana abusers may be compromised. We thus recorded blood flow velocity in the anterior and middle cerebral arteries by transcranial

S29

Abstracts

Doppler sonography in marijuana abusers (n = 16) and control subjects (n = 30) to access the existence of any potential abnormalities. Blood flow velocity was recorded within 3 days of admission to the inpatient research unit in order to evaluate the subacute effects of the drug. The measurements were retaken after about 28 days after being on the inpatient research ward in order to ascertain if there were any changes during monitored abstinence. The pulsatility index, a measure of cerebrovascular resistance, and systolic velocity were increased in marijuana abusers and the increases persisted even after the month of abstinence. These data are discussed in view of the possibility that chronic abuse of marijuana might be a risk factor for stroke. 81 GABA AGONISTEFFECTSONCOCAINE-ANDFOODMAINTAINED RESPONDING IN RATS: INFLUENCE CAINE DOSE AND LIQUID FOOD CONCENTRATION

OF CO-

S.B. Caine, S.S. Negus, and N.K. Mello, McLean Hospital, Harvard Medical School, Belmont, MA Recent evidence suggests that GABA agonists may attenuate some physiological and behavioral effects of cocaine. We tested the hypothesis that these drugs attenuate the reinforcing effects of cocaine at doses of the drugs that do not alter responding maintained by food. In one group of rats (n = 8). responding was maintained by various unit doses of cocaine in multiple components of each test session (20 min components with ascending unit doses of cocaine, 0.032-3.2 mg/kg iv; from 5 to 20 s). In another group of rats, responding was maintained under identical schedule conditions by various concentrations of liquid food (EnsureR; 3.2100% in water). In initial studies, pretreatment with the GABA-B agonist baclofen (1.8-5.6 mg/kg ip) or the GABA transaminase inhibitor y-vinyl-GABA (GVG; 0.18-0.56 g/kg ip) produced downward shifts of the inverted U-shaped dose-effect function for cocaine selfadministration (P < 0.05). Both drugs were more effective in reducing responding maintained by lower (0.032-0.32 mg,!kg) rather than higher (1.0-3.2 mg/kg) doses of cocaine. Comparable decreases in responding maintained by liquid food, particularly lower (3.21O”/;,) rather than higher (32- 100%) concentrations, were produced by these doses of the GABA agonists. The results do not support the hypothesis that baclofen or GVG reduces cocaine maintained behavior selectively. In ongoing studies, the effects of the GABA-A agonist muscimol and the GABA-A modulators pentobarbital, midazolam and enazenil (an analog of imidazenil) are also being investigated. We thank M. Nader and R. Mach for GVG and E. Costa and A. Guidotti for enazenil. Supported by NIDA DA07252, DAOOlOl, and DA04059

82

SYNTHESIS OF NEW ANALOGUES TENTIAL CANNABINOID LIGANDS

OF PF460 AS PO-

T.M. Caldwell, A.C. Howlett, and K.C. Rice, NIDDK, NIH, Bethesda, MD, and St. Louis University, St. Louis, MO Cannabinoid receptors (CBl and CB2) are activated by several different classes of agonists. Analysis of the structure activity relationships of these agonists has identified some of the possible pharmacophoric elements required for ligand binding and activation of cannabinoid receptors. From these analyses, molecular models have been developed for the cannabinoid receptor. Based upon these models, we have proposed and synthesized a new set of chiral analogues of PF460 (Drug Des. Disc., in press, 2000). These analogues should allow us to further elucidate the structural features that affect ligand binding to and activation of the cannabinoid receptor subtypes. Synthesis and biological activity of these analogues to date shall be presented. R = H (PF460) 83 POST-MARKETING SURVEILLANCE TION'S ACTUAL ABUSE: EXPERIENCE RAMINEAND DEXFENFLURAMINE

OF A MEDICAWITH FENFLU-

S.R. Calhoun, G.P. Galloway, and D.E. Smith, Haight Ashbury Free Clinics, Inc., San Francisco, CA Following approval of a new medication with abuse potential, the FDA may recommend or require monitoring for both adverse events and epidemiological evidence of abuse. The monitoring strategies for adverse events and for abuse are different. Abuse monitoring relies on identifying instances of abuse in patients seeking treatment, as well as evidence of abuse showing up in non-treatment settings. The specific information sources and populations monitored for abuse vary depending on the pharmacology of the drug. The Haight Ashbury Free Clinics was engaged to monitor fenfluramine and dexfenfluramine to identify cases or situations of abuse (for recreational or non-medical uses, often at above-therapeutic levels) or misuse (use outside of a medically supervised context but for purposes in keeping with its medicinal uses). Based on existing biomedical literature we hypothesized that there would be little if any abuse of these medications. However, concern was expressed by some regulators that availability of fenfluramine or dexfenfluramine might revive a ‘diet drugs’ abuse cycle similar to that of amphetamines in the 1970s. There was also concern that it could be misused by normal- or underweight individuals who might use it to assist with further weight loss, individuals with eating disorders who might use it to facilitate their disease, athletes who might use

90

Ah.WYlCYS

it in an effort to lose body fat, or body builders who might use it for body sculpting. The conclusion was that evidence of abuse was not detected. This presentation discusses the data sources and other methods that were found useful in assessing abuse of fenfluramine. The monitoring of abuse is a developing technology and provides an important ancillary source of information for interpreting quantitative epidemiological data. ACKNOWLEDGMENTS: The postmarketing surveillance program was supported by Wyeth-Ayerst and Interneuron Pharmaceuticals.

rates or alcohol were observed in YR 1 vs YR 0. Statistically significant changes in cocaine ( - 1.5%) and benzodiazepine (+ 0.08%) positives were observed. Conclusion: MS was effective in retaining noncompliant clients in treatment and providing a mechanism for them to obtain compliance, and did not lead to an increase in use by previously compliant clients. 85

MDMA

PHETAMINE) MANS:

84 MENT

EVALUATION TRACK

NON-COMPLIANT

OF AS AY

A

‘MINIMAL

ALTERNATIVE

CLIENTS

IN

SERVICES’ TO OPIOID

TREAT-

DISCHARGE

(3,4-METHYLENEDIOXYMETHAMAND

ALCOHOL

PHARMACOKINETICS

INTERACTIONS AND

IN

HU-

NEUROENDOCRINE

EFFECTS

FOR

SUBSTITUTION

TREATMENT

D.A. Calsyn, F.J. DeMarco, A.J. Saxon, K.L. Sloan, and K. Gibbon, VA Puget Sound Health Care System, University of Washington School of Medicine, Seattle. WA Continued illicit drug use by clients in opioid substitution treatment presents programs with the dilemma of discharging these patients (potentially increasing harm to the patients and society) versus tolerating ongoing drug use. Studies of treatment outcome suggest that discharged patients increase illicit drug use and engage in more HIV risk behaviors. However, a ‘no discharge’ policy may be perceived as condoning illicit use and could lead to increased drug use by clients who would otherwise discontinue illicit use for fear of discharge. In response to these concerns a ‘Minimal Services’ track (MS) was initiated in lieu of discharge. Non-compliant clients placed in MS received only LAAM 3 x per week, were required to dose during a limited time frame when most other clients were not present, and attended a monthly case management group. These patients’ former individual counselors were assigned new clients so waiting lists would not be extended because of fewer discharges. The effectiveness of MS was evaluated by using an A/B design comparing all clients in treatment during the year prior to initiation of MS (YR 0) and the year following (YR 1) on treatment retention, program status and UA results. Of the 189 clients in treatment, 35 (18.5%) were placed in MS in lieu of discharge. Of these, 25 (74.1%) were still in treatment at the end of YR 1. Nine MS clients (25.7%) returned to the regular program by meeting the criterion of providing 3 months of negative UA results. MS patients as a group reduced their detectable illicit drug use by 50% during the 6 months following MS placement. For non-MS clients, no increase in positive UA results for opiates, amphetamines, barbitu-

J. Cami, C. Hernandez-Lopez, P.N. Roset, M. Mas, J. Ortufio, N. Pizarro, J. Segura, R. de la Torre, and M. Farrt, Institut Municipal d’brvestigacio Medica, Universitat Autbnoma de Barcelona and Universitat Pompeu Fabra, Barcelona, Spain Epidemiological and forensic data show that MDMA is usually consumed simultaneously with alcohol and other drugs of abuse. There are not human experimental studies of the pharmacological interactions of MDMA and alcohol. Nine healthy male recreational users of MDMA (23 years; 67 kg; 1.75 m) participated in four different experimental sessions (l-week wash-out interval between sessions). Single oral doses of MDMA (100 mg), alcohol (0.8 g/kg), both drugs combination, and placebo were administered in a double-blind, double-dummy, placebo controlled, cross-over trial. Blood samples were obtained to measure neurohormones (cortisol and prolactin) and plasma concentrations of ethanol, MDMA and three of its metabolites: 3,4-methylenedioxyamphetamine 4-hydroxy-3-methoxy-methamphetamine (MDA), (HMMA), and 4-hydroxy-3-methoxy-amphetamine (HMA). Other variables included vital signs, psychomotor performance and subjective effects (results not shown here, presented at CPDD-99). Ethanol plasma levels after drug combination were lower in comparison to alcohol condition (AUCO-6h - 9%; Cmax 15%), and peak ethanol concentrations appeared later (a 30 min delay in the T,,,). The concentrations of MDMA were higher (C,,, 11%) and those of HMA lower (C,,, - 20%) in the combination condition, without significant changes in blood levels of MDMA and HMMA. Plasma cortisol and prolactin levels significantly increased after the two conditions including MDMA as compared with placebo and alcohol. No significant differences were found in blood hormonal levels between both MDMA-containing conditions. Supported by grants: FIS 97/1198, FIS 98/0181, CIRIT 1999-SGR-00246, ISC-III 98/4344, and PNSD.

Abstracts 86 MINOXIDIL-INDUCED ANTINOCICEPTION IS ANTAGONIZEDBYTHE A OPIOIDRECEPTORANTAGONISTNALTRINDOLE

V. Campbell and S. Welch, Virginia University, Richmond, VA

Commonwealth

Minoxidil is a K + opener that produces antinociception which is attenuated by opiate antagonists, suggesting the release of endogenous opioids. Lack of cross-tolerance between the K + channel openers and morphine indicates a lack of direct interaction between K-ATP openers and opioid receptors. Utilizing the spinal perfusion method, male SpragueeDawley rats were anesthetized with Na-pentobarbitol (65 mg/kg) and an 8.5 cm spinal catheter was inserted for the administration of drugs and collection of a CSF. Minoxidil was administered following a 5 min pretreatment with endopeptidase inhibitors. Three minutes post administration of minoxidil, antinociception was measured using the tail-flick latency test. Minoxidil produced antinociception in the rats with an ED50 of 71 mgikg, (it.). Minoxidil(200 ug/rat) antinociception was also antagonized by the delta opioid receptor antagonist naltrindole AD50 of 1.69 mg/kg, (i.t.). We have also shown that minoxidil (100 ug/rat i.t.) releases leucine enkephalin at 19 + 6 pg/ml, which was significantly higher than the DMSO control of 3.1 + 2 pg/ml (P < 0.05, Fisher test) which further indicates delta minoxidil opioid receptor involvement in antinociception. Supported by DAO1647, K02DA00186, and DA07027. 87 DRUGDISCRIMINATIVECONTROLWITHTHEAAGONIST SNC-80 IN RATS F. Cafiadas, G.W. Stevenson, M. Gomez, and A.L. Riley, American University, Washington, DC Although drug discriminative control has been reported with a variety of opioid peptides selective for the S-receptor subtype of the opiate receptor, assessments of such control with systemically administered F-agonists have been limited, due in part to their unavailability and/or their accompanying side effects that limited their general use. Recently, the acquisition of stimulus control in monkeys with the systemically active S-agonist SNC-80 has been reported. Given that interspecies differences in opioid sensitivity in drug discrimination learning have been reported, the present study extended this analysis by assessing SNC-80 discriminative control in rats within the taste aversion baseline. Specifically, rats were injected with SNC-80 immediately prior to a saccharin-LiCl pairing and its vehicle prior to saccharin alone. Control subjects were treated similarly except they were injected with distilled water following saccharin consumption on conditioning days. Experimental subjects acquired the

s31

SNC-80 discrimination within seven trials. On subsequent generalization tests, various doses of SNC-80 (0.56-5.6 mg/kg) and the selective F-agonist SNC-162 (1.8- 18 mg/kg) substituted for the training dose of SNC-80. However, at no dose did the relatively selective u-agonist morphine (3.2- 10 mg/kg) substitute for SNC80. These data indicate that SNC-80 is an effective discriminative stimulus in rats and that its stimulus properties may be mediated by its activity at the delta opiate receptor subtype. 88

DOPAMINERGICACTIVITYINDEPRESSEDSMOKERS

L. Cardenas, L. Tremblay, U.E. Busto, and C.A. Naranjo, University of Toronto, Sunnybrook and Women’s College Health Sciences Centre, Centre for Addiction and Mental Health, Toronto, Canada Major Depressive Disorder (MDD) and nicotine dependence are highly comorbid. The physiopathology of these disorders remains elusive. The dopaminergic Brain Reward System (BRS) mediates pleasure-seeking behaviours (e.g. sex drive, drug abuse). A dysfunctional BRS may mediate some symptoms of MDD (e.g. lack of pleasure). Nicotine enhances dopamine release in the BRS, relieving depressive symptomatology. BRS activity was assessed in MDD smokers using a probe [30 mg p.o. of D-amphetamine (D-amp)] and neuroimaging (PET). Eighteen MDD (untreated) and 16 daily smokers (FagerStrom score 2 3) were randomly assigned to our probe or placebo. Drug effects were assessed by tests and questionnaires (e.g. Addiction Research Centre Inventory) at baseline and post-treatment. D-amp increased effects (e.g. blood pressure, euphoria) in MDD and control subjects (P .< 0.05). However, D-amp effects were higher in MDD (e.g. positive mood) (P < 0.001). Control subjects reported different D-amp effects in smoking and smoking abstinence (2’ = 0.01). Cl 1 Raclopride PET scans in six control smokers showed a change in dopamine-mediated C 11-Raclopride displacement (%) at 2, 4 and 24 h post-D-amphetamine. Cll-Raclopride displacement following D-amp administration ranged from 8 to 20%. Thus, D-amp response is enhanced in smokers. 89 ESTIMATEOFPREVALENCEOFCOCAINEANDCOCA PASTEAMONGSTHTO12THGRADESTUDENTSINCHILE: RESULTS OF 1999 NATIONAL SURVEY ON STUDENTS CHILE

IN

L. Caris and J. Anthony, University of Chile, Santiago, Chile and The Johns Hopkins University, Baltimore, MD We used data from a National survey in secondary students in Chile conducted in 1999. The National sample in 1999 included 46 907 students, from 723 372 students in the entire country. The sample consisted of

S32

Abstracts

public and private students in 8th to 12th grade, aged 12-20 years old, in 62 cities with more than 50000 inhabitants, in Chile. Assessments were done using an adapted version of the Drug Use Screening Inventory (DUSI) in Spanish. The survey is based on self-administered questionnaires. We used exploratory analysis for identifying characteristics which set the cocaine and coca paste user and performed confirmatory multivariate logistic regression analysis to examine which variables remain independently associated with cocaine and cocaine use. In Chile 4.9% of students used cocaine at least once in their life (1997), and 5.3% have already used coca paste, in the prevalence of last year 4.0”/0 for cocaine and 2.7% for coca paste. The sex difference was 4.5% in male and 3.5% female for cocaine, and 3.3% for male and 2.2% female for coca paste in the last year. The students in private school used more cocaine, 4.8% as compared to public 3.5%. On the other hand, coca paste was used the same in public school and private (5.6%). Factor analyses for the dichotomous format of questions was done using the M-plus program and then selecting the main constructs that are the latent root to create multi-item scales. We select five items of the DUSI to create the aggressive scale and four items to create deviant peers. The level of cocaine and coca paste use among secondary students in Chile is increasing. Compared to a study done in 1997, it is lower than in the United States. Using factor analysis, we found the aggression scale as well as the peer use scale to be associated with the increase of the use of cocaine and coca paste independently of other characteristics. These results should be important for setting up prevention programs for youth in Chile. 90

THE

CHANGING

PHILADELPHIA SYSTEM

(DENS):

FROM

FACE THE

GETTING

OF

DRUG YOUNGER,

HEROIN

EVALUATION USING

USERS

IN

NETWORK MORE

D. Carise, A.T. McLellan, and H.D. Kleber, Treatment Research Institute at the University of Pennsylvania, and the National Center for Addiction and Substance Abuse at Columbia, New York, NY Data from the Drug Evaluation Network Study (DENS), a nationwide electronic system providing clinical information on substance abuse patients, was used to evaluate differences in heroin use among patients entering treatment between January 1997 and May of 2000. Data are from a sample of 6518 patients entering the same inpatient, residential, and outpatient substance abuse treatment programs in Philadelphia. New York, Chicago, and San Francisco. Our pilot findings show significant changes in heroin use among those entering treatment over this time period. Most noticeably, the percentage of patients in the 16-25 year old age group, who had used heroin in the 30 days prior to

treatment, increased steadily from 11% in 1997 to 24% in 2000. The overall increase for all age groups from 1997 through 2000 was 17-21%. The increase for the 26635 age group was 15-230/o, for the 36-45 year age group there was a slight increase in percentage of patients using heroin (15-19%) and for the 46- and older age group, the increase was 8% points, from 13 to 21%. One of the most striking findings; of those patients age 45 and older reporting heroin use in the 30 days prior to treatment, the percentage reporting injecting as their route of administration went from a high of 75% IV use in 1997 to 60% IV use in 2000. The youngest age group, those aged 16-25, had the opposite trend with 35% of heroin users reporting injecting in 1997 and 49% injecting in 2000. Increased knowledge of this newly identified cohort of ‘new onset heroin users’ could lead to better awareness of their needs, and how to best target resources available in a cost effective and outcomes-based approach. Data presented at CPDD reflect treatment admissions collected up to the month prior to the conference. 91

SUBSTANCE

ABILITY

AND

DEPENDENCE VALIDITY

SEVERITY OF

ICD-10

SCALE: SUBSTANCE

RELIUSE

DISORDERS

K.M. Carpenter, G.M. Miele, D.S. Hasin, and J. Blaine, Columbia University and Research Assessment Associates, Inc., New York, NY, and National Institute on Drug Abuse, Rockville, MD The Substance Dependence Severity Scale (SDSS) is a semi-structured clinical interview designed to assess the severity of DSM-IV and ICD-10 substance use disorders. Consisting of substance-specific scales across a range of substances, the SDSS provides continuous ratings of both the severity and frequency of DSM-IV and ICD-10 symptoms. Prior reports have demonstrated the good to excellent reliability and concurrent validity of DSM-IV alcohol, cocaine and heroin dependence diagnoses. This study investigated the reliability and concurrent validity of the SDSS for ICD-10 alcohol, cocaine, heroin and cannabis dependence and harmful use. The test-retest reliability of the SDSS in 175 (112 male and 63 female) treated substance users ranged from good to excellent for ICD-10 alcohol, cocaine, heroin and cannabis dependence (ICCis = 0.76-0.90 for severity, 0.69-0.85 for frequency). The internal consistency reliabilities of severity and frequency variables were also good to excellent for the same diagnoses (alphas ranging from 0.80 to 0.93). The test-retest reliability of ICD-10 harmful use was generally lower, ranging from fair to good for alcohol, cocaine and heroin (ICCis = 0.54-0.73 for severity and frequency) and poor for cannabis (ICCis = 0.3990.40).

Abstracts

The internal consistency reliability of harmful use was generally fair to poor for all substances (0.39-0.60). The implications of these findings will be discussed. Concurrent validity data will also be presented and scale applications, particularly involving the use of the SDSS in treatment outcome studies, will be discussed. ACKNOWLEDGEMENT: Supported by NIDA contract N44DA-6-650 1. 92 DOESREDUCINGSMOKINGCHANGEREADINESSTO QUIT SMOKING?

M.J. Carpenter, J.R. Hughes, and J.P. Keely, University of Vermont Smokers not currently interested in quitting were randomized to an experimental group, which received behavioral treatment and NRT (patch, gum, or inhaler) to reduce smoking by 50% over a 4-week period followed by brief advice to quit, or to a control group, which received only brief advice to quit and then NRT if they decided to quit. The results for the first 60 subjects to complete 12 weeks are as follows. The two groups were similar on baseline measures of cigarettes per day (26), CO level (31 ppm), and stage of change (60% precontemplators, 33% contemplators). After 12 weeks, the experimental group had decreased to 16 cpd vs 19 cpd for the control group. CO had decreased to 18 ppm for experimental and 24 ppm for the control group. Through 12 weeks, 47% (14/30) of both experimental and control subjects moved forward in their stage of change; only 3% (l/30) of subjects in the reduction group regressed, while none of the control subjects did so. Four (13%) of control subjects quit smoking vs three (10%) of the experimental group. There were no significant Adverse Events from smoking and using NRT. These preliminary results suggest that adding a reduction option does not increase readiness to quit, but it does not undermine cessation either. Further study of smoking reduction among less-motivated smokers may be necessary. Supported by NIDA Training Grant T32DA07242 (MJC and JPK), NIDA Career Development Award DA00109 (JRH), and NIDA Grant DA11557. 93 EFFECTS OF BEHAVIORALLY MACOTHERAPY ON TREATMENT DEPENDENTOUTPATIENTS

CONTINGENT PHAROUTCOME OF OPIOID-

J. Carter, V. King, M. Kidorf, K. Staller, and R. Johns Hopkins University School of Brooner, Medicine, Baltimore, MD This clinical trial evaluated the effects of behaviorally contingent pharmacotherapy (BCP) on the treatment outcome of opioid dependent outpatients. Behaviorally

s33

contingent pharmacotherapy (BCP) integrates pharmacotherapy (i.e. methadone) and psychosocial treatment (i.e. counseling) using structured behavioral contingencies. We are reporting results for the full study sample (n = 127) over a three month (post-baseline) evaluation period. New admissions were initialized stabilized on 55 ( + 10) mg of methadone during a 6-week baseline period, and then randomly assigned to either the BCP (n = 65) or Control (n = 62) condition. Patients in both conditions were referred to increased intensity of weekly counseling due to continued positive urinalysis results and/or missed counseling sessions. BCP patients were informed that the convenience and continuation of methadone-substitution was contingent upon attending scheduled counseling sessions and achieving brief periods (2-4 weeks) of verified abstinence. Patients in the Control condition were told that continued availability of methadone was unrelated to counseling attendance or urinalysis results. BCP treatment resulted in higher rates of counseling attendance (BCP = 83%; Control = 44%; P < 0.001) and lower rates of drug-positive urine samples (BCP = 44%; Control = 58%; P < 0.05) than Control treatment. Rates of retention were excellent for both conditions (A4 = 89 (out of 90) days post-baseline for both groups). These results support the use of BCP to motivate outpatients receiving methadone to attend counseling sessions and decrease drug use. 94 PRIVATE OFFICE TREATMENT OF OPIATE DEPENDENCE WITH BUPRENORPHINE/NALOXONE: THE NEW YORKEXPERIENCETODATE

P. Casadonte, R. Walsh, F. Vocci, W. Ling, P. FudalaNew York University Medical School, National Institute on Drug Abuse, University of California, LA, University of Pennsylvania, Philadelphia, PA It is estimated that there are 810000 opiate dependent individuals in the United States and that approximately 200000 are currently in treatment. For over 30 years methadone, and more recently LAAM have been the only approved treatments for opiate dependence. Both medications are highly regulated by Federal and State agencies and can only be given in the structured setting of licensed methadone clinics. Although Federal rules to improve quality and oversight of methadone clinics have been recently proposed, it is expected that methadone treatment will remain highly regulated and monitored. Concerns about diversion, methadone overdose and negative perception of methadone contribute to restrictive practice. The introduction of buprenorphine/ naloxone (bup/nx) in a sublingual tablet may offer an alternative for individuals who do not have easy access to methadone clinics, or simply would prefer treatment in a private medical setting. In 1999 The National

s34

Abstracts

Institute on Drug Abuse and VA Cooperative Studies Program initiated a six-state ‘best practices’ study to examine the transportability of bup/nx treatment to private office and other medical clinic settings for the treatment of opiate dependence. A total of 600 volunteers in New York, California, Texas, Florida, Illinois, and Washington State with 6-10 investigators per state will be recruited for a 52-week study of buprenorphine/ naloxone treatment. The New York City site began enrolling patients in August 1999, and to date 30 individuals have been inducted on medication. Patients have been evaluated and treated in private medical offices without serious events. Patients have been compliant with study procedures, and diversion appears non-existent. The high safety profile of the medication has reduced concerns about overdose in non-tolerant individuals if the drug is diverted. Treatment of this population has been remarkably simple and is no different, in our experience, from the treatment of medical or psychiatric disorders. This presentation will focus on the experience of the New York investigators, and will review study procedures, patient characteristics, induction, maintenance and taper schedules. We will overview issues related to non-methadone clinic treatment of opiate dependence. 95 CONTINGENCY MANAGEMENT PERSONALITY DISORDER

AND

ANTISOCIAL

K. Chart, A. Huber, and V. Gulati, Friends Research Institute, Inc., Los Angeles, Long Beach Research Foundation/VAMDRU, Long Beach, and UCLA Integrated Substance Abuse Programs, Los Angeles, CA Contingency management (CM), a behavioral reinforcement technique, has been shown to be effective in the treatment of cocaine dependence, and there is emerging data on its effectiveness for methamphetamine (MA) dependence. The prevalence of Antisocial Personality Disorder (ASPD) is considerably higher in drug-abusing populations than in the general population and the outcome of traditional therapies should be evaluated separately for that subpopulation. A recent report indicated that opiate and cocaine abusers with ASPD responded particularly well to a CM program (Brooner et al., 1999). This report examines whether the efficacy of CM as a treatment for MA dependence differs depending on the co-occurrence of ASPD. Data from 166 participants in a NIDA-funded study evaluating medication and CM as MA treatments were examined to consider how ASPD affects the efficacy of CM. Thirty-seven percent (N = 61) were diagnosed with ASPD as determined by the Structured Clinical Interview for DSM-IV Diagnoses (SCID). Those randomized to the CM condition achieved significantly longer periods abstinence that those individu-

als randomized to no CM regardless of ASPD diagnoses. These findings suggest that CM can be a powerful intervention in the treatment of MA dependence and that this effect may be independent of ASPD diagnoses. This work was supported by NIDA grant ROl DA 10923. 96 CARDIOVASCULAR CHANGES NEOUS METHADONE WITHDRAWAL TELEMETRICMETHODS

DURING SPONTAIN THE RAT USING

R.M.C. Chan, J.M. White, R.J. Irvine, and A. Salem, University of Adelaide, Australia The post-withdrawal increase in arterial blood pressure has been shown to be superior as a predictor of the degree of morphine physical dependence compared to several other signs (Buccafusco, 1983). We have also shown that cardiovascular measures using telemetry techniques can provide an objective and sensitive animal model of morphine effects and spontaneous withdrawal (SWd) in freely moving animals (Chan et al., 1999). The aim of the present study was to use the same animal model to determine the relationship between methadone (MET) dose administered and cardiovascular changes during SWd. Dependence was induced with MET administered via minipumps with a variation of dose and duration: 20 mg/kg per day for 7 days, 30 mg/kg per day for 7, 14 and 21 days, respectively, in four groups of animals. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were continuously recorded radiotelemetrically at 10 min intervals throughout the experiment. With 7 days infusion of maintenance doses of 20 and 30 mg/kg per day of MET, no significant changes of SBP, DBP and HR were found during SWd. However, 30 mg/kg per day maintenance dose (both 14 and 21 days MET treatment) caused significant increase in SBP and DBP during SWd. These results indicate that change of blood pressure during methadone SWd as measured by telemetry provides an objective measure of methadone withdrawal. This model is currently used for pharmacokinetic and pharmacodynamic studies of methadone withdrawal. 97 PATTERNSOFSEXUALRISKBEHAVIORSINOPIATEAND COCAINE-DEPENDENT WOMEN M.C. Chawarski and R.S. Schottenfeld, Substance Abuse Center, Yale University School of Medicine, New Haven, CT We compared the HIV sexual risk behaviors for opiate dependent women entering opioid agonist maintenance treatment (n = 82) and cocaine dependent women enter-

s35

Abstracts

ing outpatient cocaine treatment (n = 88). Opiate dependent women were on average older [35 (6.5), 31 (5.5) years old] and a higher proportion of them were white [76%, 8%] and injection drug users (IDU) [55%, O%]. A higher proportion of opiate dependent women reported having an IDU sex partner [23%, l%] and having sex with this partner while high on drugs or alcohol [66%, 40%]. Cocaine dependent women reported a higher prevalence of other HIV sexual risk behaviors, including multiple sexual partners [17%, 7%], unprotected sex in exchange for money, gifts [31%, lo%], or drugs [27%, IO%], or sex with strangers [26%, 21%]. They also report these behaviors as more recent and frequent than opiate dependent women. These results suggest the need for identifying specific sexual HIV risk behaviors and development of treatments that target different HIV risk behaviors for different populations of substance abusing women. 98 TRANSPORT-DEPENDENT ACCESSIBILITY OF A CYTOPLASMICLOOP CYSTEINEINTHEHUMANDOPAMINE TRANSPORTER N.H. Chen, J.V. Ferrer, J.A. Javitch, and J.B. Justice Jr., Emory University, Atlanta, GA, Center for Molecular Recognition and College of Physicians and Surgeons, Columbia University, New York, NY The effect of covalent sulfhydryl modification on dopamine uptake by the human dopamine transporter was determined by rotating disk electrode voltammetry. A transporter construct, X5C, with five mutated cysteines (C90A, C135A, C306A, C319F, and C342A) and the constructs into which the wild-type cysteines were substituted back into X5C, one at a time, were studied. Restoring the cytoplasmic loop residue Cys-342 (XA342C) increased the turnover rate towards that of wild-type DAT. The reaction rate of MTSEA was increased by m-tyramine in wild-type DAT and in X-A342C, but not in any of the other mutants. The m -tyramine-induced increase in reactivity was rapid and appeared to require the inward transport of mtyramine, rather than simply the presence of the substrate on either or both sides of the membrane. Although cocaine did not protect against MTSEA-induced inactivation of DA uptake in the absence of m-tyramine, it prevented m-tyramine from increasing the reactivity of Cys-342 with MTSEA. Thus, Cys-342 is exposed to MTSEA during conformational changes associated with substrate transport, suggesting either that it is located on a part of the transporter associated with cytoplasmic gating or that it lies within the transport pathway itself.

99 HYPOTHERMIA INDUCED TRICULARINJECTIONOFORPHANIN ITSOWNRECEPTOR

BY INTRACEREBROVENFQ ISMEDIATEDBY

X.H. Chen, E.B. Geller, and M.W. Adler, Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA Previous studies have shown that: (1) orphanin FQ/nociceptin (OFQ) can block the antinociception induced by opioid receptor agonists in the cold water tail-flick test, the radiant heat tail-flick test and warm water tail-withdrawal test; and (2) the effect of OFQ on the antinociception induced by opioid receptor agonists acting at any of the opioid receptor types is mediated by the OFQ (ORL-1) receptor in the rat. Our studies have also shown that icv injection of a high dose of OFQ (18 ug) produced hypothermia in rats and that the opioid receptor antagonist, naloxone (10 mg/kg, SC), did not reduce this hypothermia. The present studies were designed to further explore the mechanism and specificity of hypothermia induced by OFQ in adult male SD rats. The OFQ receptor antagonist, [PhelY(CH2-NH)Gly2] nociceptin (I - 13)NH2, was used in doses ranging from 0.1 to 50 ug, icv. The results showed that these doses, by themselves, had no effect in the CWT test. The OFQ receptor antagonist (0.1 ug, icv) had no effect on the body temperature. However, icv injection of higher doses of OFQ receptor antagonist (1 and 50 ug) was found to produce hypothermia in rats. The data also showed that the low dose (0.1 ug) of OFQ receptor antagonist significantly reversed the hypothermia induced by OFQ (18 ug) (P < 0.01 compared to the corresponding control group, ANOVA following by Duncan’s test). These findings indicate that hypothermia induced by icv injection of OFQ is mediated by its own receptor. Supported by NIDA grant DA 00376. 100 SER~T~NIN RELEASE EFFECTS AGGRESSION AND IMPULSIVITY IN SUBJECTS WITH CONDUCT DISORDER D.R. Cherek, S.D. Lane, and J.L. Steinberg, University of Texas-Houston, Health Science Center, Houston, TX Research subjects participated after giving their informed consent. Subjects were divided into a conduct disorder (CD) group and a matched control group. Subjects were excluded if screening indicated any history of medical or psychiatric illness, or recent drug use detected by urine drug screen analysis. Subjects received doses of 0.1,0.2 and 0.4 mg/kg of D-fenfluramine in an ascending sequence with intervening placebos. Each drug dose was separated by 1 week. Echocardiograms were performed prior to drug dosing and after participation ended. Each experimental day involved alternat-

Abstracts

S36

ing sessions in which aggression and impulsivity were measured in the same subject. Subjects participated in eight sessions (four aggression and four impulsivity) each day, 2 or 3 days per week. D-fenfluramine produced decreases in aggressive and impulsive responding in CD subjects, but had no effect on controls. Escape responses were decreased in both groups, while monetary reinforced responding, a measure of motor activity, was unaffected. 101 EVALUATIONOFTHEUTILITYOFSWEATCOCAINE LEVELS FOR THE ASSESSMENT OF COCAINE USAGE IN CLINICAL TRIALS

C.N. Chiang, S.H. Li, B. Tai, C. Marschke, K.L. Preston, R.L. Hawks, and F. Vocci, NIDA, Bethesda, and IRP, NIDA, Baltimore, MD To reduce or eliminate cocaine use is the major goal in the treatment of cocaine addiction. Currently, urine benzoylecgonine (BE) concentration is the only biological surrogate marker for objectively monitoring patient cocaine use in clinical trials. Recent advances in analytical and patch technologies allow cocaine and its metabolites to be collected in sweat patches and be reliably quantified. In contrast to urine where BE, the major metabolite, is the predominant species excreted after cocaine administration, unchanged cocaine is the predominant species excreted in the sweat. Using combined data collected from clinical studies, the inter- and intra-subject variabilities of sweat cocaine levels and the potential for using the sweat data in assessing the amount of cocaine ingested will be presented. Results will also be presented from various statistical analyses, comparing the reliability and sensitivity of sweat cocaine levels with urine BE levels to detect a change of cocaine use in clinical trials. 102 BEHAVIOR PROBLEMS ACROSS PREDICTOR OFEARLY DRUGINITIATION

SETTINGS

AS A

H.D. Chilcoat and N. Breslau, Johns Hopkins University, Baltimore, MD, and Henry Ford Health Sciences Center, Detroit, Ml Early behavior problems have been identified as important predictors of later drug use in children. This report extends earlier findings by testing whether children who exhibit behavior problems in different settings at age 6, specifically at school’ and home, are at increased risk of drug use later in childhood (age 11). A total of 823 children and their mothers from a community-based sample initially were assessed when the children were 6 years old. Children’s level of externalizing behavior problems were measured using the Child Behavior Checklist (CBCL) using both mothers and teachers as

informants. At age 11 years, 717 (87%) children and their mothers were reassessed. Regardless of informant, increased levels of externalizing problems signaled increased risk of drug use, although the magnitude of association was slightly stronger for mothers’ versus teachers’ reports. Children who exhibited high level of externalizing problems at school and at home (CBCL T-Score > 60 based on mothers’ and teachers reports were at very high risk for drug use (incidence = 43%). The risks of drug use for children with high levels of externalizing based at home only (incidence = 20%) or school only (incidence = 16%) were nearly identical to children with no behavior problems in either setting (incidence = 17%). These findings indicate that children who exhibit behavior problems at home and school as early as first grade are at very high risk for initiation of drug use later in childhood, an important predictor of later, more problematic drug involvement. 103

GABAERCICS MAY

DURING CUE-INDUCED

BLUNT LIMBIC COCAINE CRAVING

ACTIVATION

A.R. Childress, T. Franklin, W. McElgin, P. Acton, and C.P. O’Brien, University of Pennsylvania School of Medicine, and VA Medical Center, Philadelphia, PA Cue-induced drug desire (‘craving’) is a cardinal feature of addictive disorders, and may precede drug usejrelapse. We and others have used drug-related videos to evoke cocaine craving in the brain imaging setting, enabling study of its brain substrates. Our initial studies demonstrated appetitive drug craving, accompanied by limbic (amygdala, anterior cingulate) activation and basal ganglia deactivation in cocaine patients (vs. controls) viewing a 25 min cocaine (vs. nature) video. Amygdalar activation to cocaine cues has been a consistent finding across several labs able to visualize the structure. Encouraged by recent preclinical reports that certain GABAergic agents (the GABA B agonist baclofen, or gamma-vinyl-gaba, an inhibitor of GABA transaminase) may reduce cocaine motivation in several animal models, we are now testing whether pre-treatment with the GABA B agonist baclofen (10 mg b.i.d. to 20 mg b.i.d., for at least 10 days prior to imaging) can blunt or eliminate the characteristic subjective and brain response to cocaine cues. Radioactively-labeled (O-15) water is the flow tracer for rCBF (regional cerebral blood flow), and PET scans for each subject are co-registered with an MRI (magnetic resonance image) to permit anatomical localization of radioactivity. Pilot results (n = 4, data collection ongoing) are encouraging, and if confirmed in a controlled design, will represent the first imaging evidence of GABAergic efficacy, and mechanism, in cue-induced craving.

s37

Abstracts

104

TREATMENTOUTCOMEFORPATIENTSENROLLED IN OUT-PATIENT METHADONE TO ABSTINENCE DETOXIFICATION MODALITIES

AND

M.M. Chu, R.E. Sage, J. Rawls, L.S. Brown, L.E. Bingham, and B.J. Primm, Addiction Research and Treatment Corporation, Brooklyn, NY Despite the demonstrated efficacy of Methadone/ LAAM maintenance treatment for opiate addiction, wide-spread opposition to this modality exists among those who mandate that addicts seek treatment, those who develop drug treatment policy, and among addicts themselves. However, little is known about the efficacy of outpatient Detox and MTA treatment for opiate addiction. The purpose of this pilot study was to evaluate the treatment outcome of 93 patients enrolled since October, 1998 in these modalities, who were mandated, and those who voluntarily selected short-term treatment when offered. Data was collected at intake and discharge, and analyzed according to source of referral, participation status, addiction history and other variables as they relate to treatment outcome. Results indicated that (1) a significantly higher percentage of mandated patients (60%) completed Detox when compared to the self-referred group (20%); (2) the majority of self-referred patients (73%) who participated in Detox transferred to another modality; (3) 42.3% of Detox and 47% of MTA participants did not achieve substance use goals; (4) there were no significant differences between length of prior opiate addiction and outcome for both modalities. A majority of self-referred patients elected to extend their treatment to another modality, and many patients may utilize Detox and MTA as a ‘bridge’ to long-term treatment, indicating that some patients may need more intensive treatment than the one mandated.

105 ASSESSMENT ADOLESCENTS

OF CANNABIS

TOLERANCE

AMONG

T. Chung, C. Martin, and N. Pollock, University Pittsburgh School of Medicine, Pittsburgh, PA

of

DSM-IV defines tolerance, in part, as a > 50% increase in consumption to produce the same effect. This study tested the percent increase in consumption that best distinguished adolescents with and without lifetime DSM-IV cannabis dependence diagnoses. Subjects were 277 adolescent cannabis users (ages 13-19) whose use increased from a baseline of regular consumption, recruited from community (32%) and clinical (68%) sources. Lifetime patterns of cannabis use were assessed using the Lifetime Drug Use History (LDUH), and DSM-IV diagnoses were made with a modified version of the SCID. More than half (55%) met criteria for

lifetime cannabis dependence; 59% of those with dependence were assigned the cannabis tolerance symptom on the SCID. Units of the quantity of use/occasion were standardized to a ‘joint’. The median quantity of use was 0.5 joints/occasion (mean = 1.l + 1.5) at baseline, and 3.0 joints/occasion (mean = 5.5 + 7.2) during the year of heaviest use. The median percent increase in consumption from baseline use to heaviest use was 300% (mean = 600% increase). The DSM-IV 50% guideline (sensitivity = 0.97, specificity = 0.09) was outperformed by a 300% increase (sensitivity = 0.60, specificity = 0.53) in predicting cannabis dependence. A higher percent increase in consumption may better characterize a clinically significant level of tolerance among adolescent cannabis users. Supported by NIAAA grant # P50 08746.

106 NON-OPIATE SUBSTANCE USE AND OUTCOME BEHAVIORAL THERAPY FOR NALTREXONE-MAINTAINED OPIATE-DEPENDENT PATIENTS

IN

S.H. Church, J.L. Rothenberg, M.A. Sullivan, G. Bornstein, E.V. Nunes, NY State Psychiatric Institute/Columbia University, College of Physicians and Surgeons, New York, NY Non-opiate drug use was assessed in 47 patients receiving Behavioral Naltrexone Therapy (BNT) for opiate dependence. The relationship between cocaine, marijuana and benzodiazapine use and treatment outcome variables was explored. Outcome was defined as the number of days in treatment, level of compliance with Naltrexone maintenance and amount of opiate use during treatment. No significant correlations between non-opiate drug use and principle outcome measures of opiate dependence were found. Univariate comparisons of abstinent, intermittent and heavy users of each nonopiate substance were performed to examine the association between level of concurrent drug use and opiate dependence outcomes. When trichotomized, intermittent users of marijuana showed significantly fewer opiate positive urines and a greater percentage of days of Naltrexone compliance when compared to both heavy users of and marijuana abstainers. Additionally, intermittent cocaine and benzodiazepine users demonstrated better treatment retention than participants who abstained from these substances. This data suggests that concurrent drug use during Naltrexone maintenance treatment for opiate dependence does not have a detrimental effect on gross measures of treatment outcome. In contrast, patients who display an intermittent pattern of non-opiate use demonstrated significantly better outcomes than those who abstained from all drugs and those who used non-opiate drugs heavily throughout treatment.

Abstracts

S38

107

ABSTINENCE

DRUG

DETOXIFICATION

INITIATION

IN

AN

OUTPATIENT

PROGRAM

M.A. Chutuape, E. Katz, M. Fingerhood, D. Jasinski, and M.L. Stitzer, Johns Hopkins University School of Medicine, Baltimore, MD Outpatient detoxification is a desirable and humane service for opiate abusers, but one that frequently fails to produce significant amounts of sustained abstinence from drugs. The purpose of the present study was to determine whether a voucher incentive program would promote increased rates of abstinence initiation among a group of outpatient opiate detoxification patients. To date, 95 patients have been enrolled and completed study procedures (58% F, 70% AfAm, M age 35 years, M of 3 prior drug abuse treatments). Admission urines were positive for opiates in 96% and positive for cocaine in 59% of subjects. Patients enrolled in the detoxification on Monday or Tuesday of each week and completed treatment on Friday. Medication was buprenorphine (0.3 mg i.m. x 4 days) and a 7-day clonidine patch (0.1 mg/day) applied on Friday. Random assignment was by weekly cohort. Contingent patients could earn $100 in voucher incentives for delivering a drug-free (opiates and cocaine) urine on Friday. Control patients could participate in a lottery on Friday in which they had a chance to earn $100 independent of urine test results. All patients were scheduled to return for a follow-up visit on the next Monday. The contingent incentive approximately doubled rates of Friday abstinence (39.6% versus 21.4%; P < 0.06).Although relapse occurred over the weekend, the intervention also boosted the percent of patients maintaining abstinence through Monday (13% versus 5%). The study shows that contingent incentives can be useful as a tool for increasing abstinence initiation in outpatient opiate detoxification. However, follow-up treatment appears necessary to maintain abstinence. Research supported by DA10192 and T32 DA07209. 108 MAN

SINGLE

NUCLEOTIDE

SEROTONIN-1B

CATIONS FOR DEPENDENCE/ABUSE

POLYMORPHISM

RECEPTOR COCAINE

GENE:

IN THE

HU-

POSSIBLE IMPLIAND ALCOHOL

T. Cigler, K.S. LaForge, P.F. McHugh, and M.J. Kreek, The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY Several lines of evidence from both animal self-administration and human genetic studies suggest that genetic variations of the serotonin-1B (SHT-1B) receptor gene may be associated with alcohol or cocaine dependence/ abuse. We hypothesize that genetic variability in the human SHT-1B receptor gene may alter the function or

expression of the receptor which, in turn, may contribute to individual variability in susceptibility to alcohol or cocaine dependence/abuse. To date, 180 subjects, each rigorously characterized with respect to medical history, psychiatric history, substance use and dependence history, and ethnic background, have been included in this study. Of the subjects, 60 individuals have a primary diagnosis of cocaine dependence/abuse, 32 have a primary diagnosis of alcohol dependence/ abuse, and 88 are controls. DNA is isolated from each subject. From each genomic DNA sample, PCR is used to amplify 1842 base pairs, encompassing the entire coding region, as well as parts of the 5’ and 3’ flanking regions of the SHT-1B receptor gene. Amplified DNA is sequenced by automated sequencing and examined for the presence of novel, as well as previously identified single nucleotide polymorphisms (SNPs). Analysis of the sequences has revealed two novel SNPs in noncoding regions of the gene. Overall allele frequencies of SNPs will be determined and the frequencies of known SNPs will be compared to published reports. Also, the frequencies of SNPs among study groups will be compared. Statistical analysis of the difference in occurrences of each SNP will be presented. Supported by HHMI Research Training Fellowship for Medical Students, NIDA grants K05 DA00049 and ~50 DA05 130. 109

NEFAZODONE-INDUCED

CAINE

CRAVING

AND

ALTERATIONS USE IN DYSPHORIC

COCAINE

OF

coUSERS

D. Ciraulo, J. Rotrosen, D. Leiderman, C. Knapp, A. Ciraulo, 0. Sarid-Segal, and E. Villagio, Boston University School of Medicine, VAiNIDA MDRU, Boston, MA, NYU School of Medicine, VAiNIDA MDRU, NY, and NIDA, Bethesda, MD Some cocaine users may self-administer this drug to reduce dysphoric/depressive feelings. We tested the hypothesis that administration of nefazodone, an atypical antidepressant with 5HT2A antagonist activity, administered for 3-4 weeks, would produce a reduction in cocaine use by dysphoric users. Sixty-nine subjects with Ham-D scale scores of 12 or greater were enrolled into this study. These subjects were assigned double-blind to either nefazodone or placebo. Subjects received study medications over an 8-week period. Nefazodone was titrated to 400 mg during the first 10 days of the study, and maintained at that daily dose until Study Day 44, and then tapered. Reported mean dollar expenditure for cocaine was significantly lower for the nefazodone as compared to the placebo group during Week 5. Cocaine craving scores were significantly less for the nefazodone than for the placebo group for Study Weeks 7and 8. BE levels declined in the nefazodone group and increased placebo group between Study

s39

Abstracts

Weeks 1 and 6. Quantitative BE levels supported nefazodone/placebo differences when log transformed values, but not when absolute values, were used. The results suggest that nefazodone may reduce cocaine craving, and possibly cocaine use, in dysphoric cocaine dependent subjects.

ability of such external cues to trigger drug seeking may prove to be very effective in managing cocaine addiction. Supported by USPHS grant DA0601 3 from the National Institute on Drug Abuse. 111

CUE

REACTIVITY

PTSD

CRIME-RELATED 110

A

ROLE

FOR

CONDITIONED

CUES

IN

COCAINE

RELAPSE

D.M. Clampitt, R.L. Peltier, and N.E. Goeders, Louisiana State University Health Sciences Center, Shreveport, LA Exposure to external cues previously associated with drug taking is a powerful stimulus that can trigger craving and relapse to cocaine use in humans. The experiments described below were therefore designed to investigate conditioned cues potentially associated with relapse to cocaine-seeking behavior in an animal model of relapse using a reinstatement procedure. Adult male Wistar rats (n = 6) were trained to self-administer cocaine under a FR2 schedule of reinforcement with a 90-s limited hold. Illumination of a stimulus light located above the cocaine response lever indicated the availability of cocaine. Completion of the response requirement (i.e. pressing the cocaine lever twice within 90 s) resulted in an infusion of cocaine (0.25 mg/kg/inf) delivered over 5.6 s. Responding on the other lever had no scheduled consequences. A 3-min timeout period, during which the cocaine lever light was extinguished and responding on either lever produced no programmed consequences, followed each infusion. Once stable self-administration was observed (i.e. < 10% variation for three consecutive sessions) extinction training began. During extinction training, levers were presented, but no stimulus lights were illuminated, and responses made on either lever had no programmed consequences. When responding on the cocaine lever decreased to < 30% of baseline self-administration for two consecutive sessions, the animals were tested for reinstatement. During reinstatement, the light above the cocaine lever was illuminated for 90 s, but responding on either lever produced no scheduled consequences. A 3-min timeout followed the 90-s presentation of the cocaine lever light, after which another 90-s ‘drug-availability’ cue was presented, and the behavioral schedule continued to cycle in this way until the end of the session. Blood was taken via the implanted catheters at regular intervals to measure plasma corticosterone. Presentation of the stimulus light previously associated with cocaine availability increased responding on the cocaine lever to approximately 84% of that observed when cocaine served as a reinforcer. These data demonstrate a role for conditioned stimuli in relapse to cocaine seeking. Pharmacotherapies aimed at attenuating the

IN AND

WOMEN

WITH

COCAINE

DEPENDENCE

COMORBID

S.F. Coffey, M.E. Saladin, D.J. Drobes, B.S. Dansky, and K.T. Brady, State University of New York at Buffalo, Buffalo, NY, and Medical University of South Carolina, Charleston, SC The prevalence of crime-related PTSD in substance use disordered (SUD) females is alarmingly high and research has documented poorer treatment outcome in SUD patients with PTSD compared to SUD patients without PTSD. Poorer treatment outcome may be a consequence of the negative affect that is elicited by traumatic memories. Research has shown that both negative affect and drug cues are associated with drug craving however no published study has examined the impact of trauma cues on PTSDjSUD comorbid women. To address this void in the literature, the present study examined the hypothesis that women with PTSD and a SUD (n = 23) would exhibit differential cue reactivity to substance-related cues and trauma-related cues compared to neutral control cues. Audiotaped scripts were presented via headphones (i.e. either subjects’ worst crime-related trauma or a neutral image) followed by an in vivo cue (i.e. either simulated crack cocaine and drug paraphernalia or a neutral cue). Following each cue exposure, subjects were asked to provide computerized ratings of the imaginal and in vivo cues on the following dimensions: (1) craving; (2) desire to approach their substance; (3) desire to avoid their substance; and (4) arousal. Data were analyzed using repeated measure ANOVA. Consistent with the hypothesis, subjects reported higher craving, approach, and arousal toward the drug cue and the trauma cue compared to neutral cues. Treatment implications for women with both PTSD and cocaine dependence are discussed. 112

MOTIVATIONAL

SMOKERS: INTERVENTION

INTERVIEWING

A RANDOMIZED IN MEDICAL

CLINICAL

FOR TRIAL

ADOLESCENT OF

BRIEF

SETTINGS

S.M. Colby, P.M. Monti, T.A. O’Leary, N.A. Barnett, A. Spirito, and D.J. Rohsenow, Brown University, Providence, RI This study was designed to test the efficacy of motivational intervention for reducing smoking adolescents in medical settings. Patients aged years (N= 85) were recruited from a hospital

a brief among 12-20 Emer-

s40

Abstracts

gency Department or adolescent outpatient clinic and randomized to receive either a 1 h motivational interview (MI) or brief advice (BA) to quit smoking. All participants completed a detailed baseline assessment. Participants were unmotivated to quit smoking and were not seeking smoking treatment. MI consisted of open-ended discussion of pros and cons of smoking, personalized assessment feedback, and individualized goal setting. Analysis of covariance evaluated betweengroups differences at 3-month follow up, covarying corresponding baseline measures. Follow-up rate was 89% and equivalent across groups. Although self-reported smoking rates did not differ between the groups at follow up, saliva cotinine levels were significantly lower among MI recipients (Adj. M= 164.9 + 150.5 rig/ml) than among BA recipients (Adj. A4 = 226.4 + 140.6 rig/ml), F(1, 67) = 4.06, P < 0.05). These findings support the efficacy of MI for reducing adolescent nicotine exposure, and highlight the importance of biochemical verification of self-reported smoking data. 113 COMOTOR

K OPIOID

AGONISTS

ACTIVITY

AND

ALTER COCAINE

COCAINE-INDUCED

LO-

SENSITIZATION

S.L. Collins, C. D’Addario, and S. Izenwasser, University of Miami School of Medicine, Miami, FL K opioid receptor agonists have been shown to modify some of the behavioral effects of cocaine. To further investigate the effects of k-opioid agonists on locomotor activity produced by acute and repeated administration of cocaine, either U69 593 or bremazocine was given in combination with cocaine for 5 days. Locomotor activity was observed for 1 h each day, starting 15 min after injection. Both k-opioid agonists blocked the locomotor-activating effects of cocaine. In addition, the k-opioid pre-treated groups exhibited decreased locomotor activity in response to a cocaine challenge 3 days later. When U69 593 alone or vehicle was administered for 5 days it decreased activity compared to vehicle. A cocaine challenge 3 days later did not increase activity, and no sensitization to cocaine was observed after U69 593 treatment. Upon continued administration of cocaine, no increase was seen in activity, compared to the initial administration of cocaine. Ten days after the last injection of U69 593 the response to a cocaine challenge remained significantly lower than in the vehicle treated rats. Overall, these experiments show that k-opioid agonists reduce locomotor effects associated with acute cocaine administration, and that no sensitization occurs in rats pretreated with a K agonist. These findings show that treatment with a ic-opioid receptor agonist blocks the stimulant effects of acutely administered cocaine, and greatly diminishes the adapthat during repeated cocaine tations occur administration.

Supported by grant DA 11960 from NIDA. 114

VALIDITY

HEROIN

USE

PUERTO

RICO

OF IN

SELF-REPORTS

A HIGH-RISK

OF

COCAINE

HOUSEHOLD

AND

SAMPLE

IN

H.M. Colon, R.R. Robles, G. Canino, and H. Sahai, Universidad Central de1 Caribe, Bayamon, and University of Puerto Rico, San Juan, PR As part of a larger study of substance use disorders in the household population of Puerto Rico, we collected hair specimens from a sub-sample of 114 respondents. Household segments in high risk areas and young male adults were oversampled. Hair specimens were screened using radio immunoassay assay. All specimens exceeding 2 ng/lO mg of cocaine or heroin or its metabolic equivalents were confirmed using gas chromatography/ mass spectrometry. Using the hair test results as the standard, specificity rates of self-reports were 99”/0 or higher for both drugs. ‘The sensitivity rates were all low and did not improve with reports of drug use on more remote time periods. The sensitivity rate was particularly low for cocaine, with a sensitivity rate of 7.1%. The sensitivity rate of the heroin use reports was somewhat higher, 33.3%. The estimate of recent cocaine use based on the hair tests was 11 times the estimates generated from the interview reports. For heroin use, the test-based estimate was 2.8 times the rates generated from the interview reports. The results suggest that drug use estimates derived from household studies may not provide a true picture of the extent of use of cocaine and heroin because drug users substantially underreport their use of these drugs. 115 TO

IV

EFFECTS

OF

HEROIN

IN HUMANS

DEPOT

NALTREXONE

ON

RESPONSE

S.D. Comer, E.D. Collins, H.D. Kleber, and M.W. Fischman, New York State Psychiatric Institute and Columbia University, New York, NY Heroin-dependent individuals participated in an 8-week inpatient study evaluating the time course, safety, and effectiveness of a depot formulation of naltrexone. After a l-week detoxification phase, participants received depot naltrexone (192 mg naltrexone base in 2.4 ml/injection). Half of the participants received one active and one placebo injection, and half of the participants received two active injections of depot naltrexone. The effects of intravenous heroin (0, 6.25, 12.5, 18.75,25 mg) were evaluated for the next 6 weeks. One dose of heroin was tested per day on Mondays through Fridays, with the entire dose range being tested each week. Heroin doses were administered in ascending order, with the exception that the placebo dose could occur on

Abstracts

any day. During each experimental session, subjective, performance, and physiological effects were measured both before and after heroin administration. Preliminary results indicate that the low dose of depot naltrexone antagonized heroin-induced ratings of ‘I Feel High’ and ‘I Feel a Good Drug Effect’ for up to 3 weeks; the high dose of naltrexone antagonized these subjective ratings for up to 5 weeks. Plasma levels of naltrexone remained above 1 rig/ml for approximately 3 and 4 weeks after administration of the lower and higher doses of naltrexone, respectively. Other than the initial discomfort associated with the injection of depot naltrexone, there were no untoward side-effects. These results suggest that this depot formulation of naltrexone provides a safe, effective, long-lasting blockade of the effects of IV heroin. ACKNOWLEDGMENTS: Supported by DA09236 116 CAN DRUG USERS OBTAIN COUNTER? A MULTI-SITE TRIAL

SYRINGES

OVER-THE-

W.M. Compton, J.C. Horton, L.B. Cottler, R. Booth, C. Leukefeld, M. Singer, R. Cunningham-Williams, and W. Reich, Washington University, St. Louis, MO, University of Colorado, Boulder, CO, Hispanic Research Council, and University of Kentucky, Lexington, KY Background: In 42 states no specific laws prohibit Overthe-Counter (OTC) sale of syringes. On the other hand, pharmacies and pharmacists may refuse to sell to suspected drug users or place restrictions on such sale by requiring bulk purchases. This means that pharmacies are a potential site for HIV prevention interventions, but the type and extent of such interventions are uncertain. Methods: To examine these issues, we are conducting a multi-site study of OTC syringe purchase in Missouri, Colorado, Connecticut, and Kentucky, states which vary in policies and regulations governing syringe purchase and possession. The field experiment has a balanced, stratified design. Male, female, white and minority (African American or Latino, depending on the site) research assistants (RAs) attempt to purchase syringes at 100 urban and rural pharmacies in each site. Results: Results indicate that of 1600 overall purchase attempts, 35% were refused (either directly or indirectly). States varied significantly in rates of refusal (25 vs. 28% vs. 41 vs. 47X, P < 0.05). Furthermore, in urban settings 40% of purchases were refused compared to only 31% in rural settings (P < 0.05). Although race and gender of the RA did not seem to impact refusal in Colorado, Kentucky or Missouri, the white RAs in Connecticut were refused significantly less often than the minority RAs (23 vs. 34%, P < 0.05). Discussion: The overall goal is to understand syringe purchasing in more detail because this may lead to new interventions

s41

to reduce HIV transmission and will help to explain how an important component of HIV transmission may be influenced by local practices above and beyond existing state laws and regulations. Supported by NIDA grants DA12340 (Compton, PI) and DA05786 (Horton, PI). 117 THE IX&LIKE AGONIST 7-OH-DPAT ATTENUATESTHEDEVELOPMENTOFMORPHINE-INDUCEDTOLERANCE,BUT NOT PHYSICALDEPENDENCE,INTHERAT

C.D. Cook, A.C. Barrett, C. Syvanthong, M.J. Picker, University of North Carolina, Chapel Hill, NC The purpose of the present investigation was to examine the ability of ‘I-OH-DPAT to modulate the development of morphine-induced tolerance and physical dependence in the rat. Tolerance development (15 mg/ kg morphine, b.i.d., 5-9 days) was assessed using a warm-water tail-withdrawal procedure in rats. The development of morphine tolerance was attenuated by the co-administration of 7-OH-DPAT (0.3-3.0 mg/kg, b.i.d., 559 days) In rats rendered tolerant to morphine’s (15 mg/kg, b.i.d., days l-5) effects, the co-administration of 7-OH-DPAT (1.0-3.0 mg/kg, b.i.d., days 6- 10) attenuated the further development of tolerance. Physical dependence (7.5 and 15 mg/kg morphine, b.i.d., 4 days) was assessed in morphine-dependent rats following administration of 1.0 mg/kg naloxone. The level of physical dependence (number and frequency of withdrawal symptoms) was greater in rats treated with 15 than 7.5 mg/kg morphine. Under both treatment conditions, physical dependence was not attenuated by the co-administration of 7-OH-DPAT (1 .O- 10 mg/kg b.i.d.). Unlike naloxone, in morphine-dependent rats (15 mg/kg) 7-OH-DPAT (3.0 and 10 mg/kg) failed to precipitate withdrawal. That the D2 like agonist 7-OHDPAT attenuated morphine-induced tolerance but not physical dependence suggests that the manner in which the DA system modulates the development of tolerance is not the same as for physical dependence. Supported by NIDA grants DA10277 and DA05888. 118 PIPERIDINES TOR LIGANDS

AND PIPERAZINES

AS ORLi

RECEP-

A. Coop, D.Y. Maeda, W. Guang, K.C. Rice, J.V. Aldrich, and J.B. Wang, University of Maryland, Baltimore, MD The endogenous ligand (orphanin FQ) for the ORLl receptor has been shown to possess an unusual profile of hyperalgesia and/or analgesia depending upon the assay conditions. To delineate the properties of agonists at the receptor, systemically active non-peptide selective agonists and antagonists are required. Simple piperidi-

S42

Ahstructs

nes related to fentanyl have been shown to bind with high affinity and efficacy to the ORLl receptor, however they also display high affinity and efficacy at the opioid receptors. These studies were recently extended by Iwasawa, who discovered the first selective non-peptide antagonist at ORLl. This ligand will aid in the delineation of the effects of orphanin FQ; however selective non-peptide agonists are urgently required, especially due to our observation that orphanin FQ gives inconsistent results in binding assays. Our library of piperazines and piperidines were screened at the ORLl receptor to further investigate the structural requirements necessary for selective recognition of this series of ligands. Although most of the ligands displayed very low affinity, it was noted that the greatest affinity occurred when an N-phenethyl substituent was present. This is consistent with the high affinity of certain fentanyl derivatives, but not with the low affinity of fentanyl itself. 119 HISTORY OF PHYSICAL AND SEXUAL AND CURRENT PSYCHOSOCIAL STRESSORS: TIONSFORDRUGTREATMENTOUTCOMES

ASSAULT IMPLICA-

L. Cooper, V. Gil-Rivas, C. Grella, Y.I. Hser, and E. Hall, Drug Abuse Research Center, University of California, Los Angeles Numerous studies have shown that histories of physical/sexual assault are related to substance use disorders, and poorer drug treatment outcomes. Other studies suggest that current stressful life events are associated with an increase in alcohol/illicit drug use, and can also lead to poor treatment outcomes. Few, if any, studies have concomitantly examined the relationship between histories of physical/sexual assault, current life stressors and drug treatment outcomes. This study presents findings from an analysis of a treatment process study conducted in Los Angeles County. Male and female subjects (N = 565) were recruited from 18 drug treatment programs, randomly selected to represent four treatment modalities. Data were collected at treatment entry and 12 months later. Relationships between psychosocial stressors at treatment entry and at follow-up, histories of physical/sexual assault, gender differences, and treatment outcomes were examined using logistic regression and structural equation modeling. Treatment outcomes include drug/alcohol use status, psychiatric status, criminal justice involvement, and employment status. Preliminary analyses suggest that exposure to recent psychosocial stressors, and not histories of physical/sexual assault, are significantly related to drug treatment outcomes for women. The clinical and policy implications of these findings are discussed. Supported by National Institute on Drug Abuse (5ROl-DA08757-03).

120

IQ, ACADEMIC

ACHIEVEMENT

AND EARLY

DRUG

INITIATION

E.A. Corby, H. Chilcoat, and N. Breslau, Henry Ford Health System, Detroit, MI School achievement has been linked to drug use and other problem behaviors, but little is known about the causal pathways between these behaviors. Using longitudinal data from a community-based sample: we test (1) whether IQ and externalizing behavior problems measured early in childhood (age 6) signal an increased risk of drug use later in childhood (age 11); and (2) whether school achievement might act as a mediator in the pathway to early drug initiation. A total of 823 children and their mothers initially were assessed when the children were 6-years-old. Children completed a battery of neuropsychological testing and mothers were interviewed about children’s history of psychiatric disorders and behavior problems using the DISC and CBCL. When the children were 11 years old, 717 (87%) of the children and mothers were reassessed, including assessment of reading and math achievement. There was no evidence of a mediating effect of achievement - IQ and externalizing problems in early childhood and later school achievement independently were associated with drug use. Children with above average achievement scores had approximately l/3 the risk of drug initiation relative to children with average and below average scores (OR = 0.33, 95% CI = 0.17-0.64). These findings provide strong support for the protective effect of high academic achievement against children’s early initiation of drug use, independent of IQ and preexisting behavior problems. 121 OPEN-LABEL FLUOXETINE STANCE-ABUSING ADOLESCENTS

IN DEPRESSED

SUB-

J.R. Cornelius, 0. Bukstein, K. Lynch, S. Gershon, and D.B. Clark, University of Pittsburgh School of Medicine, Pittsburgh, PA A recent open label study suggested efficacy for fluoxetine for decreasing the depressive symptoms of adolescents with comorbid depression and a Substance Use Disorder (Riggs et al., 1997), but that study did not include level of substance use as an outcome measure. In the current study, the authors conducted a 12 week open label study of fluoxetine (20 mg) in 13 adolescents with comorbid major depression and an Alcohol Use Disorder, eight of whom also demonstrated cannabis abuse or dependence. The authors hypothesized that fluoxetine would decrease the depressive symptoms, the alcohol consumption, and the cannabis use of this population. The subjects included 10 girls and 3 boys, of whom 12 were Caucasian and one was African-

s43

Abstructs

American, who ranged in age from 15 to 19. During the course of the study, the Beck Depression Inventory score dropped from a mean of 22.6 f 6.4-6.4 k4.8 (t = 6.6, df = 12, P < 0.0001). On the Timeline FollowBack scale, the number of drinks per drinking day dropped from 6.7 f 5.4-3.7 & 4.3 (t = 3.4, df = 12, P < 0.005). Among the eight subjects with cannabis abuse or dependence, no significant change in level of use of cannabis was noted during the course of the study. However, two of the eight subjects who had demonstrated cannabis abuse or dependence at baseline no longer did so at the conclusion of the study. These findings suggest promise for fluoxetine for the depressive symptoms, the alcohol consumption, and the cannabis abuse of adolescents with major depression and an AUD/SUD. 122

FACTORS

IORS

AMONG

PREGNANT

RELATED YOUNG

TO ADULT

HIGH-RISK MOTHERS

SEXUAL WHO

BEHAVWERE

TEENAGERS

M.D. Cornelius, H. Lebow, N. Robles, and J.R.Cornelius, University of Pittsburgh, Pittsburgh, PA Pregnant teenagers (n = 183) were interviewed in early pregnancy, at delivery, and 6 years postpartum regarding drug use, demographic, psychological and medical information. At the 6-year postpartum interview, when the women were young adults, information regarding sexual history and practices was assessed. On average, women were 22.9 years old (19-25) 72.5% were African-American, and 13% were married. Their average gravidity and parity at the 6-year follow-up were 3 (I-9) and 2.3 (I-6) respectively. Based on CDC selected behaviors identified as high risk for HIV infection (history of STD’s, multiple sex partners, casual sex, anal sex, and sex with IV drug users), 42.6% of these women were categorized in a high risk sexual behavior group. Current factors that discriminated (ANOVA’s: P < 0.05) higher from lower risk women included the following psychological and drug use characteristics: more symptoms of depression, anxiety, hostility, lower self-esteem, lower social support; more marijuana use, tobacco use, nicotine dependence, and partner drinking alcohol at most recent sexual occasion. Higher risk women also had significantly more illnesses, hospitalizations, and were less likely to use a condom during most recent sexual occasion than lower risk women. Several factors from the teenage years were significantly related to higher risk sexual behaviors in young adulthood including: more depressive symptoms, lower social support, more marijuana use, earlier age at first sexual intercourse, alcohol and/or drug use at first sexual intercourse, and more frequent intoxication. Both psychological problems and substance use factors play important roles in current sexual high-risk behav-

iors among young mothers; several of these factors can be identified during the teenage years as predictive of later high-risk sexual behaviors in early adulthood. 123 TRATION NONDRUG

EFFECTS

OF

OF COCAINE, REINFORCERS

BREMAZOCINE ETHANOL, IN

ON AND

RHESUS

SELF-ADMINIS-

OTHER

DRUG

AND

MONKEYS

K.P. Cosgrove, M.E. Roth, and M.E. Carroll, University of Minnesota, Minneapolis, MN Bremazocine, a kappa-receptor agonist, has been shown to reduce the self-administration of oral ethanol in rats (Nestby et al., 1999) and intravenous cocaine in monkeys (Mello and Negus, 1998). The purpose of the present study was to investigate the effects of bremazocine on the demand for oral ethanol and smoked cocaine base in rhesus monkeys by varying the cost (fixed-ratio, FR) and measuring consumption (mg/kg). In order to determine the selectivity of bremazocine on ethanol and smoked cocaine base, the effects of bremazocine pretreatment on the self-administration of phencyclidine (PCP), saccharin and food were also examined. Adult male rhesus monkeys were trained to self-administer oral ethanol, PCP, saccharin (n = S), food (n = 4) or smoked cocaine base (n = 6) and water during daily 3 h sessions. Bremazocine (0.32, 1, 2.5 mg/kg) injections were given i.m. prior to session. The four stable days of behavior prior to pretreatment served as baseline. Preliminary results showed that bremazocine dose-dependently decreased drug and saccharin-maintained responding, but food-maintained responding was reduced only at the highest dose. Furthermore, preliminary results suggest that bremazocine shifts the demand curve for ethanol and PCP to the left. Supported by NIDA grants T32 DA 07097 (M.E.R.) and ROl DA 02486 (M.E.C.). 124 COCAINE

PUBLIC USE

HEALTH AMONG

MEASURES WOMEN

TO NOT

IN

REDUCE

CRACK/

TREATMENT

L.B. Cottler, R.M. Cunningham-Williams, W.M. Compton, T.A. Ridenour, A.B. Abdallah, Washington University School of Medicine, St. Louis, MO A focus on the pilot work that preceded a recent grant award from NIDA to reduce crack/cocaine use and high risk behaviors among out of treatment female drug abusers. Pilot data are available due to a supplement from the Office of Women’s Studies to the St. Louis NIDA Cooperative Agreement study. Several years ago supplements were offered to grants to increase the number of women enrolled in HIV intervention studies. Our addition of a well-woman exam (WWE) to our Standard and Enhanced interventions, while unique, also took advantage of our partnership

s44

Abstracts

with the Public Health Department. The WWE included a breast and gyn exam, and screening for cervical cancer, gonorrhea, syphilis, chlamydia and Human Papilloma Virus. Several years after this intervention, we reinterviewed a sample of women from the Cooperative Agreement to determine longer-term changes. We believed that educational messages delivered in the context of a WWE would serve to reinforce a healthy lifestyle, including a drug-free lifestyle (based on Health Belief Model). One hundred and fifty three women were reinterviewed from 2 to 4 years after the Co-op 3month follow-up. The crack/cocaine users who also had a history of STD had greater reductions in crack/cocaine use if they received a WWE, compared to women without a WWE (43 times per month down to 12 times per month vs. 36-25 times) and were more likely to have stopped use all together (37 vs. 12%). This interaction effect - of an STD and WWE to reduce crack/cocaine use held even after controlling for the standard vs. enhanced intervention assignment, baseline crack/cocaine use and other characteristics. The WWE is unique in the substance abuse prevention armory and holds great promise for primary care settings. 125

EFFECTS OF D-AMPHETAMINE AND THE GABA-B RECEPTOR AGONIST BACLOFEN ON CRAVING FOR NICOTINE AND CIGARETTE SMOKING

M.S. Cousins, H.M. Stamat, and H. de Wit, University of Chicago, Chicago, IL We examined the effects of D-amphetamine (20 mg) and baclofen (5 and 10 mg) in smokers on craving and withdrawal following overnight abstinence (‘Pre-Cig Phase’), after a single smoked cigarette (‘Post-Cig Phase’), and on smoking behavior during an ‘Ad Libiturn Smoking Phase’. Based on previous clinical studies, D-amphetamine is hypothesized to increase cigarette use and craving; based on preclinical studies, baclofen is hypothesized to have opposite effects. In the Pre-Cig Phase, overnight abstinence produced mild reports of craving (mean ( + SEM) B-QSU score of 5 + 0.4 out of 7 max), mild symptoms of withdrawal (Hughes-Hatsukami score of 5 ( + l), out of 32 max) and ‘anxiety’ (score of 15 ( + 6) mm out of 100 mm max). D-Amphetamine produced its prototypic subjective effects (e.g. increased scores on the Benzedrine scale of the ARCI) but it did not affect either craving or withdrawal symptomatology during this Phase. During the Post-Cig Phase, 5 min after subjects smoked a single cigarette they reported reduced withdrawal symptomatology (Hughes-Hatsukami score = 3 ( + 1)) and ‘anxiety’ (9 ( + 2) mm). There was also a significant decline in craving (B-QSU). Notably, this decline in craving was significantly greater after D-amphetamine than after placebo. During the Ad Libitum Smoking Phase,

when subjects were allowed to smoke freely, subjects treated with D-amphetamine smoked significantly more cigarettes than when treated with placebo. This increase in smoking is consistent with previous studies, but it was somewhat paradoxical because D-amphetamine decreased smoking urges after the single cigarette. This dissociation suggests that factors in addition to self-reported craving affect cigarette use. We are presently examining factors such as cigarette satisfaction, harshness, and taste. The effects of baclofen on craving and smoking will be presented during the meeting because the study is still in progress. Support from NIH DA02812 and MOlRR00055. 126 THEEFFECTIVENESSOFTWOINTENSITIESOFPSYCHOSOCIALTREATMENTFOR COCAINEDEPENDENCE

D.M. Coviello, A.I. Alterman, M.J. Rutherford, J.S. Cacciola, J.R. McKay, and D.A. Zanis, University of Pennsylvania, Philadelphia, PA, and Alcohol and Drug Abuse Institute, University of Washington, Seattle, WA Structured treatments for cocaine dependence have been shown to be effective despite high attrition rates. What is unclear is what level of treatment intensity is needed to improve and sustain patient outcomes, especially among low SES urban residents. This research evaluates whether there are differences between two levels of treatment intensities for cocaine dependence in terms of reducing substance use and improving health and social indicators at 7 months post-treatment. Ninety-four cocaine dependent predominantly AfricanAmerican male veterans were randomly assigned to either a 12 h per week day hospital program (DH12) or a 6 h per week outpatient program (OP6) and were evaluated at baseline, during treatment and at 4 and 7 months post-treatment. Both treatments stressed abstinence, behavior change and prosocial adjustment and only differed in level of treatment intensity. During treatment measures included urine toxicologies, program attendance, treatment completion and aftercare attendance. Participants reported a 52% reduction in days of cocaine use and experienced significant improvements in employment and psychiatric functioning at 7 months post-treatment. However, there was no significant difference between the DH12 and OP6 programs in terms of abstinence during treatment, treatment completion, treatment or aftercare attendance or any Addiction Severity Index (ASI)-related variable assessing level of functioning at 4 and 7 months. While future research with a larger community-based sample that includes female clients is necessary, the current findings demonstrate that a 6 h per week program is just as effective and thus has a significant cost savings compared to a 12 h per week treatment modality for cocaine dependence.

S45

Ahstructs

127

PHOTIC

SUBJECTS:

ACTIVATION AN

IN

FMRI BOLD

COCAINE

WITHDRAWN

STUDY

R.L. Cowan, B. de B. Frederick, M. Rainey, J. Levin, L.C. Maas, J. Bang, P.F. Renshaw, and S.E. Luk, McLean Hospital/Harvard Medical School, Belmont, MA Dopamine is present at all points along the visual pathway and altered brain response to visual stimuli in perturbed dopamine conditions has been demonstrated using fMRI, electroretinogram, EEG, and PET. The fMR1 blood oxygen level dependent (BOLD) method allows a sensitive assay of human brain function without exposure to ionizing radiation. We used fMRl to investigate primary visual cortical (Vl) activation in response to blue and red light in four cocaine-withdrawn and 4 age and sex-matched controls. Photic stimuli with two intensities (0.12 and 1.2 Lux) of red and blue light flashing at 8 Hz were delivered during fMRI acquisition. Mean activations within a 1 x 4 pixel region of right and left Vl were averaged. The low intensity stimuli revealed a non-significant trend for diminished activation to blue light and a significant (P = 0.05) increase in activation to red light in the cocaine-withdrawn subjects. There were no significant differences in activation to red or blue light at the higher intensity. This preliminary finding suggests that fMR1 can be used as an objective non-invasive method for monitoring risk factors for substance abuse, disease progression, treatment intervention, and in vivo assessment of novel therapeutic agents. Supported by DARSPP to R.L. Cowan, DA09448 to P.F. Renshaw and DA00343 to S.E. Lukas. 128

SEX

MORPHINE

DIFFERENCES ON

LOCOMOTOR

IN

THE

EFFECTS

OF

CHRONIC

ACTIVITY

R.M. Craft and K.R. Drexel, Washington versity, Pullman, WA

State Uni-

Morphine is more potent in male than female rodents in its acute analgesic and sedative effects, and males develop greater analgesic tolerance than females to a given dose of morphine. The purpose of the present study was to compare the effects of chronic morphine on locomotion in male vs. female rats; it was hypothesized that males would develop greater tolerance/sensitization than females. On Day 1, either saline or morphine was administered S.C. using a cumulative dosing procedure to adult Sprague-Dawley rats (N= 8 IO/sex/group), and all rats were tested for spontaneous locomotor activity. Saline or 10 mg/kg morphine was then injected BID for 1 week, whereupon the morphine doseeeffect curve was redetermined. After another week during which no injections were given,

the effects of saline or morphine were redetermined a third time. When tested with saline, females were more active than males at each of the 3 weekly tests. On the first test, morphine was significantly more potent in males than females in suppressing locomotor activity; intermediate doses of morphine also slightly increased activity above that of saline-treated controls, but in females only. On the second morphine test, males and females that had been injected BID with saline for a week showed equivalent sensitization to morphine, whereas males that had been injected BID with morphine for a week showed significantly greater sensitization than did their female counterparts. Males’ body weight also decreased significantly during the week of morphine treatment, whereas females’ did not. In contrast, after a subsequent week of no injections, female rats that had been treated previously with saline or morphine (and tested twice with morphine) showed greater sensitization to morphine than did their male counterparts. These results suggest that the development of tolerance/sensitization to the locomotor effects of a u opioid agonist differs between males and females. 129

THE

TIME,

RESPONSE

MOOD

IN

OF PATERNAL

EFFECTS

s-HT

OF

INHIBITION,

YOUNG TYPE

MEN II

WITH

DEPLETION REWARD AND

ON

REACTION

PREFERENCE WITHOUT

AND

HISTORIES

ALCOHOLISM

J. Crean, J. Richards, and H. de Wit, University of Chicago, IL, and West Virginia University, Morgantown, WV Several lines of evidence support the existence of a heritable form of alcoholism (i.e. type II) characterized by an early onset, predominance in males, impulsive aggression and impaired CNS serotonin (5-HT) functioning. The aim of the current study was to determine whether tryptophan depletion, which reduces CNS 5HT function, produces greater behavioral impairment in young men with a positive family history (FHP) of this disorder compared to matched controls. Behavioral impairment was assessed by the Stop Task, a measure of inhibition of pre-potent motoric responses (Logan, 1982). Healthy non-alcoholic males aged 18-25 years, with a paternal (biological) history of type II alcoholism and age-matched controls participate in two laboratory conditions: Dietary (tryptophan) depletion of 5-HT (T-) and a non-active control condition (B). Dependent measures include reaction time and response inhibition time on the Stop task, measures of delay discounting, and self-report measures of subjective state. The first four subjects (2 FHP and 2 FHN) all exhibited poorer response inhibition during the T-condition relative to the B-condition. Measures of primary reaction time, delayed reward discounting and self-reported mood-state were not affected. These preliminary

S46

Abstracts

findings suggest that 5HT neurons may be specifically involved in the mediation of behavioral inhibitory processes, regardless of family history of alcoholism. This research was supported by The National Institutes on Drug Abuse (DA 09133) and Alcohol Abuse and Alcoholism (1 F31 AA05542-01) and the General Clinical Research at the University of Chicago (MO1 RR00055). 130 GIC BENS

NEUROADAPTATIVE RECEPTOR DURING

SELF-ADMINISTRATION

BINDING

CHANGES SITES EXTINCTION IN

IN THE

OF

D4

DOPAMINER-

NUCLEUS OF

ACCUMCOCAINE

RATS

J.A. Crespo, A.M. Gonzalez, S. Martin, C. GarciaLecumberri, J.M. Oliva, B. Gonzalez, R. Ferrado, and E. Ambrosio, Hospital Universitario Marques de Valdecilla, Santander, Spain It is widely accepted that dopaminergic system is one of the most important target of cocaine actions. The aim of the present work has been to test the effect of cocaine self-administration and its withdrawal on D4 dopaminergic receptor binding sites of the nucleus accumbens. Seventy-two littermate male Lewis rats were randomly assigned in triads according to a yoked-box procedure to one of three conditions: (a) contingent intravenous self-administration of 1 mg/kg/injection of cocaine(CONT); and (b) non-contingent injections of either 1 mg/kg/injection of cocaine(NONCONT); or (c) saline yoked (SALINE) to the intake of the self-administering subject. The self-administering rats were trained to self-administer cocaine under a FR5 schedule of reinforcement during daily 2 h sessions for at least 4 weeks. After stable baseline levels of drug intake had reached. saline was substituted for drug during 5 days. Following this first extinction period, cocaine self-administration was reinstated for an additional minimum period of 2 weeks and saline was again substituted for cocaine during 0 (last day of intravenous cocaine selfadministration), I, 5 and 10 days (second extinction period). On each one of these extinction days, animal brains in each triad were removed to be procesed for quantitative autoradiography using 1 nM 3H-YM 0915 I for labeling D2-like family of receptors and 800 nM of raclopride to displace D2 and D3 binding. Non-specific binding was defined using 10 mM of ( + )Butaclamol. Binding to D4 receptors in DAY 0 showed up a statiscally significant decrease compared to DAYS I, 5 and IO of extinction in the CONT versus NONCONT and SALINE groups. Binding to D4 receptors was also lower in NONCONT group compared to SALINE group. These results suggest that changes in D4 receptor binding in the nucleus accumbens could mediate some of the effects of cocaine withdrawal from long-term cocaine self-administration.

Supported by DGES PM27-0027. 131

CHRONIC

PHYSIOLOGY

EFFECTS

OF HEROIN

ON

HIPPOCAMPAL

IN VW0

J.R. Criado, M. Sanchez-Alavez, R.A. Gallegos, R.-S. Lee, SC. Steffensen, and S.J. Henriksen, The Scripps Research Institute, La Jolla, CA We sought to characterize the chronic effects of heroin on dentate physiology in halothane-anesthetized Sprague-Dawley rats. Our main objective was to determine the acute effects of heroin on animals chronically treated with heroin. Population spikes (PS) were elicited in the dentate gyrus by stimulation of the perforant path. High frequency stimulation (HFS; 400 Hz for 10 ms) of the VTA markedly increased PS amplitudes, but had no effect on perforant path to dentate population excitatory postsynaptic potentials (EPSPs). Our previous data showed that systemic administration of heroin produces dose-dependent effects on VTA facilitation. Low doses of heroin (0.1 mg/kg, s.c.) decreased, whereas higher doses of heroin (0.6 mg/kg, s.c.) significantly increased VTA facilitation. We also found that while heroin (0.1 and 0.6 mgikg, sc) had little effect on the induction of LTP, both doses markedly suppressed PS amplitudes and the higher dose markedly reduced paired-pulse (PP) inhibition. In the present study, drug treatment consisted of 8 days of chronic administration of heroin (0.5 mg/kg, s.c.). Electrophysiological studies were performed 3-4 h after the last heroin administration. Our data show that chronic heroin had no effect on stimulus-response curves, PP inhibition, LTP and VTA facilitation. In contrast to our findings in naive rats, acute administration of heroin (0.1 and 0.6 mg/kg) in chronically treated rats had no effect on stimulus-response curves and on PP inhibition, but at higher doses inhibited the induction of short-term potentiation. Chronic heroin also blocked the effects of acute heroin on VTA facilitation. ‘These data suggest that chronic heroin treatment produces significant neurophysiological changes in basal hippocampal physiology altering the sensitivity of dentate responses to subsequent acute heroin administration. Supported in part by DA-12669, DA-08301, AA-10075 and AA-06420. 132 OF

CONFORMATIONALLY

NON1

AND

THE

PUTATIVE

TOR

(NACHR)

RESTRAINED

NDNI a&

ARE

NICOTINIC

SELECTIVE

ANAL~GUES ANTAGONISTS

ACETYLCHOLINE

AT RECEP-

SUBTYPE

P.A. Crooks, R. Xu, V.P. Grinevich, A.J. Haubner, and L.P. Dwoskin, University of Kentucky, Lexington, KY

Abstructs

Previous work has shown that quaternization of the pyridine-l\r atom of S-( - )-nicotine (NIC) affords compounds such as NON1 and NDNI that possess nicotinic receptor antagonist activity at asaz and CC,&subtypes, respectively. To ascertain the rotameric preference of the C(3)-C(2’) bond of NON1 and NDNI for interaction with several nAChR subtypes, we have designed and synthesized bridged analogues representing two extreme rotameric conformations (svn- and anti-) of both NON1 and NDNI. The NIC evoked [3H]dopamine ([3H]DA) release assay utilizing rat striatal slices determined antagonist activity at putative a,& nAChRs. Binding assays utilizing [3H]methyllycaconitine ([3H]MLA) and [3H]NIC probed the affinity for a, and ~(~p~ nAChRs, respectively. Fifteen analogues were evaluated. None of the conformationally restrained analogs exhibited any affinity for 1, nAChRs. All the syn- and anti-rotameric analogues with an &carbon alkyl chain inhibited NIC-evoked [3H]DA release with a similar potency to NONI, while exhibiting lower affinity than NON1 for the [3H]NIC binding site. Surprisingly, the IO-carbon alkyl chain bridged analogues exhibited no inhibition of [3H]NIC binding to striatal membranes, while their activity in the NIC-evoked [3H]DA release assay was retained when compared to NDNI. These results suggest that restricting the rotation of the C(3))C(2’) bond of NONI and NDNI affords both greater affinity and greater selectivity for the CX$,nAChR subtype. This conformationally restrained analogue approach may provide a useful means for the development of subtype-selective nicotinic receptor antagonists. Supported by DA1 0934 and DA00399. 133 COMPARISONOFINCOMESOURCESANDAVOIDED EXPENDITURES OF DAILY CRACK USERS WITH HARD DRUGUSERS

OTHER

J.C. Cross and B.D. Johnson, Medical Health Research Association, and National Development and Research Institutes, Inc., New York, NY Illegal drugs often promote compulsive use patterns that prompt users to invest substantial amounts of money in their habit. In economically deprived areas with few legitimate avenues for income generation, this is often associated with increased income through illegal and/or informal mechanisms as well as the avoidance of non-drug expenditures such as housing costs. According to ethnographic research, this is especially true for compulsive crack users. To test this finding, this project will use data from a 1998-1999 ‘criterion representative’ sample of 648 hard drug users in Central Harlem, a predominantly African-American and economically deprived inner-city area of New York City. Using logit modeling and standard and logistic regres-

S41

sion, the analysis will describe the income generating activities of daily crack users and compare them with those of other hard drug users (including non-daily crack users). Income sources will be coded according to the following categories: legal employment (divided into formal and informal categories); formal and informal cash transfers; drug distribution and non-drug illegal income; and the avoidance of housing expenses. Education, age and gender will be used as controls, We anticipate that daily crack users will have significantly more informal and illegal income sources and greater avoidance of housing costs. 134 DRUGABUSERSWITHPATHOLOGICAL ANDSUBTYPESOFANTISOCIALBEHAVIOR

GAMBLING

R.M. Cunningham-Williams, L.B. Cottler, W.M. Compton, A.B. Abdallah, and E.L. Spitznagel, Washington University School of Medicine. St. Louis, MO Pathological gambling disorder (PGD) has been shown to be highly comorbid with both psychiatric and substance use disorders. The current paper examines comorbid associations for St. Louis area drug abusers recruited from drug treatment and Pathological gambling disorder (PGD) has been shown to be highly comorbid with both psychiatric and substance use disorders. The current paper examines comorbid associations for St. Louis area drug abusers recruited from drug treatment and community settings and stratified by subtypes of PGD, namely: full DSM-III-R PGD (449 criteria; n = 108) sub-threshold PGD (I-3 criteria; n = 109) at-risk gamblers (gamblers with 0 criteria: IZ= 586) and non-gamblers (M = 185). Results reveal a lifetime prevalence of PGD of 11% overall and a conditional prevalence of 13.5% among gamblers only. After examining several hi-variate and multi-variate models, we found an increased risk for subtypes of pathological gambling (;c2 = 177.44; P = 0.0000) for drug abusers with the following characteristics of: recruitment from drug treatment settings, male gender, African-American race/ethnicity, antisocial personality disorder (ASPD), and illicit drug dependence. In fact, in this model, those dependent on illicit drugs compared to those not dependent were 1.8 times as likely to be an at-risk gambler, 2.9 times as likely to be sub-threshold for PGD, and 4.2 time as likely to have full PGD. Furthermore, when we looked at drug dependence severity as defined by the number of distinct illicit drug criteria met, we further specified this association (x’ = 183.49; P = 0.0000).Dependence severity was a particularly important predictor of subtypes of PGD when considering severity of cocaine dependence. These results imply the importance of screening for pathological gambling disorder by clinicians who treat drug abusers, especially among drug abusers who are African-American. male, have ASPD,

Abstracts

S48

and who have severe illicit drug dependence, especially on cocaine. 135

SEVERITY

LICIT OPIATE TREATMENT:

OF

PSYCHIATRIC

SYMPTOMS

USE IN EARLY METHADONE A PILOT STUDY

AND

IL-

MAINTENANCE

E. Curet, L. Borg, S.H. Kellogg, J. Kleeger, and A. Wells, Weill Medical College of Cornell University and The Rockefeller University, New York, NY Illict drugs may be used to modulate psychiatric problems and feeling states among former opiate addicts in methadone maintenance treatment (MMT). To further elucidate this possible relationship, new and transfer patients entering into MMT were administered the Symptom Checklist-90-Revised (XL-90-R) within the first month of entering treatment in order to ascertain whether psychiatric problems may impact on the efficacy of methadone treatment. The subjects of this study were 24 of 32 consecutive admissions over a lo-month period. This group included 14 men and 10 women and the mean age was 39 years old (SD = 11). Patients were divided into high-score and low-score groups for each scale of the SCL-R-90. Two raters looked at the pattern of drug use in the 3 months following the completion of the SCL-90-R and categorized each subject as opiate positive or negative and as cocaine positive or negative. These two scores were combined for a third score drug use positive or negative. A chi-square was performed for each scale using high score/low score against drug use/no drug use. While no scores reached significance, there were two trends in the data. The first trend suggested that the high depression score group (n = 13) was more likely to use any drug than the low depression score group (n = 1 l), Fisher’s exact Test (l-sided) P < 0.097. The second trend showed that those who endorsed a greater number of psychiatric symptoms on the SCL-90-R (regardless of the endorsed intensity) (n = 12) to be more likely to use either or both cocaine and/or heroin that those who endorsed fewer (n = 12), Fisher’s Exact Test (l-sided) P < 0.097. We will continue to screen and follow all new and transfer patients entering this clinic to assess the possible interaction between psychiatric distress and successful reduction of illicit opiate use. This information may be useful for management of clinical issues and in treatment retention. It is possible that these psychiatric problems may pose difficulties for patients in MMT. 136

COCAINE-INDUCED

LAR

DOPAMINE

INCREASES ARE

ATTENUATED

IN BY

EXTRACELLUSEROTONIN

AGONISTS

P.W. Czoty, B.C. Ginsburg, and L.L. Howell, Yerkes Regional Primate Research Center, Emory University, Atlanta, GA

The development of effective medications to treat cocaine dependence will depend on a clearer understanding of the neurochemical interactions which underlie cocaine reinforcement. While inhibition of neuronal uptake of dopamine (DA) has been implicated as a primary mediator of cocaine’s reinforcing effects, evidence indicates that brain serotonin (5-HT) systems can modulate the behavioral pharmacology of cocaine. For example, the 5-HT uptake inhibitor, alaproclate, and the 5-HT direct agonist, quipazine, decreased response rate in squirrel monkeys trained to self-administer cocaine. To investigate the neurochemical mechanisms that underlie this modulation, microdialysis experiments were conducted in awake squirrel monkeys. Commercially-available guide cannulae were implanted to reach the caudate nucleus based on coordinates derived from a standard squirrel monkey brain atlas. Repeated experiments were conducted in each anatomical site. Cocaine (1 .O mg/kg) increased extracellular dopa-mine to approximately 300% basal levels. Doses of alaproclate (10.0 mg/kg) and quipazine (1 .O mg/kg) which were effective in reducing self-administration of 0.1 mg per infusion cocaine significantly attenuated the ability of cocaine to increase extracellular dopamine when administered 30 min prior to cocaine. The results suggest that the ability of serotonergic drugs to attenuate the behavioral effects of cocaine is due to direct interactions between serotonin and dopamine. Supported by USPHS grants DA05804, DA10344 and RR00165. 137

RAPID

AND

NICOTINE

SMOKING: ON

CRAVING

THE

ROLE AND

OF

SENSORY

CUES

SMOKING

J. Dallery, E.J. Houtsmuller, W. Pickworth, and M.L. Stitzer, Johns Hopkins University, and National Institute on Drug Abuse, Baltimore, MD Controlled laboratory research has examined the relationship between subjective reports of craving and drug self-administration (smoking behavior). In a previous study we found that aversive rapid smoking (up to nine cigarettes with puffs taken every 6 s) relative to selfpaced smoking, significantly reduced cigarette craving during a subsequent 3 h abstinence period. However, despite suppressed cravings, smoking behavior at 3 h was unaffected by prior exposure to rapid versus selfpaced smoking. The present study was designed to: (1) more closely examine the time course of changes in craving and smoking behavior; and (2) examine the role of nicotine versus sensory cues in mediating craving suppression, smoking behavior, and the relationship between the two. Subjects (n = 15) engaged in one session each of rapid and normal paced smoking with denicotinized and nicotine-containing cigarettes (total of four sessions). During the next 3 h, craving assess-

s49

Abstracts

ments and smoking opportunities were scheduled every 15 min. Plasma nicotine levels were measured at baseline, after the smoking procedure, and subsequently at the time when the subject first chose to smoke. Preliminary results indicate that although craving is equally suppressed by nicotine-containing and denicotinized cigarettes, subjects choose to smoke sooner after the denicotinized versus nicotine-containing cigarettes. This pattern of results implies that the sensory cues associated with smoking are strong determinants of craving suppression, but that blood nicotine levels play an additional role in determining smoking behavior. Supported by NIDA grant # . 138 BURDEN OF ILLNESS IN WITHOUTPRIMARY MEDICALCARE

ADDICTED

PERSONS

I. DeAlba, J.H. Samet, and R. Saitz, Boston University, Boston, MA Hypothesis: Persons with alcohol and drug addictions are known to be at risk for a variety of medical illnesses. However, little is known about the frequency of illness in persons with addictions who lack primary medical care. We hypothesized that the burden of disease in this population would be high and that substance of abuse and demographics would impact this burden. Procedures and Analysis: We interviewed 470 patients without primary medical care, admitted for residential alcohol/drug detoxification. Burden of disease was assessed by self-report of physicians’ diagnoses, and by the Short Form Health Survey (SF-36). We assessed the relationship between patient characteristics and SF-36 Physical Component Summary (PCS) score in bivariate and multivariable analyses. Results: The mean age was 35.7 (SD 7.8) years, 76% were male and 46% were African-American; 57% had an annual income of less than $20 000 and 38% were unemployed. Almost half of all patients (45%) reported being diagnosed with a chronic illness, 80% had prior medical hospitalizations and 21% had been prescribed medications for chronic physical conditions. Only 2.6% reported being HIV positive. Many (45%) reported acute medical illness (i.e. pneumonia), serious injury or a sexually transmitted disease in the past 6 months. The mean PCS score for the group was 48 (SD 10.7) which is similar to norms for the U.S. population. Cocaine and alcohol abuse were not associated with lower scores. In a multivariable analysis adjusting for race (model R2 = 0.16) older age ( - 2.6 PCS points per decade, P = O.OOOl),female gender ( - 3.5, P = O.OOOl), unemployment ( - 3.3, P = O.OOl), living alone ( - 3.4, P = 0.01) problem heroin ( - 3.08, P = 0.002) and hallucinogen use ( - 2.6 P = 0.04) were associated with significantly lower PCS scores. Importance of jindings: Despite youth’s protective effect, alcohol and drug de-

pendent persons without primary care had a substantial burden of serious medical illness. While all persons in this population would benefit from linkage to primary care, risk factors associated with worse health in our analysis may help to identify those with the greatest need. NIDA Grant # DA 10019. 139 PACOMPONENT OF MIDDLELATENCYAUDITORY EVOKED POTENTIALS ARE NOT RELATED TO IMPULSIVITY/AGGRESSIVITY IN HEROIN-DEPENDENT INPATIENTS

J. Perez de 10s Cobos, M.J. Manresa, J. Trujols, J. Conill, and M. Casas, Hospital de Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain Background: Pa component of middle latency auditory evoked potentials (MLAEP) is a relatively stable parameter generated by the temporal lobe’s primary auditory cortex. Temporal lobe dysfunction has been related to impulsivity and aggressivity. Objective: To assess a possible association between Pa component and impulsivity/aggressivity in heroin-dependent patients. Methods: MLAEP was elicited with 75 db binaural clicks, and recorded in 40 recently abstinent (lo-14 days) heroin-dependent inpatients, as well as 23 normal controls. The ages of these groups differed significantly (t[60.95] = 3.54, P = 0.001). Patients filled out the Eysenk’s Impulsiveness scale (EIS), and the Buss-Durkee Hostility Inventory (BDHI). Results: We did not detect a statistically significant correlation between Pa amplitude or latency, and EIS or BDHI scores. Pa amplitude (mean + SD) was 1.19 + 0.49 mV in heroin-dependent inpatients, and 0.81 + 0.43 mV in normal controls. An ANCOVA comparing Pa amplitude showed a significant effect by group (P[1,60] = 5.92, P = 0.018) after adjusting for age. Our results suggest that in recently abstinent heroin-dependent patients, there is a dysfunction in the temporal lobe’s primary auditory cortex, which is unrelated to impulsivity or aggressivity. Supported by: Organ Tecnic de Drogodependencies, Generalitat de Catalunya. 140 PROBLEMSEVERITYANDTREATMENTOUTCOMES FOR INJECTION AND NON-INJECTION METHAMPHETAMINEUSERS

N. De Veauuse Brown and Y. Hser, UCLA Abuse Research Center, Los Angeles, CA

Drug

This paper examines pre-treatment characteristics and treatment outcomes for injection and non-injection methamphetamine users. Our sample was comprised of clients (N = 235) reporting methamphetamines as their primary drug problem or regular use of the drug. Clients were recruited from 18 treatment programs

S50

Abstracts

randomly selected to represent four major modalities (outpatient drug-free, inpatient, residential, methadone maintenance) in Los Angeles County. Their drug use and related behaviors were assessed at baseline and at the l-year follow-up interviews. Preliminary analyses indicate that 82 were IV users and 153 were non-IV users, and that the two groups did not differ in gender or ethnicity. The IV-users were older (36.4 vs. 33.5). Additionally, IV methamphetamine users had greater psychological distress (e.g. depression, anxiety) than non-IV users as measured by the Symptom Check List (SCL-58) and they had lower self-esteem (2.76 vs. 3.06). Future analyses will examine problem severity in multiple domains (e.g. criminality, health), other risk factors (e.g. unprotected sexual practice), client motivation and readiness, and treatment retention rates. Multivariate analysis will also be conducted to determine differential treatment outcomes between IV and non-IV users, controlling for demographics and pre-treatment characteristics. 141 INDIVIDUAL Dmm~13NcEs COGNITIVE RESPONSES TO AMPHETAMINE

H. de Wit and L. Holdstock, Chicago, Chicago, IL

IN SUBJECTIVE AND ETHANOL AND D-

The University

of

In some individuals, ethanol (EtOH) produces marked stimulant-like subjective effects resembling those of stimulant drugs, like D-amphetamine (AMP). In this study we examined the mechanism underlying individual differences in the stimulant-like effects of EtOH in humans by testing the same subjects with acute doses of both EtOH and AMP and examining the correlation between them. If the stimulant subjective and cognitive effects of both drugs are mediated by the same mechanism, the subjects’ responses to the two drugs should be positively correlated. Twenty-seven volunteers (17 male, 10 female), aged 21-35, received beverages or capsules containing EtOH (0.8 g/kg), AMP (10 or 20 mg) or placebo on four separate sessions in a random order and under double-blind conditions. Various self-reported and objective drug effects were measured, including measures sensitive to subjective and cognitive stimulant-like effects. EtOH and AMP produced their prototypical subjective and behavioral effects. AMP increased ratings of stimulant-like subjective effects, increased heart rate and blood pressure and improved performance on a vigilance test. EtOH increased ratings of sedative-like subjective effects, increased heart rate and blood pressure, and impaired performance on the vigilance test. However, as reported previously, there was substantial inter-subject variability in subjective responses to EtOH, with some subjects reporting pri-

marily stimulant-like and others primarily sedative-like effects. To examine the relationship between responses to EtOH and AMP, correlations were examined between stimulant effects of EtOH and AMP (20 mg). For all subjects together, the correlation between EtOH and 20 mg AMP on the ARC1 A scale (a measure of stimulant-like subjective effects) was 0.41 (P < 0.05). Among only those sub.jects who reported feeling stimulated from EtOH, the correlation between EtOH and AMP was 0.64 (P < 0.05). These correlations suggest that the subjective stimulant effects of EtOH and AMP may be mediated through similar mechanisms. However, subjects’ performance on the vigilance test and the DSST after EtOH and AMP were not correlated, suggesting that the cognitive/behavioral effects of EtOH and AMP may be mediated by different mechanisms. Supported by NIDA (DA 02812) and the Alcoholic Beverage Medical Research Foundation. 142 EFFECTS OF LEVEL AND SOURCE OF SELF-EFFICACY AND ADDICTION SEVERITY IN PREDICTING TREATMENTOUTCOMES

T. DeHardt, University of California search Center, Los Angeles, CA

Drug Abuse Re-

Drug treatment outcomes research has suggested that an addict’s perceived self-efficacy to abstain from drugs and addiction severity are both important predictors of treatment success. The current study measured these variables as an empirical replication, but a new variable, the perceived ‘source’ of self-efficacy (i.e. self-efficacy from the self, or from something or someone else), was also assessed. Given supportive evidence for the benefit of accepting ‘powerlessness’ over a drug as a path to recovery (e.g. 12-step program research), it was predicted that perceiving self-efficacy as coming from a ‘not-self source would be associated with better treatment outcomes as defined by less drug use and better overall physical and psychological functioning. Less severe addiction and higher self-efficacy were also predicted to be associated with better treatment outcomes. These hypotheses were tested on a sample of 356 polysubstance-abusing outpatients in the greater Los Angeles area, with data collected both before and after one of 25 six-month substance abuse treatment programs. Bivariate correlational analyses supported the predictions. Higher self-efficacy (P = 0.464), less severe addiction (P = 0.372) and a ‘not-self source of self-efficacy (P = 0.200) were all significantly associated with better treatment outcomes. These findings suggest that future treatment outcomes studies should include a measure of self-efficacy source in conjunction with the measure of self-efficacy.

Abstracts

143

FLUNITRAZEPAM

DISRUPTS

RETENTION

IN RATS

S. Delatte, P.J. Winsauer, and J.M. Moerschbaecher, LSU Health Science Center, New Orleans, LA The effects of flunitrazepam on retention in six LongEvans rats were characterized using a repeated acquisition and delayed-performance baseline. This procedure had three phases: acquisition, delay, and performance. During the acquisition phase of each test session, subjects acquired a new four-response sequence maintained by food presentation under a second-order FR4 schedule of reinforcement. The key lights were turned off and a 30- or 60-min delay (retention interval) began when an acquisition criterion (seven errorless sequences or 28 consecutive correct responses) was met. Otherwise, the session ended after 45 min. The key lights and the house light were illuminated for a 30-min performance phase that followed either delay. The house light served as a discriminative stimulus for the performance phase. Retention was quantified as percent savings in the errors to criterion. The subjects were administered either saline or 0.1-0.56 mg/kg of flunitrazepam by intraperitoneal injection, 15 min before the performance phase, regardless of the delay. When flunitrazepam was administered during the 30-min delay, each subject showed a decrease in percent savings. With the exception of one subject, there was a decrease in response rate when flunitrazepam was administered, and error-increasing effects were evident in three of the subjects when the highest dose was administered. Administered during the 60-min delay, flunitrazepam produced similar decreases in retention. Interestingly, decreases in retention also occurred when 10 mg/kg of a benzodiazepine antagonist, flumazenil, was administered to three subjects. Supported by DA04775 and DA 11417. 144 EFFECTS OF METHAMPHETAMINE AND 3,4METHYLENEDIOXYMETHAMPHETAMINE ON CULTURED ADULTRATVENTRICULARCARDIOMYOCYTES

J.B. Delcarpio, M.L. Johnson, and K.J. Varner, Louisiana State University Health Sciences Center, New Orleans, LA Methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA) are widely used as recreational drugs. Recent studies, have shown that METH and MDMA can cause lesions to the myocardium of rats when administered in vivo. These cardiac lesions are histologically similar to those associate with myocardial infarctions and include contraction bands, myocardial necrosis, fibrosis and scaring. Intracellular aberrations include swelling of the sarcoplasmic reticulum and mitochondria, and cytoplasmic edema.

s51

These pathological changes are thought to be due to vascular spasm-induced ischemia resulting from the sympathomimetic action of these drugs. Whether other factors are involved is unknown. The present study tested the hypothesis that the cytological damage produced by METH and MDMA in vivo may also involve a direct effect of METH and/or MDMA on cardiomyocytes independent of ischemia and/or endocrine responses to the drugs. To accomplish this, METH (10-4, - 5 M) and MDMA (10-4, - 5 M) were administered to lo-day-old cultures of isolated ventricular cardiomyocytes from adult Sprague-Dawley rats. In the treated cultures, transmission electron microscopy revealed an increase in the amount of mitochondrial matrix granules, an absence of sarcomeric M-lines, heterochromatic nuclei, elongated mitochondria, poorly organized Z-discs and unusual cytoplasmic vesicles. TUNEL analysis was used to determine whether these changes resulted from either necrosis or apoptosis. Preliminary results indicate that METH and MDMA can induce apoptosis in both cardiomyocytes and non-myocytes in tissue culture. This suggests that METH and MDMA may have a direct detrimental effect on cardiac muscle cells independent of ischemia. Supported by grant DA 08255. 145 PREDICTING OUTCOMES IN ADULT AND ADOLESCENT TREATMENT WITH CASE MIX VS.LEVEL OF CARE: FINDINGS FROM THE DRUG OUTCOME MONITORING STUDY

M.L. Dennis, C.K. Scott, M.D. Godley, and R. Funk, Chestnut Health Systems, Bloomington, and Chicago, IL The field is increasingly shifting from stand-alone modalities to a continuum of care model as advocated by ASAM. At the same time, there is increasing interest by JCAHO and funders in looking at the treatment outcomes and finding a way to compare them with what would have been expected given the mix of cases presenting at a given program. This paper evaluates a case mix adjustment based on a cluster analysis of presenting clinical issues (patient level data) with the initial level of care (program level data) in terms of predicting individual outcomes related to retention, substance use, other behaviors, and service utilization. This paper uses data from the Drug Outcome Monitoring Study (DOMS) that was conducted from 19951997 and includes intake and follow-up assessments (93.4% of those attempted) with the Global Appraisal of Individual Needs (GAIN) on 576 adolescents and adults from 21 outpatient, methadone, and inpatient treatment units. Adding in the ASAM case mix (ACM) reduced the variance explained by Level of Care (LOC) in seven of the nine indices by 26683%; in the other

s52

Abstracts

two it increased it by 2%. This is important because in a continuum of care system patients typically go through multiple levels of care so the old approach is increasingly less useful. The impact on subsequent frequency of use (- 72%) and time in an (expensive) controlled environment ( - 83%) is particularly important for policy/program evaluation. 146 'NEWCOMERS' AND ‘RETURNEES': RISK IORSAMONGPUERTORICANDRUGINJECTORSINNEW YORKANDPUERTO RICO

BEHAV-

S. Deren, S.-Y. Kang, R. Robles, J. Andia, H. Colon, D. Oliver-Velez, A. Finlinson, NDRI, New York, NY, Universidad Central de1 Caribe, Bayamon, PR Background: High rates of HIV/AIDS have been found among Puerto Rican injection drug users (IDUs), with higher levels of risk behaviors reported for those who reside on the island of Puerto Rico than those who reside in New York. The high mobility between Puerto Rico (PR) and New York (NY) provides an opportunity to examine whether mobile IDUs adapt local levels of risk behaviors or maintain prior levels of risk behaviors. This study of Puerto Rican IDUs will compare HIV risk behaviors for those who are ‘newcomers’ to NY with other NY IDUs; and those who are ‘returnees’ to PR with other Puerto Rican IDUs in PR. Procedures/subjects: A dual-site study of Puerto Rican IDUs, using qualitative and quantitative methods, was conducted in East Harlem, NY (n = 561) and Bayamon, PR (n = 313). For the NY subjects, 40% were born in NY, and 56% in PR; among those recruited in PR, 10% were born in NY and 87% in PR (P < 0.001). Results: IDUs in NY who could be considered ‘newcomers’ (previously lived in PR for at least one year and injected in PR; reported riskier injection practices than other NY IDUs, e.g. any sharing of any injection equipment (in the prior 30 days) was reported by 41% of newcomers vs 29% of other NY IDUs (PC 0.01). The qualitative team in NY found that homeless new arrivals to NY from PR reported difficulty in accessing services, and were observed engaging in high risk behaviors. ‘Returnees’ to PR (those who were born in PR, previously lived in NY for at least 1 year and injected in NY) were not significantly different in terms of injection risks than other IDUs recruited in PR, e.g. sharing of injection equipment was reported by 82% and 79%, respectively. Conclusions: Intervention efforts geared to mobile IDU populations, enhancing their ability to access risk reduction mechanisms (e.g. NEPs and MMTPs) may be needed. Further study of mobility patterns and risk behaviors, including information regarding length of residence and risk networks, can be helpful in refining targeted interventions.

147

ISOTROPANE

DOPAMINE

UPTAKEINHIBITORS

H.M. Deutsch, D.-I. Kim, and M.M. Schweri, Georgia Institute of Technology, Atlanta, and Mercer University School of Medicine, Macon, GA A series of isotropanes (3-aza-8-phenyl bicyclo[3.2. lloctane) derivatives was synthesized and tested for inhibitory potency in [3H]WIN 35 428 (WIN) binding to dopamine transporters, [3H]citalopram binding to serotonin transporters and synaptosomal [3H]dopamine uptake. Synthesis was accomplished by a condensation reaction of benylamine, cyclopentanone and formaldehyde. The resulting 3-benzyl-3-aza-bicyclo[3.2.l]octan-8one (A) was transformed to the final products using a number of standard synthetic methods. Some of the compounds bound with high affinity to the cocaine binding site as marked by WIN. For example, the isotropane [R = Bn, X = H( ) and Y = H] has an IC50 for WIN binding of 224 nM. Further biological testing is in progress. These and related compounds may be promising candidates for testing as replacement agonists or partial agonists in cocaine abuse therapy. 148 BEHAVIORALLYACTIVEDOSESOF TO ALTERCIGARETTESMOKING

SCH 39166~~1~

E.C. Donny, E.M. Vernotica, S.L. Walsh, and G.E. Bigelow, Johns Hopkins School of Medicine, Baltimore, MD Dopaminergic compounds have been targeted as potential treatments for cocaine and nicotine dependence because of the known role of the mesolimbic dopamine system in drug reinforcement. We previously reported that chronic treatment with SCH 39166, a Dl/D5 antagonist, failed to alter the pharmacodynamic effects of iv. cocaine (Vernotica et al. CPDD 1999). Additional data from that study focused on the effects of SCH 39166 on smoking behavior and its direct subjective and performance effects. Four doses of SCH 39166 (0, 10, 25, 100 mg/day p.o.) were administered once daily for 1 week each in double blind, random order to inpatient cocaine dependent volunteers (n = 10). Smoking questionnaires revealed no significant effects of SCH 39166 dose on desire to smoke, smoking satisfaction or the number of cigarettes smoked. SCH 39166 produced reliable dosedependent deficits of psychomotor performance on the DSST and the circular lights, but not a balance task. Impairment on the DSST appeared to wane over days suggesting development of tolerance. These doses of SCH 39166 did not result in subjective effects. Although the performance effects verify that these doses of SCH 39166 were behaviorally active, the absence of a change in smoking behavior suggests this compound may not be an effective pharmacotherapy for nicotine dependence.

s53

Abstracts

Supported by Schering-Plough Research Institute, NIDA ROl DA05196, T32 DA07209, K05 DA00050. 149 THE ROLE OF ALCOHOL OUTCOME .EXPECTANCIES IN RISK FOR ALCOHOLISM AMONG WOMEN WITH ANDWITHOUTAFAMILYHISTORYOFALCOHOLISM

A.L. Dorlen and S.M. Evans, Columbia University and New York State Psychiatric Institute, New York, NY The present study compared beliefs about alcohol’s effects in women with a confirmed history of alcoholism in one or both parents (FHP) to women with no parental history of alcoholism (FHN). Beliefs about the effects of alcohol are termed alcohol outcome expectancies. In previous studies, stronger expectancies have been associated with increased drinking behavior, as well as alcohol abuse and dependence symptoms among alcohol users. To date 50 women who range in age from 18-35 years old have been recruited. The women in each group are equally distributed with respect to age, socioeconomic status, race and drinking level. Expectancy scores were assessed using a Likert-style Alcohol Expectancy Questionnaire (AEQ), which consists of six scales assessing alcohol’s effect on a variety of domains. A composite AEQ score was also assessed. In addition, the study prospectively tracked these women with regard to mood, alcohol use and daily positive and negative consequences of alcohol use across one menstrual cycle. Data show that composite AEQ scores were higher in FHP women (211.3 + 8.13) than FHN women (194.5 I 7.63) regardless of drinking level. Both greater positive and negative daily consequences of drinking were found among heavier drinkers. These preliminary analyses suggest that alcohol expectancies prospectively predict drinking behavior, and may be associated with further risk for the development of alcohol use problems among high-risk women. 150 PARENTAL ATTENTION ANDRISKOFCOCAPASTE SMOKING IN CHILE:PRELIMINARY DATAFROMTHE~~~~ NATIONALSCHOOLSURVEYINCHILE

C. Dormitzer, L. Caris, and J.C. Anthony, kins University, Baltimore, MD

Johns Hop-

Aim: This study sought to estimate recent risks of starting to smoke coca paste among teenage students in Chile, and possible protective influences of parental attention (e.g. see Dishion, 1985; Chilcoat and Anthony, 1996), in a country generally characterized by close family ties and high levels of parental attention. Methods: In 1999, a nationally representative sample of 46 907 students age 12-21, completed anonymous classroom questionnaires. Standardized questions on age and recency of first use were administered; 556 newly

incident cases of coca paste smoking were identified, as were 34 950 students who had no coca paste experience. A five item parental attention, and monitoring scale was also administered, separately. Survey estimates appropriate for classroom samples and conditional logistic regression (CLR) relative risk estimates were derived, with CLR holding constant age, sex, and shared aspects of local environment (e.g. coca paste availability), via STATA software. Results: Some of Chile’s communities now face outbreaks of coca paste smoking. The risk of initiating coca paste smoking is related to levels of parental attention: relative risk estimates suggest a 48% decline in risk for every unit increase in level of parental monitoring (P < O.OOl), for both males and females. Sorted from highest to lowest parental attention quartiles, the risk estimates (per person-year of observation) are 0.6%, 0.8%, 1.7%, and 3.2%, respectively. Discussion: In local outbreaks, Chilean students now face quite high risk of starting to smoke coca paste (close to 1% per year, on average). With little time to launch research on the best preventive procedures, public health officials in Chile might use media campaigns, social marketing and other techniques to foster increased parental attention, in an effort to curb the outbreaks. ACKNOWLEDGMENTS: Republic of Chile Ministries of Health and Education. 151

ANTINOCICEPTIVE

MORPHINE PILOT

IN

METHADONE

EFFECTS

OF

MAINTENANCE

INTRAVENOUS PATIENTS:

A

STUDY

M. Doverty, J.M. White, A.A. Somogyi, C.H. Beare, A. Menelaou, F. Bochner, and W. Ling, University of Adelaide, Australia, and University of California Los Angeles, Los Angeles, CA We have previously reported that, compared with control subjects, patients in methadone maintenance treatment are hyperalgesic to pain induced by cold pressor test but not by electrical stimulation (Doverty et al. in press). To date there is little evidence regarding the antinociceptive effects of administering additional opioids to these patients. This pilot study was designed to determine the antinociceptive responses to i.v morphine amongst a group of patients on stable doses of methadone (three males and one female; mean age = 32 years; mean dose = 81 mg), and to compare these to the responses of controls. Each patient was tested on two occasions from 0800-2000 (7 days apart): once when their plasma methadone was at trough levels, and again when at peak plasma levels. Morphine was administered intravenously via a two step, controlled infusion designed to produce consecutive steady-state plasma concentrations. Pain was induced using a cold pressor test and cutaneous electrical stimulation of the ear lobe. Blood samples were taken concurrently with pain test-

S54

Abstracts

ing. Control subjects were age and sex matched with the methadone group. Preliminary analysis of results from methadone patients suggests that at steady-state morphine concentrations of 15 and 57 rig/ml there was a concentration related morphine effect in both nociceptive tests. The antinociceptive effects of morphine were additive with methadone. However, even with the addition of i.v. morphine, methadone patients remained considerably hyperalgesic to pain induced by the cold pressor test compared to controls without morphine. 152 REINFORCEMENT OF POLYDRUG VERSUS coCAINE ABSTINENCE IN BUPRENORPHINE-MAINTAINED, HEROIN-DEPENDENTPOLYDRUGABUSERS

K.K. Downey, C.R. Schuster, J.A. Hopper, Tansil, Wayne State University, Detroit, MI

and D.

Our previous studies targeting polydrug abstinence via contingency management have yielded disappointing results. We are now investigating whether targeting single-drug (cocaine) abstinence yields improved treatment outcome over targeting poly-drug abstinence in this population. During a l%-week intervention phase, provision of urine samples negative for both heroin and cocaine is reinforced in the Poly-Drug Abstinence (PDA) condition, and cocaine abstinence only is reinforced in the Cocaine Abstinence (CA) condition. To date, 24 PDA and 21 CA Intention-to-Treat participants have enrolled in the protocol. There are no group differences in age, sex, race, marital status, employment status, education or rates of ASPD. Early (pre-intervention) drug abstinence and employment status were important independent predictors of treatment outcome and retention, but group assignment was not. However, after controlling for early cocaine abstinence, the CA condition yielded significantly higher rates of polydrug abstinence than the PDA condition. Also, during a post-intervention &week maintenance phase and a 4week withdrawal from buprenorphine thereafter, those who had been reinforced for cocaine abstinence had significantly higher rates of heroin abstinence than those who had been PDA participants. Results were in the same direction but non-significant for cocaine abstinence post-intervention. Targeting single-drug abstinence may yield overall improved treatment outcome in this population. Several remaining CA participants and a group of yoked controls are presently completing the protocol. Data on the full sample will be presented. 153 OFFICE-BASED METHADONE PRESCRIBING MARYCAREzPRELIMINARYRESULTSOFARANDOMIZED CLINICAL TRIAL OF SAFETY AND EFFICACY

IN PRI-

E. Drucker, D. Hartel, and E. Tuchma, Albert Einstein College of Medicine, Bronx, NY

Hypothesis: Patients with > 6 months of stable methadone treatment can be transferred to office-based prescribing OBP by primary care providers with rates of treatment retention and illicit drug use equivalent to controls in methadone maintenance (MM) clinics. Subjects: 150 consenting women with at least six months stability in methadone treatment and some take home privileges. Procedures: Prescribing authority over methadone dosage and pickup schedules for 50 randomly selected patients was transferred to 12 primary care practitioners (MDs. PAS. NPs) All OBP patients continued to attend their MM clinics for methadone dispensing and ancillary services, with monthly visits to their outpatient medical care providers. Results: Treatment Retention: with 12 months follow up of 128 enrollees, one of 56 OBP (0.4%) patients left methadone treatment, as compared to 5 of 72 (6.9%) MM clinic controls; Use of ZlZicit Drugs: The overall percentage of women with at least two positive tests, (average 18 specimens per person), was 25% for opiates and 21% for cocaine. Experimental and control arms did not differ by urine toxicology test results. Statistical analysis: This is an equivalency study with an intent-to-treat statistical model. No significant difference in retention or positive urine toxicology for OBP and usual MM clinic care was found. Importance of findings: These findings support the safety, practicality, and efficacy of primary care practitioners assuming responsibility for the prescription of methadone in a wide range of primary care clinical settings and for a more heterogeneous patient population than previously undertaken in the U.S. 154 HT3

ARYLGUANIDINES LIGANDS

AS NOVEL

HIGH-AFFINITY

s-

M. Dukat, Y. Choi, C. Smith, A. DuPree, M. Teitler, and R.A. Glennon, Virginia Commonwealth University, Richmond, VA, and Albany Medical College, Albany, NY There is some, albeit conflicting, evidence that 5-HT3 receptors might be involved in the actions of central stimulants. For example, 5-HT3 antag-on-ists left-shift the methamphetamine (MA) dose-effect curve in rats trained to discriminate MA from vehicle (Munzar et al., 1999), and 5-HT3 receptor subsensitivity may represent a partial explanation for tolerance induced by cocaine administration (Mate11 and King, 1997). However, the few 5-HT3 agonists available for investigation either possess low affinity for 5-HT3 receptors (e.g. PBG, 2-Me 5-HT) and/or have difficulty penetrating the blood-brain barrier (e.g. mCPBG, 2-Me 5-HT). We have identified a novel agent with 5-HT3 agonist character: MD-354 (3-chlorophenylguanidine; Ki = 35 nM). MD-354 serves as a training drug in drug discrimina-

S55

Abstracts

tion studies, and the MD-354 stimulus is potently antagonized by 5-HT3 antagonists. In order to determine how MD-354 binds relative to the phenylbiguanide mCPBG, and to develop higher-affinity agents, we prepared a series of guanidine analogs for comparison with their phenylbiguanide counterparts. Results with 14 compounds indicate that (a) the two series bind in such a manner that their aryl moieties are superimposable; and that (b) 1-(3,4,5trichlorophenyl)guanidine (TCPG: Ki = 0.7 nM) represents a novel high-affinity 5-HT3 ligand that could be useful in future investigations of stimulant action. 155 REDUCED NAA LEVELS IN FRONTAL GRAY MATTEROFHEROIN-DEPENDENTSUBJECTSDETERMINEDBY IH MRS

K.M. Diirsteler-Mac Farland, R. Haselhorst, K. Scheffler, D. Bilecen, D. Ladewig, R. Stohler, J. Seelig, and E. Seifritz, Universities of Basel, Zurich, Switzerland. and Freiburg, Germany Structural and functional brain changes and injuries after heroin exposure have been demonstrated by magnetic resonance and computer tomography imaging, neuropsychologic testing, biopsy, and necropsy. In this study, we tested the hypothesis that long-term intravenous (IV) heroin use may lead to decreased levels of N-acetyl aspartate (NAA) in the frontal lobe as determined by localized proton magnetic resonance spectroscopy (1H MRS). NAA is a putative marker of neuronal integrity due to its exclusive presence within neurons. Twelve heroin-dependent subjects with a history of long-term IV heroin use who were enrolled in heroin or methadone maintenance treatment were examined by 1H MRS of two adjacent voxels in the frontal lobe. They were compared with 12 age and sex matched controls. Absolute metabolite concentrations were obtained by referencing to the brain water signal. Separate NAA concentrations were assigned to white and gray matter using image segmentation combined with linear regression analysis. Compared to controls, the concentrations of NAA in patients were significantly reduced by 7% in gray matter (11.8 f 1.O vs. 10.9 + 0.6 mmolikg wet weight, P = 0.015) but this was not the case in white matter (9.1 f 1.2 vs. 9.1 ) 0.9 mmol/kg ww). To our knowledge, this is the first demonstration of decreased NAA levels in the frontal gray matter of long-term IV heroin users without overt signs of functional brain damage. The findings of slightly, but significantly reduced NAA concentrations suggest minor neuronal damage in the frontal cortex after long-term IV heroin use implicating direct or indirect neurotoxic effects of heroin or contaminants. ACKNOWLEDGMENTS: Supported by the Swiss National Science Foundation.

156 NOVEL N- AND 0-SUBSTKUTED METHOXY)-ETHYL]-l-[(PHENYL)METHyL] ANALOGS

4-[Z(DIPHENYLPIPERIDINE

A.K. Dutta, X.S. Fei, P.M. Beardsley, and M.E.A. Reith, Wayne State University, Detroit, MI, University of Illinois, Peoria, IL, and Virginia Commonwealth University, Richmond, VA In our effort to develop pharmacotherapeutics for cocaine addiction, we embarked on synthesizing novel molecules targeting the dopamine transporter (DAT) in the brain as DAT has been implicated strongly in the reinforcing effect of cocaine. Our ongoing structure-activity relationship studies of piperidine analogs of GBR 12909 led us to explore the significance of the contribution of the benzhydrilic 0- and N-atoms in these molecules in interacting with the DAT. To that effect, we replaced the benzhydrilic O-atom with the N-atom, altered the location of the benzhydrilic N-atom to an adjacent position, or converted the benzhydrilic Oether linkage into an oxime-type derivative. Furthermore, we also evaluated the contribution of the piperidine N-atom in binding potency by altering its pKa value chemically. Most of these modifications were introduced in our parent lead compound 4-[2(diphenylmethoxy)ethyl]-1-[(4-fluorophenyl)-methyl] -piperidine. The results indicated that the benzhydrilic 0- and N-atom are exchangeable without compromising activity although derivatization of the N-atom affects the activity significantly. On the other hand, an enhanced interaction with the SERT was observed when the benzhydrilic N-atom was moved to an adjacent position. All compounds were characterized for their binding to the DAT, SERT and NET. Preliminary behavioral assays of selected compounds indicated that these compounds are much less stimulating when compared with cocaine at comparable doses. Details on synthesis and biological characterization will be presented. Supported by DA 12449. 157 MAINTENANCE AND CAINE SELF-ADMINISTRATION RATIOSCHEDULE

REINSTATEMENT OF coUNDER A PROGRESSIVE-

S.I. Dworkin and S.K. Winn, University Carolina Wilmington, Wilmington, NC

of North

The treatment of compulsive cocaine use is consistently beset with the event of relapse. A better understanding of the reinforcing effects of cocaine and factors underlying relapse would aid in the treatment of this devastating behavioral disorder. To this end male, Fisher-344 rats were trained to self-administer cocaine under a progressive ratio (PR) schedule. A lo-min, time-out

S56

Abstracts

period followed each infusion to reduce the direct effects of the drug on subsequent responding. Doses of cocaine (0.083-0.67 mg/inf) resulted in a monotonic increasing function. Moreover, run rates tended to be independent of ratio value but increased as the dose of cocaine was increased. Following determination of the dose-response curves, the effects of extinction and response-dependent priming doses of cocaine (0.33- 1.OO mg/inj) were determined. This reinstatement procedure resulted in an inverted ‘U’ function for which single response-dependent injections of 0.67 mg resulted in the largest break point. A more complete understanding of the factors associated with the conditions underlying maintenance and relapse of drug self-administration are essential for the development of effective drug abuse treatments. Research supported by NIDA DA-06284. 1%

SIGNS

WITH

ANTAGONIST

STIMULATION

OF

ACUTE PROFILE

OPIOID IN

DEPENDENCE

VARY

AN INTRACRANIAL

SELF-

PROCEDURE

K.W. Easterling and S.G. Holtzman, sity, Atlanta, GA

Emory Univer-

Lower (0.001-1.0 mg/kg) doses of the opioid antagonist naltrexone produce few behavioral effects in otherwise drug-free subjects responding for ICSS, but reduce response rates by up to 75% after a single dose of morphine (MOR, 10 mgikg). The present study represents an effort to verify that other opioid antagonists produce this acute opioid dependence effect, and to characterize their relative pharmacological profiles. We implanted bipolar electrodes in the lateral hypothalamus (medial forebrain bundle) of adult male SpragueDawley rats (N= - 6-8) and then trained them to lever-press on a free-operant ‘autotitration’ ICSS schedule. This schedule produced stable responding at approximately 1.5 resp/s. During twice-weekly test sessions, cumulative doses of 5 of 7 drugs with opioid antagonist action produced significant response rate decreases (30&800/o) in saline pretreated rats; nalorphine (ED25 = 15.6 mg/kg) > naltrexone (ED25 = 13.1 mg/ kg) > naloxone (ED25 = 7.3 mg/kg) > levallorphan (ED25 = 5.9 mg/kg) > ( - )cyclazocine (ED25 = 0.5 mg/kg). A single MOR pretreatment (10 mg/kg, 4 h) significantly enhanced the rate-decreasing effects of 6 of 7 antagonists tested; by 6-fold [( - )cyclazocine] > 13fold (nalorphine) > 39-fold (levallorphan) > 972-fold (naloxone) > 2190-fold (naltrexone). The pure non-selective antagonist diprenorphine potently decreased rates after MOR pretreatment (ED25 = 0.01 mg/kg), but did not reduce responding after saline pretreatment. In contrast to the other antagonists, the mixed opioid agonist-antagonist drug nalbuphine (1 .O-30 mg/kg) did not affect responding after either saline or MOR.

Therefore, antagonists with a high affinity for, and a lack of intrinsic activity at, the u-opioid receptor precipitate the greatest behavioral changes in rats acutely dependent on MOR. 159

ARE

STANCE

THERE

USE

DOMESTIC

AND

DIFFERENCES VIOLENCE

VIOLENCE

IN AMONG

SEVERITY

OF

SUB-

SUBSTANCE-USING

OFFENDERS?

C.J. Easton and R. Sinha, Yale University Medicine. New Haven, CT

School of

This study examined differences in severity of substance use and violence among court-mandated substance using offenders of domestic violence (SADV + ) versus court-mandated substance users (SADV - ). Two groups of male substance using participants (N = 28) were evaluated in the first 3 months of treatment for number of sessions attended, number of drop-outs, age of onset for substance use, anger and hostility scores, types of violent behaviors, and domestic violence arrests. The results indicate that the SADV + group had significantly higher reported hostility (P < 0.006) and anger (P < 0.050), significantly more alcohol related problems (P < 0.035), and a near significant finding for earlier age of onset for substance use (P < 0.086). Further, the SADV + group had significantly more reported physical aggression (P < 0.003), threats toward partner (P < 0.015), more domestic violence arrests (P < 0.013), and significantly more protective orders filed against them (P x 0.000). The findings illustrate the importance of assessing violence in individuals entering substance abuse treatment, as this may be an important indicator for treatment retention and outcome among this population. Supported by P50-DA09240. 160 OIDS

MAINTENANCE WITHIN

BILIZING PENDENT

THERAPY

A MULTIDISCIPLINARY NECESSITY

FOR

WITH

SYNTHETIC PROGRAM

PREGNANT,

OPI-

A STA-

OPIOID-DE-

WOMEN

H. Eder, G. Fischer, A. Peternell, A. Topitz, A. Habeler, and D. Kraigher, University Hospital of Vienna, Austria Aims: In opioid dependent pregnant addicts early intervention during the prenatal period is highly desirable for maintaining the health of the woman, the fetus, and infant after birth. The aim of our study was to perform an analysis of different variables to determine which factors are responsible for stabilzing the mother so that she could keep the child. Participants: 98 pregnant women who met DSM-IV criteria for opioid dependence (DSM-IV 304.0) or polysubstance dependence (DSM-IV 304.8) who were seeking treatment in our

s51

Abstracts

multiprofessional treatment program were investigated. The addicts received oral opioid maintenance therapy (methadone, slow-release morphine, buprenorphine) and psychosocial and psychotherapeutical treatment at the University Clinic; 82 children were born during a period of 36 months. Measurements: Length of treatment period, duration of maintenance therapy, type of maintenance therapy as well as attendance of psychotherapy were used to evaluate which of these parameters are predictors of whether the child can live with its own mother or had to be placed elsewhere. Findings: At the end of our investigation period, 59% (n = 48) of the children were still raised by their mothers. Duration of involvement in a maintenance therapy (P = 0.002) as well as early intervention (P = 0.03) had a significant influence towards mothers keeping the child. In addition to successful pharmacological treatment, psychosocial and psychotherapeutical services influenced the outcome. Conclusion: Early intervention and effective multiprofessional treatment approaches facilitated a better outcome for this population at risk with respect to mothers retaining custody of their child. 161 FEMALE TION AS A EXPERIENCE

SUBSTANCE ABUSER: WELFARE UTILIZAFUNCTION OF CHILDHOOD WELFARE

M. Edwards, D. Carise, D. Festinger, A.T. McLellan, and H.D. Kleber, Treatment Research Institute at the University of Pennsylvania, Philadelphia, PA, and the National Center for Addiction and Substance Abuse at Columbia, New York, NY Recent reforms in welfare eligibility guidelines have led to increased pressure on persons receiving welfare to obtain employment. Considerable portions of welfare recipients have drug and alcohol problems that may hinder or prevent successful employment. The DENS system is a nationwide electronic tracking system that provides standardized, timely information on patients entering into substance abuse treatment and has been in position to changes such as these in the nation’s drug treatment system. This report describes the nature and severity of problems seen in a sample of women entering the DENS system between January 2000 and May 2000 who were receiving welfare. One benefit of the DENS system is the ability to add additional questions via modem. For this study, we added the following questions: (1) Were you raised in a household which was supported by welfare/public assistance? and (2) Total time (Years/Months) in your life, receiving welfare/public assistance? 170 women answered these two questions at intake. The women with a history of childhood welfare did not differ from women without a childhood history of welfare in areas such as age, education, and prior substance abuse treatment. How-

ever, women with a childhood welfare history did receive seven times the amount of welfare funding than women without a childhood history of welfare. These findings can help to inform social policy and efforts to reduce welfare dependence. 162

PERCEIVED MOTIVATIONS FOR DRUG USE: ADOLESCENTS INSUBSTANCETREATMENT

K.M. Ehlers, E.,4. Whitmore, P.D. Riggs, M.C. Stallings, SK. Mikulich, and T.J. Crowley, University of Colorado School of Medicine, Denver, CO Increasingly, substance abuse treatment has focused on antecedents and consequences for on-going drug use. Yet, there are few reports on adolescent patients’ motivations for drug use or their perceptions of the rewards and consequences of substance use. More specific information on the perceptions of adolescents with substance use disorders (SUD) is needed to refine treatment interventions. Aims: We investigated whether adolescents’ perceived motivations and risks/benefits of drug use were related to patterns of use, psychiatric comorbidity or severity of substance use disorders. Methods: We evaluated 226 adolescents in treatment for SUD and 91 community controls who used at least one non-tobacco substance more than five times. Results: Most patients preferred marijuana as their drug of choice whereas most controls preferred alcohol. Primary reasons for use of the preferred drug fell into several categories, including: excitatory; inhibitory; escape/coping; availability; sociability and others. Most (82%) patients reported they used their drug of choice for a psychopharmacological effect (e.g. excitatory, inhibitory, escape). Only 26% of controls reported they used their drug of choice for psychopharmacological effects; they reported other reasons including safer/ fewer problems relative to other drugs (27%) and availability (26%). Analyses will first address potential main effects and interaction between group (patient/ control) and preferred drug (alcohol/marijuana) on motivations for use. We will then relate additional information about motivations, rewards, and liabilities of substance use to diagnoses, patterns of use, and severity of SUD for adolescents in treatment. Results will be used to develop an instrument to better describe these relationships and pilot data from this instrument will also be presented. 163 LORAZEPAM WITHDRAWAL SIGNS ZOLPIDEM OR VIGABATRIN SUBSTITUTION

FOLLOWING

E.E. Elliot and J.M. White, University of Adelaide, South Australia, and NIDA/NIH, Baltimore, MD

S58

Abstracts

The emergence of discontinuation signs limits the clinical use of sedative-hypnotics. One strategy to minimize these aversive events involves administration of adjunctive pharmacotherapies following drug cessation. The anticonvulsant vigabatrin has been reported to minimize alcohol withdrawal severity in humans (Stuppaeck, et al., 1996 Alcohol.Alcohol. 31(l), 1099111). Similarly, the imidazopyridine alpidem was reported to ameliorate benzodiazepine withdrawal in a multi-centered clinical trial (Cassano et al., 1996, Eur. Psychiatry, ll(2) 93-99). Thus, it was hypothesized that both vigabatrin and the imidazopyridine zolpidem would ameliorate benzodiazepine cessation signs. Hooded Wistar rats were surgically implanted with radioelectrodes whilst fully anaesthetized. Radiotransmitters were inserted into the abdomen and two electrodes were sutured into the left thigh muscle of four groups of rats, n = 6 per group. One week after recovery rats were administered lorazepam (0.19 mg/ml) or lorazepam vehicle (lo/o beta cyclodextrin) in drinking water for 12 days. Over the following 4 days, either vigabatrin (1 mg/ml) or zolpidem (0.2 mg/ml) was substituted for lorazepam in the drinking water. The measures electromyographic activity, locomotor activity and body temperature were recorded every 30 min during those 4 days and over the following 2 weeks to assess lorazepam withdrawal signs. Compared to vehicle treated controls, neither zolpidem nor vigabatrin were effective in abolishing lorazepam withdrawal signs during the 4 days of substitution treatment. However, vigabatrin was able to attenuate lorazepam withdrawal signs 18 days after lorazepam cessation. These withdrawal signs included large increases in the proportion of daytime locomotor activity and phase shifts in diurnal temperature rhythms. Thus, vigabatrin may be of use as an adjunctive therapy during benzodiazepine discontinuation in humans. 164 SELECTIVE DEGENERATION IN BRAIN IN FASCICULUS RETROFLEXUS PRODUCED BY DOPAMINE-RELATEDSTIMULANTSBUTALSOBYNICOTINE

G. Ellison, J. Carlson, and B. Armstrong, California, Los Angeles, CA

University of

Using sensitive silver-staining techniques, we have studied degeneration produced in rat brain following administration of a variety of drugs of abuse when given at the lowest possible doses but continuously over several days (in an attempt to mimic the ‘binge’ drug regimen which develops in chronic stimulant addicts). Over 300 rats have now been studied. Although amphetamine and methamphetamine induced degeneration in dopamine terminals in caudate, cocaine does not. Yet all of these drugs, as well as cathinone and MDMA, induce identical degeneration axons running

in the portion of fasciculus retroflexus (FR) which begins in lateral habenula and passes through the sheath of the tract to substantia nigra, VTA, and the raphe nuclei. Nicotine induces profound and selective degeneration in FR, but in this case in the cholinergic portion of the tract (medial habenula through core of tract to interpeduncular nucleus). It is remarkable that all of these addictive compounds have degenerative effects - in fact their main degeneration effects - in the same tract in brain. FR appears to be a weak link in brain for stimulants. 165 GENDER DIFFERENCES IN CRAVING, MOOD STRESSAMONGNON-TREATMENTSEEKINGINDIVIDUALS WITHCOCAINEDEPENDENCE

AND

I. Elman, K. Karlsgodt, S. Lukas, and D.R. Gastfriend, Massachusetts General Hospital, Boston, and McLean Hospital, Belmont, MA This study sought to examine potential gender differences in a relatively underinvestigated population of non-treatment seeking individuals with cocaine dependence. Ten female and 11 male individuals matched by demographic characteristics and severity of drug use were assessed with regard to their craving, mood and psychosocial stress exposure using a craving questionnaire devised by Weiss and Griffin (1995) measuring five different aspects of this construct including desire not to use, ability to resist, current intensity, responsiveness to drug-related conditioned stimuli and imagined likelihood of use if in a setting with access to drugs, the Hamilton Rating Scale for Depression and the Tension-Anxiety subscale of the Profile of Mood States (POMS). Female subjects (8 were studied at the midfollicular phase of their menstrual cycle and 2 were on oral contraceptives) had significantly higher scores for craving (P < 0.05) depressive symptomatology (P < 0.01) and stress (Y < 0.01). Exploratory analysis in females revealed significant correlation (TS= 0.63) between lifetime years of cocaine use and POMS TensionAnxiety scores but not with those for craving. In contrast, in males, years of cocaine use significantly correlated with craving scores (YS= 0.65) but not with those for the POMS subscale. These results replicate a recent report that female cocaine dependent patients were more likely than males to have laboratory-based cue-induced craving (Robbins et al., 1999) and extend this finding by suggesting that gender differences may generalize to different aspects of cocaine craving. In addition, our findings suggest that gender may influence the role played by craving and stress in the course of cocaine dependence. As estrogen is purported to modulate craving-related dopaminergic systems, further studies to examine the factors related to these observed gender differences, i.e. estrogen-dopamine interactions and their effect on craving and mood will be needed.

Abstructs

166 CONTINGENCYMANAGEMENTAUGMENTEDWITH COGNITIVE-BEHAVIORALTHERAPYTOREDUCECOCAINE USEINMETHADONE-MAINTENANCEPATIENTS

D.H. Epstein, W. Hawkins, A. Umbricht, and K.L. Preston, NIDA Intramural Research Program, Baltimore, MD The benefits of contingency management (CM) for cocaine abuse are rapid but may be transient (Silverman et al., 1996), whereas the benefits of cognitive-behavioral therapy (CBT) are less rapid but may continue to emerge after therapy ends (Carroll et al., 1994). We hypothesized that the combination of CM and CBT would be superior to either alone: CM may produce a window of abstinence during which CBT can ‘take’ and CBT may subsequently prolong that abstinence. We tested this in a 2 x 2 design in which 198 methadonemaintained outpatients were randomly assigned to a group-therapy condition (CBT vs. a social-support therapy in which the counselor taught no coping skills) and a voucher condition (CM with vouchers contingent on cocaine-negative urines vs. noncontingent vouchers). There were four phases: Baseline assessment (5 weeks), Intervention with vouchers and group therapy (12 weeks), Maintenance (12 weeks), and Withdrawal from methadone (10 weeks), plus follow-up interviews 3, 6, and 12 months after exit. The study is completed, though follow-ups are ongoing. Preliminary analyses of the urine data suggest that, during the Intervention phase itself, cocaine use was reduced by CM and not by CBT. but that in the subsequent maintenance phase, many of the patients who had received CM alone returned to more frequent cocaine use, while those who had received the CM + CBT combination did not. This finding suggests that CBT during CM inoculates against subsequent relapse; however, there may have been some selective attrition of heavier users from the CM + CBT group. A more complete analysis will be presented. 167 NICOTINEEFFECTSONCOGNITIVEPERFORMANCE IN SMOKERS,EX-SMOKERS,ANDNEVER-SMOKERS

M. Ernst, S.J. Heishman, L. Spurgeon, AS. Kimes, and E.D. London, National Institute on Drug Abuse, Baltimore, MD Findings on the cognitive effects of nicotine are inconsistent. The discrepancies may reflect differences in degree of nicotine exposure, length of abstinence, nicotine delivery form and route of administration, and the targeted cognitive domain. In this study, cognitive performance was assessed as a function of (1) abstinent state in smokers; (2) smoking history; and (3) interaction of nicotine administration with smoking history.

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Four tasks were used: The Two-Letter Search for visual attention; the Logical Reasoning for verbal information processing, and the Two-Back and Three-Back for working memory. Fourteen heavy smokers, 15 exsmokers and 9 never-smokers participated each in a non-abstinent training, and a 12 h abstinent nicotine (4 mg gum) and placebo condition. Gum administration was double-blind, and the order of treatments (nicotine, placebo) was randomized across participants. The nicotine effects varied with the task. Only performance on the Two-Letter Search revealed a possible negative impact of abstinence in smokers. This negative effect, however, was confounded by a potential loss of practice effect. Performance on the Two-Back and Three-Back, but not on the other tasks, was sensitive to previous exposure to nicotine, such that chronic smokers performed worst and never-smokers best. Performance on the Logical Reasoning was insensitive to either acute or chronic nicotine exposure. The cognitive processes and their respective neural networks underlying task performance influenced by nicotine need to be systematically investigated. 168 ASSOCIATION BETWEEN FAMILIAL AND SOCIAL SUPPORT NETWORKS AND CRIMINALITY IN SUBSTANCE ABUSERS

H. Eshelman, D. Festinger, D. Carise, A.T. McLellan, and H.D. Kleber, Treatment Research Institute at the University of Pennsylvania, Philadellphia, PA, and the National Center for Addiction and Substance Abuse at Columbia, New York, NY It has been argued that substance abuse treatment has historically been geared toward men, and subsequently, has failed to address certain issues specific to women and their corresponding treatment needs. We hypothesized that women with a history of sexual victimization would show: (1) increased utilization of acute care services, as seen by prior medical, psychiatric, and drug and alcohol treatments; (2) increased current use of alcohol and other drugs; and (3) increased current legal, employment, and family problems. We analyzed data from the Drug Evaluation Network System (DENS). Funded by ONDCP and CSAT, DENS is an ongoing, nationwide electronic system collecting standardized, clinical information on patients entering into treatment. Using the Addiction Severity Index, a sample of 2717 women presenting for admission between June 1996 and May 2000 were examined, from over 25 treatment programs in six cities and four treatment modalities. Baseline AS1 data were utilized to compare women who report a history of sexual victimization vs. those who do not. Results indicated that women with a history of sexual abuse reported a higher number of prior medi-

Abstracts

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cal, psychiatric, and drug and alcohol treatments. Furthermore, they reported more current use of alcohol and other drugs, with the exception of heroin. Finally, at the time of admission, women with a history of sexual victimization reported less income from recent employment, a higher prevalence of recent criminal activity, and a higher likelihood of serious problems getting along with family and others. 169

CLIENT

ACCESS TO IN-TREATMENT

E. Evans and Y. Hser, UCLA Center, Los Angeles, CA

SERVICES

Drug Abuse Research

This paper examines therapeutic services received by clients while they are in treatment. Our sample was comprised of clients (N = 511) recruited from 18 treatment programs randomly selected to represent four major modalities (outpatient drug-free, inpatient, residential, methadone maintenance) in Los Angeles County. To assess clients’ perceptions of their needs and access to services during treatment an expanded version of the Treatment Services Review (TSR) was used. Additionally, services during the past two months were abstracted from clients’ clinical records. Preliminary analyses based on the TSR indicated that services are commonly available to address alcohol and drug problems, but are relatively in short for those related to employment and support difficulties, medical troubles, basic survival skills, and especially psychological or emotional issues. For example, in the week prior to the interview, more than a quarter of the clients had experienced physical medical problems (27%) but less than half of that had received medication (lo%), saw a physician (12%) or had a significant discussion pertinent to their medical problems (13%). Only a small percentage saw a counselor about work opportunities or unemployment compensation (4% or less). Half of the respondents had recently experienced significant loneliness or boredom (50%) and a significant percentage had experienced emotional problems (42%) but few had seen a psychologist specialist (2% or less). Almost a quarter (23%) had received HIV education, most commonly in a group setting. Less than 10% had received help for abuse problems, obtaining public assistance or fulfilling basic needs. Additionally analyses on services data from the record abstraction should provide a description for a longer time period of what services were accessed by the clients. 170 THE EFFECTS OF REPEATED ADMINISTRATION DURING THE LUTEALPHASESOFTHEMENSTRUALCYCLE

SMOKED COCAINE FOLLICULAR AND

S.M. Evans, M. Haney, and R.W. Foltin, Columbia University and New York State Psychiatric Institute, New York, NY

Non-treatment seeking female cocaine smokers resided on a CRC during the follicular phase and again during the midluteal phase (when progesterone levels were high). The order of menstrual cycle phase was counterbalanced across women and the order of cocaine doses was randomized. During each phase, cocaine administration sessions occurred at 9 h and again at 13 h on 2 consecutive days, for a total of four sessions. During each session, participants could smoke up to six doses of cocaine (either 0, 6, 12.5 or 25 mg cocaine base depending on the session) at 14 min intervals. To date five African-American women have completed the protocol; all had normal ovulatory menstrual cycles ranging from 24 to 32 days. During the follicular phase, mean estradiol levels were 97 pg/ml and progesterone levels were 0.52 rig/ml, whereas during the midluteal phase mean estradiol levels were 145 pg/ml and progesterone levels were 8.6 rig/ml. Systolic pressure and heart rate, expressed as a change from baseline, were increased during the follicular phase following repeated doses of 12 and 25 mg cocaine. Correspondingly, ‘Good Drug Effect’ and ‘Bad Drug Effect’ clusters were increased during the follicular phase compared to the luteal phase. However, there were no differences in the number of cocaine doses administered or cocaine plasma levels between the two phases. These preliminary results indicate that there may be differences across the menstrual cycle in response to repeated doses of smoked cocaine. Supported by NIDA grant DA-08105 and NIH grant MOI-RR-00645 171 EXAMINATION OF PLACE PREFERENCE WITH ANDTESTINGIN RATS

MORPHINE REPEATED

CONDITIONAL DRUG PAIRING

M. Evola, S. Bowen, E. Clark, and A.M. Wayne State University, Detroit, MI

Young,

Conditional place preference (CPP) is a behavioral model that examines the association of environmental cues with reinforcing drug effects. In the usual CPP assay, a single preference test follows repeated pairings of distinct environments with drug or saline. Because substance abuse is a chronic condition, long-term preferences for a drug-paired environment should be examined. We therefore examined the stability of a CPP established by morphine (MS). Preference was tested in the traditional ‘drug-free’ state and in a novel test in the presence of MS. The stability of CPP was examined over six cycles of pairing and testing. A two chamber place preference apparatus was used in which distinctly different chambers were paired with either SAL or MS (5.6 mg/kg) S.C.All sessions were one hour in length. In control rats, both chambers were paired with SAL. When tested with SAL or MS (5.6 mg/kg), control rats

Abstracts

demonstrated no change in the amount of time they spent in either chamber over the six cycles of testing. When the MS paired group was tested with SAL or 1.8 mg/kg MS, there was an increase in the amount of time spent in the MS paired chamber, which persisted as the hour progressed. However, when the MS paired rats were tested in the presence of 5.6 mg/kg MS there was no increase in the amount of time spent in the drugpaired chamber. In all test conditions, preferences progressively changed over six cycles of place conditioning. Therefore, although associations made between environmental cues and reinforcing drug stimuli produce a preference for the drug-paired environment these associations may change with repeated exposure to the CPP procedure. Supported by DA03796, K02 DA 00132, and GM08167 from NIH. 172

PATTERNS

HOMELESS

OF

SERVICE

USE

IN

A DRUG-ABUSING

POPULATION

K.M. Eyrich, C.S. North, and D.E. Pollio, Washington University, George Warren Brown School of Social Work and School of Medicine, St. Louis, MO While the prevalence of drug abuse in the homeless population is substantial, little is known about the patterns of service utilization and the types of services used (drug abuse, housing, or substitute services), or about the interrelationships between homelessness and drug abuse in the use of these services. To address these knowledge gaps, a current NIDA-funded study in St. Louis, MO was designed to examine these relationships among 300 drug abusing and 100 nonabusing homeless individuals randomly selected from a variety of public settings (shelters, day centers, homeless rehab programs, and streets) and tracked longitudinally. Structured psychiatric interview data, systematic drug and homelessness histories, and urine drug testing were obtained by interview. Approximately 50% of subjects with active drug abuse had received treatment for it in the last year. Service utilization patterns were tracked across the community through local agency databases. Early results suggest that relationships of predisposing (sociodemographic) and enabling characteristics, need for drug abuse services, and utilization of treatment are uniquely different among homeless drug abusers compared to other homeless populations and to other nondrug abusing homeless populations. 173

MDMA

A DOSE-FINDING

REPEATED PILOT

ADMINISTRATION

IN HUMANS:

STUDY

M. Farm, P.N. Roset, A. Tomillero, C. HernandezLopez, S. Poudevida, R. de la Torre, J. Ortuiio, and J. Cami, Institut Municipal d’Investigacio Medica, Uni-

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versitat Autbnoma de Barcelona and Universitat peu Fabra, Barcelona, Spain

Pom-

MDMA (3,4-methylenedioxymethamphetamine) is frequently consumed more than one dose along a party session (‘rave’). In humans, repeated administration of other stimulants as cocaine, amphetamine or nicotine, have evidenced the appearance of acute tolerance to physiologic and subjective effects. This pilot study was designed to select the MDMA doses to be used in future repeated administration studies in humans. Six healthy male recreational users of MDMA participated in four experimental sessions. The study was doubleblind, double-dummy and randomised. Drugs were administered twice during each session with a between-dose interval of 4 h. Drug conditions were: MDMA plus placebo (MDMA first administration), placebo plus MDMA (MDMA second administration), MDMA plus MDMA (MDMA repeated administration), and placebo plus placebo (placebo). Two doses of MDMA were assayed (75 and 100 mg, lower doses were allocated before higher ones for safety reasons). Study variables included vital signs, ECG, psychomotor performance, endocrine and subjective effects, and pharmacokinetics. The effects of MDMA after single administration (first administration and second administration) were similar, and in agreement with previous studies. Plasma concentrations after the second dose in the repeated administration were higher than the double-fold expected increase considering a superposition of concentrations. The effects of the repeated administration on physiologic and subjective variables were only slightly higher, in spite of the above mentioned double-fold increase in MDMA concentrations. It seems that tolerance developed for most physiologic measures and selected subjective feelings, except for oral temperature, Maddox-wing scores and psychomotor performance tasks. The highest dose level assayed (100 mg + 100 mg) was well tolerated in all safety measures and selected for the future definitive trial. Supported by grants: FIS 9810181, CIRIT 1999SGR00246, and PNSD. 174

A

PLACEBO ING

CROSS-OVER IN

TRIAL

OPIOID-DEPENDENT

SELF-REPORTS

OF SUBSTANCE

OF

DESIPRAMINE

COCAINE ABUSE

VS.

ABUSERS

US-

AS OUTCOMES

A. Feingold, A. Oliveto, R. Schottenfeld, Kosten, Yale University, New Haven, CT

and T.R.

We conducted a randomized, double-blind, 26-week clinical cross-over trial to test the hypothesis that 109 opioid-dependent cocaine abusers would show a greater decrease in illicit substance use during weeks they were maintained on desipramine than during the weeks they were maintained on a placebo. Accordingly, half of the

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Abstructs

sample was randomly assigned to receive desipramine for the first half of the trial, and placebo for the remainder of the trial, whereas the other half of the sample had been randomly assigned to receive placebo for the first half and desipramine for the second half. Hierarchical linear modeling (HLM) found that the hypothesis was generally supported when substance use was measured by self-reports, with significance levels varying depending on which self-reports were used. These findings confirmed earlier results from the crossover trial that had found that desipramine was more effective than placebo at reducing substance use when substance use was measured by urinalysis. The implication is that self-reports of substance use may have some validity and should be considered when collections of biological measures of substance use are not available. 175 SYNERGISTIC EFFECTS OF MORPHINE AND LIPOPOLYSACCHARIDE ENDOTOXIN ON THE PERMEABILITY OF INULIN ACROSS A MICROVASCULAR ENDOTHELIAL CELL BARRIER IN VITRO

B.A. Felix, J. Anday, S.D. House, and S.L. Chang, Seton Hall University, South Orange, NJ In a previous study we reported that morphine decreases cell viability and potentiates the endotoxic effects of LPS on cell viability of microvascular endothelial cells (MVEC) in vitro. A parallel study investigated morphine’s ability to increase the permeability across MVEC barriers in vitro to small macromolecules, such as 14C-inulin, dose dependently (Chang et. al., 2000). In this study, we further investigate morphine and LPS’s synergistic effects as it relates to the permeability across MVEC barriers, specifically human coronary artery endothelial cells (hCAEC), and their effects on cell viability. LPS was shown to increase inulin permeability across a MVEC barrier as assayed by 14C-inulin radioisotope counting using an in vitro microvascular barrier model (Fiala et al., 1998). This effect was also potentiated by morphine dose-dependently. Our data is consistent with previous findings that the endotoxic actions of LPS are mediated via apoptotic pathways, and this phenomenon was potentiated by morphine, dose dependently; as determined by cell counting, flow cytometry and DAPI nuclear staining. The mechanisms underlying morphine potentiation of LPS-induced apoptosis and increased permeability are not yet understood. Also, we have observed LPS to change the morphology endothelial cells at 12 and 24 h exposure thus possibly altering tight-junction integrity. Taken together, the data suggests bacterial endotoxins, such as LPS, may enhance how small pathogenic viruses, such as HIV-l, penetrate host MVEC barriers, and this effect potentiated in hosts abusing opioid drugs, such as morphine.

Supported by NIDA

07058.

176 PROBLEMSEVERITYANDTREATMENTOUTCOMES OFSUBSTANCE-ABUSING FEMALE OFFENDERS

D.S. Festinger, J.C. Merrill, D.B. Marlowe, A.V. Harrell, P. Lee, J. McNellis, and A.T. McLellan, Treatment Research Institute at the University of Pennsylvania, Philadelphia, PA, and The Urban Institute, Washington, DC At arrest, female offenders have been shown to have more overall psychosocial problems than their male counterparts. This may be due to gender bias, different intervention opportunities, physiological differences, etc. In addition, there is evidence to suggest that available substance abuse and correctional interventions are often poorly tailored to the special needs of females. To investigate these issues, we examined individuals recruited for the Birmingham Breaking the Cycle (BTC) Project. Funded by the National Institute of Justice, this project examines the effectiveness of diverting substance abusing offenders from prosecution to case management and monitoring. The study first recruited a non-treatment (NT) group (n = 137) followed by a BTC-treatment group (n = 245). Participants had to be 18 or older, be convicted of a felony, and present with urinalysis confirmed substance use. Subjects were recruited after booking and administered the Addiction Severity Index (ASI) at baseline and 9-month followup. The current study examined between gender AS1 differences across both the BTC and non-treatment groups, at baseline and follow-up. Results indicated that across both the BTC and NT groups, females (n = 80) presented with significantly more severe baseline problems in medical, drug and psychiatric domains than males (n = 302). Controlling for baseline differences, a two-way ANOVA indicated that females in both groups had significantly more severe medical and psychiatric problems at follow-up, while males had significantly more severe employment problems. There were no significant main effects for group or group x gender. Findings point to the differential needs of males and female substance abusers entering the criminal justice system, and the questionable effectiveness of current correctional treatments. 177 METHADONE MEDICAL MAINTENANCE: FROM THE CONNECTICUT PILOT

RESULTS

D.A. Fiellin, P.G. O’Connor, M. Chawarski, J.P. Pakes, M.P. Pantalon, C. Latka, and R.S. Schottenfeld, Yale University School of Medicine, New Haven, CT Medical maintenance (MM), using physician’s offices for coordination of methadone services, is an alterna-

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Abstracts

tive to narcotic treatment programs (NTP) for stable opioid dependent patients. The current pilot seeks to determine the feasibility and efficacy of MM compared to NTP for stable patients on methadone maintenance. We enrolled methadone maintained patients in a 6month randomized clinical trial of MM vs. NTP. Eligibility criteria included NTP treatment for more than 1 year without evidence of illicit substance use, no acute medical or psychiatric disorders, stable income, and no plan for detoxification. Outcome measures include rates and reasons for non-participation, relapse to illicit drug use, as assessed by self-report, urine and hair toxicology testing, and patient and provider satisfaction. Of the 87 patients who met the eligibility criteria, 41 declined participation and 46 were randomized to receive methadone at the NTP (n = 24) or a physician’s office (n = 22). The primary reasons for non-participation were: conflict with work schedule 19/41 (46%), perceived inconvenience 4141 (lo%), lack of interest in medical maintenance 2/41 (5%) or unknown 15/41 (36%). One patient refused to participate after being randomized to the NTP arm. The subject’s mean age was 42 (26-56) and the majority were male, 30/46 (65%), white, 36/46 (78%), and employed, 34/46 (70%). The mean duration of methadone maintenance was 7.5 years (l-27), the former primary drug of abuse was intravenous heroin in 33/46 (72%), and 42/46 (91%) had previously attempted detoxification. We will present the main findings from the trial, which will be completed in March 2000, and discuss the implications of the refusal rate and of the observed rates of illicit drug use for medical maintenance program design and implementation. 178 NUCLEUS THE

THE

INFLUENCE ACCUMBENS

DISCRIMINATIVE

s-HTzC

OF AND

RECEPTORS

PREFRONTAL

STIMULUS

IN

CORTEX PROPERTIES

D/V = - 4 mm). After recovery and retraining, the 5-HT2C agonist MK 212 or RO 60-0175 was microinfused (0.2 ul/side) into the NAc shell or PFC immediately prior to an injection (IP) of saline or cocaine; test sessions started 15 min later. Given in combination with saline, intra-NAc MK 212 (0.1 ug total) or RO 60-0175 (1 ug total) elicited 37% and 48% drug-lever responding, respectively, but MK 212 (O.l- 1 ug total) induced no effects in the PFC. Combined intra-NAc shell injections of 5-HT2C agonists with submaximal doses of cocaine (0.625-2.5 mg/kg) produced a significant enhancement (to 73375% drug-lever responding) of the discriminability of cocaine. Contrary, intra-PFC MK 212 (0.1-I ug total) slightly shifted to the right the dose-response curve of cocaine. Intra-NAc shell infusion (0.2 m/side) of the selective 5-HT2C antagonist RS 102221 (0.1-3 ug total) did not substitute for the training drug but did dose-dependently attenuate the cocaine discrimination. Intra-PFC RS 102221 (10 ug total) produced 40% drug-lever responding and a leftward shift of the dose-response curve for cocaine. These results support a site-specific role for mesocorticolimbic 5-HT2C receptors in the stimulus effects of cocaine. Supported by II Fund M. Sklodowska-Curie (98-328) DA 06511 and DA 00280. 179

ALCOHOL

MECHANISMS SOCIAL TENTIONAL

SUPPRESSES IN

DRINKERS:

ATTENTION-BASED A

TEMPORARY

COGNITIVE

INHIBITORY

PERFORMANCE DRUG-INDUCED

OF AT-

DEFICIT?

M.T. Fillmore and CR. Rush, University of Kentucky, Lexington, KY

THE ON OF

COCAINE

M. Filip and K.A. Cunningham, Institute of Pharmacology PAS, Krakow, Poland, and University Texas Medical Branch, Galveston, TX Mesocorticolimbic dopamine pathways play a critical role in the behavioral effects of cocaine in rats. We have found that serotonin (5-HT)2C receptors in the shell of the nucleus accumbens (NAc) or prefrontal cortex (PFC) modulate cocaine-induced hyperactivity and that the directional effect of this modulation was site-dependent. To test the hypothesis that 5-HT2C receptors in the NAc shell and PFC may also regulate the discriminative effects of cocaine, male SpragueDawley rats (300-320 g) trained to discriminate between cocaine (10 mg/kg, IP) and saline (1 ml/kg, IP) were implanted with bilateral cannulae (in relation to bregma) into the NAc shell (A/P = 1.4, M/L = + 0.75, D/V= -8 mm) or PFC (A/P=2.7, M/L= f0.75,

Alcohol abuse is seen as part of a general disinhibitory psychopathology that has some commonalities with other disorders of self-control, such as Attention Deficit Hyperactivity Disorder (ADHD). In particular, problem drinkers display deficits in attention which may reflect an impaired ability to inhibit or ‘gate’ the processing of irrelevant (i.e. distracting) information. The present research tested the hypothesis that acute administration of alcohol can reduce a drinker’s ability to inhibit the intrusive effects of distracting information, and thereby produce a temporary deficit in attention. The study used a negative priming paradigm to measure basic inhibitory processes of selective attention. The paradigm required subjects to perform a reactiontime color-naming task to identity target stimuli while ignoring distracting stimuli. Twenty-eight social drinkers performed a baseline test on the task. After baseline testing they received either 0.56 g/kg of alcohol, or a placebo, and then performed the task twice. Reaction times under alcohol and placebo were analyzed by variance analyses. In accord with the hypotheses, alcohol significantly impaired the ability to inhibit

S64

Abstracts

the intrusive effects of distracting stimuli during the ascending limb, but not during the descending limb of the blood alcohol curve. No changes in the ability to inhibit distracting information were observed in response to placebo. The suppression of this process by alcohol may represent a basic mechanism by which the drug reduces the ability to efficiently allocate attention, and this acute drug-effect may exacerbate preexisting attentional deficits in individuals, such as adults with residual ADHD. 180 DROME

MANAGEMENT OF NEONATAL ABSTINENCE SYNIN NEWBORNS OF OPIOID-MAINTAINED WOMEN

G. Fischer, A. Peternell, H. Eder, K. Rohrmeister, A. Topitz, and D. Kraigher, University Hospital of Vienna, Austria Aims: To assess incidence, timing and frequency of persistence of neonatal abstinence syndrome (NAS) in neonates who were born to mothers maintained on oral opioids during pregnancy without concomitant abuse at delivery under the consideration of two different psychopharmacological treatment approaches in NAS (morphine hydrochloride versus phenobarbiturates). Participants: Fifty-three neonates born to opioid maintained mothers during pregnancy (22 women on methadone, 17 women on slow-release morphine and 14 women on buprenorphine maintenance) were studied. Concomitant substance abuse during pregnancy could be excluded through urine toxicology. Results: Sixty percent (n = 32) required treatment for NAS. The mean duration from birth to initiation of treatment was 33 h for slow-release morphine, 34 h for buprenorphine and 57 h for methadone. Neonates treated with oral morphine had a significantly shorter mean treatment duration of NAS (9.9 days) in comparison to the treatment with phenobarbiturates (17.7 days). Conclusion: Progress in treatment for the opioid dependent women as well as standardized treatment for NAS are beneficial for women/fetus/neonates. 181 METHAMPHETAMINE-INDUCED DECREASES IN DOPAMINE AND SEROTONIN TRANSPORTER FUNCTION: COMPARISONOFEXVIVOANDINVITROMODELS

A.E. Fleckenstein, H.M. Haughey, R.R. Metzger, Y.V. Ugarte and G.R. Hanson, University of Utah, Salt Lake City. UT A single injection of methamphetamine (METH) causes a rapid and reversible decrease in dopamine transporter (DAT) activity as assessed ex vivo in synaptosomes prepared from METH-treated rats; a phenomenon as-

sociated with a decrease in transporter I’,,, and no change in Km. This transient decrement is not due to residual METH introduced by the original drug treatment, nor is it associated with a change in binding of the DAT ligand, WIN35428. Similarly, METH treatment causes a rapid and transient decrease in serotonin (5-hydroxytryptamine; 5HT) transporter (SERT) activity. Because we believe that these transient decreases represent regulatory phenomena meriting additional investigation, the purpose of this study was to attempt to model these effects in an in vitro preparation. It was determined that, as observed ex vivo, exposure of synaptosomes prepared from non-treated rats to METH caused a rapid decrease in DAT and SERT activity that persisted even after ‘washing’ METH from the synaptosomal preparations. The decrease in DAT activity was not associated with a change in WIN35428 binding. The characteristics and selectivity of these phenomena, as well as their implications regarding rapid regulation of transporter function, will be discussed. Supported by USPHS grants DA00869, DA00378, DA1 1389 and DA04222. 182 SUBJECTIVE AND CARDIOVASCULAR EFFECTS OF INCREMENTAL AND CONSTANT DOSES OF SMOKED COCAINEINHUMANS

R.W. Foltin, A.S. Ward, M. Haney, and M.W. Fischman, New York State Psychiatric Institute and College of Physicians and Surgeons, New York, NY The purpose of this study was to examine the subjective and cardiovascular effects of the administration of incremental cocaine doses. Experienced heavy users of smoked cocaine participated in two laboratory sessions per day for 3 consecutive days. During each session, 1 group of participants (n = 8) smoked consecutively l12 mg dose, l-25 mg dose and 4-50 mg doses of cocaine base at 14-min intervals, while a second group of participants (n = 10) smoked 6-50 mg doses of cocaine base at 14-min intervals. Maximal ratings of ‘Good drug effect,’ ‘High,’ and ‘Stimulated’ were about 40% greater in the group receiving all 50 mg doses compared to the group receiving incremental doses. The group receiving all 50 mg doses also reported greater dose ‘Liking,’ and larger estimates of dose value during the afternoon, but not morning sessions. By contrast, maximal increases in cardiovascular activity were similar in the two groups. Thus, the administration of smaller cocaine doses before larger doses leads to greater acute tolerance, with tolerance developing more rapidly to the subjective than the cardiovascular effects of cocaine within a session.

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Abstracts

183 THE MODERATING EFFECT OF ALEXITHYMIA COGNITIVE-BEHAVIORALSUBSTANCEABUSETREATMENT

ON

C. Fong, A. Rosenblum, and S. Magura, National Development and Research Institutes, Inc., New York, NY Past research has suggested that substance users with cognitive-affective impairment may be poor candidates for cognitive-behavioral therapy (CBT). This study examines the impact of alexithymia (ALX) (an inability to identify and express one’s emotions) on treatment outcome. Methodology: Current cocaine-dependent methadone patients were randomly assigned, in a non-balanced design, to six months of high-intensity CBT (5 x week individual and group) [N = 441 or low intensity therapy (1 x week group) [N = 181. All regular methadone clinic services were provided. Subjects were 66% male; 45% Hispanic, 44% African-American, mean age = 38; mean methadone dosage = 70 mg. The Toronto Alexithymia Scale and a psychological distress measure, the Brief Symptom Inventory (BSI) were administered at baseline. ANOVA was conducted with patients coded for the presence of ALX and therapy condition as independent variables and the proportion of positive cocaine-urines during the first 12-week post-therapy period (weeks 25-36) as the dependent variable. Baseline cocaine (proportion of positive cocaine-urines for the 12 weeks prior to starting treatment) and the global score of the BSI were entered as covariates. Results: 55% of the subjects scored within the ALX range. BSI and ALX were correlated (Y = 0.36, P = 0.005). At follow-up ALX subjects compared with non-ALX subjects had a higher proportion of cocaine positive urines (0.70 vs. 0.53, P < 0.05). The ALX by CBT interaction showed that non-ALX subjects receiving CBT had the least amount of cocaine use at follow-up (0.44) compared with ALX CBT subjects (0.72) and ALX and non-ALX subjects receiving low intensity therapy (0.66 and 0.69, respectively); (P < 0.05). Similar results were obtained when BSI was not entered as a covariate. Conclusion: Alexithymia, even when controlling for its modest association with psychological distress, appears to have a negative effect on the efficacy of CBT for substance-abusing patients. The inclusion of alexithymia in patient-treatment matching studies and specific treatments for alexithymic substance abusers should be considered. Supported by NIDA Grant No ROl DA06959. 184

CANYOUEVERGETENOUGHTREATMENT?

K.H. Fortuin, C.F. Kwiatkowski, J.T. Brewster, E.P. Ennis, T.J. Crowley, and R.E. Booth, University of Colorado, Denver, CO Studies show that increased length of methadone maintenance treatment leads to better ontcomes, including

reduced heroin use. We recruited active heroin injectors through street outreach to participate in a study designed to increase entry and retention in drug treatment. Incentives to enter treatment were provided and 168 participants (44%) entered methadone maintenance. A logistic regression analysis was run to determine what variables were associated with having a negative urinalysis test for morphine at the 6-month follow-up interview. The number of days subjects were in treatment was not significantly associated with urinalysis results. Other than baseline heroin use (heavier users were less likely to have a negative UA), current participation in treatment was the only significant variable: 50% of those who were in treatment at their 6 month interview had a negative UA while only 25% of those who dropped out of treatment had a negative UA. Implications of these findings will be presented. 185 COMPARISON OF THE BEHAVIORAL fl-CCTANDFLUMAZENILINRHESUSMONKEYS

EFFECTS OF

C.P. France, L.R. Gerak, C. Ma, and J.M. Cook, University of Wisconsin-Milwaukee, WI The functional significance of benzodiazepine (BZ) receptor subtypes remains to be established. This study compared the purported BZl receptor selective antagonist p-CCt to flumazenil using drug discrimination in monkeys. The positive GABA-A modulator triazolam and the purported BZl receptor selective positive modulator zolpidem substituted for midazolam in four monkeys discriminating 0.56 mg/kg of midazolam. Like flumazenil, p-CCt antagonized the discriminative stimulus effects of midazolam and triazolam in a dose-related manner; however, p-CCt was 30-100 fold less potent than flumazenil with a dose of 5.6 mg/kg of beta-CCt shifting the midazolam dose-effect curve lo-fold rightward. Beta-CCt also antagonized the discriminative stimulus effects of zolpidem in a manner that was not different from its antagonism of other positive modulators. Unlike flumazenil, Schild analyses for a-CCt yielded slopes that did not conform to unity, thereby precluding calculation of affinity estimates for the latter. In a separate group of four monkeys treated with 5.6 mg/kg/ day of diazepam, p-CCt (ED50 = 5.3 + 1.8 mg/kg) substituted for the flumazenil (ED50 = 0.03 + 0.01 mg/kg) discriminative stimulus. This effect of a-CCt had a slow onset ( > 60 min), which could have influenced dose-effect analyses in other studies. p-CCt has effects that are qualitatively similar to flumazenil; however, antagonism of positive modulators by p-CCt does not appear to be consistent with a simple, competitive interaction at a single receptor subtype. These results suggest that apparent differences between flumazenil and p-CCt could result from pharmacokinetic, and not pharmacodynamic, factors. USPHS Grant DA091 57.

S66

Abstracts

186

EFFECTS

206553

ON

OF

LSD-INDUCED

THE 5-HTzBpC

SB

ANTAGONIST

HYPOACTIVITY

P.S. Frankel and K.A. Cunningham, Texas Medical Branch, Galveston, TX

University

of

Psychopharmacological analyses suggest that 5-HT2A receptors mediate the behavioral effects of D-lysergic acid diethylamide (LSD). Because this hypothesis is based upon studies with relatively non-selective 5HT2A/2C receptor antagonists, we have begun to analyze the relative contributions of the 5-HT2A vs. 5-HT2C receptors in the behavioral effects of LSD utilizing the most selective compounds available. In the present study, we assessed the ability of the 5-HT2B/2C antagonist SB 206553 (I. 2 or 4 mg/kg, ip) to alter basal activity and/or block the hypomotility evoked by LSD in nai’ve rats unhabituated to modified open field test chambers (N = 8/group). As previously reported, LSD (0.08,O. 16 mg/kg, ip) dose-dependently suppressed activity in the peripheral and central portions of the monitor and depressed vertical activity during the initial 30 min after drug administration. SB 206553 dosedependently suppressed peripheral, central and rearing activity during this same time period. The inhibition of activity evoked by LSD (0.16 mg/kg) was further suppressed by pretreatment with SB 206553 in a dose-related manner, with the duration of effect extending for 60 min. These data suggest that tonic activation of 5-HT2C receptors contributes to the generation of spontaneous activity. Furthermore, although stimulation of 5-HT2C receptors is associated with the production of hypomotility in a novel environment (Lucki et al., JPET 249: 155, 1989), the present data suggest that the manner in which LSD evokes hypomotility is not simply a consequence of agonist actions at the 5-HT2C receptor. The interesting potentiation evoked by SB 206553 will be further analyzed in both locomotor and drug discrimination analyses. Supported by NIDA DA07287, DA 0651 I, and DA 00260. 187 CAINE

IMPACT CHALLENGE’

OF

GABAERGICS

IN

A NOVEL

‘CUE

+ co-

PARADIGM

T. Franklin, K. Kampman, R. Ehrman, C. O’Brien, and A.R. Childress, Addiction Treatment Research Center, University of Pennsylvania and Philadelphia VAMC, Philadelphia, PA GABAergics interfere with cocaine-motivated behavior in several preclinical paradigms (cocaine self-administration, cocaine’s threshold-lowering effects on brain self stimulation reward, cocaine conditioned place preference, and cocaine-seeking). Moreover, baclofen, a GABA B agonist, may simultaneously reduce the desire

for cocaine and reduce CNS activation measured by PET in brain regions activated by cocaine-related cues, suggesting that GABAergics could be helpful in treating cocaine dependence. However, the effects of GABAergics on cocaine’s direct (e.g. euphorigenic; priming) and cue-conditioned (craving and arousal) effects have not yet been systematically studied in humans. In a unique “cue + cocaine challenge” paradigm, 3 groups of randomly-assigned cocaine inpatients will be challenged with cocaine cues + cocaine (30 mg) prior to, and following, 3 days of intervening double-blind treatment with baclofen (10 or 20 mg, b.i.d) or placebo. This single paradigm efficiently measures: (1) cue reactivity in the context of actually expecting cocaine (similar to street-life conditions); (2) the medication’s safety when taken in conjunction with cocaine (a clinical reality); and (3) the medication’s impact on cocaine’s direct and cue-related effects. Though the data presented will describe baclofen’s effects in the novel paradigm, it will be used as the new standard in our ongoing medications-development research. It offers efficacy information that may predict outpatient effectiveness, but with minimal additional cost to a standard Phase 1 ‘safety-only’ trial. Preliminary results suggest that baclofen may blunt responses to cocaine and cues for cocaine demonstrating the importance of testing this medication as a treatment for cocaine dependence. NIDA ROI-DA-12162. 188 RISK SEXUAL

THE

IMPACT

BEHAVIORS MEN

OF METHAMPHETAMINE IN

AND

HOMOSEXUAL

USE MEN

AND

ON

HIV

HETERO-

WOMEN

T.E. Freese, C.J. Reback, A. Huber, S. Shoptaw, J. Peck, Friends Research Institute, Inc., Van Ness Recovery House, Matrix, Los Angeles, CA A growing body of work suggests that stimulant use increases sexual HIV-related risk behaviors in heterosexual males and females, and among gay and bisexual men. In evaluating sexual HIV-related risk behaviors, it may be important to distinguish between behaviors committed under the influence of methamphetamine and those committed during periods of abstinence. The objective of this study is to compare differences in risk behaviors among homosexual men (n = 98) in treatment in Hollywood, California, and heterosexual men (n = 57) and women (n = 39) in treatment in Ranch0 Cucamonga, California. Results indicated that gay and bisexual men reported a significantly higher rates of HIV-risk behaviors, such as unprotected anal receptive intercourse (UAR), when under the influence of methamphetamine when compared to behaviors during periods of abstinence (MUAR + meth = 3.30, MUAR + abstinent = 0.59, P < 0.001). No significant association in rates of HIV-related sexual risk behav-

Abstracts

iors and methamphetamine intoxication was reported by heterosexual men or women. These findings suggest that drug related sexual risks are exaggerated for gay and bisexual men (a group known to have high prevalence of HIV-infection). The association between drug use and high risk sex appears to differ across distinct methamphetamine using groups. This work supported by NIDA grants # 1 ROl DA11031 and # 1 ROl DA10923. 189 DIFFERENCES IN VICTIMIZATION EXPERIENCES FOR HOMELESS WOMEN AND MEN IN A COCAINE DEPENDENCE TREATMENT PROGRAM: IMPLICATIONS FOR TREATMENTOUTCOMES

S. Frison, J. Milby, S. Usdan, C. McNamara, and J. Schumacher, University of Alabama at Birmingham, Birmingham, AL Previous research has shown a high prevalence of trauma and victimization experiences for the homeless and discordant findings about the role of victimization in recovery. In a 2 group, randomized controlled study of abstinence contingent conditions and behavioral day treatment for cocaine use disorders, this study explores victimization histories for homeless women and men and possible implications for drug treatment recovery outcomes (Total N = 141, 28% women). More men reported having been a victim of robbery (66% vs. 44%, P = 0.02), while more women reported rape (46% vs. 4%, P < O.OOl), physical abuse (64% vs. 27%, P < 0.001) and sexual abuse (28% vs. 7%, P < 0.001). There were no gender differences in reported criminal assaults and emotional abuse. Women did report almost twice as many incidents in combination of robbery, assault and rape (X women = 6.30, SD = 10.6 vs. X= 3.3, SD = 5.03) and being a victim of physical, emotional and/or sexual abuse (X women= 1.72, SD=0.83 vs. X= 1.04, SD = 1.08). Mann Whitney test statistics reveal that being a reported victim of robbery at baseline assessment was related to higher levels of drug use, alcohol use, and family problems at 2 months and psychological problems at 6 months; assault reports at baseline were related to higher levels of employment, family, legal, and psychological problems at 6 months; reports of emotional childhood abuse at baseline were related to alcohol use, family problems, and psychological problems at 2 months and family problems at 6 months. These findings have implications for design and implementation of treatment programs and areas that need to be better addressed (such as family and legal interventions) for homeless substance abusers, particularly women, who have long been recognized as experiencing higher rates of victimization.

5x3

Supported by NIDA

grant ROl DA08475.

190 COMMON GENETIC AND ENVIRONMENTAL VULNERABILITY TO SUICIDALITY AND DRUG DEPENDENCE

Q. Fu, A.C. Heath, K.K. Bucholz, J. Goldberg, M.J. Lyons, S.A. Eisen, W.R. True, T. Jacob, and M.T. Tsuang, Washington Univ. Schl of Med., St. Louis, Univ. of Illinois Schl of Pub. Health, Chicago, IL, Harvard Med. Schl, Southborough, MA, and St. Louis Univ. Schl of Pub. Hlth, St. Louis, MO Current literature has suggested that drug dependence is a risk factor for suicidality (suicidal ideation and attempts). Both conditions are also heritable. However, little is known about the mechanism underlying the relationship between drug dependence and suicidality. We examined whether DSM-III-R drug dependence and suicidality share common genetic and environmental vulnerablity. Data from 3361 middle aged male-male monozygotic and (MZ) and dizygotic (DZ) twin pairs from the Vietnam Era Twin (VET) Registry who participated in a telephone administration of the Diagnostic Interview Schedule Version 3 Revised in 1992 were analyzed. Lifetime persistent suicidal thoughts or suicide attempts were reported by 18% of the sample; 9.5% of the sample met DSM-IIIR criteria for drug dependence (primarily marijuana dependence). Polychoric correlations suggested familial effects on both drug dependence (rMZ = 0.61; rDZ = 0.45) and suicidality (rMZ = 0.47; rDZ = 0.24). Structural equation modeling was performed to estimate the additive, shared environmental and unique environmental contributions common and specific to drug dependence and suicidality simultaneously. A chi-square test of goodness-of-fit was used to assess overall fit of the model. The results showed that the additive, shared environmental and unique environmental influences accounted for 30,31, and 39% of the variance in risk for drug dependence and 46,1, and 53% for suicidality. The additive, shared environmental and unique environmental correlations between drug dependence and suicidality were 0.62, 1, and 0.34, respectively. Thus, 18 and 6% of genetic and unique environmental variations in risk for suicidality shared with the genetic and unique environmental risk for drug dependence, respectively. Our data suggest that there is a common genetic and environmental vulnerability to drug dependence and suicidality in adult men. This common risk may partially explain the association observed between these two conditions. Supported by: AA07728, AA10339, AA1 1667, AA11822, AA11998, DA04604, MH37685, MH31302.

Abstracts

S68

191

SCOPOLAMINE

FORCING

EFFECT

POTENTIATES IN RHESUS

MORPHINES

REIN-

MONKEY

Z. Fuqiang, Z. Wenhua, W. Zhaolin, and Y. Guodong, Ningbo Addiction Research and Treatment Center, Ningbo, China Rhesus monkeys are trained to press lever for intravenous morphine self-administration under a FRlO schedule using both upper and lower dose-effect curve, on a daily 4 h session. In monkeys trained for high dose morphine injection (0.25 mg/kg/injection), 5 min pre-session treatment of scopolamine decreases total response rate at doses of (0.015,0.03,0.06,0.12 mg/kg). In monkeys trained for low dose morphine injection (0.05 mg/kg/injection), low dose scopolamine (0.015,0.03 mg/ kg) treatment increases total response, in contrast, naloxone treatment (0.08 mg/kg) suppresses total response rate. Seven days after extinction of morphine self-administration when reinforcement schedules are changed to extinction during which morphine is substituted with saline, scopolamine treatment (0.25 mg/kg) reverses the extinction. These results suggest that scopolamine could potentiate morphine’s reinforcing effect, or scopolamine alone have reinforcing effect, this is consistent with reports that scopolamine could be self-administered by rate. But for the reversal of extinction, scopolamine induced memory impairment also played an important role. 192

LAAM

TOLERANCE OF II OPIOID

INDUCES TO THE

EFFICACY-DEPENDENT

DISCRIMINATIVE

STIMULUS

CROSSEFFECTS

AGONISTS

R. Galici and C.P. France, Louisiana State University Health Sciences Center, New Orleans, LA LAAM is currently administered to opioid dependent individuals; however, the relative importance of crosstolerance to the therapeutic success of LAAM is not fully understood. The goal of this study was to evaluate whether the repeated administration of LAAM produces cross-tolerance to the discriminative stimulus effects of mu opioid agonists. Six pigeons were trained to discriminate 0.32 mg/kg of heroin from saline under a fixed-ratio 20 schedule of food presentation. Heroin, buprenorphine and nalbuphine occasioned > 80% drug-appropriate responding and the order of potency (ED50 f SEM) was buprenorphine (0.06 f 0.03) > heroin (0.14 + 0.03) = nalbuphine (0.17 + 0.11); cocaine did not occasion drugappropriate responding. A dose of 3.2 mg/kg of LAAM was administered (i.m.) once daily for 3 or 7 consecutive days; on separate occasions dose-effect curves were re-determined for heroin, buprenorphine, nalbuphine and cocaine after LAAM treatment. The nalbuphine dose-effect curve was shifted to the right of the control

dose-effect curve after 3 (ED50 = 3.02 + 1.12, P < 0.05) or 7 (ED50 = 10.54 f 4.92, P < 0.05) days of LAAM treatment and returned to control in a time-dependent manner within 7 days. Similarly, the buprenorphine dose-effect curve was shifted to the right of the control dose-effect curve after daily LAAM treatment. However, under conditions where the nalbuphine and buprenorphine dose-effect curves were shifted up to 60-fold rightward, there was no change in the sensitivity of pigeons to the discriminative stimulus effects of heroin. In conclusion, the repeated administration of LAAM produces cross tolerance to mu opioid agonists with the magnitude of cross-tolerance being inversely related to efficacy. These results suggest that the subjective effects of high efficacy agonists (e.g. heroin) might not be significantly altered by a therapeutic regimen of LAAM. Supported by USPHS Grant DA 05018. 193 TASK:

REPEATED DRUG

ACQUISITION EFFECTS

IN ON

THE

MORRIS

LEARNING

SWIM VERSUS

PERFORMANCE

M. Galizio, J.R. Keith, and R. Pitts, University of North Carolina at Wilmington, Wilmington, NC The present studies used an adaptation of the repeated acquisition/performance procedure to the Morris swim task. Rats were trained to swim to a hidden platform that was always in the same location in the presence of one set of extra-pool cues (performance), and in a new location each session in the presence of a second set of extra-pool cues (acquisition). Direct comparison of acquisition and performance of place responses in individual subjects within single sessions is permitted by this procedure, and dose-response functions were determined for individual rats for morphine (0.3320 mg/kg), pentobarbital (l-30 mg/kg), and dizocilpine (0.01-0.3 mg/kg). Each dose was determined on 2-4 separate occasions, and 5- 8 rats were studied with each drug. Morphine (but not dizocilpine or pentobarbital) selectively impaired acquisition. That is, some doses of morphine (3-5.6 mg/kg) produced statistically significant impairments (longer latencies and less direct swim paths to the platform) in the acquisition, but not in the performance, component. In contrast, dizocilpine and pentobarbital impaired acquisition only at doses that also produced comparable impairments in the performance component. These results suggest that the repeated acquisition procedure can be successfully adapted to the Morris Swim Task. 194 TOXIC

CHLORMETHIAZOLE: EFFECTS OF COCAINE

EFFECTIVENESS IN MICE

AGAINST

M. Gasior, J.T. Ungard, J.M. Witkin, NIDA Intramural Research Program, NIH, Baltimore, MD

S69

Abstracts

Chlormethiazole (CHLO) positively modulates the GABAA receptor and is primarily used to treat refractory seizures and ethanol withdrawal syndrome. Cocaine (COC)-related seizures continue to be a serious medical problem due to the lack of effective modalities. In the present study, CHLO was tested for its effectiveness against the toxic (seizures and lethality) effects of COC in mice. The protective effects of CHLO were evaluated against a single, submaximal convulsive (75 mg/kg) and lethal (110 mg/kg) dose of COC. CHLO was also tested against the expression (anticonvulsant effect) and development (anti-epileptogenic effect) of COC-kindled seizures during kindling acquisition, and against fully-developed kindled seizures. The invertedscreen test was used to assess behavioral side-effects of CHLO and enabled the assessment of a protective index (PI), i.e. a separation between side-effect and anticonvulsant potencies (PI = toxic TDSO/anticonvulsant ED50). CHLO protected against acute COC-induced convulsions (ED50 = 7 mg/kg) and lethality (ED50 = 22 mg/kg) with a robust separation (PI = 22 and 7, respectively) from doses producing behavioral side-effects (TD50 = 156 mg/kg). CHLO suppressed the behavioral expression of COC-kindled seizures. It also prevented the development of sensitization to the convulsant effects of COC (anti-epileptogenic effect) and was effective in suppressing fully-developed COC-kindled seizures. The protective profile and index of CHLO were superior to those of the benzodiazepines, clonazepam and diazepam, which were not anti-epileptogenic against COC-kindled seizures, showed a limited efficacy and low protective index (PI = h 1) against convulsions and lethality. The results of this study predict the potential utility of chlormethiazole for the treatment of life-threatening complications of cocaine abuse. 195

CURRENT

PHETAMINE

OBSERVATIONS SUPPLY

TRENDS

IN THE

OF UNITED

METHAM-

manufacture dextro-methamphetamine. In contrast, 70 ‘super labs’ (those that have a production capacity of over 10 lbs.) comprised 4% of the total labs seized in 1998 and accounted for 78% of the total ‘meth’ capacity in the U.S. While 93% of these ‘super labs’ used ephedrine/pseudoephedrine as the precursor, none of these labs used bulk materials. Over-the-counter cold medications sold in small quantity bottles and blister packs were the precursor source for all of the ‘meth’ production within the ‘super labs’. These ‘super labs’ have been found to primarily utilize hydriodic acid or iodine in combination with red phosphorus to produce d-methamphetamine. Less than 7% of these ‘super labs’ have been found to utilize the phenyl-2-propane (P2P) method of production of dl-methamphetamine. Although the number of illicit ‘meth’ labs seized continues to increase, some law enforcement and DEA indicators suggest that efforts to curb ‘meth’ production, trafficking, and abuse are beginning to succeed. While federal analytical laboratory samples of ‘meth’ have increased over the last few years, the potency of the samples have generally declined over the same period. While the quality of the ‘meth’ has declined the price of a gram of ‘meth’ in U.S. cities has increased to $35-200. DEA has continued taking steps to control the growth in ‘meth’ abuse and clandestine laboratory production through regulatory processes associated with importation of precursor chemicals, control of reagents and bulk materials used in production, and the criminal targeting of ‘rogue’ suppliers. 196 SMOKING

NEUROPSY~HOLOGICAL CESSATION

FUNCTION

DURING

IN SCHIZOPHRENIA

T.P. George, J. Vessicchio, A. Termine, T. Pepper, B.E. Wexler, and T.R. Kosten, Yale University School of Medicine and The Connecticut Mental Health Center, New Haven, CT

STATES

D.V. Gauvin, C.A. Sannerud, D.A. Snyder, and F.L. Sapienza, Drug Enforcement Administration, Washington, DC Methamphetamine (‘meth’) has been, and continues to be, a significant threat to the public health and safety in the United States. 98% of all clandestine laboratories seized by the DEA are imethi labs. The number of clandestine ‘meth’ labs have increased as they have slowly migrated from the west to east coasts of the U.S. over the last 5 years. The majority of these labs are small ‘mom and pop’ labs which have under a 4 ounce production capacity, There were over 1550 of these labs seized in 1998, which accounted for less than 22% of total ‘meth’ production. These small labs have primarily utilized the lithium or sodium metal reduction to

Schizophrenic patients have high co-morbid rates of nicotine dependence (58-88%) and deficits in neuropsychological function. In particular, schizophrenic patients have abnormalities in executive function, visuospatial working memory and attention and concentration. Cigarette smoking by schizophrenics may reduce negative symptoms and cognitive deficits through amelioration of prefrontal cortical dopaminergic (DA) hypofunction, and nicotine abstinence leads to reductions in central DA function. There is evidence that atypical antipsychotic agents, which augment cortical DA function, may reduce negative symptoms, neuropsychological deficits and cigarette smoking in schizophrenics. Thus, evaluation of neuropsychological function in schizophrenics during a smoking cessation trial may yield important information on the effects of cigarette smoking and tobacco abstinence on neuropsy-

s70

Abstracts

chological function in these patients. The present study evaluated the effects of two catecholaminergic agents, Bupropion SR [a DA and norephinephrine (NE) reuptake inhibitor] and selegiline [an MAO-B inhibitor which preferentially augments DA and NE function], on neuropsychological function in schizophrenic (Bupropion SR) and control smokers (selegiline) participating in placebo-controlled smoking cessation trials. We have utilized a computerized neuropsychological battery which includes the Wisconsin Card Sorting Test and Stroop Test (executive function), Continuous Performance Test (attention and concentration), and tests of visuospatial working memory and fine motor control. Preliminary results indicate discrete deficits on a subset of neuropsychological tests (i.e. visuospatial working memory, Stroop Interference) in schizophrenic smokers during nicotine abstinence vs. continued smoking. A more complete characterization of neuropsychological function during tobacco abstinence and the effects of catecholamine augmentation in schizophrenic vs. healthy smokers will be presented. 197

ANALYSIS OF THE INTEGRATED TREATMENT METHODUSEDONSUBJECTSWITHDUALDISORDERSIN AN URBANPSYCHIATRICHOSPITAL

D. Geyen, A. Henniker, T. Sharma, and J. Beal, Sam Houston State University, Cambridge Health Care System, Huntsville, TX Research literature suggest that the percentage of individuals plagued with substance use disorders coexisting with mental illness continue to increase. These people are said to have a dual disorder. They may present a matrix of different substances used combined with various mental disorders. In order to effectively treat those with a dual disorder it becomes imperative to define the substance use disorder and identify the type of mental illness. Proper, reliable, and valid assessment is a crucial element to this procedure. Traditionally, people with dual disorders were either treated for their substance use or their mental illness. However there is growing need for researchers, practitioners, and programs designed to simultaneously address the needs of individuals who suffer from dual disorders. This approach is called the integrated method. The integrated method combines the assessment and treatment for psychopathology co-existing with substance use disorder. It incorporates simultaneous attention given to both mental illness and substance use disorder from a professional in a setting intended to accommodate persons with dual disorders. This clinical research project was designed to invesitgate the assessment and treatment methods used for subjects with dual disorders. Subjects in this study were diagnosed with a dual disorders. They were in the sub-acute phase and under-

going the integrated method of assessment and treatment in a psychiatric hospital in Houston, Texas. The demographic and baseline descriptive data gathered from the subjects serve as the foundation for this investigation. The data taken from demographic items were analysed on the measures of central tendency and variablity. Items addressing the integrated method gathered using an ordinal scale in order to obtain the median response. A correlation was quantified by computing the correlation coefficient. This provided an index of the strength and direction of the relationship on items regarding the demographics and the integrated method. 198 TREATMENT SERVICES FOR DUALLY DIAGNOSED ADULTS IN LOS ANGELES COUNTY: FINDINGS FROM A SURVEYOFPROGRAMADMINISTRATORSANDSTAFF

V. Gil-Rivas, C.E. Grella, L. Cooper, and A. Hamilton, University of California, Los Angeles, CA Administrators and staff from mental health and substance abuse treatment programs are critical in efforts to improve service delivery to dually-diagnosed patients. Yet administrators and staff may hold conflicting views on the service needs and treatment approaches most beneficial to this population. This study will present findings from a survey conducted with administrators and staff from 12 substance abuse treatment programs and 10 mental health treatment programs within Los Angeles County. Comparisons between responses from program administrators and staff will be made on the types of services most frequently provided to dually diagnosed patients, services needed but not provided, linkages with other service providers, types of service models used by programs (e.g. parallel or integrated), referrals sources, staff training regarding dual diagnosis, use of specialized treatment protocols for dual diagnosis, treatment approaches, assessment instruments, admission and discharge policies, attitudes and beliefs about mental illness and substance abuse, and their overall evaluation of the service delivery systems for dually-diagnosed patients. The findings will provide information useful for developing policies and training protocols on improving service delivery to the dually diagnosed. 199 SENSITIZATION TO COCAINE CHRONICANTIPSYCHOTICTREATMENT

PRODUCED

BY

K. Gill and N. Fukuyama, Montreal General Hospital Research Institute and McGill University, Montreal, Quebec, Canada Individuals with schizophrenia abuse psychostimulants such as cocaine at a far higher rate than the general

Abstracts

population. Some animal research has suggested that chronic antipsychotics may increase sensitivity to drugs of abuse. The present studies examined the effects of chronic haloperidol treatment on stress and cocaine-related behaviours as well as dopamine (DA) uptake parameters. Male CD-l mice were administered lactic acid (LA controls) or haloperidol (0.1 mg/ml) in the drinking water for 21 days and responses to stress (novel environment) as well as locomotor activation and stereotypy in response to single and repeated IP injections of 0, 15 or 30 mg/kg cocaine were monitored. One haloperidol pretreated group was tested following 4 days of withdrawal from the drug (H-W group). Mice in the H-W group showed increased stress and cocaineinduced activational responses compared to LA controls. Additional groups of mice were sacrificed and brains removed for 3H-dopamine uptake assays and 3H-GBR12935 binding studies in synaptosomes. There were no significant differences between groups for 3HGBR12935 binding (B,,,,, or &). However, there were significant differences between LA and Haldol treated mice in terms of IC50 values for cocaine-inhibition of 3H-DA in the striatum. Haloperidol-induced changes in the affinity of the dopamine transporter (DAT) for cocaine is a novel finding that requires further study.

200 EFFECTS OF THE SELECTIVE DOPAMINE PORTERLIGANDFECNTONOPERANTBEHAVIOR1NTHE SQUIRRELMONKEY

TRANS-

B.C. Ginsburg, J.A. O’Connor, M.M. Goodman, L. Martarello, H.L. Kimmel, R.G. Hunter, and L.L. Howell, Yerkes Regional Primate Research Center and Emory University, Atlanta, GA The dopamine transporter (DAT) is a critical site of action for cocaine and is linked to its reinforcing and behavioral-stimulant effects. Understanding the contribution of the DAT to cocaine’s mechanism of action is important to the study of cocaine reinforcement and addiction. The selective DAT ligand, 8-(2-[ 18F] fluoroethyl)-2-beta-carbomethoxy-3-beta (4-chlorophenyl) nortro-pane (FECNT), was developed as a probe for positron emission tomography (PET) and has been used in both clinical and preclinical studies examining DAT occupancy. PET imaging studies with FECNT in nonhuman primates indicates that it labels a cocaine-sensitive binding site. Despite its use as a selective DAT ligand in PET studies, no research on the behavioral properties of FECNT has been conducted. The present study utilized operant techniques in squirrel monkeys to characterize the effects of FECNT alone and in combination with cocaine. In monkeys trained to lever-press under a fixed-interval 300 s schedule of stimulus termination, FECNT (0.03 and 0.1 mg/kg) had behavioral-stimulant effects similar to cocaine but was

s11

more potent and had a longer duration of action. Pretreatment with FECNT (0.03 mg/kg) enhanced the behavioral-stimulant effects of cocaine, indicative of additivity of effects and a common site of action. The results presented demonstrate that FECNT has cocaine-like behavioral-stimulant effects, consistent with its ability to occupy a cocaine-sensitive binding site in vivo. Supported by USPHS grants DA10344 and RRO0165.

201 COMPARINGDRUGSELF-ADMINISTRATIONUNDER PROGRESSIVE-RATIO AND FIXED-RATIO SCHEDULES L.A. Giordano, W.K. Bickel, and T.A. Shahan, University of Vermont, Burlington, VT Rationale: Progressive-ratio schedules have been used widely to examine the relation between drug consumption and drug price (i.e. demand curves) in the study of the behavioral economics of drug abuse. Sequential effects produced by the increasing response requirements of progressive-ratio schedules might influence the shape of demand curves for drug reinforcers. Objective: This study compared progressive ratio across sessions and random sequences of ratio requirements in a within-subject design to see if they produced similar behavioral economic and traditional measures of reinforcer efficacy. Method: Self-administration of standardized cigarette puffs (70 cc each) was studied with eight smokers. Puffs were available at different ratio requirements (e.g. 3, 100, 300, 600, 1500, 3000, 6000 responses/3 puffs) presented in ascending (progressive-ratio schedule) or random order across daily sessions. Results: Similar measures of reinforcing efficacy (e.g. breakpoint, peak response rates, elasticity of demand) were obtained for the two methods of changing prices across sessions. Conclusions: Different sequences of exposure to prices of self-administered drug produce similar outcomes, and thus, demand curves generated with progressive-ratio schedules or other sequences of ratio values may be used interchangeably to assess reinforcer efficacy and to conduct demand analyses for self-administered drugs.

202 HERBAL XTC PRODUCES STIMULUS EFFECTSIN RATS

(+)AMPHETAMINE

R.A. Glennon and R. Young, Virginia Commonwealth University, Richmond, VA Various ephedra/caffeine-containing herbal dietary supplements have been promoted for such uses as weight loss, increased energy and mental concentration, heightened sexual sensation, euphoria, and as alternatives to illicit street drugs. Although it is thought that such

Abstracts

s72

products might produce amphetamine-like effects, and although ( - )ephedrine substitutes for ( + )AMPH, to date no herbal preparation has been examined directly. Six male SD rats, trained to discriminate ( + )-AMPH (1 mg/kg, i.p.) from saline (VI-15 s schedule of reinforcement) were administered ( + )AMPH, ( - )ephedrine, and caffeine by the i.p. and i.g. routes. A powdered herbal preparation (Herbal XTC”) was also administered via the i.g. route. Substitution occurred with all agents: ( + )AMPH (ED50 = 0.4 mg/kg i.p.; 1.0 mg/kg i.g.), ( - )ephedrine (ED50 = 4.5 mg/kg i.p.; 10.8 mg/kg i.g.), caffeine (ED50 = 12.9 mg/kg i.p.; 32.9 mg/ kg i.g.), and powdered Herbal XTC (535 mg/kg i.g. of powder representing, according to product labeling, 9.5 mg/kg of ( - )ephedrine). The herbal product produced ( + )amphetamine-like stimulus effects and its potency was approximately the same as ( - )ephedrine administered via the i.g. route. Caffeine also produced AMPHlike effects via the i.g. route and could contribute to the actions of herbal preparations. Supported by PHS grant DA 01642.

203 NARIDINE

MECHANISMS AND

OF

ACTION

OF

18-METHOXYCORO-

IBOGAINE

SD. Glick, I.M. Maisonneuve, K.K. Szumlinski, H.A. Dickinson, and L.M. Warner, Albany Medical College, Albany, NY 18Methoxycoronaridine (l&MC) is a novel iboga alkaloid congener that may be effective and safe for treating multiple forms of drug abuse. Like ibogaine, 18-MC decreases the self-administration of morphine, cocaine, ethanol and nicotine in rats; unlike ibogaine, 18MC does not affect responding for a non-drug reinforcer (water) nor does it produce tremors, cerebellar damage, or bradycardia. The mechanism of action of these agents has not been established. While 18-MC and ibogaine have similar affinities for mu and kappa opioid, 5HT3, and possibly nicotinic receptors, 18-MC has much lower affinities than ibogaine for NMDA and sigma-2 receptors, sodium channels, and the 5HT transporter. Both drugs decrease extracellular levels of dopamine (DA) in the nucleus accumbens (NAC) but only ibogaine increases serotonin (5HT) in the NAC. Both ibogaine and 18-MC block acute morphine-induced and nicotine-induced DA release in the NAC, but ibogaine enhances while 18-MC has no effect on acute cocaine-induced increases in NAC DA. However, recent data show that both 18-MC and ibogaine block sensitized increases in NAC DA produced by chronic cocaine. Other new data show that 18-MC is at least twice as potent in decreasing i.v. nicotine self-administration as in decreasing the self-administration of other drugs. And preliminary studies indicate that mecamylamine, a nicotinic antagonist, can enhance the potency

of 18-MC to decrease morphine self-administration. Considered along with other data, the results suggest that Is-MC and ibogaine reset neuroadaptive changes in the mesolimbic DA system that occur during chronic administration of addictive drugs. A nicotinic receptor subtype may be an integral part of this mechanism.

204

COMPARISON

1418394

AND

OF

THE

EFFECTS

CHLORDIAZEPOXIDE

NON-PUNISHED

RESPONDING

OF

ON IN RHESUS

WAY-

THE

PUNISHED

AND

MONKEYS

J.R. Glowa, D. Stafford, and J.E. Barrett, Louisiana State University, Shreveport, LA, and Wyeth-Ayerst Laboratories, Princeton, NJ Drugs that increase punished responding in nonhumans may be suitable candidates for development as medications to treat anxiety in humans. The present study examined whether a novel neurosteroid, WAY-1418394, could increase punished responding. Rhesus monkeys were trained under a multiple fixed-ratio (FR) 20-response schedule of food delivery with two components. In one component (non-punishment) responding produced food deliveries under the FR20 schedule. In the other, responding was punished: the 10th response of each FR20 in that component produced a foot shock. The components alternated throughout the session and up to five food deliveries could be obtained in each component before alternation. When responding was stable, the effects of a range of doses of WAY-141839-4 (0.33 10 mg/kg) and chlordiazepoxide (CDAP, 1~ 17 mg/kg) were assessed on both punished and non-punished responding. Both CDAP and WAY-141839-4 were given orally. Acute treatment with both compounds increased punished responding at doses that had no effect on non-punished responding. Blood/ plasma samples were taken just before, and 0.5, 1, 2,4,6, 8, 12 and 24 h after the administration of 2 mg/kg WAY-141839-4 to associate blood level with behavioral effect. These results suggest that WAY141839-4 has potential as an anti-anxiety drug.

205

CHANGES

SKILLS

FOLLOWING

IN

ADOLESCENT OUTPATIENT

RELAPSE

COPING MARIJUANA

TREATMENT

S.H. Godley, R. Funk, and M. Godley, Health Systems, Bloomington, IL

Chestnut

This study examined the changes in coping skills among adolescents in the Cannabis Youth Treatment (CYT) study. The sub-study examined: (a) whether the factor structure of the Adolescent Relapse Coping Skills Questionnaire (ARCQ) could be validated using confirmatory factor analysis; and (b) whether changes in the ARCQ scores could serve as mediators for explaining

Abstracts

response to the 5 CYT treatments. Subjects (N = 600) were adolescents between 12 and 18 who met inclusion and exclusion criteria for the CYT study and who were randomly assigned to one of five outpatient interventions designed for the treatment of marijuana abuse or dependence. While exploratory factor analyses replicated the original three factor solution described by Myers and Brown (1996), confirmatory factor analysis results were mixed. The Bentler-Bonett Normed Fit Indices were above 0.9 for the three, two and one factor solution, but with no significant differences between them, the ARCQ measure statistically appears to be more simply viewed as unidimensional. Next, the role of the three original factors and the combined scores were evaluated as mediators (i.e. early/process outcomes) for the CYT treatments. Using the three ARCQ factors of Cognitive and Behavioral Problem Solving, Self-Critical Thinking, Abstinence-Focused Coping and the total score, changes in coping were examined over time and by treatment condition design using SPSS GLM repeated measures procedures. Scores on the Self-Critical Thinking factor reduced from intake to the 3 month follow-up interview (P < 0.05). This factor was previously found to be a poor predictor of long term drug use (Myers and Brown, 1995). There were group differences that appeared to be attributable to intake differences. There were no interaction effects to suggest that any of the interventions had much impact on coping skills as measured by the ARCQ. These findings suggest that either there were no differential changes in coping skills among the five CYT interventions or that the ARCQ does not measure a mediating process for explaining differences in their outcomes. Further analyses are still needed to assess the relationship between coping skills as measured by the ARCQ and the outcome measures used in CYT. Such analyses will examine if coping skills are better classified as a moderator than as a mediating variable. 206 AMONG

SOCIAL NETWORK FACTORS AND DRUG USE RISK NEEDLEEXCHANGECLIENTS

A. Gogineni, J. Clarke, and M.D. Stein, Brown University School of Medicine, Providence, RI Despite participation in needle exchange programs (NEP’s), drug users continue to engage in risky injection drug use practices. Purpose: To examine the social network factors associated with drug risk among needle exchange clients. Hypotheses: Individuals with live-in partners who also use drugs, those who have a greater proportion of friends who also use drugs and have a greater number of people to shoot up with will engage in greater risky drug use. Further, males will be more likely to engage in greater risky drug use than females. Methods: A cross-sectional interview of 193 subjects

s13

enrolled in a NEP in Providence, RI for at least 6 months. Participants are 67% male, 85% white, with a mean age of 36 years and a mean educational level of 12 years. Drug risk is a summative score of 8 items from the HIV Risk Assessment Battery. Results: Using multiple regression analysis, the overall model is statistically significant and explains 19% of the variance in drug risk (R2 = 0.186, F(6,183) = 7.01, P = 0.0001). Being male (B = 1.37, P = 0.05), having live-in partners who also use drugs (B = 2.30, P = 0.04) having a greater proportion of friends who use drugs (B = 0.90, P = 0.0004), and having a greater number of people to shoot up with (B = 0.77, P = 0.04) significantly account for the variance in drug risk. Conclusions: These findings indicate that attention to the partner’s drug use and social network factors are important for intervening with needle exchanger’s drug risk. 207 GROUP PROCESSES IN AN GRAMFOR MMTP DROP-OUTS

ALTERNATIVE

PRO-

M.F. Goldstein, M. Seligman, S. Deren, and K. Stuven, National Development and Research Institutes, Inc., and Center for Psychological Services, Pace University, New York, NY Objective: Describe group process and participation rates for an Alternative Program for MMTP Drop-outs developed to increase treatment reentry. Methods: 444 MMTP drop-outs were recruited in East Harlem, NYC. The Matrix and Enhanced Reinforcement Models were used as the basis of the group sessions. The intervention consisted of street outreach worker contacts, group sessions 4 days/week for 3 months and 2 individual counseling sessions. Results: Of the first 178 subjects randomly assigned to the intervention, 78% had at least one outreach contact, 65% attended at least one group session (of these, 84% attended more than one, mean # = 23) and 36% had at least one individual session. Main issues for groups were dealing with ongoing effects of drug use (e.g. physical illness, depression), loss of family ties, economic hardship, problems dealing with the system, shame about their drug use, and lack of trust. Efforts 1:o establish trust are made by staff from the first contact. The aim of the group work was to promote drug treatment readiness: it focused on establishing rapport and trust, teaching social skills, and using relapse prevention techniques for early recovery as a basis for further treatment. Group process issues included providing a safe space in which to interact and modeling of respectful social interactions by the group leader and later by group members. The structured format of group sessions offering a predictable, positive, drug-free experience was reassuring to subjects for whom an open discussion may have been too difficult because of the emotions it might engender.

Abstracts

s74

Conclusion: This model has an appeal to MMTP dropouts and may be useful with other groups of out-of-treatment drug users as well. 208 WOMEN-FIT: A HIV/STD IN DRUG-USING

PILOT

STUDY

TO REDUCE

RISK

OF

WOMEN

E.L. Gollub, K. Mayer, B. Koblinv, D. Mercer, A. Davis-Vogel, A. Coletti, and D. Metzger, University of Pennsylvania, Treatment Research Center, Philadelphia, PA, Brown University, Providence, RI, NY Blood Center, New York, NY, and Abt Associates, Boston, MA Objective: To test the feasibility of a group intervention for drug-using women at persistent high risk of HIV/ STD. Methods: Subjects from a completed HIVNET study (VPSII) who showed continued high levels of exposure to risk ( > 30% unprotected sex acts) have been recruited in Philadelphia, Providence and New York, to test an intensive group-based behavioral intervention, via a randomized controlled trial design. Intervention sessions ( k 2 h) are highly structured and aim to: increase knowledge and comfort with the anatomy and risk of HIV/STD; increase knowledge and use of various risk-reduction methods, including male condom, female condom, diaphragm, cervical caps, spermitides and withdrawal; and develop a sense of individual and collective empowerment to reduce risk of HIV/ STD and improve reproductive health. “Near-peers” who live and/or work in the communities providing potential subjects were hired as Group Leaders, and provided training and ongoing oversight. The comparison arm received Enhanced HIV testing and counseling, including information on the female and male condoms, and free supplies. Results: At this time, prestudy focus group data on 21 women indicate a high level of interest in this study, including a 82% appearance rate at the group sessions.Feasibility data to be presented on the first 60 subjects enrolled include: rate of enrollment beginning in March 00, participation rate at group sessions; pre-post intervention ‘body and methods knowledge’ scores; and intervention acceptability. Conclusion: Evidence from the first 60 women of a targeted 180 in 3 cities will provide interim data on whether a full-scale trial of this intervention is justified. 209

IMMUNOPOTENTIATING

NON-PEPTIDIC

OPIOIDS

EFFECTS ON

IN

VITRO

OF

THE

NOVEL

T LYMPHOCYTE

FUNCTION

R. Gomez-Flores, K.R. Vietti, W.J. Dunn III, and R.J. Weber, University of Illinois College of Medicine at Peoria, and University of Illinois College of Pharmacy, Chicago. IL

Opioid receptors have been reported on leukocytes of several species and shown to subserve effector functions of these cell types. We have previously reported immunopotentiating properties of non-peptidic delta opioid receptor selective ligands on T lymphocytes. In this study, we have evaluated the effects of morphinans with pyrimidino and a pyrazolo group substituted in the 6,7-positions, (la-d, 2) on rat thymocyte proliferation and splenic macrophage functions. We observed that these compounds at concentrations of 10-4 to 10-S M were associated with increased T lymphocyte proliferation with the order of potency lb&2 > lc, Id > la > CON A alone (control). example at 10-5 M the percent increase in lymphocyte proliferation was 634 (lb), 198 (2), 151 (lc), 132 (Id), and 17 (la) at Con A concentration of 1.25 ug/ml compared with Con A alone. The effect of the most active of these compounds, lb, was antagonized by naloxone and nor-binaltorphine (49 and 16% inhibition of lymphoproliferation at equimolar doses, respectively), but not by naltrindole. No changes in macrophage functions were observed, suggesting a selective effect on lymphocytes. These results indicate that the inclusion of a phenyl substituent at the 2’ position of the pyrimidine group significantly potentiated Con A-induced thymic cell proliferation, and that this effect may be mediated through p-opioid receptor subtype. The design and synthesis of non-peptidic opioid immunostimulants could have clinical impact in the treatment of infectious diseases including AIDS and cancer. Supported by Grants DA/AI08988, DA12095, DA08867, and F32-DA05865. 210

EFFECTS

OID-MAINTAINED NALOXONE

OF

CLONIDINE HUMANS

DISCRIMINATION

AND UNDER

YOHIMBINE

IN

OPI-

A NOVEL-RESPONSE

PROCEDURE

K. Gonsai, K. Sevarino, T.R. Kosten, and A. Oliveto, Yale University, New Haven and VA CT Healthcare System, West Haven, CT The pharmacological specificity of the instructed novelresponse naloxone discrimination procedure was examined further by determining the effects of agents acting on the adrenergic system in opioid-dependent subjects trained to discriminate the opioid antagonist naloxone (NX) from placebo. Opioid-maintained volunteers were trained to distinguish between a low dose of NX (0.15 mg/70 kg, i.m.; e.g. Drug A) and placebo (e.g. Drug B) under an instructed novel-response drug discrimination procedure in which subjects identify the drug condition as “A”, “B”, or “N” (neither A nor B-‘novel’). Once the discrimination was acquired, dose-effect curves were determined for NX (O--O.15 mg/70 kg, i.m.) alone, the alpha-Zadrenergic antagonist yohimbine (YO, O-10 mg/70 kg, p.o.) alone, and the alpha-2-adrenergic agonist clonidine (CL, O-O.2 mg/70 kg, p.o.) alone and in

Abstracts

combination with NX (0.15 mg/70 kg). Data collection is in progress. Thus far, 3 subjects have completed the entire study and one completed all but the YO dose-effect curve. NX produced dose-related increases in NXand little or no appropriate responding ‘novel’-appropriate responding. YO produced 67% NXappropriate responding and 33% novel responding at the IO-mg dose. CL alone produced little or no NX- or novel-appropriate responding. When administered with NX (0.15 mg/70 kg), CL produced dose-related decreases in NX-appropriate responding and 50% novelappropriate responding at the two highest doses. Supported by NIDA grant DA10017. 211

CONTINGENCY

BEHAVIORAL

CHANGE

MANAGEMENT: AMONG

INCENTIVES

FOR

METHAMPHETAMINE

USERS

R. Gonzales, V. Gulati, J. D’Sa, and A. Huber, Friends Research Institute, Los Angeles Addiction Research Consortium, CA This report will provide a descriptive analysis of one CM program of 75 methamphetamine users. Clients were enrolled in a NIDA-funded program at the Matrix clinic in San Bernardino County, California. Clients participated in a randomized la-week outpatient treatment program that is designed to evaluate the efficacy of medication and CM for 220 primary methamphetamine users. Several studies have demonstrated the efficacy of CM on producing behavior change and there has been growing interest in CM, a therapeutic approach based on clients earning vouchers for providing clean urine samples. Vouchers can be exchanged for items and services that promote an addiction free lifestyle. A utilization review of purchases was conducted to assess the types of items or services clients requested and received. The most common services requested among female clients were grocery certificates and items consisting of clothing apparel, cosmetics, household furniture and supplies. Many items and services males obtained focused on self-sustaining wants that satisfied their hobbies, e.g. a karaoke machine, concert tickets, and mobile train sets. The differences in the types of items and services requested between male and female clients suggest that women are more likely to take care of basic family needs while men focus on their own self interests. The majority of clients (55.6%) reported that the value accumulating from successive urine tests was a motivator for recovery. Sixty percent believed that working towards the items and services they wanted through remaining abstinent was very helpful in their recovery process. Findings show that CM is a powerful method of intervention among methamphetamine abusers in reinforcing sustained abstinence.

s15

212 MENT OPIATE

NALOXONE/LOFEXIDINE COMPARED

COMBINATION

WITH

LOFEXIDINE

TREAT-

MONOTHERAPY

DETOXIFICATION

M. Gossop, J. Bennett, T. Martin, J. Bearn, and J. Strang, National Addiction Centre, and Institute of Psychiatry, London, UK We have tested the hypothesis that naloxone/lofexidine combination treatment accelerates the resolution of the opiate withdrawal syndrome compared with lofexidine monotherapy using an open comparison study design in 49 opiate dependent polysubstance misusing inpatients. We compare symptom severity, side effects, treatment compliance and rates of induction onto naltrexone maintenance under a 5-day naloxone/lofexidine treatment regimen compared with 10 days of lofexidine treatment. under the curve analysis indicated that withdrawal severity for the naloxone group (96.4 + 33.9 SD) was significantly less than the lofexidine group (121.6 + 49.9) (P= 0.04). High rates of detoxification were achieved in both groups (92% in the naloxone/lofexidine group and 83% in lofexidine group. CHII = 1.1, P = 0.30). There was no significant difference in blood pressure measures between the two groups. 17(57%) patients in the naloxone treatment group commenced naltrexone, but compliance was poor, patient only continuing treatment for a mean of 4.5 days (range 1 - 17). This study will be discussed in the context of our previous work comparing the clinical efficacy of naltrexone/lofexidine combination treatment with lofexidine monotherapy in opiate withdrawal, which suggests that continuous rather than intermittent opiate receptor blockade may be a significant determinant of clinical efficacy. 213

VASOMOTOR

FUNCTION

IN

CHRONIC

COCAINE

DEPENDENCE

C. Gottschalk, A. Feingold, L. Mauzi, C. McCullough, and T. Kosten, Yale School of Medicine and VA-Connecticut Healthcare, West Haven, CT We present a preliminary study of the efficacy of isradipine in normalizing regional cerebral perfusion deficits in chronic cocaine abusers. Cocaine is a potent cerebral vasoconstrictor (Kaufman MJ, Levin JM, Ross MH, et al. JAMA 1998; 279: 376). Isradipine, a dihydropyridine L-type calcium channel blocker (CCB) like nimodipine, can prevent the acute, transient reduction in CBF seen after intravenous doses of cocaine (Johnson B, Barron B, Fang B, et al. Psychopharmacology 1998; 136: 335). Chronic cocaine abusers often have persistent, multifocal reductions in cerebral blood flow. If these represent cerebral vasospasm, vasodilating agents such as isradipine should augment perfusion in

Abstracts

Sl6

abnormal areas acutely, but this effect would likely only last as long as the agent is in circulation. We recruited 14 active, long-term cocaine abusers without another Axis 1 diagnosis, HIV, or any medical condition or treatment that might alter cerebral blood flow. Each subject had three 99m-Tc-HMPAO SPECT cerebral perfusion studies over 6 days. The first study was performed before medication, within 10 days of the last reported cocaine use. Over the next 48 h, each subject received 5 mg of isradipine three times a day, for a total of six doses. The second perfusion study was performed within 2 h after the last dose. The third study occurred 5 days later, or drug-free for more than five half-lives of the study medication. Changes in CBF were assessed in each subject on and off medication by generating SPMs contrasted with repeated SPECT studies in normal controls. All 14 subjects had significant changes in perfusion on isradipine; none of the 9 subjects who completed three scans showed any differences in cerebral perfusion from baseline after medication washout. This preliminary study provides strong evidence that chronic cocaine abuse causes vasomotor dysfunction which responds to pharmacotherapy. Supported by NIDA P50 DA-04060 and DA 00167. 214

CHRONIC METHYLPHENIDATE PRODUCES ADAPTIVE CHANGES IN ACTIVITY AND SLEEP DISTURBANCES IN MONKEYS: A MODEL FOR ASSESSING CANDIDATE COCAINE MEDICATIONS

M. Goulet and B.K. Madras, School, New England Regional Center, Southborough, MA

Harvard Primate

Medical Research

The side-effects associated with long-term treatment of candidate cocaine medications that block the dopamine transporter (DAT), such as sleep disturbances, have not been fully evaluated. We developed an experimental method to continuously monitor the effects of DAT inhibitors on spontaneous activity and sleep in monkeys. The DAT inhibitor methylphenidate (MPH [Ritalin]), the most widely prescribed stimulant medication to treat attention deficit hyperactivity disorder and a compound assessed as a cocaine medication, was used as a paradigm for this study. MPH was administered three times a day (0.3 mg/kg/dose) for 2 weeks (excluding the week-end) to young monkeys (2-3 years old, Macaca mulata). Monkeys were continuously monitored 24 h for 5 weeks with an accelerometer placed in a jacket and motor activity was analyzed. Two of three monkeys responded to MPH with increased day time activity. In one very active monkey, MPH had little stimulant effect and reduced motor activity. On the second week of treatment, the increase in locomo-

tor activity was more pronounced than in the first week for one animal, suggesting sensitization, and was less pronounced for another animal, suggesting the development of tolerance. Acute challenge with another DAT inhibitor indatraline (1.0 mg/kg) produced pronounced stimulation, which persisted for 2 or more days following administration. Sleep patterns were altered by MPH and indatraline, resulting in increased periods of wakefulness. The results suggest that the development of either sensitization or tolerance is subject-dependent in monkeys and support the view that DAT inhibitors promote adaptive changes in monkeys. The results also indicate that sleep disturbances should be assessed in the development of candidate cocaine medications. The accelerometer provides an effective method for continuous monitoring of drug-induced changes during day-night activity in primates and is useful for evaluating candidate cocaine medications. Supported by DA 11558, DA 06303, DA00304, RR 00168. 215 WHAT HAPPENED WITH FRENCH THE PAST5 YEARS (1994-1998)?

OVERDOSES

IN

L. Gourarier, B. Lepere-Prevot, C. Adda, E. Peyret, F. Nordmann, W. Lowenstein, Centre Monte Cristo, Hbpital Laennec, Faculte Necker, Paris, France As methadone programs began in France in the early seventies, substitution treatments had been reserved to a very small group of patients for a quarter of a century. Health policy dramatically changed in this field during the year 1994. As General Practitioners advocated for and were allowed to prescribe buprenorphine, the number of methadone programs significantly increased. During the 1994498 period, the population of patients treated rose from 56000 to 65 000. A discussion held the scientific community on two points. First, diversion of treatments could involve a new population of young drug users. Second, lethal overdoses might increase because of the lack of control. The total number of overdoses is given by French Police Nationale each year since 1970. Even underestimated, this data is collected by the same teams, in the same places with the same method and takes evolution into account. This number began to decrease rapidly, progressively and continuously since the year 1994. Moreover, ODs decreased more rapidly in the regions where substitution was first available, and through the whole French territory this decrease appears to be proportional to the quantity of treatment officially available. These evolutions will be shown and discussed. Other factors such as behaviors relating to HIV/AIDS will also be presented.

Sll

Abstracts

216

D-AMPHETAMINE

DEPENDENCE:

RANDOMIZED

CONTROLLED

TRIALS

FOR

TREATMENT

OF

DOUBLE-BLIND,

COCAINE PLACEBO-

J. Grabowski, H. Rhoades, A. Stotts, J. Schmitz, D. Creson, G. Moeller, and L.-A. Daruzska, Substance Abuse Research Center, University of Texas, Houston, Houston, TX Stimulant dependence can have diverse medical, psychological, and social adverse consequences. There are no uniquely effective medications for treatment. Agonist treatment, effective for opioid and nicotine dependence, provides one avenue for the pursuit of medications. Some clinical success has been reported (Charnaud and Griffith, 1998; Grabowski et al., in press) A properly implemented agonist treatment regimen should improve retention and reduce illicit drug use. Our most recent clinical trials of the agonist model have examined amphetamine analogs for treatment of cocaine dependence. An exemplar of a simple large clinical trial involved 128 cocaine dependent subjects enrolled in a 12-week randomized, double blind, placebo controlled trial. In the multistage dosing design, subjects initially received PBO, 15 or 30 mg of D-amphetamine sulfate, sustained release capsules. At week 5, dose doubled for active groups to 30 or 60 mg. Subjects attended the clinic twice/week, provided urine samples, obtained medication, and had one behavioral therapy session/week. Retention was best for the 15-30 mg group while proportion of benzoylecognine (BZ) positive urine screens was from lowest to highest 30-60, 15-30 mg, and PBO at study end. In another study, 30 mg desoxyephedrine immediate release and sustained release enhanced retention but only 30 mg sustained release diminished BZ positive urine screens compared to PBO. The results provide support for further examining the agonist model in psychostimulant dependence treatment. Support: NIDA P-50-DA09262 and ROl-DA06143. 217 LOWING

HALLUCINATION-LIKE SCOPOLAMINE

BEHAVIORS AND

IN

RATS

FOL-

AMPHETAMINE

Z. Graczyk, University of Maryland School of Medicine, Baltimore, MD

above. In particular, scopolamine produced catalepticlike behavior, rearing and a visual/olfactory searchingtype behavior. In contrast, amphetamine did not produce the cataleptic-like behavior, and the rearing and searching were less pronounced. To the degree that the searching-type behavior represents a possible hallucinatory response, then these results suggest the effects are more prominent following scopolamine. 218

INFLUENCES

DENCE

AND

MARIJUANA

BETWEEN

GENETIC

DSM-IV

ON

AND

ENVIRON-

ALCOHOL

DEPEN-

DEPENDENCE

J.D. Grant, A.C. Heath, K.K. Bucholz, P.A.F. Madden, and N.G. Martin, Washington University School of Medicine, St. Louis, MO, and Queensland Institute of Medical Research, Brisbane, Australia We investigated the genetic overlap between alcohol dependence and marijuana dependence risk in a sample of young adult twins. Data from 4955 individuals who completed a telephone diagnostic interview for the Australian Twin Study (11989 cohort?; 2087 complete pairs: MZF = 525, MZM = 353, DZF = 415, DZM = 296, DZO = 498; 386 female and 395 male singletons) were analyzed. Participants had a mean age of 29.5 years at the time of interview. Twenty-two percent of the sample (1070 individuals) met DSM-IV criteria for alcohol dependence; 2906 individuals had tried marijuana, with 295 having three or more marijuana dependence symptoms. Tetrachoric correlations indicated significant familial influence on dependence for both substances (range: 0.51-0.58 for MZs, 0.26-0.38 for DZs). Structural equation modeling indicated significant genetic influence on both measures, with genetic factors accounting for 46 and 57% of the variance in alcohol and marijuana dependence, respectively, and with a genetic correlation of 0.87. In contrast, the nonshared environmental correlation was 0.13. These analyses indicate significant genetic overlap between alcohol and marijuana dependence risk. Supported by: AA10249, AA07728, DA07261, DA00272, AA 11998. 219

DIFFERENTIAL

STIMULANT PAMINE

Hallucinatory effects of scopolamine and amphetamine are well known in humans, but less well recognized in laboratory animals. The purpose of this experiment was to determine whether these types of behaviors could be observed in rats. Following injections of placebo, scopolamine (0.01-2.2 mg/kg, SC) or amphetamine (0.25-5.0 mg/kg, SC), rats were placed in a sensory conditioning chamber and their behavior observed and scored for a period of 20 min. Both scopolamine and amphetamine produced changes in behavior at doses of 0.25 mg/kg and

ASSOCIATIONS

MENTAL

PROPERTIES, METABOLISM

REARING BUT IN RESPONSE

ALTERS NOT

SENSITIVITY MESOLIMBIC

TO NICOTINE

TO DOIN RATS

T.A. Green, M. Thompson, L.P. Dwoskin, and M.T. Bardo, University of Kentucky, Lexington, KY Previous enriched stimulants compared sought to differential

research has shown that rats raised in an environment show enhanced sensitivity to such as cocaine and amphetamine when to their isolated cohorts. The present study determine if differential rearing would confer sensitivity to the behavioral and neurochem-

Abstracts

S78

ical effects of nicotine. Male rats were raised in either an enriched condition (EC) consisting of novel toys and social interaction with cohorts or in an isolated condition (IC) with no toys or social interaction. Rats were then assigned to saline, 0.2 or 0.8 mg/kg nicotine (SC, free base) treatment groups. Locomotor activity was measured for 60 min following injection. Rats were tested daily for a total of 8 days. On test day 9, all rats received a challenge injection of 0.8 mg/kg nicotine and assessed for locomotor activity. Regardless of drug treatment, IC rats displayed higher rates of locomotor activity than EC rats throughout the experiment. IC rats also showed an enhanced sensitivity to the stimulant effect of nicotine, even taking into account higher basal activity in the IC group. In a separate experiment, EC and IC rats displayed dose-dependent increases in DOPAC concentrations in mesolimbic terminal fields in response to nicotine treatment. However, this increase was not different between EC and IC rats. Taken together, these results suggest that environmental isolation enhanced the stimulant effect of acute and repeated nicotine, which is not reflected by changes in dopamine utilization. Supported by USPHS grants DA05312, DA12964 and DA00399. 220 COCAINE-OPIOID INTERACTIONS UNDER CONDITIONS OF ACUTE OPIOID TOLERANCE AND ACUTE OPIOIDDEPENDENCE

K. Green-Jordan, Boston University,

L. Warren, Boston, MA

and K.M.

Kantak,

Increasing simultaneous abuse of cocaine and morphine-like opiates (‘speedballing’) has prompted a number of studies designed to identify factors that are relevant for mediating their combined behavioral effects. The primary objective of the present study was to determine if variations in opioid pretreatment time would affect how mu opioid agonists interact with cocaine. To address this hypothesis, pretreatment times known to induce states of acute opioid tolerance (1 h) or acute opioid dependence (4 h) were selected and employed in two drug discrimination experiments. For the first experiment, adult male Wistar rats (n = 6) were trained to discriminate 10.0 mg/kg cocaine from saline under a FRlO schedule of food reinforcement.In test sessions following training, morphine (5.6 mg/kg) was administered either 0.5, 1 or 4 h prior to cumulative doses of cocaine. After 1 h, morphine produced an almost 3-fold leftward shift, while after 4 h, morphine produced a modest (1.5-fold) rightward shift in the cocaine dose-response function. There were no changes following the 0.5 h pretreatment time. The attenuation of the discriminative stimulus effects of cocaine while rats were acutely dependent on morphine was investi-

gated using a second group of animals (n = 6) trained to discriminate cocaine as above, then administered either morphine (5.6 mg/kg) or methadone (3.0 mg/kg) 4 h prior to cumulative doses of cocaine. Also, in order to enhance the state of acute opioid dependence, either 0.1 or 0.3 mg/kg naloxone was administered 5 min prior to the start of the test session. Cocaine was nearly 2-fold less effective in engendering cocaine-appropriate responses following pretreatment with morphine and the higher dose of naloxone. Similar results were revealed following pretreatment with methadone and 0.3 mg/kg naloxone, where cocaine was over 2-fold less effective. Overall, these findings demonstrate the importance of temporal parameters for determining the nature of the behavioral interactions between cocaine and mu opioid agonists. Furthermore, the different effects on cocaine produced after acute opioid tolerance vs. acute opioid dependence may have relevance for understanding the variables important for vulnerability to speedball abuse. 221 PREDICTING TREATMENT HIV/AIDS RISKBEHAVIOR

OUTCOMES

IN NTIES:

L. Greenfield, Caliber Associates, Fairfax, VA Hypothesis: Both client and service delivery unit (SDU) factors are important in predicting risk behaviors for HIV/AIDS and hepatitis C after treatment. Procedures: A secondary analysis of data from the National Treatment Improvement Evaluation Study (NTIES) was completed for N = 2671 clients from 52 service delivery units (SDUs). The treatment modalities assessed were methadone outpatient (n = 355) non-methadone outpatient (n = 996) short-term residential (n = 720) or long term residential (n = 600). At admission and follow-up, clients were asked about drug and alcohol use and two types of HIV/AIDS risk behaviors, including injection drug use and sex exchange. At admission, clients were also asked about their age, education and other characteristics. During treatment, clients were asked about the counseling/education services they received, including sessions missed. The clients’ length of stay in treatment was also assessed. SDU Directors were asked about their program’s approach to treatment planning, patient-counselor matching, and average length and frequency of individual counseling. A Hierarchical Linear Model (HLM) was developed in order to predict either or both injection drug use and sex exchange a mean of 9 months after treatment. Results: Both injection drug use and sex exchange declined significantly over time. The SDU factors associated with less frequent risk behavior at follow-up in the HLM model were: (1) Non-methadone treatment in comparison to methadone; and (2) More frequent counseling sessions versus less frequent. The client factors associated with less

Abstracts

frequent risk behavior were: (1) Less frequent risk behavior before treatment; (2) Longer treatment stays; and (3) Attending school/classes. Generally, clients who were treated in SDUs which provided weekly counseling reported less risk behavior after treatment. Conclusions: Substance abuse treatment reduces HIV/AIDS risk behavior. Both SDU and client factors are important in predicting risk behavior after treatment. 222

HISTORY

AND

DRINKING

OUTCOMES

FROM

INPATIENT

ALCOHOL

OF

SEXUAL

ABUSE,

SEX

DIFFERENCES,

FOLLOWING

DISCHARGE

TREATMENT

S.F. Greenfield, M.E. Kolodziej, R.D. Weiss, D.E. Sugarman, and L.M. Vagge, Harvard Medical School, Boston, and Alcohol and Drug Abuse Program, McLean Hospital, Belmont, MA This prospective study of 41 women and 60 men with alcohol dependence investigated the relationship between gender, history of sexual and/or physical abuse, and return to drinking following discharge from inpatient alcohol treatment. Structured interviews and selfreport measures were conducted during hospitalization and monthly for one year following discharge. We found that women were more likely than men to have a history of sexual abuse. However, there were no overall significant differences between men and women in drinking outcomes. An inability to remain abstinent was more common among those who were sexually abused (x’ = 7.16, df = 1, P = 0.007), as was relapse to drinking (x2 = 7.11, df = 1, P = 0.008). Time to first drink was found to be shorter for those who were sexually abused. Marital status, education, employment, and co-occurring major depressive disorder were also associated with poor drinking outcomes. When adjusted for these characteristics, the association of sexual abuse with shorter time to first drink became non-significant. Thus, the adverse impact of a history of sexual abuse on drinking outcomes may have been attributable to a number of other characteristics associated with sexual abuse history such as co-occurring depression, unemployment, fewer years of education, and unmarried status. 223

OPIOID

VATION FECTS

CRAVING,

DRUG

SEEKING

IN METHADONE-MAINTAINED OF

PRIMING

AND

EEG

VOLUNTEERS: INJECTIONS

AND

ACTIEFDRUG

AVAILABILITY

M.K. Greenwald and T.A. Roehrs, Wayne State University and Henry Ford Hospital, Detroit, MI This study is examining the ‘setting’ conditions for drug craving in relation to drug seeking behavior. Methadone-maintained subjects (60-70 mg/day: n = 6 to

s19

date) participate in an 8-session, double blind study. In session 1, fentanyl administered q. 20 min (cumulating to 0, 0.25,0.75, 1.5 mg/70 kg i.v.) produces dose-related decreases in heroin craving, and increases in opioid symptoms, positive affect and respiratory depression. Fentanyl produces dose-dependent EEG amplitude increases (6, 8) and frequency shifts (6 and p-2 speeding, alpha slowing) that are generalized but sometimes greater at anterior vs. posterior recording sites. In session 2, fentanyl (1.5 mg/70 kg iv. bolus) and saline placebo are self-administered 2 h apart in counterbalanced order. Bolus fentanyl injection produces effects similar to the high dose in session 1. All subjects prefer fentanyl to placebo. In sessions 3-8, subjects receive a priming injection (saline, fentanyl 0.75 mg/70 kg, or naloxone 0.1 mg/70 kg i.v.; each given in 2 sessions) and can complete 15 FRlOO schedules to earn units of fentanyl self-administration (1.5 mg/70 kg bolus) or its money equivalent (from session 2; M = $17.83) at 90 min post-treatment. Saline, fentanyl and naloxone each precede drug vs. money availability. Relative to saline, naloxone priming increases opioid withdrawal and negative affect, whereas fentanyl produces opposing effects. Rates of responding (FRlOO) and EEG activation are similar across test conditions; subjects generally earn all units of the available reinforcer. Heroin craving is not systematically higher during drug (than money) availability. Fentanyl self-administration dramatically increases EEG activation, increases opioid effects and reduces craving, similar to session 2. Supported by NIDA grant R29 DA11079. 224 DUALLY STANCE

Los

COORDINATION

OF

DIAGNOSED: ABUSE

FINDINGS AND

MENTAL

SERVICE FROM HEALTH

DELIVERY A SURVEY

TO

THE

OF SUB-

PROVIDERS

IN

ANGELES

C.E. Grella, V. Gil-Rivas, L. Cooper, and A. Hamilton, University of California, Los Angeles, CA Service delivery to patients with co-occurring substance use and mental disorders requires coordination across the substance abuse and mental health treatment systems. Yet these two systems historically have had separate administrative and financial structures and divergent treatment approaches. This study will present findings from a survey conducted with administrators and staff from 12 substance abuse treatment programs and 10 mental health treatment programs within Los Angeles County. Comparisons across substance abuse and mental health treatment programs will be made on the types of services most frequently provided to dually diagnosed patients, services needed but not provided, linkages with other service providers, types of service models used by programs (e.g. parallel or integrated), referrals sources, staff training regarding dual diagno-

Abstracts

S80

sis, use of specialized treatment protocols for dual diagnosis, treatment approaches, assessment instruments, admission and discharge policies, attitudes and beliefs about mental illness and substance abuse, and their overall evaluation of the service delivery systems for dually-diagnosed patients. The findings will provide information useful for developing policies on improving coordination across substance abuse and mental health treatment systems and service delivery to the duallydiagnosed. 225

INTERGENERATIONAL

PACT

ON

THE

THIRD

SUBSTANCE

ABUSE:

THE

IM-

GENERATION

A.S. Griffing, D.F. Ragin, S.M. Morrison, R.E. Sage, L. Madry, L.E. Bingham, and B.J. Primm, Urban Women’s Retreat, New York, Urban Resource Institute, Brooklyn, NY This study examines the relationship between two variables - intergenerational substance abuse and suicide - for battered women. Preliminary analysis on a sample of 50 battered women residing in an emergency domestic violence facility reveal that a family history of substance abuse, specifically grandmother’s alcohol abuse and mother’s drug abuse, correlates significantly with higher incidents of attempted suicide for this group of battered women during their teenage and/or early adult years. While other variables such as step-father’s drug abuse and father’s alcohol abuse also show a strong correlation with attempted suicide, logistic regression analyses reveal that only grandmother’s alcohol (P < 0.01) and mother’s drug abuse (P < 0.03) account for a significant amount of the variance for incidents of attempted suicide. These findings may provide new insight into one of the long-term impacts of parents’ substance use on their children. Past studies suggest that children of substance abusing parents may perpetuate the cycle of abuse as a coping mechanism or as a means of self-medicating against the neglect of care. These findings, which report on multiple generations, may suggest that in the absence of coping mechanisms this population may attempt suicide when substance abuse is present in more than one generation. The implications of this study for programs that provide services to battered women will be explored. An analysis based on 150 women will be reported at the conference. 226

TIME-DEPENDENT

IN RESPONSE

J. Grimm, NIDA/IRP,

TO

CHANGES DRUG-RELATED

IN COCAINE CUES

J. Yap, D. Highfield, Baltimore, MD

SEEKING

IN RATS

and Y. Shaham,

Drug-paired cues provoke relapse to cocaine seeking in drug-free rats. The effect of these cues on relapse at different time points after cocaine withdrawal, however, is not known. Rats were trained to press a lever for IV cocaine for 10 days (0.5 mg/kg per infusion, two 3-h sessions/day). Each response on the drug-associated lever resulted in a cocaine infusion, and a presentation of a tone + light compound cue for 5 s. The rats were then tested for reinstatement of cocaine seeking after 1 (n = 11) or 15 (n = 9) days of withdrawal from the drug. During the test day, rats were given 6-8 60-min sessions (separated 5 min apart) during which lever presses were not reinforced and the tone + light cue was not presented. After reaching a criterion of less than 15 responses per 60 min on the lever previously associated with cocaine, the effect of the tone + light cue on reinstatement of cocaine seeking was assessed in a session in which each lever press resulted in the cue presentation. Presentation of the tone + light resulted in a large increase in responding on the lever previously associated with cocaine after 15 days of withdrawal (P < 0.05). In contrast, 1 day after withdrawal from the drug, the drug cue had a minimal effect on reinstatement of responding (P > 0.05). Furthermore, after 1 day of withdrawal, the rate of non-reinforced lever pressing prior to the cue session was markedly lower than that observed after 15 days of withdrawal from cocaine (P < 0.05). We are currently studying molecular changes associated with the differential susceptibility to relapse at these different time points. Supported by NIDA/IRP. 227 FOR

RIGID 01,

NICOTINE

ANALOGS

SUBUNIT-CONTAINING

ACETYLCHOLINE

PROVIDE NEURONAL

SELECTIVITY NICOTINIC

RECEPTORS

V.P. Grinevich, R. Xu, P.A. Crooks, A.J. Haubner, R. Papke, and L.P. Dwoskin, University of Kentucky, Lexington, KY, and IJniversity of Florida, Gainesville, FL To determine the rotameric preference at the C(3)-C(2’) bond of the nicotine molecule for interaction with several nicotinic acetylcholine receptor (nAchR) subtypes, we synthesized rigid analogs of nicotine representing syn- and anti-rotamers. The binding assays used [3H]methyllycaconitine ([3H]MLA) to probe the a7 and [3H]nicotine ([3H]NIC) to probe the alpha4beta2 nAchRs on Sprague-Dawley rat brain membranes. NIC-evoked [3H]dopamine release from striatal slices probed putative c& nAchRs. Neither the syn- nor the unti-rotameric NIC analogs interacted with the qp2 subtype. The anti-rotameric analogs did not displace either [3H]MLA or [3H]NIC. The syn-rotameric analogs ACME and ATME displaced [3H]MLA with a similar potency to NIC (Ki = 0.59, 2.49 and 0.77 PM,

Abstracts

respectively) and were markedly less potent in displacing [3H]NIC than was NIC (Ki = 0.4,0.6 PM and 1.3 nM, respectively). The results suggest that restricting the rotation of the C(3)-C(2’) bond of the nicotine molecule to the syn conformation affords analogs that interact with a, receptors in a manner similar to NIC, but in contrast, disrupt the interaction with c& receptors. An electrophysiological evaluation was conducted on nAChR subtypes expressed in Xenopus oocytes. Several of the compounds behaved as partial agonists of CI, receptors, with ATME being the most efficacious, activating about 20% maximal currents and having a potency similar to ACh. In contrast, responses to ATME were less than 1% the ACh maximum for a,& a&, and muscle-type receptors, confirming an apparent selectivity for q-type AChR. This drug design approach may therefore be of use in the development of novel therapeutic agents targeting q-containing receptors. Supported by DA10934 and DA00399. 228 SUS NENCE

A

COMPARISON

CONTINGENT DURING

OF CONTINGENT DOSE

REDUCTIONS

BUPRENORPHINE

VOUCHERS ON

OPIOID

VERABSTI-

TREATMENT

A. Gross, W.K. Bickel, and E.A. Jacobs, University of Vermont, Burlington, VT This study compares the relative efficacy of contingent vouchers with the efficacy of contingent dose reductions in promoting abstinence from illicit opioids and cocaine. Following an 8 week baseline period, opioid-dependent subjects are assigned to one of three treatment groups, contingent vouchers, contingent dose reductions or a control group for a duration of 12 weeks. Subjects in the contingent voucher group receive vouchers for each opioid-and cocaine negative sample. Subjects in the contingent dose reduction group have their buprenorphine doses reduced for 2 consecutive days for each opioid- or cocaine positive urine sample. Subjects in the control group receive standard-drug counseling and do not receive any additional incentives to promote drug abstinence. All subjects are maintained with buprenorphine according to a 3 x per-week dosing regimen (4 mg per 70 kg or 8 mg per 70 kg daily) and participate in standard drug counseling. Treatment retention and the mean number of consecutive weeks of opioid- and cocaine abstinence generated by the two incentives will be compared to determine the relative efficacy of the two conditions. Preliminary data from 28 opioid-dependent subjects (voucher group = 9; dose reduction group = 11; control group = 8) suggest that participants in the dose reduction group achieved greater mean weeks of consecutive opioid- and cocaine abstinence compared to both other groups. Seventythree percent (S/l 1) participants in the dose reduction

S81

group completed the 12 weeks treatment versus 67% (6/9) in the voucher group. All participants in the control group completed treatment. Participants’ subjective ratings of effectiveness appear to parallel results from urinalysis. 229

NEUROCOGNITIVE

METHADONE

DEFICITS

IN

SUBJECTS

ON

MAINTENANCE

S.A. Gruber, A.D. Young, M.H. Pollack, M.J. Kaufman, C.I. Diaz, P.F. Renshaw, and D.A. YurgelunTodd, McLean Hospital, Harvard Medical School, Belmont, MA Studies of opiate-dependent methadone maintenance patients have identified decreased neurocognitive performance. However, the studies have been limited by a number of factors, and have produced inconsistent results. In the present study, neuropsychological tests were administered to a group of opiate-dependent subjects enrolled in a methadone maintenance program (N= 30) and a comparison group of healthy control subjects (N = 23). In general, methadone maintenance subjects performed significantly more poorly than controls on the figures subtest of the Wechsler Memory Scale (t = 5.11, P < O.OOOl), the Trailmaking Test Part B (t = - 4.47, P <. O.OOOl), and the Wisconsin Card Sort Test (perseverative errors, t = - 2.322, P = 0.02, total categories achieved, t = 2.81, P < 0.01). The pattern of scores displayed by the methadone maintenance subjects indicated reduced encoding on immediate recall of simple visuospatial information with no additional decay of newly learned information. In contrast, these subjects did not perform significantly worse on the immediate or delayed recall of verbal information. This data indicates that compared to healthy controls, individuals undergoing methadone maintenance display cognitive deficits in a number of functional domains including verbal and visuospatial memory, sustained attention and mental flexibility. The presence of neuropsychological impairments identified in these patients indicates that there is potential to assess improvement in cognitive function as well as cerebral metabolism with extended methadone maintenance. 230

DESIGN,

TIES

OF

SYNTHESIS

SEVERAL

AND

HYDROXYLATED

BIOLOGICAL DERIVATIVES

PROPEROF

INDATRALINE

X.H. Gu, H. Yu, R.B. Rothman, C.M. Dersch, J.S. Partilla, and K.C. Rice, NIDDK, NIH, and Intramural Research Program, NIDA, NIH, Baltimore, and Bethesda, MD The abuse of methamphetamine (METH) and other amphetamine-like stimulants is a growing public health

Abstracts

S82

problem in United States. Although selective DA reuptake inhibitors might block the reinforcing effects of METH, such agents would not protect against the other adverse effects mediated by NE and 5-HT transporters. As part of our research program to discover nonselective reuptake inhibitors with high affinity for DA, 5-HT and NE transporters and which are also amenable to formulation as a long-acting depot medication, we have designed and synthesized several hydroxylated derivatives of indatraline. Pharmacological studies are underway, and the results will be presented. 231

THE HPA AXIS AND METHAMPHETAMINE

ADMlNISTRATION

SELF-

1N RATS

G.F. Guerin, R.L. Peltier, and N.E. Goeders, LSU Health Sciences Center, Shreveport, LA Research from our laboratories and others has demonstrated an important role for stress and the subsequent activation of the hypothalamo-pituitary-adrenal (HPA) axis in the reinforcing properties of drugs of abuse. More specifically, this laboratory has demonstrated that pretreatment with the corticosterone synthesis inhibitor, ketoconazole (Goeders et al., 1998) or the small molecule CRF receptor antagonist, CP-154 526 (Goeders and Guerin, 1999) decreases low-dose cocaine selfadministration in rats. The current experiments were designed to examine whether or not these same compounds would also affect methamphetamine (METH) self-administration. Adult male Wistar rats were implanted with chronic indwelling jugular catheters and trained to respond on an alternating schedule of food and METH self-administration. Rats were allowed 30 min access to food (45 mg pellets), which was followed by 30 min access to METH (0.03,0.06 or 0.12 mg/kg per infusion) during daily 4 h sessions. Once stable rates of responding were observed, rats were pretreated intraperitoneally with vehicle (5% emulphor in 0.9% saline), ketoconazole (25 mg/kg) or CP-154 526 (20 mg/kg) 30 min prior to the start of the behavioral session. Pretreatment with either ketoconazole or CP154 526 significantly reduced low-dose METH self-administration, although ketoconazole appeared to be slightly more effective than CP-154 526. When the dose of CP-154 526 was increased to 40 mg/kg, ip, responding maintained by METH was completely eliminated, These results are very similar to the effects of these drugs on cocaine self-administration and clearly demonstrate that the HPA axis can also influence METH reinforcement. This work was supported by USPHS grant DA06013 from the National Institute on Drug Abuse.

232 PREVALENCE OF HEPATITIS MARY METHAMPHETAMINE USERS

VIRUS

AMONG

PRI-

V. Gulati, A. Huber, K. Chan, P. Chhabra, and R. Gonzales, Friends Research Institute, Inc., Easton, MD, Long Beach Research Foundation/VAMDRU, Los Angeles, CA Hepatitis infection is a major cause of chronic liver disease. Hepatitis virus is prevalent among injection (IV) drug users, but less so among non-injection users. Illegal drug use and high-risk sexual behavior are two factors strongly associated with hepatitis infection among individuals aged 18-59. This report examines the risk behaviors and hepatitis status of 98 primary methamphetamine-abusing participants (64 males and 34 females) who entered treatment in a NIDA-funded study in San Bernardino County between 1999 and 2000. Participants completed a physical exam including CBC, Chem. 40, urine toxicology and hepatitis screening. Socio-demographic, drug use, HIV-risk behavior and psychosocial data were also obtained. Results indicate a high incidence of hepatitis virus in both IV and non-injecting methamphetamine users. Prevalence of Hepatitis was found at a higher rate than national average: Hep A-21.0%, Hep B-16.3%, and Hep C-23.5%. Intravenous methamphetamine use was reported by 27 (27.6%) participants, and 91.3% of the Hep C-infected individuals in the sample were from this group. Results also indicate that 66.7% (18 of the 27 participants) of IV users were infected with Hep C virus. Results showed that many participants were unemployed (44.8%), had more than one sexual partner (66.7%), and used multiple drugs (90.8%). Results suggest that a substantial number of subjects who engage in hepatitis-risk behaviors fail to employ preventive practices. Majority of them (66.7%) had unprotected sex in the last month and 18.8% of IV users reported using dirty needles. These data support the need for expanded community outreach education to this population to prevent transmission and the need for increasing resources to make Hepatitis testing more accessible to MA users. This work was supported by NIDA grant ROl DA 10923 233

THEINFLUENCEOFNONCONTINGENTVOUCHERS ONDRUG USE BEHAVIOR

A.E. Gupman, D. Epstein, A. Umbricht, Preston, NIDA-IRP, Baltimore, MD

and K.L.

We have conducted several studies using noncontingent vouchers to control for the possible beneficial effects of financial support in voucher-based contingency management drug treatment trials. A frequently asked question in oral presentations and grant and manuscript reviews has been whether noncontingent vouchers might inadvertently reinforce drug use and worsen out-

Abstracts

come in control groups. In this retrospective study we tested this by comparing urine screen results and voucher earnings from a recent opiate treatment trial. Patients in the contingent group received vouchers with monetary value for each opiate-negative urine specimen. Patients in the noncontingent group received vouchers independent of their urine results in a seemingly random fashion, but matched in value and pattern to participants in the contingent group. All vouchers were exchangeable for goods and services; maximum earnings were $554 over 8 weeks. Patients receiving noncontingent vouchers had 17% opiate-negative urines during the 5 week baseline and 39% during the 8 week intervention. On average they received vouchers worth $182.56 in the intervention phase. Analyses indicate no correlation between proportion of vouchers received on opiate positive days, nor proportion received on opiate negative days, although baseline opiate use, methadone dose and number of days missed during intervention were correlated. Thus, there was no evidence that noncontingent vouchers increase use of heroin. 234 ON

COMORBIDITY WELFARE:

ABUSE,

MENTAL

MONTH

OUTCOMES

IN

SUBSTANCE

RELATIONSHIP DISORDERS,

ABUSING

BETWEEN VICTIMIZATION,

WOMEN SUBSTANCEAND

3

M. Gutman, R. Ketterlinus, A.T. McLellan, J. Willem, L. MacPherson, and B. Harris, Treatment Research Institute at the University of Pennsylvania, Philadelphia, PA Recent epidemiologic studies have shown that between 30 and 60% of drug abusers have concurrent mental health diagnoses. Research shows that comorbidity complicates drug abuse treatment, and therefore must be accounted for in treatment outcome studies (Leshner, 1999). The present report utilizes interim data to present a description of patterns of comorbidity among a sample of substance abusing women on welfare who are participating in a demonstration program (CASAWORKS for Families, CW) that provides integrated services in multiple domains including substance abuse treatment, employment services, psychiatric services, and other social services. Of particular interest is the relationship between victimization history (physical or sexual), mental disorders, and alcohol/drug abuse. Patterns of comorbidity in this sample are compared to patterns among similar types of women in a) standard drug/alcohol treatment programs (Philadelphia Target Cities, TC), and b) a general population of women on welfare (WAGES Florida study). Women with different patterns of comorbidity are compared on key outcomes (substance abuse status and employment status) at 3 months post-baseline. The key measures of comorbid conditions and outcomes include the ASI-Welfare-to-

S83

Work (WTW) version, TSR-WTW, CES-D4, and PDS (self-report measure of PTSD). Interim findings indicate that a larger percentage of substance abusing women on welfare have multiple co-morbidities (victimization, mental disorders, and alcohol/drug abuse) than a general sample on welfare, and that a larger percentage of women in CW have multiple co-morbidities than women in standard treatment (TC). Further substance abusing women on welfare (CW sample only) who have a history of victimization, more severe alcohol problems, and at least one prior episode on welfare of 1 year or more, are less likely to be employed at 3 months post-baseline. Substance abusing women on welfare who have a more severe alcohol problem are less likely to be abstinent at 3 months after enrollment. 235 POUNDS FORCING

DIFFERENTIAL ON

EFFECTS

THE

DISCRIMINATIVE

EFFECTS

OF COCAINE

OF

DI-

AND

D&LIKE

STIMULUS IN LEWIS

COM-

AND AND

REIN-

FISCHER

RATS

C.N. Haile and T.A. Kosten, Thomas Jefferson Medical College, Philadelphia PA, and Yale University School of Medicine, New Haven, CT Lewis (Lew) and Fischer (F344) inbred rats differ in their behavioral response to cocaine (Cot). They also show altered D2-like, but not Dl-like, receptor concentrations in N. accumbens. Thus, we tested if DI- and DZlike agents produce differential effects on the discriminative stimulus (DS) and reinforcing effects of Cot in these strains. Rats were trained to discriminate Cot (10 mg/kg IP) from saline in a 2-lever, food-reinforced FRlO) procedure. Trials to acquire Cot DS (4 days > 90% lever-appropriate responding) did not differ between strains and pharmacological specificity was seen in both strains. The highest dose of the DZlike agonist, quinpirole (1 mg/kg), substituted but the partial Dl-like agonist, SKF38393, did not in both strains. At the highest dose tested, the Dl-like antagonist, SCH23390 (1 mg/kg), but not the D2-like antagonist, eticlopride antagonized the Cot DS in both strains. Overall, most drugs decreased response rates more in F344 rats. Separate groups of rats self-administered Cot (0.25-l mg/ kg per infusion; FR3). SCH 23390 (0.01 mg/kg) shifted the Cot dose response function to the right more so in F344 rats. In contrast, eticlopride (0.03 mg/kg) produced a complete rightward shift of the dose-response function in Lew, but not F344 rats. These differential effects of Dl- and D2-like compounds on Cot self-administration but not in Cot DS between Lew and F344 rats may be due to differences in DA receptor sub-type populations involved in the reinforcing but not DS effects of Cot. Support: NIDA 04060.

Abstracts

S84

236

COCAINE,

AMONG BAN,

ALCOHOL,

UNDER-SERVED, AFRICAN

AMERICAN

MARIJUANA,

AND

PREDOMINATELY

ANXIETY POOR,

UR-

WOMEN

H. Hall and L. Singer, Case Western Reserve University, Rainbow Babies and Children’s Hospital, Cleveland, OH We tested the hypothesis that 53 women from an under-served population with a history of cocaine use during pregnancy (Group 1) would have higher levels of state and trait anxiety and dissociative states than women who were either negative for cocaine, alcohol and marijuana during pregnancy (Group 0); or negative for cocaine, but positive for alcohol and/or marijuana (Group 2). Women who were being followed as part of a neurodevelopmental study (NIDA grant # 07957 and # 07957-06) on cocaine and infant development were administered scales for anxiety and dissociative tendencies. Analysis of Variance conducted to examine group differences found no statistically significant differences between the three groups on any of the measures. There was some suggestion that Group 2 had higher levels of state anxiety (M= 43) than either Group 0 (M = 40), or Group 1 (M= 39). The same pattern was seen for trait anxiety for Group2 (M = 43) versus Group 0 (A4 = 37) and Group 1 (M = 39). This study should be replicated with a larger sample size to determine if anxiety states differ for women with a positive history of cocaine use, negative history of cocaine use, but positive history of alcohol and/or marijuana use, or no history of drug use. Such information may provide new insight on the neurobiological impact of cocaine and other drugs on anxiety states in women. 237

DRUG

DEPENDENT

WOMEN

AS

VICTIMS

AND

VICTIMIZERS

D.L. Haller, D. Miles, D.S. Svikis, and A. Amponsah, Medical College of Virginia of Virginia Commonwealth University, Richmond, VA Drug dependent women frequently report experiences of both childhood and adult abuse. Less is known about their abuse of others, however. This study explored associations between childhood abuse, psychiatric morbidity, addiction severity, and current victimization/perpetration among 111 perinatal substance abusers presenting for residential treatment. Incidence of victimization (past 30 days) was 71% emotional, 34% physical, 30% sexual, 42% personal freedom violations and that of perpetration was 74% emotional, 3 1% physical, 4% sexual and 11% personal freedom violations. The final model in the stepwise regression on current victimization included childhood

physical abuse, AS1 drug composite score, dysthymia, and borderline personality disorder. The strongest predictor of current victimization was a diagnosis of borderline personality disorder (OR = 7.94). The final model for perpetration included AS1 drug and psychiatric composite scores, narcissistic and aggressive-sadistic personality disorders. Hundred percent of women with aggressive-sadistic personality disorder were admitted perpetrators (OR = 10.78) although this was not significant due to the value 1 falling in the confidence interval. Surprisingly, childhood sexual abuse, anxiety, somatic complaints, PTSD, and antisocial personality disorder failed to predict current abuse or perpetration in this population. Presence of predictive variables should raise the ‘index of suspicion’ for involvement in abusive relationships and may assist the clinician in treatment planning. This work was supported by Grant # HS4 T100555. 238

EFFECTS

TOMS

FOLLOWING

OF

BUPROPION SMOKED

ON MARIJUANA

ABSTINENCE IN

SYMP-

HUMANS

M. Haney, AS. Ward, S.D. Comer, C.L. Hart, R. W. Foltin, and M.W. Fischman, New York State Psychiatric Institute and Columbia University, New York, NY Symptoms of withdrawal after daily smoked marijuana smoking include increased ratings of irritability and depression. Medications that ameliorate these symptoms may improve outcome for individuals seeking treatment for marijuana dependence. Given the successful use of sustained-release bupropion in treating nicotine dependence, this study investigated how maintenance on bupropion influenced symptoms of marijuana withdrawal compared to maintenance on placebo. Marijuana smokers (n = 10) were maintained outpatient on active (300 mg per day) or placebo (0 mg per day) bupropion for 11 days, and were then maintained inpatient on the same bupropion dose for 17 days. For the first 4 inpatient days, participants smoked active marijuana (2.8% THC) 5 times per day. For the remaining inpatient days, participants smoked placebo marijuana (0.0% THC) 5 times per day. Participants were then maintained outpatient on the alternate dose of bupropion for 11 days, followed by a second inpatient residential stay, paralleling the first. Mood, psychomotor task performance, food intake and sleep were measured daily during each inpatient phase. The order of active and placebo bupropion maintenance was counter-balanced between groups. Bupropion had few behavioral effects when participants smoked active marijuana. During placebo marijuana smoking, i.e. active marijuana withdrawal, ratings of irritability, restlessness, depression, and trouble sleeping were increased by bupropion compared to placebo mainte-

S85

Abstracts

nance. These data suggest that bupropion would not be an effective treatment medication for marijuana dependence. 239

GENETIC

POLYMORPHISMS

AND TEMPERAMENT

J.M. Harrer, S.L. Neale, B. Singal, N.M. Richtand, D. Feldman, S. Lipsom, J. Nolan, E. Somoza, and D.W. Nebert, VA Medical Center and University of Cincinnati, OH Several studies have pointed to a possible relationship between various dimensions of temperament, novelty seeking (NS), harm avoidance (HA) or reward dependence (RD) and the neurotransmitters dopamine or serotonin. This observation is important because some of these behaviors may be related to the propensity for development of substance abuse. In this study, multivariate analysis was used to determine whether NS, HA or RD, as measured by the Tridimensional Personality Questionnaire (TPQ), is associated with polymorphisms in the D4 dopamine receptor (D4DR), dopamine transporter (DATl), or serotonin transporter (SHTT) genes. The study population included 110 medically stable volunteers. No significant associations were found between HA or RD and any of the polymorphisms analyzed. A significant association was found between the D4DR polymorphism and NS when age and gender were included in the model as possible confounding variables. Although there was no significant effect of the DATl polymorphism on NS alone, there was a significant interaction between DATl and D4DR polymorphisms. Results from this study indicate that age and gender are important confounding variables in determining the relationship between genetic polymorphisms and personality traits. The data offer further confirmation of a relationship between the brain dopamine system and NS behavior. Moreover, the development of human temperament is likely to be associated with the interaction of multiple genes and environmental factors. Supported in part by NIDA grant YOl DA.500038. 240 PREVALENCEOFPERSONALITYDISORDERSINAN OUT-OF-TREATMENT SAMPLE OF YOUNG DRUG USERS

C. Harrington, C. Latkin, and S. Strathdee, Johns Hopkins School of Public Health, Baltimore, MD Objective: Previous research of psychiatric comorbidity among injection drug users (IDUs) has primarily focused on antisocial personality disorder (ASPD), mainly among clinic populations and/or adults. We determined the prevalence of Axis II personality disorders among an out-of-treatment sample of young IDUs and non-IDUs (NIDUs) in Baltimore, Maryland.

Methods: Young adults aged 15-30 who initiated injection drug use < 5 years prior (IDUs), or who had smoked, snorted or sniffed cocaine and/or heroin for 1 - 10 years (NIDUs) were recruited into a prospective study of HIV risk behaviors, At baseline, subjects underwent interviewer-administered questionnaires, which included the Millon Clinical Multiaxial Inventory personality test (based on DSM- III and IV). Results: Of 71 subjects recruited to date, 54% were IDUs and 46% were NIDUs. Most were female (60%) and African American (85%). Mean age was 27 years. Frequencies of Axis II personality disorders were as follows: Antisocial (ASPD): 8X/o, Narcissistic (NPD): 10.9% and Avoidant (APD): 8.0%. Relative to males, a higher proportion of females met criteria for NPD (18.3% vs.7.0%) and ASPD (9.9’h vs. 7.0%); however, prevalence among males was higher than females for APD (9.9’/, vs. 5.6%). Prevalence rates were not significantly higher for IDUs compared to IDUs (P > 0.05). Conclusion: These preliminary data suggest that personality disorders are relatively common among young drug users in our setting. Female drug users had higher a higher prevalence of NPD, whereas males had a higher prevalence of APD. Further studies will be conducted to confirm gender differences in these personality disorders and will focus on the relationship between these conditions and drug using behaviors. 241 LOBELINE NONCOMPETITIVELY AMPHETAMINE SELF-ADMINISTRATION

INHIBITS IN RATS

METH-

S.B. Harrod, J.E. Klebaur, S.B. Phillips, P.A. Crooks, L.P. Dwoskin, and M.T. Bardo, University of Kentucky, Lexington, KY Lobeline inhibits amphetamine evoked dopamine (DA) release from striatal slices in vitro and appears to reduce the cytoplasmic pool of DA available for reverse transport by methamphetamine. To determine if lobeline’s mechanism of action would translate to inhibition of methamphetamine’s effect in vivo, the present experiments determined if lobeline inhibited methamphetamine self-administration in rats. Rats (n = 6) were surgically implanted with jugular catheters and following recovery, were trained to lever press on an FR5 schedule for intravenous methamphetamine. Another group of rats (n = 6) were trained to lever press on an FR5 schedule for sucrose, but did not undergo surgery. Lobeline (0.03-3.0 mg/kg, pretreatment 15 min prior to the operant session) dose-dependently inhibited responding for methamphetamine and for food reinforcement. Following repeated administration, tolerance developed to the lobeline (3.0 mg/kg)-induced suppression of responding for food; however, the lobeline-induced suppression of responding for methamphetamine persisted. The lobeline-induced suppression of respond-

Abstracts

S86

ing for methamphetamine was not surmounted by increasing the unit dose of methamphetamine. The results suggest that acute lobeline has a nonspecific rate suppressant effect. More importantly, repeated lobeline specifically, and in a noncompetitive manner, reduced responding for methamphetamine. Thus, lobeline may be an effective, novel pharmacotherapy for methamphetamine abuse. 242 METHAMPHETAMINE DISCRIMINATION MANSUNDERANOVELRESPONSEPROCEDURE:EFFECTS OFTHE NMDA ANTAGONISTMEMANTINE

BY

HU-

C.L. Hart, M. Haney, C. Pudiak, R.W. Foltin, and M.W. Fischman, Columbia University and New York State Psychiatric Institute, New York, NY The purpose of this study was to test the discriminative stimulus effects of methamphetamine (MA) following acute memantine (a noncompetitive NMDA antagonist) pretreatment. Four male volunteers were trained to discriminate oral MA (10 mg) from placebo. During these sessions, they also received placebo memantine (oral) 2 h prior to MA administration. Following acquisition of the MA discrimination, the effects of memantine (0,40 mg) were examined across several MA doses (0, 5, 10, 20 mg) using a novel-response drug discrimination procedure. This procedure offered participants a ‘novel’ response alternative appropriate for effects unlike the training drugs. In the presence of placebo memantine, the training dose of MA (10 mg) produced 95% methamphetamine-appropriate responding. Lower and higher MA doses were experienced as placebo (0, 5 mg) and novel (20 mg), respectively. Active memantine produced novel responding across all MA doses, and disrupted MA-appropriate responding produced by the training dose. Active memantine pretreatment increased subjective ratings produced by methamphetamine, including ‘High,’ ‘Stimulated,’ ‘Good Drug Effect,’ ‘Drug Liking,’ and the amount of money willing to pay for the drug. These preliminary data suggest that the discriminative stimulus effects of MA are dissimilar to those of memantine, but that memantine enhances subjective effects produced by MA. Moreover, the present findings are consistent with data from clinical laboratory studies reporting that memantine increased several cocaine-induced subjective effects. Supported by NIDA grant DA09236. 243 SYNTHESISANDPHARMACOLOGYOFNEW,OPTICALLYPURE N-SUBSTITUTEDPHENYLMORPHANS A. Hashimoto, R.B. Rothman, C.M. Dersch, R. Horel, A.E. Jacobson, and K.C. Rice, NIDDK, and ARC, NIDA, NIH, Baltimore, and Bethesda, MD

Interest in the phenylmorphans was stimulated by the reports of May et al. (1950’s), that the enantiomers of N-methylphenylmorphan had potent opioid agonist and agonist-antagonist activity, depending on the enantiomeric form. We previously reported (Hashimoto et al., CPDD Abstracts, 1999) our initial finding that ( - )-N-phenylethylphenylmorphan (1) had unexpected pharmacological activity. Our data indicated that it was a relatively pure narcotic antagonist. Since the Nphenylethyl moiety generally confers potent agonist actions in the well-known multi-ring morphinan and benzomorphan series of opioids, we questioned whether other well-known N-substituents, besides the Nphenylethyl, could act differently in the phenylmorphans than they do in the morphinans. We have, thus, now synthesized a number of different enantiomeric N-substituted phenylmorphans, and we will report their synthesis and pharmacology. 244 DEPRESSIVE EPISODES DURING FOLLOW-UP REDUCE THE CHANCE OF SUSTAINED REMISSION FROM HEROIN,COCAINEANDALCOHOLDEPENDENCE:METHADONE AND DUAL-DIAGNOSIS PATIENTS D. Hasin, X-H. Liu, E. Nunes, S. Samet, S. McCloud, and J. Endicott, Columbia University, New York, and Psychiatric Institute, New York, NY Among patients with heroin, cocaine and alcohol dependence, we hypothesized that major depressive episodes occurring during follow-up would reduce the subsequent chances of stable remission from alcohol, cocaine and heroin dependence. Longitudinal studies often focus on the effects of clinical predictors as evaluated at the time of a baseline evaluation. However, conditions such as depression can change, so we focussed on depression as a time-varying predictor. We studied 457 patients (a subset from a larger study) who met full criteria for DSM-IV heroin, cocaine and/or alcohol dependence, 207 from methadone maintenance and 250 from dual-diagnosis programs. Patients were evaluated with the PRISM interview and re-evaluated one to three times subsequently, with a mean of 54 weeks of follow-up. Survival analysis was used to analyze the effects of depressive episodes (primary and substance-induced) during the follow-up as time-varying predictor variables, in conjunction with other demographic and clinical features. The outcome variable was the onset of stable remission (at least 26 weeks) from all symptoms of heroin, cocaine and/or alcohol dependence. Depressive episodes assessed only at baseline were not related to remission. In the dual-diagnosis patients, substance-induced depressions during the follow-up reduced the chances of subsequent remission. In the methadone patients, primary depressions exerted a more complex effect, interacting with age. These results

ss7

Abstracts

suggest that clinical attention to depression may improve the outcome of dependence on one or more substances, and that the DSM-IV primary/substanceinduced distinction is clinically meaningful. 245

CHARACTERISTICS

WITHOUT

COCAINE

OF

COCAINE

WITHDRAWAL

USERS

WITH

AND

SYMPTOMS

D.K. Hatsukami, S. Brown, D.A. Babb, and M. Sofuoglu, University of Minnesota, Minneapolis, MN Cocaine users frequently report withdrawal symptoms although the clinical implications of the presence of cocaine withdrawal symptoms are not well understood. The purpose of this study was to better characterize cocaine users with or without self-reported cocaine withdrawal symptoms. The study sample was 555 nontreatment seeking cocaine users who were screened on the phone as potential subjects for inpatient studies. Of the 555 subjects, 462 (82%) fulfilled DSM-IV criteria for cocaine withdrawal symptoms and the other 93 (18%) did not. Cocaine users reporting cocaine withdrawal (group I), compared to those who did not (group II), had a significantly (P < 0.05) longer duration, higher amount and frequency of cocaine use and spent more money on cocaine. Group I was more likely use smoked cocaine and use marijuana and narcotics, compared to group II. History of medical complaints including headaches, dizziness, chest pain and racing heart, emergency room visits and change in personal values, family relations, appearance and sexual values as a result of drug use were more frequent in group I. Similarly, group I was more likely to have a history of depression or seriously consider suicide and have chemical dependency treatment. With few exceptions, these group differences continued after correcting for higher spending, a measure of quantity of use, in group I. These results suggest that the presence of cocaine withdrawal symptoms are associated with more frequent medical, mental health and psychosocial problems in cocaine users. Supported by NIH grants P-50 DA09259, and MOlRR00400. 246

MOTIVATIONAL

TOBACCO

DEPENDENCE

PREGNANT

WOMEN

ENHANCEMENT IN

THERAPY

FOR

METHADONE-MAINTAINED

N.A. Haug, D.S. Svikis, C.C. DiClemente, H.E. Jones, and M.L. Stitzer, Johns Hopkins University School of Medicine, University of Maryland, Baltimore, MD Pregnant methadone-maintained cigarette smokers are a subgroup of substance abusers in need of effective treatment for tobacco dependence due to their high risk for health complications. This two-group randomized

trial compared the effectiveness of Motivational Enhancement Therapy (MET) to standard care advice (SC) for reducing tobacco use during pregnancy. The intervention group (n = 27) received up to 4 sessions of MET tailored to stage of change over 6 weeks, and the SC group (n = 30) was given advice and written materials on smoking during pregnancy. Biochemical and behavioral data were collected upon intake, residential discharge (7 days), and ambulatory weeks 2,4, 6, 8, and 10. Participants had a mean age of 29.6 (SD = 4.8) and mean of 10.7 (SD = 1.6) years education, 86% African American, 87% single/never married, and 16.1 (SD = 6.0) weeks gestational age. The women reported smoking 17.8 (SD = 11.3) cigarettes per day, had high Fagerstrom dependence scores, (M = 7.1; SD = 1.8) and 60% were in the precontemplation stage for quitting smoking. Preliminary findings from both biological and self-reports suggest that the intervention was not effective in reducing smoking at the final end point (10 weeks) and that smoking increased in both groups as the pregnancy progressed. Repeated measures ANOVAs indicated that cotinine and CO levels were significantly higher at Weeks 6 and 10 than at baseline. These results suggest that more intensive interventions for pregnant methadone-maintained women are required. Nicotine replacement as well as close behavioral monitoring (residential treatment) may be warranted for this high-risk group of tenacious smokers. This research supported by F31 DA05980 and ROl DA12403. 247 SIVE

D-AMPHETAMINE PERFORMANCE

DISCRETE-TRIAL

DOES OF

MALE

SELF-CONTROL

NOT OR

AFFECT FEMALE

THE RATS

IMPULIN

A

PARADIGM

S.C. Haworth, S.M. Bennett, and F. van Haaren, University of Florida, Gainesville, FL Methylphenidate has been shown to improve self-control behaviors. D-amphetamine, a pharmacologically related drug, has been shown to increase impulsivity under certain laboratory preparations. The present experiment was designed to test the extent to which this latter effect is observed (a) in a different paradigmatic self-control context; (b) when baseline performance consists of exclusive impulsivity; and (c) across male and female subjects. Four male and 6 female Wistar rats were trained in a discrete-trials procedure to choose between 145 mg food pellet following a 1 s delay and 3 pellets following a 24 s delay. Following stability, the proportion of large-reinforcer choices was observed to be near 0 for all rats. That is, all rats consistently chose the impulsive, small-reinforcer choice. Next, a range of doses of D-amphetamine was administered pre-session twice weekly, first in ascending order, then in descending order. D-amphetamine had no obvious effects on

Abstracts

SF4

impulsivity relative to control performance. Results are discussed in terms of the importance of considering procedural and baseline-performance variables when assessing self-control and impulsivity, especially in the context of pharmacological manipulations.

248 SEARCHFOR BENZODIAZEPINEIGABA~ SELECTIVE LIGANDS AND IMPLICATIONS SELF-ADMINISTRATION

SUBTYPE IN ALCOHOL

X. He, C. Ma, H. June, and J.M. Cook, University of Wisconsin, Milwaukee, WI, and Indiana University, Purdue University at Indianapolis, Indianapolis, IN The novel competitive benzodiazepine (BDZ) antagonist BCCt is the most selective BZl (~1,= alp2y2) containing GABA, receptor ligand to date, and exhibits no toxic effects in rodents. In comparison with the agonist zolpidem and the antagonist flumazenil, BCCt is 3.5 and 20-fold more selective, respectively, for the a, receptor subtype. In the present study, the effects of BCCt were examined in alcohol-preferring (P) rats whose responding was maintained by the concurrent presentation of EtOH (10% v/v) and saccharin (0.025 0.10% w/v) under an FRl -FRl or FR4-FR4 schedule. BCCt (7.5 -25 mg/ kg) selectively reduced EtOH-maintained responding on the FRl schedule even when saccharin (0.10% w/v) response rates were 50% greater than EtOH, albeit the effects were not dose related. Under the FR4 schedule, when EtOH and saccharin (0.025% w/v) response rates were matched, BCCt (lo40 mg/kg) selectively suppressed EtOH response rate by as much as 61% of control levels. Furthermore, the 40 mg/kg dose continued to significantly suppress EtOHmaintained responding 24 h post-drug administration. In a second study with different subjects, the actions of BCCt (15 and 25 mg/kg) were evaluated under an FR4 schedule wherein saccharin response rates were only 75% that of EtOH responding. The magnitude of suppression on EtOH-maintained responding in the second FR4 study was similar to the initial FR4 study, while saccharin responding was not significantly altered. Together, these data suggest that the alpha1 containing GABA, receptor may be important in regulating some aspects of EtOH-motivated behavior.

249

PREVIOUS ABSTINENCE AS A DETERMINANT FUTURE ABSTINENCE FROMSMOKING

S.H. Heil and S.T. Higgins, Burlington, VT

University

OF

of Vermont,

Studies have found early periods of abstinence to be a significant predictor of future abstinence. One explanation is that subjects learn to be abstinent, making future attempts more successful. We tested this hypothesis

experimentally by manipulating abstinence over a 3 week period using two different schedules of contingent reinforcement (reinforcement for either all 3 weeks or just the third week) and measuring subsequent abstinence. Subjects came to the lab three times a day, Monday-Friday. CO level was measured at each visit and readings of < 8 ppm were reinforced as appropriate. The first time each week they presented with a CO indicating abstinence, they received $3.00. Each subsequent consecutive CO sample indicating abstinence increased their payment by $0.50. In addition, every third consecutive CO that was < 8 ppm earned a $10.00 bonus. Subjects were allowed to smoke ad lib on intervening weekends. Preliminary results indicate that abstinence increased over time in the 3 week contingent group. The group that had contingencies in place only during the final week achieved amounts of abstinence similar to that achieved in the first week by the 3 week contingent group. These results suggest that early abstinence may result in learning that increases the duration of subsequent abstinence.

250 NOVELTY SEEKING AND ITS RELATIONSHIP TREATMENTRETENTION:AREPLICATION STUDY

TO

T.C. Helmus, K.K. Downey, M.M. Michajlyszyn, and CR. Schuster, Wayne State University, Clinical Research Division on Substance Abuse, Detroit, MI Previous research has shown that high scores on the Novelty Seeking (NS) scale of the Tridimensional Personality Questionnaire (TPQ) are associated with increased rates of treatment attrition. This study was undertaken to replicate these findings. The TPQ was administered at baseline to 68 heroin dependent cocaine users participating in a 17 week clinical trial using buprenorphine and contingency management. Compared to low scores on the NS scale, high novelty seekers had a significantly greater number of substance use diagnoses (2.2 + 1.1 vs. 1.5 + 0.09; P < 0.01) and Anti-Social Personality Disorder symptoms (4.0 + 2.8 vs. 2.3 + 2.4; P < 0.01). Although the NS scale was not significantly associated with treatment retention, those scoring high vs. low on the NS subscale of ‘Impulsivity’ were significantly more likely to drop-out of treatment (64.0% vs. 37.8%, respectively; P < 0.05).The NS scale showed no significant association with levels of abstinence. Alternatively, those individuals scoring high vs low on the Impulsivity subscale provided significantly more opiate positive urine samples (70.8 + 28.5% vs. 48.9 + 30.5%; P < 0.05). Impulsivity was not associated with cocaine abstinence. Results of this study suggest that the NS subscale, Impulsivity, is associated with treatment attrition and continued drug use during treatment. These findings only partially replicate those of previous studies demonstrating an association between

Abstracts

novelty seeking and treatment outcome. Future research is necessary to determine if impulsivity reliably predicts treatment outcome. 251

GENE EXPRESSION PROFILING OF VTA PAMINENEURONSFOLLOWINGCHRONICCOCAINESELFADMINISTRATION

DO-

SE. Hemby, SVanNess, and J.S. Kluck, Emory University and Yerkes Regional Primate Center, Atlanta, GA Ventral tegmental-accumbens (VTA-NAc) dopamine projections are a critical substrate of cocaine reinforcement and undergo neuroadaptive changes as a result of chronic cocaine exposure. Previous studies have demonstrated altered expression of individual mRNAs as a result of cocaine administration, however, the reinforcing effects are the result of concomitant changes in multiple genes in specific neuronal populations. The present study examined coordinate mRNA expression of multiple genes from individual VTA-NAc projection neurons from rats self-administering cocaine (SA) compared with rats receiving yoked cocaine (YC) and saline infusions (YS; n = 5 per group). Male Sprague Dawley rats were implanted with indwelling jugular catheter and the retrograde tracer Fluorogold was iontophoresed into the NAc shell, Rats assigned to the SA group were trained to self-administer cocaine (500 mg per infusion; FR4, 8 h per day, 7 days per week, min 25 days). Following sacrifice, individually labeled neurons in the VTA were dissected and processed for expression analysis using in situ transcription and aRNA amplification. Radiolabelled aRNA was used for differential gene expression analysis: cDNA microarrays containing > 15 000 genes and PCR-based differential display (DD). Candidate mRNAs that have been investigated include monoamine transporters and receptors, amino acid receptors, G protein subunits, PKA subunits, transcription factors, cytoskeletal proteins and neurosecretory proteins. In addition, several novel genes have been found to be differentially expressed from microarray and DD analysis. Assessment of differential gene expression in a defined neuronal population will provide a preliminary molecular fingerprint of cocaine reinforcement that could aid in the development of novel pharmacotherapuetic and molecular strategies in the treatment of cocaine addiction. 252 AMONG

READINESS FOR DRUG ABUSE TREATMENT NEEDLEEXCHANGEPROGRAMATTENDERS

L. Henderson, D. Vlahov, and S. Strathdee, Johns Hopkins School of Public Health, Baltimore, MD

S89

Objective: Beyond provision of sterile syringes, needle exchange programs (NEPs) may represent a bridge to drug abuse treatment. However, NEP attenders may be less motivated to enter treatment since these programs attract severely dependent injection drug users (IDUs). We studied readiness to stop drug use among attenders and non-attenders of NEP in Baltimore. Methods: IDUs enrolled in a prospective cohort study underwent semiannual questionnaires, including NEP attendance and a 23-item readiness to stop drug use scale, based on Prochaska and DiClimente’s stages of change theory. Chi-square tests and logistic regression was used to compare NEP attenders and non-attenders with respect to readiness to stop drug use, sociodemographics, drug use patterns, and health service utilization. Results: Of 282 active IDUs, 30% reported attending NEP in the past month. The majority were male (72%) and African American (92%). Mean age was 44 and average duration of injection career was 23 years. Comparing NEP attenders to non-attenders, respectively, similar proportions were in the pre-contemplative stage (no intention of stopping drug use; 19% vs. 15%) contemplative stage (51% vs. 55%), and determination stage (recognition of drug use problem and the need for help; 30% vs. 30%). No significant differences were observed (P = 0.7). In multivariate analysis, NEP attendance was associated with high risk behaviors: speedball injection (AdjOR 2.7), injecting daily (AdjOR 2.2) and homelessness (AdjOR 2.2). Conclusions: Although NEP attenders exhibit characteristics associated with more severe drug dependence, these individuals were just as motivated to stop drug use as other IDUs in our community-based setting. NEPs therefore represent a viable and important venue for engaging greater numbers of IDUs in drug abuse treatment. 253 NICOTINE INTAKE AND MEASURES OF DEPENDENCE IN CIGARETTE SMOKERS IN CHINA: IMPLICATIONS FOR UNDERSTANDING DEPENDENCE AND TREATMENTNEEDS

J. Henningfield, J. Samet, M. Jaakkola, Y. Gonghuan, M. Ceraso, C. Dresler, K. Strahs, J. Gitchell, and N. Benowitz, Johns Hopkins University School of Medicine, Baltimore, MD World wide cigarette smoking attributable deaths are projected to increase from approximately 3 to 10 million annually by 2020. The greatest increase in mortality will be in developing nations in which there is the least amount of information pertaining to tobacco use and dependence. The first major epidemiological study of smoking in China, conducted in 1997, indicated somewhat lower levels of per smoker cigarette consumption than in the U.S. The absence of data on the relationship between cigarette intake with nicotine ab-

Abstracts

s90

sorption and measures of dependence hinder interpretation of the results. Our study included 600 cigarette smokers from major urban centers in China in 1999. Smokers provided saliva samples that were assessed for cotinine content and they completed structured questionnaires. The questionnaire included items adapted from the Fagerstrom Tolerance Questionnaire that has been used and validated in many countries and cultures including Chinese populations outside of China. Data presently being analyzed will be presented at the June meeting. The analyses will evaluate cotinine level and measures of dependence as a function of cigarettes smoked per day. Findings will be compared and contrasted against similar data sets from the United States and Europe to determine potential differences which might have implications for understanding the dependence process and the treatment needs of cigarette smokers in China. 254 HOLISM

THE EFFECTS OF FAMILY HISTORY ONTHE EEG OFCOCAINEABUSERS

OF ALCO-

R.I. Herning, W.E. Better, K. Tate, J.L. Cadet, National Institute on Drug Abuse, and National Institutes of Health, Baltimore, MD Increases in fast EEG activity and decreases in slow activity have often been reported in cocaine abusers. However, the precise nature of their origin and their general implications remain to be clarified. Since a family history of alcoholism (FH +) has been shown to be an important determinant of their presence, some researchers have suggested that the increase in fast EEG may be due to a family history of alcoholism and to be secondary to prolonged cocaine abuse. To study the effects of family history of alcoholism on the EEG of cocaine abusers, the EEG of four groups of subjects (FH - cocaine abusers (n = 42) FH f cocaine abusers (n = 27), FH - control subjects (n = 15) and FH + control subjects (n = 12)) were studied. The resting eyes-closed EEG was recorded from eight scalp sites. The FH + subjects had significantly higher absolute power in all EEG bands except ctZ and p2 than FH subjects. The cocaine abusers had significantly less absolute power in 0, l& and p2 EEG bands than control subjects. The FH + subjects had significantly higher relative alpha1 power than the FH - subjects. The group by electrode interaction was significant for CI, band. Our results suggest that the increase EEG l3 observed in cocaine abusers may be due to family history of alcoholism in this and previous studies. Furthermore, the family history of alcoholism status of the subjects needs to be considered when studying the EEG of substance abusers.

255 COCAINE'S EFFECTS ON SPEECH SOUND PERCEPTIONBYBABOONSASAFUNCTIONOFTASKDIFFICULTY

R.D. Hienz, M.R. Weed, and J.V. Brady, Johns Hopkins University School of Medicine, Baltimore, MD Auditory discrimination is typically studied using simple abstract stimuli such as pure tones. This study employed more biologically-relevant stimuli, similar in structure to baboon vocalizations, to determine how the effects of cocaine varied with the complexity of a speech sound discrimination task. Three baboons were trained to discriminate differences between a ‘standard’ human vowel sound and four ‘comparison’ vowel sounds. Baboons pressed a lever to produce a repeating vowel sound (e.g. ‘aw’), and released the lever only when that sound changed from the standard vowel to one of the four comparison vowels (e.g. ‘eh’). Continuous broadband masking noise was introduced during testing sessions, and discrimination difficulty was manipulated by adjusting the level of the background masker to produce three different performance accuracy levels. Response accuracy as well as response latencies, or ‘reaction times’, were compared following i.m. administration of saline and cocaine. Previous results have shown that in the absence of noise, cocaine reduced discrimination accuracy for all four comparison vowels. The present results show that, in presence of noise, cocaine produced greater decrements in discrimination accuracy in two of the three baboons. These results are contrasted with a previous study of the effects of morphine in this paradigm. Morphine also reduced accuracy, but to a lesser extent than cocaine. Additionally, both cocaine and morphine reduced accuracy moreso for vowels more similar to the standard vowel. These results suggest a differential sensitivity of this discrimination for cocaine and morphine, and highlight the usefulness of varying task difficulty when studying the effects of drugs on behavioral performances, Supported by NIDA grants DA 04731, DA 05831 and DA 00018. 256 CHRONIC TREATMENT WITH LOFEXIDINE ATTENUATES STRESS-INDUCED REINSTATEMENT OF ‘SPEEDBALL'SEEKING

D. Highfield, J. Yap, J. Grimm, U. Shalev, and Y. Shaham, NIDA/IRP, Baltimore, MD The a-2 adrenoceptor agonist, lofexidine, is currently used in the short-term treatment of opioid withdrawal in humans, but relapse rates after cessation of lofexidine are high. Using a reinstatement method in rats (regarded as an animal model of relapse), it has been shown that acute injections of cr-2 adrenoceptor ago-

s91

Abstracts

nists attenuate footshock stress-induced reinstatement of heroin and cocaine seeking. Here we studied whether chronic exposure to lofexidine would attenuate stressinduced reinstatement of drug seeking in rats trained to self-administer ‘speedball’ (heroin 0.025 mg/kg per infusion + cocaine 0.25 mg/kg per infusion, IV). Rats were trained to press a lever for speedball for 10 days (two 3-h sessions/day). Extinction sessions, during which the drug was removed, were then given for 11 days. On the final 2 days, rats were tested for reinstatement after exposure to 5 or 15 min of intermittent footshock (0.6 mA). Starting on day 7 of training, rats were divided into three groups (n = 9- 10 group), which received daily injections of saline or lofexidine (100 or 200 ug/kg, IP), 60 min before the first daily session for the rest of the experiment. Lofexidine pretreatment had a minimal effect on speedball self-administration and extinction behavior. In contrast, lofexidine significantly attenuated footshock stress-induced reinstatement (P < 0.01). The present data provide the first demonstration of stress-induced reinstatement of speedball seeking in rats. The results also extend previous reports with acute injections of lofexidine, indicating that the drug maintains its effect on stress-induced reinstatement after chronic treatment. These data may provide a rationale for the use of lofexidine for the prevention of relapse induced by stressors in polydrug users. Supported by NIDAIIRP. 257 BLUNTED COMOTOR

Mu

OPIOID BASAL ACTIVITY

RECEPTOR CIRCADIAN IN

KNOCKOUT RHYTHM

RESPONSE

MICE

AND TO

BLUNTED

SHOW LO-

COCAINE

A. Ho, SD. Schlussman, Y. Zhou, I. Sora, G. Uhl, and M.J. Kreek, The Rockefeller University, New York, NY, and NIH-NIDA Intramural Program, Baltimore, MD The mu opioid receptor is not required for behavioral stereotypy after ‘binge’ cocaine, as we have recently shown in u-opioid receptor knockout mice. We report here on the basal levels of spontaneous locomotor activity of these mice and on their response to cocaine. Method: Male mice were individually caged and allowed to acclimate for several weeks to a 12- 12 h light-dark cycle with free access to chow and water. Each animal’s standard cage was placed within an electronic monitoring system that records counts of breaks of three light beams as the mouse moves about its cage. (a) A 24 h sample of behavior (recorded before any drug administration) was used to examine the basal circadian rhythm of spontaneous locomotor activity. (b) Cocaine was administered in a ‘binge’ pattern 3 x 15 mg/kg i.p., at hourly intervals (saline to controls). Results: (a) u-opioid receptor knockout mice (n = 21) showed flattened circadian rhythms of locomotor activ-

ity as measured by total counts/hour compared to wild-type controls (n = 24) P < 0.05. (b) Although mice of both genotypes showed increased locomotor activity in response to ‘binge’ cocaine, F( 1,40) = 18.54, P < 0.0002, u-opioid receptor knockout mice showed lower levels of locomotor stimulation in response to cocaine than wild types (P < 0.005). Thus, subtle behavioral differences of mice with lifelong deletions of u-opioid receptor were found although these mice show normal levels of stereotypy when given ‘binge’ cocaine administration. Support: NIH-NIDA PSO-DA 05130, K05-00049 & NIDA-IRP. 258

2D

FOR

NOVEL

QSAR

MODELING

DOPAMINE

AND TRANSPORTER

DATABASE

SEARCHING

INHIBITORS

B.T. Hoffman, T. Kopajtic, and A.H. Newman, National Institute on Drug Abuse-Intramural Research Program, Baltimore, MD Converging evidence suggests a prevalent role of the dopamine transporter (DAT) in the mechanism(s) underlying the psychomotor stimulant and reinforcing effects of cocaine. A therapeutic drug in treating cocaine abuse might act by blocking the binding of cocaine to the DAT, while exhibiting no addictive liability itself. Although numerous compounds have been reported with high affinity and selectivity for the DAT, a successful pharmacotherapeutic to treat cocaine abuse remains elusive. Hence, there is a need for new, structurally divergent DAT ligands, since some novel configuration of the drug’s structural properties may be required to yield the desired pharmacological profile. In order to rapidly identify novel ligands for the DAT, we have extracted structural information from 70 existing structurally diverse DAT inhibitors for which we have obtained pharmacological data. Using the resultant Quantitative Structure Activity Relationship (2D QSAR), which allows exceptionally accurate predictive correlations between drug structures and activity, we have begun searching databases of existing drugs not previously tested at the DAT, such as the National Cancer Institute (NCI) database. Our first pharmacological screening of 20 NC1 compounds predicted by our model to have DAT activity has revealed five drugs, divergent in structure from other DAT inhibitors, that are excellent candidates for lead development. These identified lead compounds will serve as templates for the synthesis of structurally novel dopamine transporter ligands. In addition, improved 2D QSAR models will result from the incorporation of these new structures and their DAT binding affinities. Successive screenings of the NC1 and other databases will yield valuable leads for DAT ligands that may be useful in the development of a cocaine-abuse therapeutic.

Abstracts

S92

259

RELIABILITY PROBLEMSCREEN

AND

VALIDITY

OF ONLINE

DRUG

J.A. Hoffman, S. Nemes, R.D. Landis, K. Holtz, and C. Zeiler, Danya International, Inc., Silver Spring, MD Hypothesis: The Drug and Alcohol Problem Assessment for Primary Care (DAPA-PC) is hypothesized to be a reliable and valid screening instrument for use in primary care settings. DAPA-PC is a self-administered, internet-based screening instrument which features automatic scoring, generation of a patient profile for medical reference, and presentation of unique motivational messages and advice. Methodology: Tests of reliability and validity have been conducted on the DAPA-PC. The DAPA-PC was administered to 324 primary care patients; 44% male; 48% White, 42% African-American; mean educational level 14.6 years. Re-tests were administered an average of 4.2 days after initial screen. Hair (n = 302) and urine samples (n = 290) were collected at initial screen. Participants were also assessed with the Diagnostic Interview Schedule (DIS). Hair and urine results and DIS diagnoses were compared to DAPA-PC results to assess validity of the instrument. Results and Importance: Reliability tests (test-retest) indicate that the DAPA-PC has high reliability rates, both when questions were examined individually (ranging from 0.61 to 0.82, all P < 0.01) and when the total number of positive responses was examined (0.70, P < 0.01). Validity tests comparing self-report to hair and urine results indicate that the total DAPA-PC score on eight yes/no questions correlated significantly with positive urine or hair test results. Of 75 positive cases (by urine or hair result), 65% reported use in past 30 days, while 35% reported no use in past 30 days. These results suggest that the DAPA-PC is a reliable instrument that could be used in primary care settings. DAPA-PC also accurately identified most of the subjects (70%) who were not diagnosed on the DIS as having problems with substances. In addition, DAPA-PC identified 72% of subjects who were diagnosed with abuse on the DIS. Finally, of subjects diagnosed with dependence on the DIS, 80% scored three or more on the DAPA-PC, indicating the highest risk for drug problems. These findings support the validity of the DAPA-PC. 260 EFFECTS OF ETHANOL ON PLASMA ALLOPREGNANOLONE LEVELSANDMOODINWOMENACROSSTHE MENSTRUALCYCLE

L. Holdstock, A.L. Morrow, S. Penland, and H. de Wit, University of Chicago, Chicago, IL, and University of North Carolina, Chapel-Hill, NC

Ethanol has well documented sedative effects that might be mediated, at least in part, through the GABAA receptor complex. However, it is not yet known whether ethanol has a specific binding site on the GABAA receptors, or whether it exerts its actions in another manner. Ethanol may produce its sedative subjective and behavioral effects by increasing levels of the neuroactive steroid, allopregnanolone (Allo-P), a potent positive modulator of the GABAA receptor. This study was designed to investigate the effects of ethanol (EtOH) on plasma levels of allopregnanolone (allo-P) in healthy women during the follicular and midluteal phases of the menstrual cycle, and to examine the relationship between plasma levels of allo-P and the subjective, physiological and performance effects of ethanol. We utilized a double-blind within-subjects design in which 12 women received ethanol (0.7 g/kg) and placebo during both phases of their cycle. Plasma levels of allo-P and progesterone (P), as well as a measure of psychomotor performance and several validated measures of sedative-like subjective effects, including the ARC1 PCAG scale and the BAES, were assessed at regular intervals. EtOH produced a significant increase in plasma levels of P, and a marginally significant increase in levels of allo-P, in the luteal phase. EtOH also significantly increased subjective ratings of sedation and it impaired psychomotor performance. However, the effects of EtOH on the subjective and performance measures were not correlated with plasma levels of P and allo-P. These results do not support the idea that the sedative effects of ethanol result from an increase in plasma levels of allo-P. However, the possibility remains that elevated brain levels of allo-P contribute to the sedative effects of ethanol. Supported by DA02812, MO1 RR00055 and AA10564. 261 HEROIN USE AMONG ADOLESCENTS MENTFORSUBSTANCE:USE DISORDERS

IN TREAT-

C.J. Hopfer, S.K. Mikulich, and T.J. Crowley, University of Colorado Health Sciences Center, Boulder, CO Hypothesis: We hypothesized an increase in heroin use among adolescents in treatment for Substance Use Disorders. Species: Human. Number of Subjects: > 75 000. Procedures: We examined the Treatment Episode Data Set, a national database containing admitting information on over 5000 substance treatment facilities. Analyses: Between 1992 and 1997 we calculated the percent of yearly admissions who had heroin/opiates listed, for ages 0- 17. We examined intravenous administration by substance of abuse for 1997. For 1997, we examined the frequency of use and the percent treated with methadone. Results: Between 1992 and 1996, heroin-using youth represented 2.0% of youth in treatment, in 1997 they represented 2.6%. Heroin-using youth represented

Abstracts

56% of those using injecting drugs. For 1997, the greastest frequency of use was: 57.5% daily use for the past month prior to entering treatment. 8.3% were treated with methadone. Importance of Findings: Nationally, there has been an increasing number, but not percentage of heroin-using youth in treatment between 1992 and 1996. In 1997 there was an increase in both the number and percent of heroin-using youth in treatment. Heroin-using adolescents have the highest rate of injection drug use when compared with youths using other substances. Methadone is infrequently used for treatment of these youth, which will be discussed during the session. 262 APPLICABILITY OF THE LIFE CODING WITH HISPANIC AND ANGLO FAMILIES

SYSTEM

H. Hops, H.B. Waldron, A. Aragon, and S. Flicker, Oregon Research Institute, Eugene, OR and University of New Mexico, Center for Family and Adolescent Research, Albuquerque, NM Using data from an NIAAA funded study of family interaction and adolescent substance use, the applicability of the LIFE coding system to different ethnic groups was explored by comparing the mean levels and distributional properties of the individual LIFE affect and content codes for Hispanic and Anglo families. Our analysis indicated that Hispanic and Anglo mothers and fathers did not significantly differ on salient LIFE behavioral codes such as aggressive, dysphoric, facilitative, neutral content, problem-solving content, and affect codes. Moreover, the distributional characteristics, in terms of variance estimates, did not significantly differ between Hispanic and Anglo family members. Anglo adolescents, however, were observed as displaying significantly higher levels of ‘talk,’ ‘complain,’ and ‘self-referenced’ codes when compared to Hispanic adolescents. Clinical observations suggest that Hispanic children are more deferential to their parents and less likely to speak up about feelings and problems they may be having with their parents, consistent with the cultural differences detected using the LIFE codes. Within Hispanic families, significant correlations were found between adolescent directly observed aggressive behavior and adolescent, mother, and father self-report of family conflict on the Family Environment Scale (FES). In addition, adolescent observed facilitative behavior was correlated with adolescent self-reported family cohesion on the FES. These results support the viability of the LIFE code for examining patterns of behaviors within Hispanic as well as Anglo families. Implications for the use of these findings in the development of culturally specific family constructs will be discussed.

s93

263 IDENTIFICATION OF A NOVEL PARTIAL INHIBITOR OF DA UPTAKE AND DA TRANSPORTERBINDING R. Horel, S. Ananthan, C.M. Dersch, F.I. Carroll and R.B. Rothman, IRP, NIDA, NIH, Baltimore, MD, SORI, Birmingham, AL, Research Triangle Institute, Research Triangle Park, NC Introduction: Using mouse, rat caudate or cloned DATs and [125I]RTI-55, our laboratory has consistently detected one binding site. Similarly, we detect only one component of [3H]DA uptake in rat caudate synaptosomes. We report here the identification of a novel partial inhibitor of DA uptake and DA transporter binding (SORI-9804). Methods: [125I]RTI-55 binding to DA transporters (mouse caudate, rat caudate, HEK cells expressing the cloned DAT) and [3H]DA (rat caudate synaptosomes) were conducted using published procedures. Results: SORI-9804 resolved two binding sites on the DAT of mouse caudate: Parameter

Site 1

Bmax (fmol/mg protein) Kd RTI-55 (nW

7100+ 1000

Ki SORI-90 = 804 (nM)

Site 2

0.65 + 0.08 493+ 101

9200+ 1700

2.18 + 0.45 > 100 000

Similar results were obtained in rat caudate and in cells expressing the cloned DAT. SORI-9804 was a partial inhibitor of [3H]DA uptake. Conclusions: SORI-9804 discriminates two binding sites on the DAT, having moderate affinity for one site and negligible affinity for the second. Consistent with the binding data, SORI9804 inhibits only about 50% of [3H]DA uptake. The mechanism(s) of this effect remains to be determined. 264

CONFIRMATION OF AN EXCESS OFTHEHIGH ENZYME ACTIVITY COMT VAL ALLELE IN HEROIN ADDICTS IN A FAMILY-BASED HAPLOTYPE RELATIVE RISK STUDY

R. Horowitz, E. Shufman, M. Kotler, and R.P. Ebstein, Kfar Malkishua Association and Herzog Hospital, Jerusalem, Israel Association between the high activity catechol Omethyltransferase (COMT) polymorphism and polysubstance abuse in a group of North American subjects. In the current study we confirm these results by genotyping 38 Israeli heroin-addicts and both par-

s94

Abstracts

ents using a robust family-based haplotype relative risk (HRR) strategy. There is an excess of the val COMT allele (Likelihood ratio = 4.48, P = 0.03) and a trend for an excess of the val/val COMT genotype (Likelihood ratio = 4.97, P = 0.08, 2 df) in the heroin addicts compared to the HRR control group. We also genotyped an additional 101 non-related heroin addicts and 126 control subjects using a case control design and found no significant difference in COMT val allele frequency (25.4% versus 29.7%, Likelihood ratio = 1.04, P = 0.31). A significant difference is observed in COMT allele frequency among the three principal Israeli ethnic groups (Ashkenazi Jewish, non-Ashkenazi Jewish and Palestinian Arab) in a large group of control subjects we have so-far examined (x2 = 7.9, P= 0.019, df= 2, N = 1422 alleles) suggesting that population stratification is responsible for our failure to observe an excess of the COMT val allele when using the case-control design.

265 DEMOGRAPHIC EFFECTS ON THE TRAIL-MAKING TESTINA DRUG ABUSETREATMENTSAMPLE A. Horton and C. Roberts, Center for Substance Abuse Treatment, Rockville, MD Appreciation of the importance of screening for cognitive impairment among substance abusing populations has increased in recent years. In this poster, demographic effects on the Trail Making test (TMT), a test often used for screening for cognitive impairment, are examined in a sample of patients in drug abuse treatment programs. A sample of 5619 males and 2902 females was drawn from electronic files of data from the Drug Abuse Treatment outcome Study (DATOS). The DATOS was a naturalistic, prospective cohort study that collected data from 1991 to 1993 in 96 programs in 11 cities in the United States. Data were analyzed to determine the effects of demographic variables on the two parts of the TMT in this large sample of patients. Consistent with previous research, demographic variables such as age, gender, education level and ethnicity were statistically significantly related to both TMT parts A and B. More importantly, however, the percentage of variance accounted for (A = 0.11, B = 0.13) was quite small. These results suggest that, while clearly present, demographic effects on the TMT are weak.

266 EFFECTS OF THE SELECTIVE DOPAMINE REUPTAKE INHIBITOR, RTI-112, ON OPERANT BEHAVIOR IN THESQUIRRELMONKEY L.L. Howell, H.L. Kimmel, J.A. O’Connor, F.I. Carroll, and M.J. Kuhar, Yerkes Regional Primate Research Center, Emory University, Atlanta, GA, and

Research Triangle NC

Institute,

Research Triangle

Park,

The dopamine transporter (DAT) is a critical recognition site for cocaine and is linked to its addictive properties. Recent medication development efforts have targeted the DAT with a variety of compounds that share cocaine’s ability to inhibit dopamine reuptake. The present study characterized the effects of the phenyltropane derivative, RTI-112, administered alone or in combination with cocaine on operant behavior in squirrel monkeys. In vitro binding and reuptake studies indicate that RTI-112 is a potent and selective inhibitor of dopamine reuptake. In monkeys trained to leverpress under a fixed-interval, 300 s schedule of stimulus termination, RTI-112 (0.003-o. 1 mg/kg) had prominent behavioral-stimulant effects comparable to those obtained following cocaine (0.01~ 1.O mg/kg) administration. However, RTI-112 was approximately 3-fold more potent and had a longer duration of action compared to cocaine. Pretreatment with RTI-112 enhanced the behavioral-stimulant effects of low doses of cocaine, indicative of additivity and a common mechanism of action. Collectively, the results demonstrate that RTI112 has cocaine-like behavioral-stimulant effects. Its greater potency and longer duration of action may be desirable characteristics for a substitution therapy for cocaine abuse. Supported by Contract Grant OND-6069, Office of National Drug Control Policy, and USPHS Grant RRO0165.

267 LONGITUDINAL PATTERNS OF DRUG USE AND TREATMENT PARTICIPATION: FINDINGS FROM THE 5YEARFOLLOW-UPOF DATOS Y.I. Hser, C. Grella, H. Shen, and M.D. Anglin, University of California, La Jolla, CA Most treatment evaluation studies have relatively short follow-up periods. This study examines patterns of drug use and drug treatment participation during a 5-year follow-up period for individuals in the Drug Abuse Treatment Outcome Studies (DATOS). The study includes 1050 cocaine users who participated in the initial DATOS treatment episode and were interviewed in a 5-year follow-up survey. Preliminary results indicate that 43% of the clients did not relapse to cocaine use within the 5 years following the index treatment episode. About 15% of the clients relapsed to cocaine use one time and then were abstinent for the remainder of the 5-year follow-up period. Another 15% of the clients relapsed and continued to use cocaine to the end of the period. The remaining 28% had multiple relapse/ abstinent cycles. Survival analyses indicate that the multiple-relapse group relapsed the earliest and that the

Abstracts

rate of relapse accelerated across the 5-year period. Logistic regression analyses will be conducted to examine the relationship between abstinence/relapse patterns and associated variables, including cocaine addiction severity, treatment participation patterns, and sociodemographics. The study will provide information useful for reducing the incidence and frequency of relapse following treatment. 268

DETERMINATION

NABINOL

AND

NABINOL

IN PLASMA

OF

A9-TETRAHYDROCAN-

1 I-NOR-PCARBOXY-AP BY SOLID

TETRAHYDROCANPHASE

EXTRACTION

AND

GC/MS

W. Huang, D.E. Moody, and R.L. Foltz, University of Utah, Salt Lake City, UT Our previously described method for determination of A9-tetra-hydrocannabinol (THC) and l l-nor-9-carboxy-THC (THCA) in plasma (Foltz et al. Biomed Mass. Spectrom. 10: 316, 1983), required separate derivatization and injection for THC and THCA. Our current method permits simultaneous extraction, derivatization and analysis of both analytes using solidphase extraction (SPE) with gas chromatography and negative ion chemical ionization mass spectrometry. THC-d3 and THCA-d3 are added to 1 ml plasma specimens as internal standards; protein is precipitated with acetonitrile and the resulting supernatants diluted with 0.1 M sodium acetate (pH 7.0) prior to application to Clean Screen (2ST4C020) SPE columns. THC and THCA were eluted separately, pooled, dried under air and derivatized with trifluoroacetic anhydride and hexafluoroisopropanol. The derivatized THC-d0 gives abundant molecular anions (m/z 410) and the derivatized THCA-d0 gives abundant fragment ions (m/z 422) formed by loss of (CF3)2CHO from its molecular anion. The mean recoveries of THC and THCA were 74 and 17%, respectively. Intra- and inter-run accuracy and precision (ix, target + % CV) at 1 rig/ml for THC were 98.0 F 4.1% and 99.0 f 8.1%. Corresponding results for THCA were 88.6 f 6.5% and 101.2 f 8.1% at 5 rig/ml. Similar results were achieved at 10 and 75 rig/ml. A lower limit of quantitation of 0.5 was established for THC and and of 2.5 rig/ml for THCA. The upper limit of quantitation was 100 rig/ml. This method will be employed in a pharmacokinetic study of human subjects exposed to cannabis and a cannabinoid receptor antagonist. 269

SERTRAL~E

AS TREATMENT

AND FOR

CONTINGENCY

METHAMPHETAMINE

MANAGEMENT DEPENDENCE

A. Huber, S. Shoptaw, V. Gulati, R. Gonzales, Friends Research Institute, Inc., Easton, MD, Long Beach Research Foundation, VA MDRU, Long Beach, and

s95

UCLA Integrated Substance Abuse Programs, Los Angeles, CA Preliminary outcomes from a double-blind, placebocontrolled, clinical trial evaluating sertraline and contingency management (CM) as treatments for methamphetamine dependence are presented. One hundred eighty subjects were randomized to one of four treatment conditions in the 12-week trial, using a Matrix model treatment of 90 min group sessions three times weekly as the foundation for the medicationbehavioral trial. Participants were dosed with 100 mg of sertraline (or matching placebo). The CM schedule followed that of Higgins research group. The participants (40% female; 74% Caucasian and 26% Hispanic) used methamphetamine 9.1 rf~5.0 years before admission and most were using daily at the time of admission. Two-thirds (65.0%) of the sample smoked methamphetamine, but a substantial subset of the group injected (18.9%). Retention was good across the four conditions (n4= 50.4 days) and there were no significant differences in retention based on medication assignment or on contingency management condition. As the trial is ongoing at this time, only limited results are available. Results obtained without breaking the blind indicate that CM is a powerful intervention for this population with significant increases in the longest period of abstinence (CM: 31.4 days vs No CM: 16.7 days, F= 21.0, P < 0.001) and higher TES (CM:l6.8 vs No CM: 12.9, F= 8.6, P < 0.001). When evaluated at the group level, assignment to medication condition does not significantly affect retention, urine test results, or length of abstinence achieved, when levels of use at baseline are included as a covariate. Completion of the study will allow a detailed evaluation of sertraline as a potential methamphetamine pharmacotherapy. 270

HIV-POSITIVE

MENT

OUTCOME

SMOKERS

AND

SMOKING

TREAT-

G. Humfleet, R. Munoz, V. Reus, D. Hartz, and S. Hall, University of California, San Francisco, CA High smoking rates are found in HIV-positive populations. Cigarette smoking increases the likelihood of serious HIV-related medical conditions. HIV-positive individuals face psychological, physical, and interpersonal issues (for example, negative affect, increased stress) that are associated with smoking treatment failure. Smoking treatment outcome and related psychosocial variables have not been examined in a sample of HIV-positive smokers. This pilot study investigates psychosocial variables related to smoking cessation, and smoking treatment outcome as a function of HIV status. Subjects are from two on-going smoking cessation clinical trials (n = 457). Thus far, 25 male partici-

S96

Abstracts

pants have self-identified as HIV-positive. A comparison group of 25 male subjects was selected, matching on age, ethnicity, SES, and daily cigarettes. 76% of the 50 participants are Caucasian. Mean age = 40.8 years. Treatment history, motivation to quit, history of major depressive episode(s) (MDE), and mood levels are assessed at baseline for all subjects. Abstinence rates are assessed at 12, 24, 36 and 52 weeks following treatment initiation. Preliminary analyses indicate a trend for lower abstinence rates at Week 12 for HIV-positive smokers (20 vs. 40%). Complete data is not yet available at later weeks. HIV-positive smokers scored higher on measures of depression, anxiety, and anger. HIVpositive smokers reported a higher rate of MDE (52 vs. 36%). These preliminary results support the need to examine these variables, as well as others, in a larger sample of HIV-positive smokers. Supported by NIDA Grants DA02538 and P50 DA09235 and NC1 Grant CA71378.

0.25 ug/ul PTX treated animals demonstrating the greatest activity. These preliminary results support previous studies demonstrating the effects of psychostimulants on behavior and the potential role of G-proteins in this response. In future investigation, we hope to further substantiate these data by establishing a direct correlation between native CAMP levels and locomotion thereby further supporting the hypothesis for the involvement of the CAMP system in psychostimulantinduced changes in brain neurochemistry and behavior. Supported by NIDA DA09580 (EMU) and T32DA07237 (MWA).

271

CART peptides are peptide neurotransmitters and cotransmitters. They are involved in mediating the action of psychostimulants and other processes (TINS, 22: 316-320, 1999). Because of their localization in laminae I and II of the spinal cord, we decided to test if they had analgesic properties. Accordingly, rat (long form) CART peptide 555102 was injected (icv) into mice and both tail flick and hot plate tests were carried out. Doses used included 0.31, 0.625 and 2.5 ugms. At the highest dose, the mice showed tremors which progressed to convulsions. But at the two lower doses, no external toxic signs were observed and there were significant reductions in the maximal possible effects. For example, at 0.62 ugms, tail-flick responses were 58% and hot-plate responses were 77% MPE. These are the first physiologic indications of analgesic properties of CART peptides. Supported by RRO0165, DA00418, and DA10732.

PERTUSSIS

LOCOMOTOR CAINE

TOXIN

SENSITIZES

ACTIVATING

EFFECTS

ANIMALS OF

AN

TO ACUTE

THE CO-

CHALLENGE

M. Hummel and E.M. Unterwald, Temple University School of Medicine, Philadelphia, PA Enhanced behavioral activity is a phenomenon that is often characteristically associated with the repeated administration of psychostimulants. The neural and biochemical mechanisms by which stimulants produce alterations in behavior, however, have only been partially elucidated. This is the beginning of a progressive study which is seeking to establish the role of Gproteins and the CAMP system in cocaine-induced alterations in neurochemistry and behavior. It has been shown that cocaine produces behavioral activation as well as adaptations in G-proteins and increases in adenylyl cyclase and PKA activity. In this study, we attempted to mimic the locomotor activating effects of cocaine by treating animals with pertussis toxin (PTX) which ADP ribosylates Gi and Go. Bilateral injections of PTX were infused into the nucleus accumbens (0.25 or 0.15 ug/l ul/side) of male Fischer rats. Locomotor activity was measured on days 7, 14, and 21 postsurgery. Animals were allowed to habituate on test days for 30 min in test chambers, then IP saline (1 ml/kg) was administered and activity was recorded for 1 h on days 7 and 14. On day 21 following habituation and behavioral monitoring for 1 h, animals were acutely challenged with IP cocaine (15 mg/kg) and behavioral data was accumulated. PTX treatment produced a dose-dependent increase in locomotor activity. PTX also sensitized the animals to the locomotor activating effects of an acute cocaine challenge. Additionally, this sensitization appeared to be dose-dependent, with the

272

CART

PEPTIDES

HAVE

ANALGESIC

PROPERTIES

R.G. Hunter, M.J. Kuhar, I. Damaj, and B.R. Martin, Medical College of Virginia - VCU, Richmond, VA, and the Yerkes Primate Center of Emory University, Atlanta, GA

273

1CCINNAMOYL

AND

FUMAROYL

DERIVATIVES

OF

NALTREXONE

S.M. Husbands, H. Moynihan, J.H. Woods, J.R. Traynor, J. Broadbear, H. Plumer, and J.W. Lewis, University of Bristol, and University of Bath, England; University of Michigan, Ann Arbor, MI The 14-aminomorphinones having a cinnamoyl side chain (e.g. C-CAM (1) and M-CAM (2)) are potent, selective, non-competitive u-antagonists. It seemed possible that addition of the same side chain to the 14-hydroxy group of naltrexone might yield naltrexone analogues of long duration. Thus 3,4, 5 and the fumaroyl analogue were prepared and evaluated in vitro and in vivo (mouse). In binding to Hartley guinea pig brain membranes the compounds displayed nM affini-

s91

Abstracts

ties with u > K > 6. In the mouse vas deferens each behaved as an antagonist at all three opioid receptors while in the GPI the compounds were very low efficacy partial agonists that could not, in general, be reversed by antagonists for any of the three receptors. The wash resistant actions in vitro suggested that they may display prolonged or pseudo-irreversible activity in vivo. Although the compounds were effective antagonists in the tail withdrawal assay, they were less impressive as insurmountable antagonists compared to their 14amino analogues. The significance of these results, and those from further characterisation, will be discussed. NIDA grant (DA00254); NIDA contract to SRI NOlDA3-8302 and 4-8307. 274 APPLYING CONTINGENCYMANAGEMENTIN COMMUNITY SETTING&WHAT ARE WE DOING WRONG? M.Y. Iguchi, A.R. Morral, K.S. Riehman, M. Zeller, and D. Bullock, Drug Policy Research Center, RAND, Santa Monica, CA Recently, attention has focussed on the need to move efficacious behavioral interventions from research settings to community clinics. We report on a recent random assignment study (n = 80) in which two interventions with demonstrated efficacy were compared to a treatment as usual group in a community methadone treatment program that is not affiliated with an academic institution. Group 1 received an opportunity to earn one weekly take-home dose of methadone, for every two consecutive weeks of urinalysis-verified abstinence, up to a maximum of 4 weekly take-home doses. Group 2 earned up to $20 in vouchers each week for completion of a weekly verifiable task designed to meet the individual’s treatment plan goals. Group 3 received treatment as usual. Overall, performance, as indicated by the urine results, was poor. For example, of the 26 participants assigned to the Group 1, not a single individual received a take-home medication dose. These findings are surprising given the many demonstrations of treatment efficacy in the research literature. Other investigators have reported similar difficulties implementing contingency management in community settings. We discuss some barriers to effective technology transfers. ACKNOWLEDGMENT: Research supported by grant DA06096-11 (Iguchi) from the National Institute on Drug Abuse. 275 MARKERS FOR RISK OF ALCOHOL OR DRUG-AFFECTED PREGNANCY IN NON-IDENTIFIED URBAN CLINIC PATIENTS K. Ingersoll and M. Nettleman, Virginia wealth University, Richmond, VA

Common-

This study presents partial preliminary findings of an ongoing epidemiological survey designed to identify women at risk for an alcohol-affected pregnancy. Five hundred women attending 2 urban clinics for primary or ob/gyn care during 199811999 answered a 25 min survey that included questions on demographic characteristics, physical and mental health, risk markers, sexual activity, contraception, substance use, obstetric history, and knowledge, attitudes, and beliefs about drinking and pregnancy. Of the 500 women, the proportion endorsing lifetime use of illicit drugs, recent drug use, and recent alcohol use classified as risky due to quantity/frequency criteria or binge drinking criteria (more than five standard drinks on one occasion) will be identified. Using descriptive statistics, correlational analyses, and regression analyses, we will report differences between substance-using and non-substance-using women in behavioral problems, such as mental health problems, mythical beliefs, risky attitudes, AUDIT scores, and health habits identified in the population. We will discuss the utility of nicotine and alcohol use as markers for risk for alcohol or drug-affected pregnancy and identify other useful risk markers. Results will be discussed with attention to their implications for prevention opportunities with urban, African American general clinic patients. Funded by CDC grant U84CCU31458501. 276 IDENTIFICATION OF THE MRNAs ADENYLYLCYCLASEISOZYMESEXPRESSEDIN CELLS

FOR

THE

SH-SY5Y

C.E. Inturrisi, S. Jenab, T.T. Du, C. Chesnutt, and L. Levin, Weill Medical College of Cornell University, New York, NY Opioid receptors (OR) are coupled through heterotrimeric G-proteins to AC, with both alpha subunits and beta-gamma heterodimers capable of modulating AC activity. OR activation can stimulate or inhibit AC activity dependent upon the particular AC isozyme available to the OR + G-protein complex. Acute treatment with opioids appears to inhibit AC Types I, II, VI and VIII, whereas chronic treatment with opioids stimulates I, V, VI and VIII. RT-PCR, sequencing, and Northern blotting were used to determine the isozymes present in the SH-SYSY human neuroblastoma cell line which expresses mu and delta ORs, and orphanan FQ/nociception receptors. Northern blotting and RTPCR with degenerate primers corresponding to the conserved catalytic domains of all known mammalian transmembrane ACs (tmACs) revealed the presence of AC Types I, III, V, VI, VII and VIII. Differentiation by all-trans retinoic acid did not affect the levels of AC type I mRNA (ribonuclease protection). Currently, we are designing isoform selective primers based on the

S98

Abstracts

available sequence information for human ACs to perform a more comprehensive PCR analysis. We conclude that SH-SYSY cells express the mRNAs for the AC isozymes involved in both opioid inhibition and superactivation. Supported in part by DA05130, DA01457 and DAOO198.

277 IDENTIFICATION OF AUTOANTIBODIES TO PEPTIDE CANDIDATE FOR OPIATE RECEPTORS IN PERIPHERAL FLUIDS AND BRAIN C.A. Izykenova and J.E. Smith, Wake Forest University School of Medicine, Winston-Salem, NC Heroin use may increase opioid receptor turnover resulting in the production of antigenic peptides causing antibody formation. Experiments to assess the presence of autoantibodies to fragments of the opiate receptor complex in the blood of rats self-administering heroin (n = 5) have been completed. A specific fragment of the -- receptor (MDOR) peptide corresponding to common N-terminus sequences of -- and --receptors was designed using the GCG program (Madison, WI), synthesized and used to assess the presence of autoantibodies by ELISA techniques. A baseline level of autoantibodies for each antigen was detected in the sera of the naive animals (n = 7). Statistically significant elevation of autoantibody titers were measured for -receptor (40%), --receptor (251%) and MDOR (123%) in serum of heroin self-administering animals compared to naive controls. Levels were also assessed in CSF and MDOR autoantibodies found to be elevated after 3 weeks of heroin self-administration. In addtion, western blot analysis showed the presence of MDOR autoantibodies in brains of rats self-administering heroin but not in cocaine self-administering rats or naive controls. These data suggest a potential role of neurotransmitter receptor autoantibodies in the etiology of drug abuse. Supported in parts by USPHS grants DA13000, DA06634 and DA001 14.

278 TEEN SMOKERSMOTIVATIONALCORRELATESTO SEEK HELP WITH QUITTING: PRELIMINARY FINDINGS D.J. Jackson, A. Radzius, I. Berlin, J.E. Henningfield, and E.T. Moolchan, NIH, NIDA Intramural Research Program, Teen Tobacco Addiction Treatment Research Clinic, Baltimore. and Pinney Associates, Bethesda, MD Many teen smokers try to quit and fail. Adolescent motivation for complete cessation has been questioned. Psychosocial, biomedical, pharmacologic (e.g. level of addiction per FTND), and treatment history have previously been shown to influence motivation to quit.

Prospective participants in a treatment program responded to a series of standardized questions during a telephone interview. Those who met preliminary criteria were scheduled for intake into the cessation program. Descriptive analyses on 79 teenagers (mean age 15.9 * 1.8 years, range: 11-22, 68% females, 17% African American) suggest that teenagers requesting help to quit have high FTND score (mean 5.7 ) 2.2, range: O-lo), high prevalence of medical problems (21.1%) and self-report high degree of motivation to quit 8.1 Ifr 1.7. ANOVA controlling for gender and ethnicity showed that motivation score was not related to the presence of medical conditions, taking prescription medications, being under psychiatric treatment or parental awareness of participation. Gender and ethnicity did not influence motivation level. However, motivation score showed a weak and inverse correlation with years of smoking (Y= - 0.206, P = 0.09). If confirmed in further studies, this may imply that interventions to quit should target earlier phases of daily smoking. Supported by NIDA Intramural funds.

279 QUANTITATIVE MEDIAL TEMPORAL LOBE BRAIN MORPHOLOGY AND HYPOTHALAMIC-PITUITARYADRENAL AXIS FUNCTION IN COCAINE DEPENDENCE: A PRELIMINARYREPORT L.K. Jacobsen, J.N. Giedd, M.J. Kreek, C. Gottschalk, and T.R. Kosten, Yale University and VA Connecticut Healthcare System, West Haven, CT Both preclinical and clinical studies have shown that cocaine increases plasma adrenocorticotropin hormone (ACTH) and cortisol. Chronic elevation of plasma cortisol has been shown to exert direct toxic effects upon hippocampal neurons and to exacerbate hippocampal damage resulting from ischemia and seizures. To test for evidence of hippocampal damage associated with long term (5-26 years) cocaine dependence, medial temporal lobe and total brain volumes were quantified in 27 patients with cocaine dependence, nine of whom also met criteria for alcohol abuse, and 16 healthy subjects. In addition basal and ovine corticotropin releasing hormone (oCRH) stimulated ACTH and cortisol levels were examined in a subset of eight healthy and nine cocaine dependent subjects after 21 days of monitored abstinence. No evidence for decreased hippocampal or total brain volume in cocaine dependence was observed. Similarly, basal and oCRH stimulated ACTH and cortisol levels in cocaine dependent patients did not differ from those in healthy subjects. These observations suggest that cocaine abuse may not be associated with significant hippocampal neuronal loss. Supported in part by NIH grants RR00125, MH01387, AA1 1330, DAOO167, DA04060, and DA09250 and by the U.S. Department of Veterans Affairs (MIRECC).

Abstracts

280 REGIONAL VARIATION PORTUNITYAMONGYOUTH

IN DRUG PURCHASE

K.E. James, F.A. Wagner, and J.C. Anthony, Hopkins University, Baltimore, MD

OP-

Johns

Objective: This study was designed to describe the regional variation regarding drug purchase opportunity among young people in the United States defined in terms of age, gender, and residential location (rural vs. urban). Sample and Analyses: Data from the 1997 National Household Survey on Drug Abuse (NHSDA) was analyzed including 13 250 respondents who were 12-24 years old. The survey respondents were specifically asked if someone had attempted to sell them an illegal drug during the past 30 days. Although there is no geographical coding of the data set, the NHSDA data does report regional indicators for the United States (i.e. Northeast, North Central, South, and West). Proportions were estimated with proper attention to unequal probabilities of selection and clustering on primary sampling units. Results: The most affected groups included Southern urban males (21.8%), Western rural males (20.9%), Western urban males (20.5%), North Central urban males (19.1%), and Northeastern urban males (18.0%). The least affected groups included North Central rural females (6.4%), Southern rural females (7.2%), North Central rural males (8.3%), Western rural females (lO.O%), and Northeastern rural females (11.9%). Implications: These findings reveal some important regional differences which could prove helpful in understanding the pattern of illegal drug use across the United States in conjunction with targeting specific regions and groups with particular demographic characteristics for intensive education, prevention and treatment efforts. ACKNOWLEDGEMENT: This study was supported by ROlDA09897 and T32DA07292. 281 SYNTHESIS AND PHARMACOLOGY OF DOPAMINE UPTAKE INHIBITORS: 2-SUBSTITUTED-6-AMINO-5 PHENYLBICYCLO 12.2.210CTANES

S. Javanmard, H.M. Deutsch, D.M. Collard, M.J. Kuhar, and M.M. Schweri, School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta,Yerkes Regional Primate Center, Emory University, Atlanta, Mercer University School of Medicine, Macon, GA A series of 2-substituted-6-amino-5-phenylbicyclo [2.2.2]octanes was synthesized and tested for inhibitor potency in [3H]WIN 35 428 (WIN) binding at the dopamine (DA) transporter and [3H]DA uptake assays. To demonstrate transporter selectivity for the compounds, inhibitor potency was also tested using [3H]nisoxetine and [3H]paroxetine binding assays for

s99

the norepinephrine (NE) and serotonin (5-HT) transporters, respectively. Synthesis was accomplished by bisannulation of the enamine derived from phenylacetaldehyde and dimethylamine with 2-cyclohexenone to give a mixture of endo and exo-trans-6-amino-5-phenylbicyclo[2.2.2]octan-2-ones. The separated ketones were reduced to the four diastereomeric alcohols which were converted to acetyl and benzoyl esters. In all cases, the benzoates show significantly greater inhibition of WIN binding compared to the corresponding ketone, alcohols, or acetate esters. One compound, was almost as potent as cocaine in binding to the DA tranporter (IC50 = 270 nM versus 159 nM for cocaine). Its C-2 epimer, was selective and potent in binding to the 5-HT transporter (IC50 = 53 nM versus 1050 nM for cocaine) as compared to the DA transporter (IC50 = 358 nM). These compounds will be tested in the rat drug discrimination model. 282 SYMPTOMSOF PTSD AMONGADOLESCENTPROBATIONERS ENTERING RESIDENTIAL DRUG TREATMENT ORGROUPHOMES

L.H. Jaycox and A.R. Morral, Drug Policy Research Center, RAND, Santa Monica, CA As part of an evaluation of an adolescent residential substance abuse treatment program, juvenile probationers awaiting placement were interviewed about their trauma experiences and symptoms of PTSD. Preliminary results (N = 3 16) reveal high rates of trauma experience (e.g. severe car accident, fire/explosion, sudden life-threatening illness, physical attack with or without a weapon, threat with a weapon, sexual molestation, and attempted rape or rape). Only 16% of the sample neither witnessed nor experienced such events, whereas 10% witnessed, 17% experienced, and 57% both witnessed and experienced at least one. Over 80% of those who reported an event had experienced or witnessed more than one such event. Of those who described the worst traumatic event as distressing when it occurred (77% of those reporting an event), 44% reported symptoms consistent with a diagnosis of PTSD. We will present data from a larger sample (approximately N= 400) on trauma and PTSD symptoms in relation to reported drug use severity and patterns. We will also compare those placed at the treatment facility with those placed in other group home settings, and link responses at baseline to retention in the treatment program and group home placements. ACKNOWLEDGEMENT: This research was supported by grant KDl T111433 (Morral) from the Substance Abuse and Mental Health Services Administration, Center for Substance Abuse Treatment (SAMHSACSAT).

SlOO

Abstracts

283 REGULATION OF MU OPIOID RECEPTOR AND cFOS MRNA LEVELS IN SH-SY5Y CELLS BY RETINOIC ACID

S. Jenab and C.E. Inturrisi, Weill Medical College of Cornell University, New York, NY Differentiation of the human neuroblastoma cell line, SH-SYSY results in changes in ion channels, receptors and second messenger systems. Differentiating agents enhance the expression of y-opioid receptors (MOR), the inhibition of adenylyl cyclase by mu opioids and the expression of second messenger systems. We examined the time course of the effects of all-trans retinoic acid (RA) on HMOR and c-fos mRNA levels as determined by solution hybridization (using HMOR and rat c-fos riboprobes) in RNA extracts from SH-SYSY cells. The changes AP-1 DNA binding and the presence of fos related proteins (Western blot analysis) was determined in nuclear extracts from untreated, vehicle (ethanol) or RA treated SH-SYSY cells. Exposure to RA for 35 min had no effect on HMOR while after 18 h HMOR in mRNA levels were decreased by 50% and then after 7 days HMOR mRNA was increased by 50%. In contrast, c-fos mRNA was unchanged at 35 min, but increased 50% at both 18 h and 7 days. RA increased AP-1 binding after 18 h and 7 days and a fos-FRA antibody produced a supershift: Western analysis indicates that RA activates a 45 kD protein corresponding to the size of fos B protein. These results identify two signal transduction targets that are regulated by RA during differentiation. Supported in part by DAO1530, DA01457 and DAO0198. 284 GETTING TO TREATMENT: THE SOCIAL CONSTRUCTION OF PERINATAL ADDICTION AND AN ANALYSIS OF ONE CASE

M. Jessup, University of California, Nursing, San Francisco, CA

and School of

Traditional beliefs about pregnant drug dependent women’s readiness for substance abuse treatment attribute the problem of late enrollment in treatment and prenatal care to intrinsic barriers alone. The absence of data about women’s lived experiences of negotiating extrinsic barriers to treatment, as well as a prevalence of non-gender-specific theoretical models of readiness reinforce a model of individual pathology and minimize the impact of system-located barriers to care for pregnant women. The objective of this qualitative study was to document treatment-seeking experiences among pregnant drug dependent women in public sector substance abuse treatment in the Bay Area. Subjects resided in long-term residential treatment. One case is

presented here to illustrate the dilemmas facing pregnant drug dependent women as the process of recovery is sought. Through narrative analysis, findings of significance in this case include a description of passage through barriers encountered, a perinatal-specific process of treatment readiness, self-advocacy in the form of personally devised strategies for retention of child custody, the impact of state intervention, and perceptions of the health care system and its providers as collaborators with the criminal justice system. These results suggest public policy initiatives that will increase treatment access and utilization by pregnant drug dependent women in order to reduce barriers to early entry to care. 285 ADRENALECTOMY ALTERS LEUKOCYTE-ENDOTHELIAL INTERACTIONS IN RAT MESENTERIC VENULESFOLLOWING ACUTE INFLAMMATION INDUCED BY FMLP ANDSYSTEMICTREATMENTWITHLPS

Y. Jiang, S.D. House, and S.L. Chang, University, South Orange, NJ

Seton Hall

Chronic exposure to morphine has been previously shown to abolish HPA axis response to treatment with interleukin-1 beta (Chang et al 1996). In this study, intravital microscopy was used to examine the effects of adrenalectomy on leukocyte-endothelial adhesion (LEA) and white blood cell flux (FLUX) in rat mesenteric venules following FMLP (1 x 1O-6 M)-induced inflammation and systemic treatment with LPS. Both adrenalectomized (ADX) and sham male rats were from Harlan Sprague Dawley. In the first study, both groups were prepared for intravital microscopy. FLUX of ADX rats is lower than that of SHAM rats without FMLP. Decrease in FLUX induced by topical suffusion with FMLP in ADX rats (61.00/o) is significantly higher than that of SHAM animals (45.5%). Similarly, increase in LEA induced by FMLP in ADX rats (102.9%) is significantly higher than that of SHAM animals (53.7O/o). In the subsequent studies, both ADX and SHAM rats were treated with either LPS (100 ug/kg) or saline (NS) intraperitoneally. At 2- or 4 h following injection, LEA and FLUX were determined. Following 2 h injection, decrease in FLUX by LPS is greater in ADX rats (91.6%) than that in SHAM rats (71.8%). LPS results in an increase in LEA in SHAM rats; however, no obvious increase shown in ADX animals. ADX rats injected with LPS had diffusive intravascular clotting (DIC) 4 h after LPS injection, while SHAM rats showed responsive LEI as expected. Taken together, adrenalectomy appears to alter LEI in rat mesenteric venules. These studies confirm that abolishment of the HPA axis response, in the case of chronic exposure to morphine, may potentiate immune responses detrimentally. Supported by DA 07058.

Abstracts

286

DISCRIMINATION

OF

INTRAVENOUS

COCAINE

IN

HUMANS

C.E. Johanson, K.J. Schuh, and H. Schubiner, Wayne State University School of Medicine, Detroit, MI In the development of medications for the treatment of cocaine abuse, the drug discrimination paradigm can be used to identify medications that can attenuate the discriminative stimulus effects of cocaine. This preliminary study examined whether intravenous cocaine can be discriminated from placebo and whether doses higher and lower than the training dose occasion cocaine-appropriate responding. Subjective and physiological effects were also measured. Cocaine-abusing participants were trained to discriminate 10 mg intravenous cocaine from placebo. After the discrimination was learned, dose-response curves were generated with 0, 5, 10, and 20 mg cocaine. Cocaine produced dose-related increases in cocaine-appropriate responding, in subjective effects (e.g. increased subject-rated ‘high’), and increases in physiological effects (e.g. increased heart rate). These preliminary data indicate that intravenous cocaine can be used in a human drug discrimination paradigm. Future studies will examine putative treatment medications to determine whether they can attenuate the discriminative stimulus, subjective, and physiological effects of intravenous cocaine in humans. 287

EFFECTS

STEROID BEHAVIOR, MONOAMINES

OF

NANDROLONE

THE

ANABOLIC

DECANOATE

ETHANOL-INDUCED

ANDROGENIC ON

COMPETITIVE

TOLERANCE

AND

IN RAT

P. Johansson, A.S. Lindqvist, F. Nyberg, and C. Fahlke, Uppsala University and Giiteborg University, Sweden Recent studies shows that chronic treatment with anabolic androgenic steroids (AAS) stimulates voluntary alcohol consumption and defensive aggression in rat. Furthermore, AAS interact with the endogenous opioid system in brain regions controlling e.g. reward and aggression. The present study investigated whether the AAS (nandrolone decanoate, 15 mg/kg per day during 2 weeks, SC,II = 14) affects competitive behavior, acute ethanol tolerance and monoamine levels in Wistar rats. After the last injection, pairs of AAS and control rats competed for water access from a sprout with a suspension cone, which gave only one rat the opportunity to drink. The ethanol tolerance was observed by measuring the sleep-period induced by an ethanol injection (2.5 g/kg, i-p.). Statistical analysis was made by student’s t-test. The AAS-treated animals exhibited greater competitive behavior than controls. They also devel-

SlOl

oped a faster acute tolerance to alcohol than controls, which may be a possible explanation for the previously found increased alcohol consumption. Measurements of monoamines, by HPLC with electrochemical detection, are in progress. 288

FAMILIALITY

PSYCHIATRIC

OF

NICOTINE

DEPENDENCE

AND

COMORBIDITY

E.O. Johnson and N. Breslau, Henry Ford Health Sciences Center, Detroit, MI We examine the familiality of nicotine dependence (ND) and hypothesized variability in the degree to which this familiality is shared with other psychiatric conditions in a population sample of young adults. The few studies that have examined shared familiality or genetic liability have been based on special samples and/or idiosyncratic definitions of smoking behavior. Methods: Subjects were from a longitudinal study of a sample of young adults randomly selected from a large health maintenance organization in southeast Michigan. Family history data was available for 979 subjects age 24-33. Probands were diagnosed using DSM-IIIR criteria. Familiality was examined as a familial loading score (number of family members affected/number of family member exceeding the age of 15). Results: 52.8% of family members of nicotine dependent probands had a lifetime history of smoking 10 + cigarettes per day compared to 30.3% of family members of proband who were never nicotine dependent (P < 0.001). The Table shows the results for panic attacks. This pattern of results, where increased percent of affected relatives follows the presence of the primary disorder in the proband but is not increased among probands with only the secondary disorder suggests independent familiality of the two disorders. Contrary to expectations, the results for major depression (MD) were similar, suggesting independent familiality of MD and ND. For alcohol dependence increased percent of affected relatives was found for probands with ND only, alcohol dependence only and for the comorbid condition compared to probands with neither condition, suggesting some shared familial liability.Proband StatusFamilial Loading Score for Neither@ = 659) Nicotine dep. only(n = 200) Panic attacks only 289

How

FROM

BUPRENORPHINE

OID

BLOCKADE

FAST

CAN

PATIENTS TO

BE MAINTAINED?

BE

NALTREXONE

A

PILOT

TRANSITIONED AND

CAN

OPI-

STUDY

R.E. Johnson, A.B. Becker, H.E. Jones, E.C. Strain, and G.E. Bigelow, Johns Hopkins University School of Medicine, Baltimore, MD

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Abstracts

Introduction: Theoretically, a rapid transition from Bup to Nal should be possible without precipitating intolerable withdrawal. Purpose: To determine the dose and procedure for transitioning from Bup to Nal and to compare their opioid blockade. Methods: This single blind study transitioned six subjects maintained on Bup 12 mg/day (sublingual tablet) to 50 mg oral Nal. Group 1 began Nal during a 6-day Bup dose taper and Group 2 began Nal after the last dose of Bup. Group 1 (n = 2) received ascending doses of Nal starting at 1 mg b.i.d and going to 50 mg in 14 days. Group 2 (n = 4) received gradual dose increases of Nal starting at 2 mg t.i.d. and going to 50 mg in 9 days. A hydromorphone challenge (0, 6, and 12 mg, IM every 1.5 h apart) was conducted on days 7, 15, 19, and 28 to assess opioid blockade. Outcome measures included physiologic and self-reports of opioid withdrawal and opioid agonist effects. Results: The planned dose of naltrexone had to be lowered (up to lo-fold) and divided (t.i.d) due to withdrawal symptoms. Six of eight subjects completed the transition. 290

IMPROVING

BIRTH

TREATMENT-SEEKING WOMEN:

A PILOT

OUTCOMES

PREGNANT

IN

NON-DRUG-

ILLICIT-DRUG-USING

STUDY

L. Jolkovsky, H. Jones, B. Das, G. Tran, and D.S. Svikis, Johns Hopkins University School of Medicine, Baltimore, MD Identifying effective ways to improve birth outcomes in pregnant women using illicit drugs challenges health care providers. This study compared demographic and birth outcomes for two groups of non-treatment seeking drug using pregnant women attending an urban prenatal care clinic. The intensive group (N = 6) completing assessment and four sessions of a therapy pack(voucher reinforcements for drug-free age urines + Motivational Enhancement Therapy) was compared to a less intensive group (N= 8) who completed assessment and O-3 therapy package sessions, The groups were demographically similar. The women had a mean age of 26.4 years (S.D. = 5.7) were predominantly African-American (93%), had a mean of 11.5 (S.D. = 1.1) years of education and entered prenatal care at a mean of 13.7 (S.D. = 4.1) weeks pregnant. Results showed that both groups attended a similar number of prenatal appointments and delivered at fullterm (mean = 38.1 weeks, S.D. = 2.4). Although no significant differences were seen in rates of toxicological drug positive deliveries or length of infant hospital stay (less intensive group = 2.3 vs intensive group = 2.5 days), significant differences in birth weight and first APGAR scores were observed. Specifically, babies born to intensive group mothers weighed more (3340.7 vs. 2483.9 gms: P = 0.0007) and had higher APGAR scores

(8.8 vs 8.2; P = 0.03) than babies of less intensive group mothers. Results suggest that providing four opportunities for voucher reinforcement for drug free urines and MET sessions positively impacts birth weight and initial neurobehavioral testing. The study is on-going and final results (N= 20 per group) will be presented. Research supported by DA- 11476. 291

COMPARING

INDIVIDUALS:

HEROIN-

AND

PRE-TREATMENT

COCAINE-DEPENDENT

CHARACTERISTICS

H. Jones, E.C. Strain, R.E. Johnson, and G.E. Bigelow, Johns Hopkins University School of Medicine, Baltimore, MD The present study compared the pre-treatment characteristics of heroin dependent (N = 220) and cocaine dependent (N = 165) patients enrolling in an outpatient treatment/research clinic. Groups were compared on demographic characteristics, Addiction Severity Index (ASI) variables and DSM-IV Axis I and Axis II disorders. Except for gender, no significant differences in race, legal, marital or employment status were found between groups. After controlling for gender, post-hoc comparisons showed that the cocaine dependent group had significantly greater AS1 alcohol, family/social and psychiatric severity scores and significantly lower drug use severity scores relative to the heroin dependent group. The cocaine dependent group had greater rates of DSM-IV Axis I diagnosis including lifetime major depression, current and lifetime alcohol and cocaine dependence relative to the heroin dependent group. The presence of any DSM-IV Axis II diagnosis including or excluding Antisocial Personality Disorder (APD) was significantly greater in the cocaine dependent group relative to the heroin dependent group. Rates of APD did not differ between groups. Results suggest that heroin and cocaine dependent individuals entering a treatment/research clinic differ on drug use and psychiatric severity. Cocaine dependent individuals appear to have a greater range of non-substance Axis I and Axis II psychiatric problems and may require more intensive treatment for co-morbid psychiatric disorders. Supported by K02 DA00332, ROl DA10752, K05 DA00050 and P50 DA05273. 292

PHARMACOLOGIC

TRANSDERMAL

SELEGILINE

INTERACTIONS AND

BETWEEN

COCAINE

R.T. Jones, A.S. Dearborn, N. Uemura, L. Lester, N. Chiang, P. Jacob III, and J. Mendelson, Langley Porter Psychiatric Institute, University of California, San Francisco, CA Selegiline is a promising new therapy for cocaine addiction but, because it is an MAO inhibitor, there are

Abstracts

concerns about patient safety if it were to be co-administered with cocaine. In order to assess safety interactions between transdermal (TD) selegiline and cocaine, 14 nondependent, cocaine-experienced volunteers (two discharged prior to completion) were challenged with intravenous cocaine (0.5 mg/kg loading dose (d5) over 10 min followed by 4 h infusion of 2.0 mg/kg) before and after selegiline administration. TD selegiline (one 20 mg/patch per day; Somerset Pharmaceuticals, Inc.) was initiated following the first cocaine infusion and continued for 10 days. The second cocaine challenge was performed following 7 days of selegiline administration. Selegiline steady-state (determined by urine PK analysis) was obtained within the 7 day dosing period prior to the second cocaine challenge. The effects of cocaine on heart rate, systolic and diastolic blood pressure, respiratory rate, skin and tympanic temperature were not significantly altered by selegiline. Selegiline decreased visual analog (VA) ratings of craving and desire for cocaine and tension and anxiety on the Profile of Mood State scale and increased VA ratings of bad drug effect. Adverse reactions to TD selegiline were minimal and consistent with MAO inhibitors as a class. Selegiline did not produce significant orthostatic vital sign changes and no adverse cardio-vascular reactions occurred. These results suggest that TD selegiline is safe and may be useful in the treatment of cocaine dependence. Supported by NIDA contract NOlDA-4-8306 and NIH RR-00079 (GCRC, UCSF).

293 DOPAMINE RECEPTOR AGONISTS AND ANTAGONISTS ALTER DAT TURNOVER IN THE STRIATUM AND NUCLEUSACCUMBENSOFTHERAT

A.R. Joyce, H.L. Kimmel, F.I. Carroll, and M.J. Kuhar, Yerkes Regional Primate Research Center, Emory University, Atlanta, GA, and Research Triangle Institute, Research Triangle Park, NC ICV injections of the irreversible dopamine transporter (DAT) ligand, RTI-76, inhibits [3H]GBR12935 binding to DAT in the striatum and nucleus accumbens of the rat. By measuring the recovery of binding to DAT in a previous study, we determined that the half-life of DAT protein in these brain regions is 2-3 day. In the present study, we determined the effects of Dl- and D2-dopamine receptor selective agonists and antagonists on the kinetics of the DAT protein in these brain regions. Rats were treated with SKF38393 (3.0 mg/kg, SC), SCH23390 (0.5 mg/kg, IP), quinpirole (0.3 mg/kg, IP), or eticlopride (0.5 mg/kg, IP), or saline once per day for 3 days. On the 4-day, RTI-76 or saline was administered ICV, then the animals continued to receive systemic drug or saline once per day during the recovery

s103

period. At 1, 2, 3, or 7 days after ICV RTI-76 or saline, animals were sacrificed and the striatum and nucleus accumbens harvested. [3H]GBR12935 binding to DAT was measured, and the kinetics of the DAT protein determined for each treatment group. These results suggest that activation and/or blockade of dopamine receptors can alter the production and degradation rates of the DAT protein. Supported by RRO0165, DA00418, DA11178, and DA05935. 294 DEXTROMETHORPHAN PHETAMINE SELF-ADMINISTRATION

ALTERS

METHAM-

J.H. Jun and C.W. Schindler, NIH/NIDA Research, Baltimore, MD

Intramural

Various lines of evidence indicate that methamphetamine (METH) self-administration in rats is under dopaminergic control, and NMDA receptors have been shown to control the release of dopamine at its synapse. Consequently, the aim of this study was to observe the effects of dextromethorphan (DM), a non-competitive NMDA antagonist, in rats self-administering METH. Male Wistar rats were initially trained to self-administer 0.1 mg/kg/inj METH on a fixed ratio (FR) 1. The FR schedule was gradually increased to FR-5. Self-administration was deemed stable once correct responses fluctuated less than 20% over five consecutive sessions. All subjects were then tested in extinction. Following extinction, three different groups were allowed to selfadminister three different METH doses, 0.05, 0.1 and 0.25 mg/kg/inj. A separate group of rats was trained on the same regimen to respond for food. After stability was again reached, DM (25 mg/kg) was injected IP immediately before the start of five consecutive testing sessions for all three-dose groups of METH and the food control group. DM significantly altered self-administration by reducing the number of correct responses for all three METH self-administration doses (0.05, 0.1, 0.25 mg/kg). The same pretreatment did not affect responding for food reward. These findings show that DM was able to selectively alter METH selfadministration. Supported by NIDA IRP. 295 MECHANISMSOFGENDERDIFFERENCESINETHANOLWITHDRAWAL

M.E. Jung, M.B. Gatch, C.J. Wallis, and H. Lal, Institute of North Texas, University of North Texas Health Science Center, Fort Worth, TX This study hypothesizes that a female hormone, estradiol, produces a protective mechanism against ethanol withdrawal (EW) symptoms in rats. Two anxiety assays

s104

Abstracts

were employed; pentylenetetrazol (PTZ, GABA-A antagonist) and m-chlorphenyl-piperazine (mCPP, 5HTl b/2a/2c agonist) discrimination assays. In one study, gonadally intact or gonadectomized male (9- 11) and female (9-10) rats, and beta-estradiol (2.5 mg, 21 days)-replaced ovariectomized (OVX) rats (12) acquired mCPP (1.2 mg/kg, IP) discrimination under a fixed ratio 10 schedule. When tested, sham-operated females and estradiol-replaced OVX rats had higher ED5Os than sham and castrated males and OVX rats [F(4, 14) = 5.25, P = 0.009]. Rats then received a chronic ethanol diet (6.5% w/v) for 10 days. Fewer sham females or estradiol-replaced OVX rats selected mCPP-lever during acute [F(4,28) = 8.4, P < O.OOl] and protracted EW (yielding higher ED50) [F(4, 10) = 10.01, P= 0.0021 than male and OVX rats. Castrated rats did not differ from sham male rats in discriminating mCPP under tested conditions. In another study, intact male (15), sham-operated female (9), and OVX (11) rats were trained for PTZ (16 mg/kg) discrimination. When tested, nicotine (O-O.88 mg/kg) substituted for PTZ to a higher degree in male than sham female rats [F(2, 30) = 1.5, P = 0.241. Rats then received a chronic ethanol diet (4.5% w/v, 7 ds) and were tested for a spontaneous PTZ-lever selection during acute EW followed by nicotine substitution tests 1.5, 6, and 7 days after ethanol termination. More intact male rats selected PTZ-lever during acute EW than sham female and OVX rats [F(2, 9) = 5.2, P = 0.0311. Nicotine substitution for PTZ was increased during 1.5 and 6 days after EW in male (P < 0.05) and OVX rats (P < 0.05) but not in sham female rats. These data indicate that (1) EW potentiates anxiogenic stimuli induced by 5HTlb/2a/2c activation or GABA inhibition to a lower degree in female rats than in male rats normally and during EW. (2) Nicotine potentiates GABA inhibition, in particular during EW in male but not in female rats. (3) Estradiol in part produces a protective mechanism in female rats against the anxiogenic stimuli during EW. NIAAA grants # AA09567 and # AA10545. 296 ACUTE EFFECTS OF ESTROGEN PHETAMINEINPOST-MENOPAUSAL WOMEN A.J.H. Justice and H. de Wit, Chicago, Chicago, IL

AND

The University

AM-

of

In addition to its traditional function in regulating sexual development and reproduction, there is considerable evidence that estrogen may regulate mood and cognition through membrane receptor-mediated actions in the central nervous system. Estrogen treatment in post-menopausal women reportedly produces feelings of well-being and improves memory performance. Some of these effects resemble the effects of stimulant drugs,

raising to the possibility that these CNS effects of estrogen may be mediated by dopamine (DA). In this study, 16 healthy post-menopausal women not on hormone replacement therapy received acute doses of 0.2, 0.4, or 0.8 mg estradiol (transdermal), 15 mg amphetamine (AMPH; oral), and placebo during five, 12-h experimental sessions. Subjective, cognitive and physiological measures were obtained prior to, and for 12 h after drug administration. Preliminary results (n = 9) indicate that the low and intermediate doses of estradiol produced mood-altering effects resembling those produced by AMPH, such as increased Pleasant Stimulation and Talkativeness and decreased Depression. Interestingly, the highest dose of estradiol produced the opposite effects, increasing Depression and decreasing Pleasant Stimulation and Talkativeness. In this preliminary analysis, no cognitive effects of estradiol were observed. These findings provide some support for the idea that estrogen increases dopamine function. Supported by DA028 12, MH 12243, RR00055. 297

PERIODIC POSTPARTUM SEPARATION FROM THE LITTERAFFECTSPLUS-MAZEPERFORMANCE ANDSENSITIVITY TO MORPHINE IN LONG-EVANS DAMS

M. Kalinichev, K.W. Easterling, and S.G. Holtzman, Emory University School of Medicine, Atlanta, GA It has been reported that daily neonatal (days 2-14) separation from the dam produces long lasting changes in responses to stressors and sensitivity to morphine (MOR) in Long-Evans rats. Our goal was to determine whether dams that have experienced repeated postpartum (days 2-14) separations from their litter for 3 h daily (S dams), like their pups exhibit altered anxietylike behaviors and sensitivity to MOR compared to dams that have had their pups briefly handled (H) or non-handled (NH) during the same period. We tested dams (n = 8- 11) on the elevated plus-maze for 10 min, both in the dark and in the light, 6 weeks after the pups were weaned (day 22). One week after that, all dams were tested on the hot-plate before and during cumulative MOR administration (1 .O-4.0 mg/kg). When tested in the dark on the plus-maze, experimental (S) and control (H and NH) dams did not differ in the number of entries or duration of time spent on the open arms. However, in the light S dams entered open arms 2.4 times more often and spent 20% more time in these arms compared to H control animals. In the hot-plate test, MOR was less potent in S dams (ED50 > 4.0 mg/kg) producing analgesia than in H (ED50 = 1.30 mg/kg) or NH (ED50 = 1.55 mg/kg) controls. These data indicate that dams that experience repeated 3 h separations from their litter exhibit blunted anxiety to environmental challenge and reduced responsiveness to MOR. Thus, early maternal separation impacts the

Abstracts

subsequent behavioral responsiveness not only of the pups but of the dams, as well. Supported by N.I.H. Grants DA11384 and K05 DA00008. 298 HYDROCORTISONE TREATMENT IN BENZODIAZEPINE-DEPENDENTPATIENTSATTENUATESTHEWITHDRAWAL SYNDROME OBSERVED DURING DISCONTINUATION K.T. Kalogeras, P.J. Pazzaglia, V.K. Carroll, J.A. Ali, R.W. Baker, P. Kleinman, J.W. Norton, G.H. Holloman, Jr., G. Gordon, and A. Halaris, University of Mississippi Medical Center, Jackson, MS Benzodiazepines represent the most widely prescribed medication for anxiety disorders; however, their use has been challenged because of the problem of dependence. Our data from primate and rat studies have shown that discontinuation of benzodiazepines resulted in an activation of the central corticotropin-releasing hormone (CRH) system, which could possibly precipitate or modulate the withdrawal syndrome. Furthermore, treatment with hydrocortisone attenuated the withdrawal syndrome, at least in part, by suppressing the CRH rebound elevation in the brain. To evaluate the effectiveness of hydrocortisone to alleviate or attenuate the withdrawal syndrome in benzodiazepine dependent subjects, six patients that had been taking high therapeutic doses of alprazolam ( 2 4 mg/day) for more than 6 months, underwent a rapid taper (25% daily dose reductions). Withdrawal symptoms and ACTH and cortisol responses were evaluated twice daily during the taper. All subjects had to abort the taper before its completion, due to severe withdrawal symptoms. The patients were then restabilized on their initial alprazolam dose, and 3 days after the initiation of hydrocortisone treatment (50-300 mg/day, PO), underwent a second rapid taper. All patients showed an increase in plasma ACTH and cortisol concentrations during the initial taper, that was significantly attenuated during the second taper on active hydrocortisone. Hydrocortisone treatment during the second taper resulted in a significant (P < 0.025) reduction of the withdrawal symptoms as well, which permitted the patients to complete the taper. We conclude that, hydrocortisone appears to attenuate the benzodiazepine withdrawal syndrome, at least in part, by suppressing the CRH rebound elevation in the brain. 299 NANCY: LEVELS

METHADONE QUESTIONS

MAINTENANCE OF DOSE AND

DURING PREGBLOOD PLASMA

K. Kaltenbach, V. Berghella, J. Drozdick, and M.K. Hill, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA

s105

Evidence suggests that to be effective for treatment of opioid dependence, daily methadone dose should be in the 80-120 mg range with the optimum 24 h plasma level in the 400 rig/ml range. However, methadone dose during pregnancy continues to be a topic of clinical debate. While it is generally accepted that pregnant women may require dose increases during the last trimester, there is reticence to maintain pregnant women on > 80 mg. The question of dose during pregnancy has become even more salient as the purity and availability of heroin has increased significantly. This study presents methadone dose and plasma level data for 45 women maintained on methadone during pregnancy. The women were all enrolled in a comprehensive treatment program, in which the principles of methadone dose determination are based on preventing withdrawal symptoms, eliminating craving, and blocking the euphoric effects of heroin. At intake, women were admitted to the maternal-fetal unit of a university hospital for methadone stabilization/induction. After discharge, women received methadone daily at the treatment program. Five to 10 days post-induction, blood was drawn 20-24 h after the daily methadone dose to determine methadone trough plasma levels. Of the 45 women, 20 women had trough plasma levels in the therapeutic range of 200 rig/ml or greater. The mean methadone dose was 128 mg (range 80-185 mg) and the mean trough plasma level was 310 rig/ml. Twenty-five women had trough levels < 200 rig/ml. Forty percent of these women were receiving < 80 mg (X = 61 mg, range 35-75 mg) and had a sub-therapeutic mean trough level of 100 rig/ml. However, the majority (60%) were on doses > 80 mg (x = 130 mg, range 80-215) and had a sub-therapeutic mean trough level of 130 rig/ml. While these are preliminary data, the findings support the need for doses of 80 mg or greater in order to achieve a stabilized maintenance; the great variability of blood levels in similar doses in pregnant women; and the importance of measuring methadone blood levels to make dosing decisions for pregnant women. 300 GAMBLING STANCE ABUSERS

BEHAVIOR

IN

ADOLESCENT

SUB-

Y. Kaminer, J.A. Burleson, and A. Jadamec, University of Connecticut Health Center, Farmington, CT Objective: To assess the prevalence and correlates of gambling behavior (GB) in dually-diagnosed (DD) adolescent substance abusers. Hypothesis: Dually diagnosed adolescents are at high risk for GB and therefore, will manifest a higher prevalence of GB compared to adolescents from the general population. Method: Ninetyseven adolescents consecutively admitted to an outpatient treatment program were administered an

Abstracts

S106

intake battery including the Massachusetts Gambling Screen (MAGS). Results: Thirty-four percent of the cohort had never gambled, 57% were classified as social/non-pathological gamblers, 8% were labeled as at risk or in transition gamblers, and only one percent met criteria for pathological gambling. Significant findings include: males are more likely to gamble and to have a higher severity score than females. A younger age of GB onset is correlated with: being a female, history of suicide attempts, diagnosis of depression, more symptoms of oppositional behavior, more symptoms of personality disorders, and a higher need for psychiatric treatment. None of the youths identified at least with at risk GB was ever referred for GB counseling. Conclusion: There is little awareness to GB in DD adolescents. Based on the MAGS, the prevalence of GB in dually diagnosed adolescents and in community samples is similar. However, additional studies are required to confirm these findings and to understand the magnitude, severity, and potential subtypes of adolescents at high risk for pathological gambling.

301 A

PILOT

TRIAL

OF

PIRACETAM

AND

GINKGO

BILOBAFORTHETREATMENTOFCOCAINEDEPENDENCE

K.M. Kampman, M.D. Majewska, K. Tourian, C. Dackis, J. Cornish, D. Torpey, C. Henry, M. Gerhart, and C.P. O’Brien, University of Pennsylvania and the Veterans Affairs Medical Center, Philadelphia, PA, NIDA, Bethesda, MD, and Belmont Center, Philadelphia, PA Background: Chronic cocaine use is associated with cognitive deficits, especially deficits in verbal memory, attention, and executive function. These cognitive deficits may reduce the effectiveness of psychosocial treatment and promote relapse in cocaine dependent patients. No otropic agents such as piracetam and ginkgo biloba may improve cognitive function and reduce the incidence of relapse. Methods: Forty-four cocaine dependent subjects received either 4.8 g of piracetam, or 120 mg of ginkgo biloba, or placebo daily in a double-blind, placebo-controlled study. Subjects participated in a 2 week baseline evaluation phase prior to entering an g-week randomized medication phase. Subjects were required to attain abstinence from cocaine during the baseline phase document by at least one benzoylecgonine (BE)-negative urine toxicology screen prior to starting medications. Outcome measures included treatment retention, quantitative BE levels obtained three times weekly, the Clinicians Global Impression (GGI) and results from the Addiction Severity Index (ASI). Results: There was a trend toward increased treatment attrition among piracetam-treated subjects. Analysis of quantitative urinary BE levels

showed no difference between groups. Piracetamtreated subjects were less likely to be rated improved or much improved on the CGI at the end of treatment. Neither piracetam nor ginkgo was superior to placebo in preventing relapse. AS1 results did not differ between groups. Conclusions: Neither piracetam nor ginkgo appears to be a promising candidate for further study for the treatment of cocaine dependence.

302 AND

BASOLATERAL

AMYGDALA

COCAINE-SEEKING

COGNITIVE

FUNCTION

BEHAVIOR

K.M. Kantak, E. Valencia, Y. Black, T. Kremin, K. Green-Jordan, and H.B. Eichenbaum, Boston University, Boston, MA The neural basis for drug craving and relapse is not yet well understood. Recent reports suggest a link between limbic and cortical structures in mediating cocaine use and craving. These findings underscore the possible importance of cognitive processes for regulating at least some aspects of cocaine addiction. Reported here are the effects of reversible lidocaine-induced lesions of the rostra1 and caudal portions of the basolateral amygdala on conditioned cue preference (CCP) and on the reinstatement of cocaine-seeking behavior in rats. CCP is a cognitive task that measures conditioned stimulus-reward associations and requires an intact basolateral amygdala. Division of the basolateral amygdala into rostra1 and caudal portions permits an evaluation of the relative contribution of their segregated projections to the shell or core of the nucleus accumbens, respectively. Cognitive testing confirmed that lidocaine infusions into each site specifically disrupted the expression of CCP. Lidocaine infusions into the rostra1 and caudal basolateral amygdala also dose-dependently attenuated both drug cue-induced and drug prime + drug cue-induced reinstatement of cocaine-seeking behavior in rats trained to self-administer 1 mg/kg cocaine under a FIS(FR5:S) second-order schedule of drug delivery. These findings indicate that the reinstatement of cocaine-seeking behavior requires the ability to process information pertaining to conditioned stimulus-reward associations. Furthermore, functional connections from the basolateral amygdala to both the core and shell of the nucleus accumbens may be involved in regulating the reinstatement of cocaine-seeking behavior, which is an aspect of the cocaine addiction process that often leads to relapse.

303 OPIOID DRUG

SINGLENUCLEOTIDEPOLYMORPHISMOFTHEMU RECEPTOR

GENE

AND

NON-OPIOID-DEPENDENT

ABUSE

S.U. Kapadia, K.S. LaForge, V. Yuferov, K. Bell, S.M. Leal, P. McHugh, S. Kellogg, R.P. Schluger, L. Yu,

s107

Abstracts

and M.J. Kreek, The Rockefeller University, New York, NY, and The University of Cincinnati College of Medicine, Cincinnati, OH Previously we identified two single nucleotide polymorphisms (SNPs), C17T and AllSG, in the first exon of the human mu opioid receptor (MOR) gene; both result in amino acid changes in the predicted primary structure of the receptor (PNASUSA, 95: 9608-9613). We have also shown that the variant at the 118 site encodes receptors that have a higher binding affinity to beta-endorphin. There is some evidence that these SNPs play a role in variable vulnerability to opiate and possibly other addictions but apparently not to alcoholism. As part of this ongoing investigation, we studied the potential association between these SNPs and non-opioid dependent drug abuse or addictions. From a cohort of 450 consecutive subjects, we have identified the following two groups: (a) a control group of individuals with no history of drug or alcohol abuse or dependence; and (b) persons without long-term opiate addiction but with other drug abuse or addiction. Genomic DNA was isolated from subjects. PCR was used to amplify the first exon of the MOR gene from the DNA. The amplified DNA was sequenced by automated and traditional procedures. Sequences were analyzed for known and novel SNPs. One novel SNP leading to an amino acid change was identified. Variations in SNP frequency among study groups will be compared and statistical analysis of these variations will be presented. Supported by NIH-NIDA DA051 30, DA00049, DA09444 and NIH-NCRR RRO0102. 304 PHARMACOKINETICS OF NALTREXONE POLYLACTIDESUSTAINED-RELEASENALTREXONE

FROM

S.A. Kaplan, P. Pouletty, and D.R. Wesson, Drug Abuse Sciences, Inc., Menlo Park, CA The clinical utility of a long-acting, injectable formulation of naltrexone has long been recognized. Several formulations have been tested previously by others but none has been commercially developed. The pharmacokinetics of an intramuscular injection of naltrexone encapsulated in poly lactide and oral naltrexone tablets were studied in 11 healthy male volunteers. Following an intramuscular injection of 300 mg of naltrexone, plasma levels of naltrexone and 6 beta naltrexol were determined daily for the first week, and every 3-4 days thereafter for an additional 5 weeks. The sustained release naltrexone produced mean plasma levels of at least 0.6 rig/ml at all time points measured during the 30 days. Following a single oral dose of 50 mg of naltrexone, plasma levels of naltrexone and 6 beta naltrexol were determined at 0.5, 1, 2, 3, 6, 12, and 24 h. Oral naltrexone produced a mean peak plasma level

of 7.7 rig/ml (SD. + 5.9 rig/ml), and 0.22 rig/ml (S.D. + 0.09 rig/ml) at 24 h. The pharmacokinetics of the sustained release naltrexone suggests the feasibility of once-a-month dosing with naltrexone. 305 COCAINE USE IN NON-TREATMENT SEEKERS: ASSOCIATION WITH STRESS, DEPRESSIVE SYMPTOMATOLOGYANDCRAVING

K. Karlsgodt, D.R. Gastfriend, S. Krause, S. Lukas, I. Elman, Massachusetts General Hospital, Boston, MA and McLean Hospital, Belmont, MA A growing body of data from cocaine abusers engaged in treatment implicate psychosocial stress and negative mood states in craving and subsequent relapse to drug use. Untreated individuals is another subject category that may be of clinical and scientific interest. Thirty-six non-treatment seeking individuals with cocaine dependence were split into high (N = 16) and low (N = 20) stress groups at the mean on both the Tension-Anxiety subscale of the Profile of Mood States and the StateTrait Anxiety Index. The high stress as compared to low stress group had significantly more lifetime years of cocaine use (P = 0.03) higher Hamilton Rating Scale for Depression Scores (P = 0.01) and similar levels of cocaine craving. In an exploratory analysis, days of cocaine use in the last month correlated with the craving scores (P = 0.01) but not with the measures of mood or stress. These finding suggest that (1) the association between stress and depression and cocaine use can be extended to the population of non-treatment seekers; and (2) craving is a relatively specific construct in determining recent drug use. Further studies of the course of cocaine dependence should consider the impact of stress and mood. 306 VOUCHER TER ABSTINENCE

INCENTIVES: INITIATION

EXTENDING

EFFECTS AF-

E. Katz, E. Robles, M. Stitzer, K. Silverman, and G. Bigelow, Johns Hopkins University School of Medicine, Baltimore, MD Voucher incentive procedures can reliably initiate cocaine abstinence in a large proportion of methadone patients. This study examined the ability of continuing reinforcement to sustain abstinence over a 2 weeks timeframe. Forty (42% female) cocaine-abusing methadone patients participated in a within subject study design with four voucher schedules tested. Two schedules, which offered $500 for 2 weeks of continuous abstinence (Sustained), were compared to no incentive (Control) and single-day ($100) incentive conditions. Using semi-quantitative urinalysis, abstinence was defined when urinary benzoylecgonine concentrations

Abstracts

S108

were reduced by 50% from the previous M, W, or F test result or were less than 300 rig/ml. Self-report assessments of drug use were completed once weekly. Seventy to 80% initiated abstinence at the start of incentive conditions (vs 48% abstinent during no voucher condition). Patients submitted more cocaine negative urines during Sustained (M= 2.5 and 2.6 out of 6 possible) than during single (M= 1.7) and no voucher (M = 1.6) conditions. Two full weeks of sustained abstinence was seen in 32.5% and 35% of patients during sustained voucher conditions compared with 12.5% and 5% during single and no voucher conditions, respectively. Reported cocaine injections were M= 4 during no voucher, M = 1.8 during single voucher and M = 2.4 during both Sustained voucher conditions. These incentive procedures have clinical and research utility in that they reliably initiate cocaine abstinence, enhance rates of sustained abstinence, and provide a model to study factors influencing drug use cessation and relapse. Research supported by DA12439, P50 DA09258 and T32 DA07209. 307 COCAINE-INDUCED TION IS SEXAND DEPENDENT

M.J. R.A. son, and

CEREBRAL VASOCONSTRICMENSTRUAL-CYCLE-PHASE-

Kaufman, J.M. Levin, L.C. Maas, T.J. Kukes, Villafuerte, K. Dostal, S.E. Lukas, J.H. MendelB.M. Cohen and P.F. Renshaw, McLean Hospital, Harvard Medical School, Belmont, MA

We hypothesized that cerebral blood volume (CBV) changes induced by intravenous cocaine (0.4 mg/kg) administration would differ in men (n = 9) and in women (n = 13) who were occasional cocaine users. Women were studied in both menstrual cycle phases. Seven women underwent initial CBV measurements during their follicular phase (days 3-8, start of menstruation = day 1). and six were studied first during their luteal phase (days 18824), to eliminate an order effect. Global CBV was determined with a steady-state Dynamic Susceptibility Contrast MRI method, which utilizes multiple bolus injections of an MRI contrast agent to map cocaine-induced CBV changes (vasoconstriction). In follicular phase women, cocaine did not alter CBV. Cocaine reduced CBV by 10% in luteal phase women (P < 0.05) and by 20% in men (P < 0.04). No group differences in cocaine’s cardiovascular effects were noted. These findings suggest that cocaine’s cerebral vasoconstrictive effects differ as a function of sex and menstrual cycle phase. The differences may be attributable to gonadal steroid hormones, and may contribute to sex differences in the severity of brain dysfunction noted in chronic cocaine abusers. The findings also imply that gonadal steroids may have utility as vasoprotective agents.

308 ARELONG-TERMFOLLOWUPSNECESSARYTO TERMINEWHETHERATREATMENTWORKS?

DE-

J. Keely, J.R. Hughes, M. Carpenter, and S. Naud, University of Vermont, Burlington, VT Studies of drug abuse treatment have often employed long-term follow-up visits because outcomes typically worsen over time. However, whether the effect size (the difference in treatment and control) declines also is unclear. We are conducting a series of meta-analyses of different treatments for smoking cessation to answer this question. Initial analyses of abstinence rates in 17 nicotine patch studies, reporting continuous abstinence, indicate the odds ratios (a measure of effect size) were similar at 1, 3, 6, and 12 month follow-ups. The mean change in OR across follow-ups was 0.0 (l-2 months), -0.1 (2-3 months), - 0.1 (3-6 months), and - 0.2 (6-12 months). Over time, the effect size decreased by > 25% in less than 4% of early follow-ups and in 11% of late follow-ups. A previous meta-analysis of gum studies produced similar results. These early findings suggest long-term follow-ups are not be necessary to establish treatment efficacy. We are currently testing this conclusion in studies of psychosocial and other pharmacological treatments for smoking cessation. Supported by NIDA training grant # T32 DA07242, NIDA Career Development Award # K02 DAO0109, and NIDA research grant DA 11557. 309

PROBING THE SENSATIONS OF PAIN AND ITCH WITH (+)-BUPRENORPHINE, (-)-BUPRENORPHINE AND NORBUPRENORPHINE

G.B. Kehner, N.A. Grayson, K.C. Rice, and A. Cowan, Temple University School of Medicine, Philadelphia, PA, and NIDDK, NIH, Bethesda, MD We have found that centrally and/or peripherally acting kappa agonists are antipruritic in the mouse model of itch described by Kuraishi et al. (Eur. J. Pharmacol. 275: 229; 1995). With mu opioid receptors now in mind, we have compared the pharmacological bases of pain and itch with the help of ( + )- and ( - )-buprenorphine (BUP) and norbuprenorphine (norBUP), the N-dealkylated metabolite. Male Swiss mice (23-28 g; n = 6- 11) were used. Antinociception was monitored in the (0.6%) acetic acid writhing test. Antipruritic activity was measured against compound 48/80 (50 ug in 100 ~1, s.c.), which served as the scratch-inducing agent. The three compounds were clearly separated, in parallel fashion, in the two assays (figures). Antinociceptive-50 values (mg/kg, s.c.) for ( - )-BUP, norBUP and ( + )-BUP were 0.067 (0.039-0.096) 0.21 (0.12-0.31) and > 0.20,

s109

Abstracts

respectively. Corresponding antiscratchvalues were 0.021 (0.013-0.029) 0.18 (0.11-0.26) and > 0.50. The positive effects of norBUP in both tests is of note. Along with previous work, our present robust results highlight a common stereoselective mediation of (presumed) pain and itch sensations by opioid receptors in the mouse. DA 07237 and F31 DA 06028. 310

GENDER

TREATMENT OF EIGHTEEN

AND ORGANIZATIONAL INJECTION

METHADONE STYLE: DRUG-USING

MAINTENANCE A

CASE

STUDY

COUPLES

MS. Kelley and S. Meersman, University Miami, FL

of Miami,

Our primary research goal was to examine in detail the responses to methadone clinic styles by 18 drugusing couples in treatment. Our questions included: How do injection drug using couples manage their drug use and treatment? How do couples respond to different types of treatment. And, finally, how is gender inequality evidenced by partners in treatment? The data come from a longitudinal study of 233 injection drug users in contact with methadone maintenance programs in the San Francisco Bay Area (Marsha Rosenbaum, Principle Investigator). Study participants were recruited from clinics, clinic waiting lists, and needle exchange sites. Each individual was initially interviewed using a qualitative life-history guide and an extensive close-ended instrument. Each was then re-interviewed over the phone every 6 months (t = 5, 1990-1993). We provide detailed description of the experiences of a subset of 18 couples in treatment. Our methods are both qualitative and quantitative, beginning with content analysis of the in-depth interviews. We also utilize descriptive and explanatory statistical procedures to answer the research questions, including exact tests (designed for small samples), and a series of regression analysis of the quantitative data. The data provide a unique opportunity to follow the progress of couples in different treatment styles. Findings identify patterns in drugs use, treatment, family relationships, and HIV/ AIDS risk behaviors. The patterns are then examined for differences in response to clinics style and differences by gender. In particular, it was noted that for many of the couples, codependency was the primary identifying nature of the relationship. The patterns in responses to treatment are understood in the framework of the balance of control in treatment and influence of social networks. Results could have important policy implications for treatment providers for maximizing treatment success for couples.

311

THE

DRUG

SCALE:

OPERATING

PERSONALITY VALIDITY

ASSESSMENT STUDIES

CHARACTERISTICS

USING

INVENTORY THE

RECEIVER

APPROACH

S.H. Kellogg, A. Ho, R. Schluger, K. Bell, P.F. McHugh, K. McClary, and M.J. Kreek, The Rockefeller University, New York, NY The Personality Assessment Inventory (PAI) (Morey, 1991, 1996) is a relatively new, but increasingly popular, self-report measure of psychopathology. This particular study examined the ability of one scale - the Drug Scale (DRG) - to capture the problematic experiences of drug users, abusers, and dependents. All PA1 scales use standardized T scores with a mean of 50T (SD = 10) for a normal population and a mean of 70T (SD = 10) for a clinical population. The data was drawn from a sample of patients participating in an IRB-approved study on the genetics of drug addiction at The Rockefeller University Hospital (RUH). All participants gave blood and urine samples and answered other interview or self-report measures on psychopathology and family history. A subset of 324 subjects completed the PA1 questionnaire over a 14-month period, and the valid PAIs of 191 subjects who participated in the study at RUH were analyzed. This sample included 101 subjects without any recent history of drug use (as determined by urine toxicology reports and AS1 ratings) and 90 subjects who had positive urine toxicology reports for drugs of abuse and/or methadone. Using a cutoff score of 65 (problematic drug use), the ROC analysis showed that the DRG scale had a sensitivity of 86% and a specificity of 95%. Using a cutoff score of 70T (drug abuse), the DRG scale had a sensitivity of 77% and a specificity of 99%. Marijuana-only users appeared to form a small but distinct subset of drug users whose scores fell below 70T which may reflect fewer or different problems. The DRG score correlation with the AS1 Drug Composite Score was Y = 0.83, P < 0.0005. This study adds support to the validity of the PA1 Drug scale as a measure that is sensitive to the negative consequences of drug use. Supported in part by NIH grants: NIDA P50-DA-05130, K05 DA00049, and NCRR MOl-RR00102. 312

COMORBID

DER

IN ADOLESCENT

TROL

SUBSTANCE SUICIDE

USE AND ATTEMPTERS:

CONDUCT A CASE

DISORCON-

STUDY

T.M. Kelly and J.R. Cornelius, University of Pittsburgh, Pittsburgh Adolescent Alcohol Research Center, Pittsburgh, PA Major Depression (MD) is the mental disorder most highly associated with suicidal behavior. However, epidemiologic research indicates that Substance Use Disorders (SUD) may mediate the relationship between

SllO

Abstracts

disruptive behavior disorders and attempted suicide in adolescents (Gould et al., 1998). Research in our own project has shown increased rates of suicide attempts among adolescents with both Alcohol Use Disorder (AUD) and Conduct Disorder (CD). In this study we tested the hypothesis that there would be higher rates of comorbid AUDjCD and SUDjCD among adolescent suicide attempters, while controlling for the effects of MD. Seventy-four adolescents who had made a suicide attempt were matched with 74 non-attempters on age, gender, race and lifetime diagnosis of major depression. We did not control for suicidal ideation. Rates of comorbid AUDjCD were more than twice as high among suicide attempters (n = 37, 50%) compared to non-attempters (n = 16, 22%; t = - 3.9, df = 73, P < 0.001). There were similarly high proportions of SUD/ CD among suicide attempters (n = 32, 43%), as compared with non-attempters (n = 16, 22%; t = - 3.0, df = 73, P < 0.005). It is important to note that the groups differed on socioeconomic status, with attempters having a lower mean SES score (t = 2.5, df = 73, P < 0.02). The results indicate that comorbidity of SUDjCD is an important risk factor for attempted suicide among adolescents, in addition to that accounted for by MD. 313 INFL~ENCE~FAGEAND~EX~NTHEBEHAVI~RAL EFFECTS OFALPRAZOLAM

T.H. Kelly, C.S. Emurian, A.M. Fredenburg, CA. Martin, L.R. Hays, K.M. Muse, S.J. Legan, and J.F. Wilson, College of Medicine, University of Kentucky, Lexington, KY This study examined the effects of age, gender and hormone status on the behavioral effects of alprazolam. Thirteen male and 14 female healthy adults between 18-45 and 55-65 years of age, blind to the study drug, gave written consent and participated on 3 consecutive days per week over 8 consecutive week intervals. Menstrual cycle activity was monitored prior to the study, and study days for the 18-45 year old women were selected to coincide with four cycle phases (early follicular, late follicular, early luteal and late luteal). On test days, subjects consumed a standard meal at 17:30 h, received drug at 18:30 h, and completed 20 min sessions consisting of computerized performance tasks and visual-analog (VAS) ratings of drug effect 0, 0.5, 1, 2, 3,4 and 5 h after drug administration, and upon waking the next morning. Each of three doses (0,0.4 and 0.8 mg per 70 kg) was administered orally 1 day each week in random order. Blood samples were collected each week to monitor HPG hormone levels. Alprazolam decreased systolic blood pressure in older subjects to a greater extent than in younger subjects, regardless of sex. Younger female and older male reports of ‘Drug Effect’ and ‘High’ following alprazolam administration were

greater than those of the other groups, but only older males reported increased drug ‘Liking.’ The magnitude of alprazolam-induced performance impairment was also greatest in older males. These results suggest that alprazolam’s abuse liability may be increased in older males. 314

SUBSTANCE USE PATTERNS POSITIVE: MIXED PICTURE

AFTER TESTING HIV-

C. Kerner, J. Liebschutz, L. Sullivan, and J.H. Samet, Boston University Schools of Medicine and Public Health, Boston, MA Hypotheses: lack of knowledge of drug use patterns after testing HIV positive has led to controversies about timing of HIV testing during recovery from drug addiction. We examined the effect of testing positive for HIV in a cohort of HIV-infected drug-dependent persons. Subjects: HIV-infected persons with a history of alcohol abuse (n = 144) Procedures: we examined substance use patterns pre- and post-HIV testing, drug abuse treatment prior to HIV testing and recovery experiences. Statistical Analyses: descriptive statistics were generated to examine the drug use patterns before and after testing HIV positive. x2-tests assessed the relationships between HIV testing and drug use patterns. Results: Subject characteristics included: 81% male, 43% Black, 30%) White, 22% Hispanic; and a mean age of 42. Testing positive for HIV was associated with the following substance use patterns immediately after testing: Of the 129 who used cocaine, 19% decreased or stopped, 44% did not change, 37% increased their use. Of the 91 who used heroin, 11% decreased or stopped, 54% did not change, 35% increased their use. Of all 144 subjects, 18% decreased or stopped, 42% did not change, and 40% increased alcohol use. Of those who changed cocaine, heroin or alcohol use, 90, 83, and 88%, respectively, said it was due to learning of the HIV diagnosis. At a mean of 27 months after testing HIV positive, 51% of subjects eventually entered recovery. Testing for HIV within 3 months of detoxification was associated with increased use of cocaine (P = 0.007), heroin (P = 0.001) and alcohol (P = 0.09). Testing positive for HIV was not associated with change in substance use for subjects testing while hospitalized, or within 3 months of using NA/AA, half-way house, outpatient and methadone programs. Importance of findings: In the period just after testing positive for HIV, the diagnosis appears to alter drug use patterns in half of all drug dependent persons, with a trend toward increased use. Eventually half of the subjects entered recovery, often years after testing HIV positive. Protocols for HIV testing in drug dependent persons should consider this population’s particularly high risk for relapse and increased drug use. NIDA grant DA10019-0281.

Sill

Abstracts

315 IMPR~VINGTREATMENTM~TIVATIONOFNEEDLE EXCHANGECLIENTS

M. Kidorf, J. Blucher, D. Bleiler, and R.K. Brooner, Johns Hopkins University School of Medicine, Baltimore, MD Needle exchange programs (NEPs) provide injection drug users with ready access to sterile needles and syringes to reduce the frequency of sharing contaminated equipment. Approximately 6000 people have enrolled in the Baltimore NEP, most have severe opioid dependence (SO%>, yet few have pursued referral into drug abuse treatment ( < 10%). This study evaluates the outcome of a novel motivational intervention designed to enhance treatment participation of NEP clients. New registrants to the Baltimore NEP complete a comprehensive assessment battery, and are randomly assigned to one of three intervention conditions: (1) motivational enhancement (ME); (2) job readiness (JR); and (3) self-referral (SR). ME participants are administered a structured motivational interview that provides detailed feedback on the assessment results and highlights the benefits of drug abuse treatment. JR participants are engaged in a job readiness interview to control for time spent with ME participants. SR participants are not given a formal interview; this strategy is the usual NEP procedure. All participants are asked if they are interested in enrolling in drug abuse treatment, and are referred to treatment if they express interest in it. Data collection commenced in November, 1999, and to date 45 subjects have enrolled in the study. We plan to enroll approximately 120 subjects by April, 2000. We will present data on the psychiatric characteristics and drug use of study participants, the proportion of participants in each condition who express interest in and enter treatment, and the retention rate of those who enroll in treatment. This intervention is a next logical step to strengthen the impressive harm reduction already achieved by most NEPs. 316 SMOKING, NICOTINE DEPENDENCE, AND TING IN YOUNG WOMEN: IMPLICATIONS TREATMENT

QUITFOR

M.M. Kilbey, S. Fisicaro, J. Mullennix, R. Torrento, and L. Farnsworth, Wayne State University, Detroit, MI, and University of Pittsburgh, Pittsburgh, PA Many women smoke even though they wish to quit. We examined demographic and cognitive factors in women who smoked daily in order to understand this issue better. Lifetime data were used to identify 73 women who met criteria for nicotine dependence (ND) from among 4 12 randomly selected participants. Average number of quit attempts was 4.6 for nND and 8.4 for

ND women. 45.2% of ND and 16.9% of nND women had talked to a professional about smoking and 33.3% of ND and 5.7% of nND women had been treated for smoking. Thirty-four percent of the women (20.8% of ND and 47.2% of nND) had not smoked for a year or more. These included two, both nND, of the 27 women who had obtained treatment. Forty-four women quit without treatment. This included 14 ND and 30 nND women. Demographic, smoking expectancy, and dependence variables found to be significantly different between the groups were entered into a stepwise discriminative function analysis to predict current smoking status. Three smoking expectancy variables and nicotine dependence status correctly predicted smoking status for 76.4% of the sample. These findings highlight the importance of addressing cognitive aspects of ND in developing better smoking cessation treatments for ND women. 317 GENDER DIFFERENCES IN JUVENILE ARRESTEES DRUG USE, DEPENDENCY, AND PERCEIVED NEED FOR TREATMENT

J.Y.S. Kim and M. Fendrich, University Chicago, Chicago, IL

of Illinois at

Little is know about gender differences in drug use problems and attitudes toward treatment among delinquent adolescents, yet targeting this high-risk sample for appropriate treatment is important for preventing chronic substance abuse. We examined gender differences in drug use, dependency, and perceived need for treatment in juvenile arrestees, ages 9918. Hypothesis: delinquent girls, compared to boys, will report more serious drug use and higher rates of dependency, but will not report a greater need for treatment. Species: human. Sample size: 4644. Procedures: the sample, drawn from the 1992-95 Juvenile Drug Use Forecasting Survey, was matched by gender within seven sites across the United States. Drug use questions were asked about: marijuana, cocaine, crack, heroin, crystal meth, amphetamines, and PCP. Statistical analyses: bivariate gender comparisons using xl, and logistic regression analyses were conducted. Results: use severity, measured by age of onset, polydrug use, and injection history, was significantly higher among girls than boys. Current or ‘active’ use, indicated by urine test and past month frequency, was more common among boys than girls. On combined drug measures, girls were significantly more likely to report dependency on at least one drug, but were no more likely to perceive a need for treatment. Significant interaction terms indicated that girls who report greater use severity were more likely than boys to report dependency and need for treatment. However, current drug use significantly reduced the likelihood of girls admitting a need for

s112

Abstracts

treatment. Importance of findings: Findings indicate that the ways in which treatment needs among juvenile arrestees can be assessed, differ by gender. Results specify for treatment providers that among delinquents, girls with a history of early, multiple, and ‘hard’ drug use will be more amenable, and girls with active use, more resistant to treatment efforts. 318

THEUSEOFNIPSTOELUCIDATETHEPOTENTIAL ROLE OF THE VENTRAL PALLIDUM ON COCAINE ADMINISTRATION

SELF-

S.A. Kim, G. Izykenova, T.J. Martin, and J.E. Smith, Wake Forest University School of Medicine, WinstonSalem, NC It is widely acknowledged that dopaminergic systems in the nucleus accumbens play a vital role in cocaine self-adminstration. In our lab, cocaine turnover studies and microdialysis in rats indicated that dopamine levels also increase in the ventral pallidum(VP) during cocaine self-administration. To determine the role of the VP in cocaine self-administration, N-(p-isothiocyanatophenethyl)spiperone (NIPS), a D2 alkylating antagonist, was injected into the VP of rats trained to self-administer three doses of cocaine in each daily session. The trained animals were then injected bilaterally with 1 nmol. NIPS into the VP. Initially, self-administration significantly decreased from 20.7 + 2.65 (mean+s.e.m.), 10.9t0.50 and 5.7+0.41 to 3.3 + 2.14, 2.2 + 1.43 and 2.4 + 2.2 infusions of 0.17,0.33 and 0.67 mg per infusion of cocaine, respectively. After approximately 8 days, cocaine self-administration significantly increased above baseline levels, an effect that persisted for up to 30 days. Current studies are in progress to quantify the extent of the D2 alkylation following intra-VP administration of NIPS. These data indicate that dopaminergic innervations of the VP may play an important role in cocaine self-administration and that NIPS may prove to be a useful tool for understanding these processes. Supported in part by USPHS DA 03628, DA-06634 and DA-00 114. 319 CART PEPTIDES EFFECTS INTHE RAT

HAVE

PSYCHOSTIMULANT-LIKE

H.L. Kimmel, W. Gong, and M.J. Kuhar, Yerkes Regional Primate Research Center, Emory University, Atlanta, GA CART (cocaine- and amphetamine-regulated script) is a novel mRNA that is elevated in the accumbens of the rat following acute cocaine phetamine administration. Localization of this and peptide in brain regions associated with

trannucleus or ammRNA reward

suggests that CART may play a role in modulating psychostimulant action. In the present study, we showed that administration of CART 55-102 peptide (0.4-10 mg) into the ventral tegmental area (VTA), but not into the substantia nigra, produced a dose-dependent increase in motor activity in the rat. This increase in activity was dose-dependently inhibited by the dopamine antagonist haloperidol (0.03-0.3 mg/kg IP), which suggests that CART-induced increases in motor activity are mediated, at least in part, by dopamine. Repeated administration of CART 55-102 to the VTA did not produce sensitization or tolerance to the locomotor effects of subsequent administration of CART 55-102 or of cocaine. Four intra-VTA injections of 1.0 mg of CART 55-102 induced significant place preference for the compartment associated with CART administration. These results suggest that endogenous CART 55-102 may be involved in locomotor activity and reward and that CART 55-102 is an active fragment of this peptide. This is the first demonstration of the psychostimulant-like effects of CART peptides. Supported by RRO0165, DA10732, DA00418 DA05935. 320 GENDERDIFFERENCESANDREADINESSFORDRUG TREATMENT

D.E. King, R.I. Herning, J.L. Cadet, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD One hundred and eleven chronic cocaine abusers (89 men and 22 women) were recruited. All subjects were cocaine abusers who were not seeking treatment. Participants completed The Addiction Severity Index (ASI). Current cocaine use (CCU) was determined from the ASI. Two questions from the ASI’s ‘Drug/Alcohol Use’ section were combined to measure readiness for treatment for cocaine addiction. Psychological distress was measured with the SCL90R. Social support was assessed using The Norbeck Social Support Questionnaire (NSSQ). The Ellison Spiritual Well-Being Questionnaire (ESWB) was used to measure perceived well-being in social/psychological dimension. In order to consider the role of gender as a predictor of treatment readiness a hierarchical regression model was used in which gender was entered into the equation after the other predictor variables (CCU, composite scores from NSSQ, ESWB, and SCL90). Wellness, psychological distress and gender were significant (P < 0.0001) predictors of readiness for treatment and accounted for 19.57% of the variance. In addition, gender significantly (P < 0.005) predicted readiness for treatment after controlling for cocaine use, social support, perceived wellness and psychological distress. The findings suggest that women may have a lower threshold for perceiving

Abstracts

cocaine use as problematic and a greater readiness for cocaine treatment than men. 321

RESULTS

FROM

METHADONE

A

MEDICAL

CONTROLLED

TRIAL OF 6-MONTH

MAINTENANCE:

FOLLOW-UP

V.L. King, R.K. Brooner, R. Schwartz, and M. Hayes, The Johns Hopkins University School of Medicine, Friends Research Institute, Inc, Man Alive Research, Inc., Baltimore, MD The most effective therapy for chronic heroin dependence is methadone maintenance (MM). Unfortunately, MM is not available to many individuals who might benefit from it. One way to enhance availability of MM is through implementation of methadone medical maintenance for stabilized, well-functioning patients. Medical maintenance reduces the reporting schedule to once per month with counseling done by medical staff. Care is provided in traditional clinics or by physicians in private medical practices. We report on the 6 month treatment outcome of 78 highly stable MM patients from 2 MM clinics randomly assigned to one of three conditions: routine care, medical maintenance at the MM program, and medical maintenance at a private doctor’s office. Medical maintenance patients received a 2%day supply of methadone dispersible diskettes. All patients performed a medication recall once per month and gave two urine samples each month (one on a random basis). Sixty-six patients completed 6 months. Dropout was due primarily to disliking the control condition. Only 1% of urine specimens were positive for illicit drugs, though patients self-reported occassional alcohol and marijuana use. Only 557% of medication recalls were failed, with no evidence of diversion and very low rates of medication misuse. Treatment satisfaction was high in all groups, but the medical maintenance patients said they had more freedom to work and attend spontaneous friend and family outings. Preliminary results indicate excellent patient satisfaction with medical maintenance, but that less continuous abstinence prior to medical maintenance predicts subsequent treatment instability (drug use or failed medication recall). 322 RAT:

CONDITIONED EFFECTS

OF

SEXUAL ALCOHOL

INHIBITION AND

IN

THE

MALE

COCAINE

T.E. Kippin, N. Halavezos, V. Sotiropoulos, Pfaus, Concordia University, Montreal, Canada

and J.G. Quebec,

Drug use can lead to high-risk sexual activity can result in the spread of sexually transmitted

that dis-

s113

eases. The present study examined the effect of alcohol or cocaine in a model of conditioned sexual inhibition in the male rat. Males trained not to copulate with non-receptive females scented with almond odor, subsequently displayed conditioned inhibition of copulation toward a scented receptive female (as evidenced by proportion of males copulating and biased copulatory behavior toward an unscented female during a copulatory choice test). Males treated with an i.p. injection of 1.0 g/kg, but not 0.5 g/kg or 0.0 g/kg, of alcohol failed to display conditioned inhibition of copulation toward the scented female. The effects of 20 and 40 mg/kg of cocaine on conditioned sexual inhibition are currently being examined in this paradigm and will also be reported. These results demonstrate that conditioned sexual inhibition can be disrupted by drugs of abuse and suggest that sexual disinhibition may be a factor in drug induced highrisk sexual activity. Supported by NSERC of Canada (OGP-0138878) to JGP. 323

FEE-FOR-SERVICE,

PUBLIC TREATMENT:

MANAGED EFFECTS

PRIVATE CARE ON

IN

PUBLIC

SERVICES

MANAGED

CARE

SUBSTANCE AND

AND ABUSE

OUTCOMES

K.C. Kirby, L. MacPherson, A.T. McLellan, and J. Merrill, Treatment Research Institute and Temple University, Philadelphia, PA During the past decade, changes have occurred in the way that health care is financed and delivered. A profound change is the growth of ‘Medicaid waiver’ applications which propose to convert ‘fee-for-service’ payment structures used to purchase health care services with Medicaid funds to managed care companies. We used a quasi-experimental design to compare fee-for-service (FFS), For-Profit Managed Care (PMC), and Not-for-Profit Managed Care (NPMC) reimbursement arrangements for chemically dependent Medicaid clients. Our purpose was to determine if these arrangements corresponded with differences in the services clients received and in client outcomes. The study participants were 547 admissions to one of four outpatient treatment providers in the City of Philadelphia during 1991-93 (FFS); 1994-97 (PMC); or 1997-99 (NPMC). The Addiction Severity Index was administered at intake and again 7 months later. In addition, clients were interviewed regularly regarding the services they received. NPMC clients received slightly fewer drug and alcohol services than clients in the other two groups, but they received more legal, family/social, and psychiatric services. A repeated

s114

Abstracts

measures MANOVA indicated main effects by group and by time. There were no significant interactions, which would suggest differential improvement between groups. Thus, reimbursement arrangements influenced the services clients received, but not their outcomes. Caution must be exercised in interpreting these results, since historic variables were not controlled, groups differed from each other at baseline, and only two managed care arrangements were examined. 324 HOPELESSNESS, SELF-ESTEEM, ENVIRONMENTAL STRESS INDICATORS, AND OTHER PSYCHOSOCIAL MEASURES PREDICTING ADOLESCENTS' DRUG USE PATTERNS: IMPLICATIONSFORTREATMENT

H. Klein, D.L. Simon, D.J. Schwartz, M.S. Gordon, and D.M. Lucker, Friends Research Institute, Inc., Catonsville, MD Hypolhesis: Drug abusing adolescents who score higher on measures of hopelessness and environmental stress and lower on measures of self-esteem will report greater involvement in drug use, more drug-related problems, and more dysfunction in other aspects of their daily lives. Subjects: 70 adolescents, residing in the Baltimore metropolitan area, aged 12- 18, 80% white, 60% male, primarily abusers of alcohol, marijuana, cocaine, and/ or heroin. Procedures: adolescents are interviewed at treatment intake, 6 and 12 months later. All data are based on self-reports and are collected via face-to-face interviews using the GAIN-I, Environmental Stress Inventory, Beck et al.‘s Hopelessness Scale, Grasmick’s Self-Control Scale, Rosenberg Self-Esteem Scale, and other supplemental questionnaires. ResuZts: As this is an ongoing study, the most up-to-date findings (all data collected 6/3/00) will be reported at CPDD. Statistical Analyses: Descriptive statistics will be used to describe the client population. Correlation analysis, regression analysis, and analysis of variance will be done to examine the relationship between psychosocial measures and drug use patterns/problems. Importance: The data will be analyzed and discussed in terms of implications for adolescents’ treatment needs. In particular, analyses will focus on the relationship between hopelessness and drug abuse/problems, self-esteem and drug abuse/problems, etc. Analyses will also examine how well psychosocial functioning at the time of treatment intake predicts treatment retention, treatment completion, and treatment-related outcomes in the 10 domains included on the Problem-Oriented Screening Instrument for Teens (POSIT): substance abuse, mental health, physical health, vocational status, educational status, family relationships, peer relationships, social skills, recreation and leisure-time activities, and aggression and delinquency.

325 EFFECTS OF AMPHETAMINE AND STRESS ON BEHAVIOR OF TWO RAT STRAINS IN THE PASSIVE AVOIDANCESHUTTLECAGE

V. Klenerova, 0. Kaminsky, .D. Englisova, P. Sida, J. Stohr, S. Hynie, University of Prague, Prague, Czech Republic Since our biochemical data indicated some interchangeability of stress and amphetamine (AMPH) in sensitization we decided to test also behavioral changes in the passive avoidance shuttle cage. For our experiments we selected two inbred rat strains with different activity of HPA axis, namely Lewis (LE) rats (known to have defective HPA axis) and Sprague-Dawley (SD) rats (Charles River, Germany). Amphetamine (AMPH) (given in a dose 8 mg/kg b.w.) and immobilization stress combined with water immersion were applied 1 h before the start of experiment. We observed differences in behavior both in repeated settings as well as in two rat strains used. In LE rats the memory loss after stress and AMPH was stronger than in SD rats while in control groups of both rat strains we observed the increase of memory following the repeated behavioral testing. Our data suggest that AMPH and immobilization stress statistically significantly deteriorate the longlasting memory in a similar way. The overall behavioral response seems to be dependent also on the activity of HPA axis in used rats. This work was supported by Grant IGA MZCZ 4969-3 and CEZ: J13/98: 111100001. 326

EFFECTS OF LOW SEROTONIN RESPONSE INHIBITION IN RATS

ON A MEASURE

OF

T. Kline, D.B. Miller, J.P. Crean, H. de Wit, and J.B. Richards, West Virginia University and University of Chicago Low serotonin has been associated with impulsive behavior, which may be related to a diminished capacity to inhibit behavior. Response inhibition has been measured in humans using the stop task, which provides an estimate of latency to stop (or inhibit) an ongoing response (Stop reaction time; RT). Here we report the effects of serotonin (SHT) lesions in rats using the stop task. Rats were trained to respond to a Go signal (light offset) for water reward. The latency to respond to this signal is the Go RT. Occasionally, a tone (Stop signal) was presented immediately after the onset of the Go stimulus, signaling the rat to stop the ongoing response and emit a different response. The delay between the presentation of the Go and Stop signals was adjusted until the rat successfully stopped 50”/0 of the time, providing an estimate of Stop RT. Animals were lesioned (LES group; n = 12) by intraventricular injection of the neurotoxin 5,7-DHT or vehicle (CTL group;

s115

Abstracts

II = 10). 5HT lesions increased Stop RT without affecting Go RT indicating a specific impairment of behavioral inhibition. Notably, these effects of serotonin lesions in rats are similar to the effects of tryptophan depletion in humans using a similar task. These results support the validity of using the stop task in rats to explore the biological basis of response inhibition and impulsive behavior. Supported by DA10588 327

ROLIPRAM

BENS

ENHANCES

STIMULATION

INFUSION

INTO

THE

COCAINE-INDUCED REWARD

NUCLEUS

LOWERING

ACCUMOF BRAIN

THRESHOLDS

C.M. Knapp, K. Lee, D.A. Ciraulo, and C. Kornetsky, NIDA/Boston VA MDRU, and Boston University School of Medicine, Boston, MA Brain stimulation reward thresholds (BSR) were determined in rats after the infusion of either the CAMP-speinhibitor, rolipram, or cific phosphodiesterase d-amphetamine into the nucleus accumbens (NAcc). Thresholds were also determined after the systemic administration of rolipram or cocaine, as they were for rolipram infused into the NAcc in combination with systemically injected cocaine. BSR thresholds were significantly lowered below baseline levels following d-amphetamine administration. Compared to values for saline alone, thresholds were lower after the injection of cocaine or the infusion of rolipram into the NAcc. The combination of cocaine and intra-NAcc rolipram produced greater lowerings of the BSR threshold than did either rolipram or cocaine alone. Systemic administration of rolipram either blocked responding for BSR or raised BSR thresholds. These results suggest that elevation of CAMP in the NAcc may produce reinforcing effects and, can augment cocaine’s reinforcing actions. Supported in part by NIDA Grants K05-DA00099; DA02326 to CK and DA50038 to DAC. 328

LAAM

PREGNANT

MAINTENANCE

IN

OPIOID-DEPENDENT

WOMEN

J.S. Knisely, S.H. Schnoll, S. Wu-Pong, and G.C. Britt, Medical College of Virginia Commonwealth University, Richmond, VA Numerous clinical trials have demonstrated the safety and efficacy of LAAM as a maintenance drug for opioid-dependent subjects. Outcomes of LAAM maintenance include enhanced treatment retention and compliance, decreased drug use, and suppression of withdrawal symptoms. The major advantage of LAAM compared with methadone is its long duration of action that allows maintenance therapy to be accomplished by dosing three times per week. The purpose of the present study is to

characterize the transfer from methadone to LAAM and evaluate the efficacy of LAAM maintenance in pregnant opioid-dependent women. Women are recruited from a community methadone clinic and sign an informed consent approved by Virginia Commonwealth University’s Committee on the Conduct of Human Research. They are admitted to the Clinical Research Center (CRC) early in the third trimester and after 48 h on methadone void of any withdrawal symptoms, are transferred to LAAM. LAAM dosing is conducted on Monday, Wednesday, and Friday. Both objective (pupil size, vital signs and observer-rated opioid withdrawal symptoms) and subjective (visual analog scales of drug effects and craving, Addiction Research Center Inventory) measures of withdrawal are assessed immediately prior to and 15, 30, 60,90, 120, 180, 360, 720, and 1080 min following LAAM dosing. On days that LAAM is not administered, symptoms are evaluated every 6 h. Following stabilization on LAAM, women are discharged from the CRC and LAAM maintenance is continued on an outpatient basis. Fetal surveillance (non-stress test and biophysical profile) is conducted daily during the induction phase and no less than weekly during the maintenance phase. Data will be presented for three women collected during both the induction and maintenance phase along with pharmacokinetic data and neonatal and infant outcome. ACKNOWLEDGMENTS: This work supported by NIDA DA05274 and NCRR NIH MOlRR00065. 329

INTRACISTERNAL

FENTANYL-INDUCED THERMAL

ANTINOCICEPTION

CLOCINNAMOX RESPIRATORY

ANTAGONISM DEPRESSION

IN RHESUS

OF AND

MONKEYS

M.C. Ko, M.S. Song, M.D. Johnson, K.J. Willmont, and J.H. Woods, University of Michigan, Ann Arbor, Ml Clocinnamox (C-CAM) has been characterized as a functionally irreversible mu antagonist in monkeys. The aim of this study was to establish the pharmacological basis of central mu opioid receptor antagonism. Antagonist potency and duration of intracisternal (i.c.) administration of C-CAM were evaluated against systemic administration of a lipophilic mu opioid agonist, fentanyl. Respiratory function was measured in monkeys exposed to normal air or air mixed with 5% CO,. Thermal antinociception was measured by a warm water (50°C) tail-withdrawal assay. Systemic fentanyl (3.2-56 ug/kg) dose-dependently produced respiratory depression (lower minute volume, Ve) and thermal antinociception. I.c. pretreatment with C-CAM 32 ug produced approximately 9-fold rightward shift of the fentanyl baseline dose-effect curve for respiratory function (Ve) and this antagonism lasted for 3 days (n = 5). I.c. pretreatment with a smaller dose of C-CAM 10 ug only produced a 3-fold rightward shift against fentanyl and it only last for 1 day. This dose-dependent antago-

Abstracts

S116

nist profile of i.c. C-CAM was also observed in thermal antinociception (n = 4). Furthermore, a centrally effective dose of C-CAM 32 ug, when administered S.C. in the back, did not antagonize fentanyl-induced respiratory depression or antinociception. The results indicated that i.c. C-CAM produced its predominant action on central mu opioid receptors. These findings provide a valuable basis for characterizing behavioral effects of a variety of mu opioid agonists in non-human primates. Supported by USPHS Grant DA00254.

330 STANCE

IS

DELAY USE

IN

DISCOUNTING COLLEGE

ASSOCIATED

WITH

SUB-

STUDENTS?

S.H. Kollins, L.K. Murray, E.K. MacDonald, S.A. Albrecht, and A. Coates, Western Michigan University, Kalamazoo, MI Measures of delay-discounting assess the extent to which individuals discount the value of future rewards, and have been used to characterize differences among different substance using populations (e.g. smokers, heroin dependent individuals, heavy alcohol users). We investigated whether a computer-based measure of delay-discounting was associated with substance use variables in a sample of non-referred undergraduate college students. Subjects (n = 28*) completed a substance use survey and a delay discounting measure that asked participants to make a series of choices between a fixed amount of hypothetical money to be delivered immediately and a larger amount to be delivered after a range of delays. Preliminary results indicate that k values from the delay discounting task (a parameter that describes the slope of the discounting function and theoretically associated with degree of impulsivity) were significantly associated with a number of substance use variables, most notably cocaine use (Y = 0.46; P = 0.02), age of first alcohol use (r = - 0.43; P = 0.05) and age of first marijuana use (r = - 0.53; P = 0.02). A trend was also observed between the k value and age of first smoking (v = - 0.57; P = 0.09). These results suggest that individuals reporting more cocaine use and younger ages of first use of alcohol, marijuana, and nicotine tend to discount the value of future hypothetical rewards more steeply than their peers. Results are discussed with respect to understanding the relation between impulsive choice and substance use in both clinical and non-clinical populations. *Data collection ongoing.

331

RELEASE

BIODEGRADABLE

OF

COCAINE

ANTIBODY

FROM

MICROCAPSULES

H. Komiskey, T. Mandal, D. Landry, P. Homayoun, Xavier University of Louisiana, New Orleans, LA, and Columbia University, New York, NY

Biodegradable microcapsules have been developed for numerous therapeutic agents. In this study we have prepared biodegradable microcapsules with a monoclonal antibody to cocaine, mAB 15A10, using Dl-lactic/glycolic acid (PLGA). Five hundred milligrams of PLGA was dispersed in 5 ml of dichloromethane, to which 100 ul of L-phosphotidylcholine in chloroform (8 mg/ml) and 40 mg of 15AlO antibody was added. The resulting dispersed system was emulsified in 5 ml of an aqueous solution of PVA (1%) by vortexing for 15 s followed by dilution with 100 ml PVA aqueous solution (0.3%). The system was stirred magnetically for 3 h to allow complete evaporation of the solvent. The microcapsules were then collected by centrifugation at 3000 rpm and repeatedly washed with deionized water to remove PVA residual. The microcapsules were freezedried to obtain a free-flowing powder. The release antibody, mAB 15A10, from microcapsules was then monitored by incubation in a physiological buffer at 37°C for different time points. The presence of antibody in aliquots was measured using an ELISA method. Release of mAB 15AlO was detected for at least 18 h. Support by NIDA grant DA07970.

332 ABUSERS

MULTIDIMENSIONAL WITH

AND

OUTCOMES WITHOUT

IN

SUBSTANCE

PTSD

J.M. Koppenhaver, J.S. Cacciola, A.I. Alterman, J.R. McKay, and M.J. Rutherford, University of Pennsylvania Treatment Research Center, Philadelphia, PA, and Alcohol and Drug Abuse Institute, University of Washington, Seattle, WA Our prior research with male veterans indicated that outpatient substance abusers with PTSD and additional Axis 1 disorders (PTSD + ) have more severe problems at treatment entry when compared to patients with: substance dependence only (SU Only); substance dependence and additional Axis I disorders excluding PTSD (Axis I); and substance dependence and PTSD only (PTSD only). The current project examined 6 month post-admission outcomes in the same sample using the same four diagnostic groups (SU Only IZ= 222, Axis I n= 162, PTSD+n=61, PTSD Only n= 21). Groups were compared on medical, employment, drug, alcohol, legal, family/social, and psychiatric variables using the AS1 Composite Scores. All groups significantly improved across all 7 AS1 domains. PTSD + participants had more severe drug outcomes than participants in the SU Only group. Further, PTSD + participants had significantly more severe medical and psychiatric problems at both admission and follow-up than both the Axis I and SU Only participants. Finally, participants in the Axis I and PTSD Only groups had significantly more severe psy-

Abstracts

s117

chiatric outcomes than did participants in the SU Only group. These results suggest that the diagnostic heterogeneity of substance abusers with PTSD may be valuable, both clinically and for research. .

334

333 BENZODIAZEPINE ADOLESCENTS

C. Kornetsky, C.M. Knapp, B. Printseva, Boston University School of Medicine, Boston, MA

ABUSE

AMONG

ADJUDICATED

L. Korein, M.L. O’Neill, and V. Lidz, Institute for Addictive Disorders, MCP Hahnemann University, Philadelphia, PA Two established patterns of adult benzodiazepine abuse are noted in the literature: (1) dependence that develops during prescribed use (Miller and Gold, 1991); and (2) use of benzodiazepines in conjunction with other drugs, particularly, heroin and cocaine, to amplify effects and/ or moderate withdrawal (Sellers et al., 1993). However, the role of benzodiazepine abuse in the development of major substance abuse or dependence disorders among non-prescribed users has received little study. The present study examines the role and patterns of benzodiazepine use in 66 male adjudicated adolescents (aged 14- 18) treated for substance abuse problems at a 3 month partial hospital program in Philadelphia, Pennsylvania. We hypothesized that benzodiazepine abuse would follow the established adult patterns of abuse. Self-reported substance use patterns were measured during intake with the Comprehensive Adolescent Severity Index (CASI; Meyers, McLellan, Jaeger & Pettinati, 1995). Twice weekly urinalysis measured objective substance use patterns during treatment. Twenty-five participants self-reported use of benzodiazepines; urinalysis detected benzodiazepine use in 13 additional participants. Overall, at 62%, benzodiazepines were the most commonly abused drug after marijuana and alcohol. When comparing the 42 adolescents who used benzodiazepines with the 24 who did not, the former used other drugs more frequently: phencyclidine (48% vs. 24%), cocaine (26% vs. 12%), amphetamines (12% vs. 04%) and opiates (12% vs. 0%). In an overall analysis, the benzodiazepine users were significantly more likely to be users of the ‘harder’ drugs (P2 (1, N = 66) = 9.14, P < 0.01). When examining which substances were first used after marijuana and alcohol, however, benzodiazepines (52%) were the most frequently mentioned drug. Among the study participants, benzodiazepine use was more often prior to than conjunctive with use of phencyclidine, cocaine, amphetamine, and opiates, a pattern different from the ones recognized by previous research. The present findings suggest that in our study sample benzodiazepine abuse was a lead indicator for transition to subsequent use of such other substances as cocaine, phencyclidine, and heroin.

CUE-INDUCEDCHANGESINBASALCEREBRALGLUCOSE UTLLIZATION ONE WEEK AFTER SENSITIZING DOSES OF COCAINE IN THE RAT; RELEVANCE FOR CRAVING

The Ipresent experiment was designed to test the hypothesis that basal local cerebral metabolic rate of glucose (LCMRglu) would change as a function of the presence of cocaine conditioned cues at one week after the last of repeated 30 mg/kg doses of cocaine Two experimental groups (N = 8) were used. In one group the rats were placed in the test chamber in which the 2-DG experiment would take place. In the other experimental group the rats were placed in their home cage immediately after the cocaine injection. A control group received only saline. Seven days later the 2-DG experiment was conducted on rats in the undrugged state. An analysis of 31 brain regions indicated that there was a significant interaction between conditioned status and brain region. Mean basal LCMRglu was significantly lower in 11 of the 31 brain regions analyzed in the presence of conditioned cues while only five of these areas were significantly lower in the absence of conditioned cues. Most of the changes were seen in limbic structures. Except for one region in the non-conditioned group, there were no significant increases in LCMRglu. Evidence that these effects are more wide spread in rats in the presence of environmental cocaine cues suggest that these effects may model cue-induced changes in the human cocaine user that may play a role in craving. Supported by NIDA Grants K05-DA00099 and DA02326 to CK. 335 REDUCING COCAINE-RELATED SION DEFICITS WITH ANTI-PLATELET ANALYSES USING SPM

CEREBRAL PERFUAGENTS: SPECT

T.R. Kosten, J. Seibyl, H. Rinder, and P.C.H. Got&chalk, Yale University School of Medicine and VA-Connecticut Healthcare System, New Haven, CT Cocaine dependence is associated with abnormal neuropsychiatric tests and multifocal cerebral perfusion abnormalities (CPAs) that may respond to anti-platelet agents. Subjects: 69 active cocaine abusers with CPAs completed a placebo controlled randomized comparison of Aspirin and Amiloride. For determination of CPA!; and ‘normal’ variation during repeated SPECT images we used 22 normal controls. Procedure: Cerebral perfusion is assessed using Tc-99m-HMPAOSPECT (single photon emission computed tomography) on a Picker PRISM 3000XP. SPECT scanning is per-

Abstracts

S118

formed with on days 2, 14, and 30 of monitored abstinence on a treatment unit. Platelet studies and neuropsychological tests are administered the same days. Results: Data analyses are ongoing and will be completed by June, but preliminary analyses show a greater area of increased cerebral perfusion with aspirin [mean 8500 pixels vs. 55001. We also will present analyses of neuropsychological (NP) findings which show a correlation with severity of baseline CPA as well as improvement in NP function among those showing reductions in CPA. Conclusions: Aspirin (325 mg daily) reduced CPA in cocaine abusers and abusers showing reduced CPA had improved NP functioning. 336 NICOTINE PRETREATMENT ALTERS SOME OF coCAINE'S SUBJECTIVE AND PHYSIOLOGIC EFFECTS E.M. Kouri, M.E. Stull, and S.E. Lukas, McLean Hospital/Harvard Medical School, Belmont, MA Tobacco smoking and cocaine use often co-occur and the frequency of smoking has been positively correlated with the likelihood of cocaine use. In addition, nicotine pretreatment increases the rate of cocaine self-administration in rats and enhances cue-induced cocaine craving in humans. The present study was conducted to investigate whether nicotine pretreatment via a transdermal patch (placebo, 14 mg) alters the physiological, subjective and pharmacokinetic effects of an acute intranasal dose of cocaine (0.9 mg/kg). Subjects were moderate smokers who used cocaine occasionally. Results show that nicotine pretreatment potentiated cocaine-induced increases in heart rate while it attenuated the cocaine-induced rise in the Amphetamine ARC1 subscale and the subjective VAS reports of ‘stimulated’ and ‘high’. Plasma levels of Cocaine, Benzoylecgonine and Ecgonine Methyl Ester were not altered by nicotine. Our findings suggest that individuals who use the nicotine patch may experience an attenuated response to cocaine and may try to compensate by increasing the cocaine dose. Since nicotine potentiates heart rate increases after cocaine, this could place individuals at higher risk for cardiovascular adverse events. Supported by grants DA03994 and DA00343. 337 GENDER DIFFERENCES IN CLINICAL TIENTS: DOES
TRIALS PATO THE RE-

F.B. Kropp, J. Mezinskis, and E. Somoza, NIDAjVA Medication Development Research Unit, Cincinnati, OH Despite recent interest in gender issues in substance abuse treatment, few studies present clear evidence for their impact in the clinical trials setting. In this study,

researchers examined psychosocial and eligibility information obtained from 303 subjects in four clinical medication trials for crack cocaine. Information from the Addiction Severity Index (ASI), the Structured Clinical Interview for the DSM IV (SCID), the HIV Risk Assessment Battery, and a Medical History, and a Personal History were analyzed for significant (p&0.05) gender differences among enrolled study patients (n = 109) in such areas as medical problems, psychiatric problems, relationship issues, severity of substance abuse, and economic issues. Eligibility information for all 303 subjects was analyzed for retention, attendance, and enrollment. No significant gender difference was found in subject retention. Among enrolled subjects, males significantly differed in lifetime poly-drug use and abuse/dependence with stimulants other than cocaine. They had higher levels of income from employment, and were more likely to identify a marketable skill or profession. Female subjects were significantly more likely to identify difficult relationship issues, including current sexual abuse, lifetime emotional and physical abuse, and engaging in sexual activities to obtain drugs. They suffered medical problems in more body systems than males, with particular problems in the hematological and genitourinary systems. Enrolled females more frequently self-reported a history of psychiatric problems, but only current Specific Phobia and current Substance Induced Anxiety Disorder were diagnosed at a significantly higher rate. During screening, however, females were more likely to rule out of study participation due to psychiatric diagnoses. Conclusions were made regarding noted gender differences and their possible impact on study design and procedures. Supported by NIDA under agreement # YOl DA 50038-00. 338

THERELATIONSHIPBETWEENCOMORBIDPSYCHIATRIC DIAGNOSIS AND EARLY ENVIRONMENT IN PREGNANTSUBSTANCEABUSERS

J. Kulstad and D. Haller, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA Psychopathology and early environment variables share a multifaceted pathway to substance abuse. Pregnant women, in particular, present with complex issues; none the least of which is the propensity towards replicating their own pathway with their unborn child. This study further clarified the relationship among comorbid substance use, psychopathology, and early environment variables in pregnant women. All participants (N= 100) were enrolled in a comprehensive residential treatment program for perinatal substance abusers. Most were unmarried (91%), African American (79%) and had a mean age of 29.7 years. All met DSM III R substance dependence criteria and had at least one

Abstracts

previous treatment experience. The primary and secondary substances of abuse were cocaine/crack (85%) and ETOH (39%), respectively. Participants completed the MCMI, ASI, and psychosocial intake within 2 weeks of program admission. Participants scores on the MCMI AXIS II scales were submitted to Cluster Analysis. Cluster differences were evaluated using MANOVA, ANOVA, and x2-analyses, as appropriate for the data. Three distinct personality styles emerged: cluster 1, minimal or adaptive; cluster 2, externalizing; cluster 3, internalizing. In comparison to Cluster 2 and 3, women in cluster 1 tended to have more positive early environments, less severe parental problem histories, and minimal Axis I or II psychopathology. In comparison, women in Cluster 2 evidenced higher rates of abusive and neglectful family relationships, moderate rates of parental problem histories, and lower prevalence of Axis I psychopathology. Comparatively, women in Cluster 3 evidenced inconsistent and neglectful family relationships, high rates of emotional abuse, higher prevalence of maternal and paternal substance abuse and psychiatric problems, and high rates of Axis I and II psychopathology. Perinatal substance abusers are a diverse group with specialized treatment needs. Women with negative early environments and more psychopathology may require more structure and focus on interpersonal skills training (cluster 2) or a more interpersonal approach that addresses addiction, resolution of family issues, coping effectively with internal conflict, and interacting more effectively with others (cluster 3). supported by This research was Grant # 5HS4TI00555. 339 FEASIBILITY OF MOBILE LAAM TREATMENT AMONG INJECTION DRUG USERS REFERRED FROM A NEEDLEEXCHANGEPROGRAM

I. Kuo, J. Brady, R. Schwartz, C. Butler, R. Brooner, D. Vlahov, and S. Strathdee, Johns Hopkins School of Public Health and Medicine, and Friends Research Institute, Baltimore, MD, and New York Academy of Medicine, New York, NY Background and objectiue: The Baltimore NEP offers referrals into a subsidized fixed-site methadone treatment program and a no-cost mobile LAAM program. The study objective was to compare treatment acceptance, program retention and NEP usage among NEP attenders referred to these programs. Methods: Participants were non-randomly referred to either treatment program based on NEP site location. The mobile program dispensed LAAM three times a week and parked at a drug-free center where clients received counseling. The fixed-site methadone program dispensed medication daily and was located at a hospital clinic. Referral

s119

and follow-up time was 403 days for each program (methadone: 518198 to 6/15/99 and LAAM: l/28/99 to 3/7/O(I). Results: 163 and 112 NEP attenders were referred to LAAM and methadone, respectively. A significantly higher proportion entered LAAM, 70% vs. 49% (P < 0.001). Program acceptors were similar for the two groups except a lower proportion of AfricanAmericans entered methadone, and baseline AS1 composite scores were higher for the methadone group in the medical, drug and legal indices. Importantly, 72% of the LAAM referrals reported never having been in treatment before. Three-month program retention (77% LAAM and 67% methadone, P = 0.264), and cumulative retention for the study duration (56% LAAM vs. 52% methadone, P = 0.182) were similar for the two groups. NEP use significantly declined for both groups comparing 30 days before and after treatment entry, from 62% to 33% for LAAM (P < 0.0001) and 89% to 47% for methadone (P < 0.0001). Also, the LAAM group experienced significant reductions in the AS1 drug index and drug-positive urines for both opiates and cocaine. Conclusion: We found that a mobile LAAM treatment program was as effective as a standard fixed-site methadone clinic among NEP attenders requesting treatment in terms of program acceptance and retention. In this study, the mobile LAAM treatment program had high community acceptance and successfully reached a high proportion of drug users who ‘were treatment-naive. Our findings underscore the potential for NEP to be an effective bridge to drug abuse treatment. 340 ASSESSING MATERNAL AWARENESS OF RISKS ASSOCIATEDWITHTOBACCOUSEDURINGPREGNANCY M.P. Laban, H.E. Jones, P.L. Moylan, L.M. Tuten, N.A. Haug, and D.S. Svikis, Johns Hopkins University, Center for Addiction and Pregnancy, Baltimiore, MD Research has shown that tailoring interventions to specific populations enhances treatment effectiveness (O’Campo, Davis, and Gielen, 1995). Since awareness of harm often precedes behavioral change, the purpose of this study was to assess the perceived risk of smoking in two groups of pregnant tobacco users. A 15-item Perceived Risk Questionnaire (PRQ) assessing knowledge of pre- and postnatal effects of tobacco use was admi:nistered to pregnant and recently post-partum women seeking obstetrical care. Specifically, illicit substance abusing women enrolled in treatment (n = 43) and women who were not using illicit drugs (n = 38) were compared. Demographically, the two groups were similar in marital status (84% single), education levels (M= 10.8 years; SD = 1.46), and smoking status (91.4% smokers), but compared to drug users, non-drug users were younger (M = 22 years vs. A4 = 29 years),

Abstracts

s120

predominately Caucasian (74% vs. 12%) more likely to be employed (66% vs. 2%) and had fewer previous pregnancies (M = 1.3 vs. A4 = 3.9). Interestingly, the two groups did not differ significantly in perceived risk of smoking. Both groups tended to score within the 70th percentile and consistently scored lower on the same items. For example, they were less knowledgeable about several problems related to cigarette smoking (e.g. increased risk of Sudden Infant Death Syndrome, chance of caesarian section, and breastfeeding problems). Providing more explicit and tailored education concerning the maternal and infant health risks associated with cigarette smoking during pregnancy may result in a more effective group intervention. 341 ALLELES OF THE MU OPIOID AND OPIATE ADDICTION

RECEPTOR

GENE

K.S. LaForge, S.U. Kapadia, V. Yuferov, K. Bell, S.M. Leal, P.F. McHugh, S.H. Kellogg, R. Schluger, L. Yu, and M.J. Kreek, The Rockefeller University, New York, NY; The University of Cincinnati College of Medicine, Cincinnati, OH Previous studies from our laboratories have identified two common single nucleotide polymorphisms (SNPs) at nucleotide positions 118 and 17 in the coding region of the human mu opioid receptor (MOR) gene as potential candidates for heritable contributions to individual differences in the vulnerability to develop opiate addiction (PNAS 95: 9608-9613; 1998). In the present report, we have studied a second cohort of 450 consecutive persons entering a study of the genetic basis of the addictions at The Rockefeller University. Subjects were rigorously characterized with respect to drug and alcohol abuse or dependence, medical history, psychiatric and psychological profile and ethnic background. Genomic DNA was isolated from blood specimens from each subject. PCR amplified DNA from the coding region of exon I of the MOR gene was sequenced by automated or traditional sequencing methods. Sequencing gels and electropherograms were evaluated for novel and known SNPs or other polymorphisms. To date, genotypes of 443 study subjects with respect to the Al 18G and C17T SNPs have been determined. For analysis, all subjects from this study group will be selected that meet the following criteria: (a) a control group of individuals with no history of drug or alcohol abuse or dependence; and (b) persons with long-term opiate addiction, with or without codependence on cocaine, alcohol, or other drugs. All study subjects for this analysis will be unrelated. Statistical analysis of differences in genotype and allele frequencies will be presented.

342 MORPHINE-INDUCED CONDITIONED TASTE AVERSIONSIN LEW/N AND FM/N RATSTRAINS D. Lancellotti, J.R. Glowa, B.M. Bayer, R.A. Houghtling, and A.L. Riley, American University, Washington, DC, Louisiana State University, Baton Rouge, LA, and Georgetown University, Washington, DC Previously, we have reported the differential acquisition of cocaine-induced taste aversions by the LEW/N and F344/N rat strains (Glowa et al. Psychopharmacology 114: 229-232; 1994) in which LEW/N rats displayed significantly stronger cocaine-induced taste aversions than F344/N rats. To assessif the differential sensitivity to cocaine within the aversion design generalizes to other drugs of abuse, the present experiment assessed the ability of morphine to condition taste aversions in the LEW/N and F344/N strains. Specifically, every 4-day for four conditioning trials 35 LEW/N rats and 33 F344/N rats were allowed access to a novel saccharin solution and then injected immediately after with varying doses of morphine, i.e. 0 (vehicle), 10, 32 and 56 mg/kg. On intervening recovery days, all subjects were allowed 20 min access to water. A final aversion test was administered after the last recovery session following the fourth conditioning trial. At all doses of morphine, rats from the F344/N strain rapidly acquired morphine-induced taste aversions, displaying marked reductions in saccharin consumption. On the other hand, rats from the LEW/N strain displayed no significant reduction in saccharin consumption even with repeated conditioning. To determine if these differential aversions induced by morphine were a function of any pharmacokinetic differences between the two strains, 10 mg/kg morphine (or vehicle) was administered to subjects of both strains and plasma morphine levels were analyzed post injection using a radioimmunoassay for morphine. Both LEW/N and F344/N strains displayed significantly elevated plasma morphine levels 30 min post-injection which decreased significantly at the 2 and 4 h assessments. Given these findings with morphine (relative to our previous work with cocaine), the differential sensitivity of the two strains to aversion-inducing compounds seems to be drug specific. 343 EFFECTS OF CHRONIC SEROTONIN REUPTAKE HIBITION ON AGGRESSION AND IMPULSIVITY

INI-

S.D. Lane, J.L. Steinberg, and D.R. Cherek, University of Texas-Houston, Health Science Center, Houston, TX Research subjects participated after giving their informed consent. Subjects were assigned to three groups: Paroxetine 20 or 30 mg and placebo. Subjects were

s121

Abstracts

excluded if screening indicated any history of medical or psychiatric illness, or recent drug use detected by urine drug screen analysis. Subjects participated 2 days per week for 8 weeks. The sequences of conditions for subjects receiving paroxetime was: 1 week of baseline, 2 weeks of placebo, 3 weeks of paroxetine and 2 weeks of placebo. Compliance with dosing regimen was determined by MEMS bottles and plasma level determinations. Subjects participated in alternating sessions in which aggression and impulsivity were measured in the same subject. Subjects participated in eight sessions (four aggression and four impulsivity) each day. Subjects took one capsule each morning. Initial results indicate that paroxetine produced substantial decreases in aggressive responding and impulsivity, but these responses did not return to placebo levels observed prior to drug treatment. Additional subjects are now participating in 8 weeks of placebo treatment to determine if the same decline in responses will be observed over time. Supported by NIDA Grant DA10552-02.

failed to support Hypothesis 2: dependence criteria were not higher in threshold than abuse criteria. The abuse criterion of Legal Problems had the highest threshold across all three drugs. For alcohol, the second highest threshold was for the abuse criterion of Interference with Role Obligations, and for cocaine, three of the four criteria with the highest thresholds were abuse criteria. A criterion with uniformly low threshold and high discrimination ~ suggesting that it is a good measure of a mild problem like abuse - was the dependence criterion of continued use despite medical-psychological problems. The least discriminating criterion in general was the dependence criterion of tolerance, suggesting that it poorly distinguishes level of severity of substance disorders. These findings, and the high levels of item redundancy observed, suggest that for these three drugs DSM-IV abuse and dependence criteria are not well distinguished by the IRT properties of severity or discrimination. 345

FUNCTIONAL

(FMKI) 344

ITEM

CANNABIS

RESPONSE AND

COCAINE

THEORY CRITERIA

ANALYSIS IN

OF ALCOHOL,

DSM-IV

PARADIGMS

DURING IN

MAGNETIC

RESONANCE

‘DECEPTION’ NORMALS

AND

AND IN

IMAGING ‘GAMBLING’

COCAINE-DEPENDENT

PATIENTS

J. Langenbucher, E. Labouvie, P. Sanjuan, L. Kirisci, L. Bavly, and C. Martin, Center of Alcohol Studies, Rutgers University, Piscataway, NJ, and Pittsburgh Adolescent Alcohol Research Center, Pittsburgh, PA

D. Langleben, J. Maldjian, S. McDonald, F. Siddiqi, R. Ehrman, C.P. O’Brien, A.R Childress, Addiction Treatment Research Center, University of Pennsylvania, Philadelphia, PA

A promising alternative to classic psychometric methods that has seen little exposure in psychiatric nosology is Item Response Theory (IRT). IRT models a set of dichotomous test items as representing a unidimensional latent trait, and characterizes each item’s discrimination (ability to distinguish between subjects with different levels of a latent trait) and threshold (a parameter similar to item difficulty). This study tested the hypotheses (1) that DSM-IV current abuse and dependence criteria for alcohol, cannabis and cocaine could be adequately modeled by a single dimension as IRT requires; and (2) that DSM-IV dependence criteria would be higher in threshold than abuse criteria, tapping the more severe expression of substance use problems. Data were from 372 addictions treatment subjects (ages 17-69, 81% male) interviewed with the CIDISAM, yielding 340 current alcohol users, 262 cannabis users, and 225 cocaine users. Factor analyses for current DSM-IV symptoms were conducted using Mplus 1 .O (Muthen and Muthen, 1999), and each criterion’s discrimination and threshold parameters were produced using BILOG (Mislevy & Bock, 1994). Hypothesis 1 was supported by the finding of adequate one-factor solutions (root mean square residual < 0.08) for all three drugs. This permitted the use of IRT on the combined abuse/dependence criterion sets. Analyses

Background: Functional imaging of brain activation using a deception (lying vs. telling the truth) paradigm has not been reported in the peer-reviewed literature. Deception and denial are important problems in the diagnosis and treatment of drug dependence. We hypothesized that deception requires inhibition of a normal (truthful) response and is also a form of risk-taking. Increased activation of several distinct region,s of the prefrontal cortex during response inhibition tasks and risk-taking have been reported. Increased activity in the left superior temporal and supramarginal gyri has been observed with a ‘false’ memory paradigm. The areas of increased neuronal activity during deception are expected in the prefrontal (lateral and orbital) and temporal cortex. The Guilty Knowledge Task (GKT) is a forced choice paradigm, which detects simulated deception by electrophysiological techniques with a high degree of accuracy. Methods: Event-related fMR1 of 12 subjects (10 controls and two cocaine dependent in early remission) was done during performance of MRI-adapted GKT task. Statistical parametric mapping (SPM) was used to create template-matched subtraction group maps of cortical activity before, during, and after each stimulus presentation, highlighting areas of significantly higher cortical activity during ‘deception’ relative to ‘truth’. Results: Corti-

Abstracts

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cal activity during deception was significantly higher in the lateral (L > R) and ventromedial prefrontal and temporo-parietal cortex (L > R) and parts of the limbic system. Different cortical areas were activated during different parts of the 15 s period before and after a response, with lateral prefrontal cortex demonstrating the largest area of activation in the first 7 s after deceitful response. Conclusions: Simulated deception could be differentiated from the truth with event-related fMR1 and SPM. Deception activates a distributed neural network requiring inhibitory, associative and limbic input. Future work will be focused demonstrating differences in cortical activity of substance abusers and controls during deception and denial. Supported in part by NIDA grant ROl DA10241-04. 346

ORAL

COCAINE

CURRENT

MONITORING

ACTIVITY

WITHIN

TIVE

DOSE

PHARMACOKINETICS OF

AN

OPERANT

OPERANT CONTEXT

AND AND

CON-

LOCOMOTOR IN

A CUMULA-

REGIMEN

C.E. Lau, L. Sun, A. Simpao, Q. Wang, and J.L. Falk, Rutgers University, New Brunswick, NJ Despite the wide use of the cumulative-dosing procedure for evaluating dose-response relations, limited attention has been paid to investigating the concentration-effect (C-E) relations. Because serum drug concentration-time profiles (CTPs) after administration of multiple doses can be predicted from a drug’s pharmacokinetic (PK) parameters, we first characterized the PK parameters for oral cocaine (20 and 40 mg/kg) in rats. A cocaine CTP was then simulated using standard formulas for the escalating cumulativedose regimen (1, 3, 10, 30, and 75 mg/kg) and validated. The serum oral cocaine CTP was integrated with respective pharmacodynamic (PD) profiles of DRL performance and locomotor activity under the DRL 45 s schedule. The effects on three behavioral measures (i.e. increases in shorter-response rate or locomotor activity and the decreases in reinforcement rate) were characterized by integrated PK-PD models using the effectlinked sigmoid Emax and inhibitory Emax models, respectively. With the exception of the intrinsic differences in Emax and EO values among the behavioral endpoints, one set of PD parameters (i.e. EC5O/IC50 and Hill factors) characterized and predicted C-E relations across the five cocaine doses for the three behavioral indices. Concurrent monitoring of operant and locomotor activity behavior within an operant context provides a novel behavioral paradigm to investigate drug effects on spontaneous activity under conditions in which a behavioral contingency is instituted. Additionally, the proposed PK model facilitates the simulation of rational multiple dose regimens by varying dose size and/or dosing intervals in order to partition cocaine’s PK and PD effect components.

347

Do

TRAUMA?

MULTIPLE THE

MINOR

RELATIONSHIP

COMPLEX

PTSD

BILIZATION

AND

IN

OPIATE

TRAUMAS

MAKE

BETWEEN

CLASSICAL

ADDICTS

UNDERGOING

ONE

BIG AND STA-

DETOXIFICATION

F. Law, S. Latham, S. Singh, T. Raybould, E. Cockerill, D. Nutt, and J. Myles, Bristol Specialist Drug Service, Blackberry Hill Hospital, University of Bristol, UK Introduction: Classical PTSD occurs as a result of a single circumscribed traumatic event. Complex PTSD is a potential new diagnosis which develops following prolonged, repeated traumas, which it has been suggested can only occur where the victim is in a state of captivity, unable to flee, under the coercive control of the perpetrator (Herman, 1992). She further suggested that symptom are more complex, diffuse and tenacious (especially somatic, dissociative, affective), personality changes involving relatedness and identity occur, and there is an increased vulnerability to repeated self-harm or abuse. Hypothesis: Dependent opiate users may suffer from a form of complex PTSD, as they are typically exposed to prolonged repeated traumas. Opiate dependence exerts under coercive control as they suffer withdrawal symptoms whenever they try to release themselves from the grip of opiates. One indirect way of testing this idea is to examine whether PTSD scores which in classical PTSD correlate with the number of major traumatic events elicited, also correlate with PTSD scores for the types of events relevant to complex PTSD. Procedure: 67 opiate dependent addicts (DSMIV) recruited for a Suboxone (buprenorphine/naloxone) vs. methadone/lofexidine detoxification study completed a checklist of 12 major traumas and then the Impact of Events Scale (IESl) related to the event that bothered them the most. They also repeated a checklist of 12 repeated minor traumas typical of drug misuse, and again completed the Impact of Events Scale (IES2) for the type of event that bothered them the most. Correlations were performed using Spearman’s p. Results: The number of major traumas was related to the degree of intrusion and avoidance on TESl, (r = 0.63, P < 0.001) but the number of minor traumas was unrelated to the degree of intrusion and avoidance on IES2 (Y = 0.21, P= 0.06). These results do not support the idea that opiate users suffer from complex PTSD. 348 ITY

METHAMPHETAMINE AMONG

SUBSTANCE

USE

AND

CRIMINAL

ACTIV-

ABUSERS

P.A. Lee, D.B. Marlowe, J.C. Merrill, A.V. Harrell, D.S. Festinger, J. McNellis, and A.T. McLellan, Treatment Research Institute at the University of Pennsylvania, Philadelphia, PA, and The Urban Institute, Washington, DC

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Abstracts

Methamphetamine (MAMP) use has increased substantially on the west coast of the U.S. and appears to be spreading eastward. Laboratory evidence has linked amphetamine intoxication to increased aggression and risk-taking behaviors, and high doses may precipitate psychosis and delirium. Anecdotal evidence suggests that MAMP abuse is also associated with increased crime, violence, and disorganized thinking among substance users in community-based and drug treatment settings. This study investigated the link between MAMP use, criminal conduct, and psychiatric disturbance among 389 pretrial defendants in Tacoma, WA who were screened for participation in the NIJ-sponsored ‘Breaking the Cycle’ (BTC) Project. Participants were grouped as MAMP users (n = 223), Cocaine (Cot) users (n = 114) or Non-Stimulant (Non-Stim) users (n = 52) based on a positive UA and/or self-report of use in the past 30 days. The three groups differed significantly on age, gender, and race. The Cot users were the oldest (M= 35), followed by the MAMP users (A4 = 31) and Non-Stim users (M= 27). Non-Stim users had proportionately more males (85%) than the MAMP users (73%) and Cot users (61%). MAMP users were comprised of more whites (89%) than Non-Stim users (41%) and Cot users (35%). Results revealed that MAMP users had no more arrests and charges than Non-Stim users. However, MAMP users did commit more crimes than Non-Stim users - particularly drug crimes (M = 60.19 vs. M = 26.63 in the past 6 months, P < 0.05) irrespective of their arrests. Contrary to expectations, MAMP use (in this population) was not linked to increases in violent crime and psychotic behavior. These effects of MAMP appear to be a result of stimulants in general, and not specific to MAMP use. These findings are limited by the fact that BTC eligibility criteria excluded offenders with serious violent felonies. 349

RESPONSESOF VTAGABA IN FREELY MOVING RATS

NEURONSTOHEROIN

R.S. Lee, P.S. Griffin, SC. Steffensen, and S.J. Henriksen, The Scripps Research Institute, La Jolla, CA The ventral tegmental area (VTA) has been hypothesized to function as an integrator of complex limbic information. Increasing evidence implicates GABA neurons in the VTA for mediating, in part, opioid effects on mesolimbic circuits, including the dopamine projection from the VTA to corticolimbic structures. We evaluated the activity of VTA GABA neurons during heroin self-administration (SA). Heroin SA (0.06 mg/kg per injection via an indwelling catheter) was operantly controlled through nosepoking behavior (FR-1 schedule). VTA GABA neuron activity was recorded with microwires implanted into the VTA.

VTA GABA neurons were identified using the following criteria: negative-going action potentials; spike duration < 500 ps; and relatively high rates of spontaneous activity (mean = 35 f 4 Hz). During the acquisition of heroin SA, there was a progressive increase in VTA GABA neuron firing rate I- 10 s preceding, and a progressive decrease in VTA GABA neuron firing rate 0.1-10 min following each nosepoke for heroin. This pattern of behavior stabilized during the maintenance phase of heroin SA. VTA GABA neurons appear to be much more sensitive to both non-contingent and contingent heroin injection than are nucleus accum bens neurons. Our findings suggest that neuronal discharges in VTA GABA neurons are altered in a complex manner during the acquisition and maintenance of heroin SA behavior. Supported by DA-08301 to SJH.

350 BEHAVIOR PROFILES STANcE-DEPENDENT WOMEN

OF

CHILDREN

OF

SUB-

M. Leff, D. Svikis, N. Haug, and M. Jeter, The Johns Hopkins University School of Medicine, Baltimore, MD Children of substance dependent women are reported to be at greater risk for psychiatric disorders. This study examined children of substance dependent mothers attending a comprehensive treatment program. It was hypothesized that the mothers would report their children to have problematic behavior (i.e. high Tscores on the CBCL), and that the rate of ADHD would be higher in this sample than is reported in the community. Fifty women were administered the Addiction Severity Index (ASI), an ADHD questionnaire, and provided information on the behavior of one of her randomly selected children using an ADHD measure and Achenbach’s Child Behavioral Checklist (CBCL). The average age of the mothers was 30.7 (4.5), 90% were unmarried, 92% were unemployed, and the mean education level was 11.3 years (1.5). The average age of the studied child was 8.7 (3.9) and 50% of the sample was male. Twenty-three mothers reported illicit drug use during the pregnancy with the studied child, and 26 mothers denied use. The children were divided into two groups, prenatal drug exposure and no drug exposure. There were no differences in CBCL T-scores or ADHD diagnoses between the two groups. CBCL T-scores did not correlate with gender or mothers’ ASI composite scores. CBCL T-scores for the entire sample ranged from 49 (Internalizing problems) to 58 (Delinquent behaviors). Fourteen percent of the entire sample met criteri,a for ADHD and an additional 18% met subthreshold criteria. ADHD in offspring did not correlate with gender, or maternal ADHD symptoms. In this sampb:, ADHD was reported at a higher rate, but

Abstracts

S124

CBCL T-scores were in the ‘normal range’. One-third of mothers surveyed perceived that the studied child and/or siblings had behavior or emotional problems. It is unclear whether this high rate of reported offspring problematic behavior reflects unique parenting stressors for this population, and/or whether children of substance dependent mothers have greater behavioral or emotional problems. 351 LABORATORY MODEL OF RISK TAKING: OFAMPHETAMINEANDFLUPENTHIXOL

EFFECTS

C.W. Lejuez, J.E. Burnworth, H. de Wit, and J.B. Richards, West Virginia University, Morgantown, WV, and University of Chicago, Chicago, IL Risk taking may be operationally defined as engaging in a behavior that always has a rewarding consequence but is sometimes also associated with a punishing consequence. This study examined the effects of dopaminergic drugs on risk-taking, using a procedure in which rats choose between an adjusting amount of water (adjusting alternative) and a constant 200 ml of water followed by a 9 s tone associated with occasional foot shock (Risky Alternative). The amount of water on the ‘safe’ alternative was systematically adjusted across trials until the rat chose the safe and risky alternatives with equal frequency (indifference point), providing an index of the subjective value of the risky alternative. We investigated the effects of the indirect DA agonist amphetamine (0.5 and 1.0 mg/kg) and the DA antagonist flupenthixol (100 and 200 ug/kg) on the value of the risky alternative. The results indicate that amphetamine decreased the value of the risky alternative (made the rats less impulsive) whereas flupenthixol increased the value of the risky alternative (made the rats more impulsive). These results suggest that acute changes in DA function are negatively associated with risk-taking. Supported by DA10588. 352 PARTIAL-AGONIST IDE IN SQUIRREL TRIAZOLAM

EFFECTS OF CHLORDIAZEPOXMONKEYS DISCRIMINATING

S. Lelas, J.K. Rowlett, R.D. Spealman, Harvard Medical School, New England Regional Primate Research Center, Southborough, MA Previous research has suggested that the discriminative stimulus effects of chlordiazepoxide (CDP) may differ from those of other conventional BZ agonists, perhaps reflecting different profiles of activity at GABAA/BZ receptor subtypes. Alternatively, CDP may act as a partial rather than full agonist at GABAA/BZ receptors. This hypothesis was tested by administering CDP

alone and in combination with the high efficacy BZ agonist triazolam in a drug discrimination procedure. Squirrel monkeys were trained to discriminate between triazolam (0.03 mg/kg, i.v.) and vehicle under a fixedratio (FR) 10 schedule of food reinforcement. While triazolam as well as another high-efficacy agonist midazolam fully substituted (maximum 87-100% drug-lever responding, 12= 4) for the triazolam discriminative stimulus, CDP only partially substituted (maximum 60% drug-lever responding, II = 4) for the triazolam discriminative stimulus. Combined treatment with CDP (0.3-10.0 mg/kg) and triazolam resulted in leftward and upward shifts in the triazolam dose-effect curve. Isobolographic analyses of the data showed that the interaction between CDP and triazolam was consistently infra-additive, suggesting that the two compounds differed with respect to intrinsic efficacy. Collectively, these findings support the view that CDP has lower efficacy compared to triazolam at GABAA/ BZ receptors that mediate their shared discriminative stimulus effects. Supported by DA1 1792 and RRO0168. 353 PERCEIVEDRISKSOFSMOKINGANDMOTIVATION TO QUIT IN HIGH VERSUS LOW TOBACCO-DEPENDENT PREGNANT WOMEN

B. Leonhardt, D. Svikis, H. Jones, S. Benedict, M. Lantz, Virginia Commonwealth University, Richmond, VA Tobacco use in pregnancy is associated with a variety of adverse outcomes, most notably, lower infant birthweight. Many interventions use patient education to encourage smoking cessation, but such efforts have met with limited success. The present study examined the relationship between tobacco dependence severity and perceived risk of smoking as well as patient motivation and self-reported ability to quit in a sample of pregnant women seeking prenatal care in an urban hospitalbased clinic. All patients gave consent to participate in a larger ongoing behavioral research study for smoking cessation. Subjects (N= 44) were categorized as having high tobacco dependence (HD) if they smoked their first cigarette within 30 min of awakening or low tobacco dependence (L,D) if > 30 min elapsed prior to smoking. Results indicated that LD smokers were more likely to perceive smoking as harmful to the baby and they were more likely to feel that they might as well keep smoking since they were exposed to others’ smoke anyway. LD and HD smokers were similarly motivated by the health of the baby to quit smoking during pregnancy, but LD smokers were significantly more motivated to quit in order to show self-control or to demonstrate that they could quit. Likewise, LD smokers had more intrinsic motivation to quit smoking

S125

Abstracts

relative to their level of extrinsic motivation, which has been shown to predict postpartum maintenance. In addition, LD smokers were more confident that they could quit smoking compared to HD smokers. These findings could assist in the development of interventions tailored to meet the needs of pregnant women with different levels of tobacco dependence. This research was supported by ROl AA 11802. 354

EFFECTS

OF

REINFORCING

SELF-ADMINISTERING

ABSTINENCE

IN

RATS

COCAINE

M.G. LeSage and J.R. Glowa, LSU Health Sciences Center, Shreveport, LA The objective of this experiment was to model reinforcement-based clinical interventions for drug abuse by employing a differential-reinforcement-of-other-behavior (DRO) schedule of alternative non-drug reinforcement. Six rats were trained to self-administer cocaine (0.17 mg/kg per infusion) under a fixed-ratio (FR) 3 or FR 5 schedule of drug delivery. After the number of infusions per session showed no trend over five consecutive sessions, a conjoint DRO schedule of food delivery was implemented. Under this schedule, cocaine continued to be available under the FR schedule while a food pellet was delivered contingent upon every pause in self-administration responding (DRO interval) of 5, 10, 20, 40, 80, or 160 s. Pellet deliveries were always signalled by a 2 s tone. With intervals between 5 and 40 s, the DRO schedule of food delivery significantly reduced the number of infusions per session to near-zero levels. The DRO 80 s schedule produced small decreases in cocaine self-administration in some rats, while the DRO 160 s schedule had little or no effect on self-administration. In two rats, increasing the unit dose of cocaine to 0.32 mg/kg per infusion did not to attenuate the effects of the DRO schedule. The present assay approximates the conditions of reinforcement-based clinical interventions for drug abuse and might serve as a useful preclinical model of such interventions. 355

HEALTH

DRUG-USING

SERVICES

USE

AMONG

HIV-POSITIVE

PRISONERS

C. Leukefeld, M. Staton, T. Logan, B. Warner, J. Johnson, and K. Shaw, R. Purvis, University of Kentucky, Lexington, KY The number of adult prisoners in the U.S. was over 1.3 million at the end of 1998 (BJS, 1999). HIV has consistently been higher among prisoners than in the U.S. population (Brien, 1995). This exploratory study compares the health services use of Kentucky drug using prisoners who were HIV positive (n = 21) with those

who were HIV negative (n = 589). HIV testing was done with FDA approved Orasure testing. While 2.3% of U.S. prisoners were infected with HIV in 1996 (NIJ, 1999), data from this study indicate that HIV seropositivity was higher at 3.5%. When those who were HIV posit:ve were compared with those who were HIV negative, HIV positive prisoners were older (34.3 vs. 31.5 years); were less likely to be white (43% vs. 54%); were less likely to have completed high school/GED (43% vs. 51%); were less likely to be single (48% vs. 54%); and were less likely to be from a very rural area (0% ‘vs. 8%). When health services use was compared for emergency room visits, medical treatment and behavioral health treatment, only two of twelve variables were significantly different. Specifically, those who were HIV positive reported they were more likely to have a regular place to go if they were sick (67% vs. 54%; P < 0.001) and they were more likely to have been treated in an outpatient psychiatric setting (2.4 vs. 0.9; P < 0.01). However, Emergency Room (ER) visits seen in an ER, received ER care, and admitted to hospital from ER - were not statistically different. Medical treatments - times spent longer than 1 day in a hospital, number of days hospitalized in the prior year, and times treated in a doctor’s office - were not statistically different. Behavioral health treatments lifetirne alcohol treatment, lifetime drug treatment, lifetime mental health treatment, and lifetime treatment in a hospital for psychiatric problems - were not statistically different. These findings were not expected since it was hypothesized that HIV positive prisoners would use more health services. Implications will be presented. 356

TREATMENT

DIVALPROEX DOUBLE-BLIND,

OF SODIUM:

MARIJUANA A

PRELIMINARY

PLACEBO-CONTROLLED

DEPENDENCE

WITH

RANDOMIZED, TRIAL

F.R. Levin, DA. McDowell, S.M. Evans, E. Akerele, A. Sia, and S. Donovan, Columbia University and New York State Psychiatric Institute, New York, NY Not uncommonly, treatment-seeking patients report that marijuana abuse is their primary drug of addiction. Despite this, there are very few studies that have targe’ted treatment towards this sub-population. Some indivl.duals may use marijuana to self-regulate anxiety or depressive symptoms, whereas others may have difficulty ceasing their marijuana use due to withdrawal symptoms characterized by irritability, anxiety, and insomnia. Because divalproex sodium has been proven effective for mood lability and irritability, we were interested in determining whether divalproex sodium would help patients initiate and maintain their abstinence from marijuana. A double-blind, placebo-controlled, pilot crossover study comparing divalproex sodium to placebo is near completion. After a 2 week

S126

Abstracts

lead-in phase, 24 patients were randomized to divalproex sodium or placebo treatment arms for 6 weeks and then crossed-over to the other treatment arm. In addition, patients received weekly individual relapse prevention therapy. Of the 24 marijuana abusers who were randomized, 22 (92%) have been male, 5 (21%) have been African-American, 14 (58%) have been Caucasian and 5 (21%) have been Hispanic. Patients report using marijuana frequently (6.9 f 0.45 days per week) and in substantial amounts (24.7 + 20.4 joints/week). To date, 18 patients have completed at least 8 weeks of the study. Of these individuals, self-reported days of use per week and number of joints used per week decreased significantly from beginning of study compared to the last two weeks. However, divalproex sodium has not demonstrated an advantage over placebo in reducing self-reported frequency or amount of marijuana use. Further, although there have been modest reductions in marijuana use based on urine toxicology screens, there has not been a differential response based on treatment arm. Although this study is limited by its small sample size, there are no trends suggesting that divalproex sodium merits further investigation. Given the lack of proven effective treatments needed for marijuana dependence, novel targeted treatment approaches need to be developed. Supported by NIDA Grants P50 DA 09236 and K20 002114.

357 ASSESSMENT CCK ANTAGONISTS DISCRIMINATION

OF WITH

INTERACTIONS

OF

CHLORDIAZEPOXIDE

CCK

AND

IN DRUG

LEARNING

E.S. Levine, M.A. Fox, and A.L. University, Washington, DC

Riley, American

Recent literature has suggested that cholecystokinin (CCK) might function as an endogenous anxiogenic, implying that administration of CCK antagonists might alter this endogenous tone to produce an anxiolytic effect. The present study assessed the anxiolytic and anxiogenic properties of CCK antagonists and CCK, respectively. This was achieved by examining their ability to substitute for or block the anxiolytic benzodiazepine chlordiazepoxide (CDP) in rats trained to discriminate CDP from vehicle within the conditioned taste aversion baseline of drug discrimination learning. Specifically, animals were administered injections of either CDP or vehicle, then given access to saccharin solution, followed by an injection of either lithium chloride (after CDP injection) or vehicle (after vehicle injection). Various doses of the CCK-A antagonist devazepide (10 and 32 mg/kg) and the CCK-B antagonist L-365,260 (10 and 32 mg/kg) failed to generalize or potentiate the stimulus effects of CDP. However, doses of the benzodiazepine diazepam (0.1,0.32, 1 and 3.2

mg/kg) produced a dose response function similar to that of CDP, showing that generalization can be achieved in this design. Various doses of CCK (3.2, 5.6 and 10 mg/kg) failed to block or generalize to the stimulus effects of CDP. These data suggest that the anxiogenic actions of CCK, as well as any anxiolytic properties possessed by the CCK antagonists devazepide and L-365,260, operate through different mechanisms than the anxiolytic actions of the benzodiazepine CDP.

358 MU

DESOXYCLOCINNAMOX:

AN

UNEXPECTED

PURE

ANTAGONIST

J.W. Lewis, I. Derrick, Husbands, J.H. Woods, of Bristol, and University of Michigan, Ann Arbor,

C.L. Neilan, J. Andes, SM. and J.R. Traynor, University of Bath, England; University MI

C-CAM (1) is a mu-selective irreversible pure antagonist whereas MC-CAM (2) is a mu partial agonist with subsequent mu-antagonist activity. MC-CAM is metabolised to C-CAM so that its delayed antagonism could be attributed to the metabolite. Earlier SAR studies in epoxymorphinan derivatives suggested that DOC-CAM (3), which should not be converted to an antagonist metabolite, would have mu efficacy comparable to MC-CAM. Any delayed antagonism could therefore only be attributed to DOC-CAM. DOCCAM has been synthesised and evaluated in opioid receptor binding assays in monkey brain, in [35S]GTPgammaS assays for mu function and in mouse antinociceptive assays. Though binding with high affinity to mu receptors it had no efficacy in the in vivo and in vitro functional assays. DOC-CAM was a potent mu-antagonist in vitro but with in vivo assays the mu antagonism was of modest duration. The significance of these unexpected results will be discussed. ACKNOWLEDGEMENT: NIDA grant (DA00254); NIDA contract to SRI NOlDA3-8302 and 4-8307.

359 MEDIAL SION

DOPAMINE PREFRONTAL OF COCAINE

Dl

RECEPTOR CORTEX

ACTIVATION REGULATES

IN THE

THE

EXPRES-

SENSITIZATION

N. Li, W.R. Wu, R.M. Craft, and B.A. Sorg, Washington State University, Pullman, WA Our laboratory has recently found that infusion of d-amphetamine directly into the mPFC attenuated the expression phase of cocaine sensitization (Neurosci., 88: 765-774; 1999). The present study examined whether microinjection of the full Dl agonist, SKF 81297, into the mPFC would be sufficient to block the expression of cocaine sensitization. Male Sprague/Dawley rats were administered saline (1 ml/kg, ip) or cocaine (15

Abstracts

mg/kg, ip) once per day for 7 consecutive days. After a minimum withdrawal period of 1 week, rats received a microinjection of one of the following four doses of SKF 81297: 0, 0.03, 0.1, or 0.3 ug/side followed by an ip saline or cocaine (15 mg/kg, ip) injection 5 min later. Vertical and horizontal motor activities were measured over a 2 h period post-ip injection. No significant differences were found among any of the treatment groups when an ip saline injection was given as challenge. Rats given the ‘0’ dose of drug (water) demonstrated a locomotor response to an ip cocaine challenge in the following order: daily cocaine > naive > daily saline, with a significant sensitization of vertical and horizontal activities when comparing between daily saline and cocaine pretreated controls. No significant effects of SKF 81297 were obtained among naive animals. Analysis of daily saline and cocaine pretreated rats revealed a significant interaction for both vertical and horizontal activity. Saline pretreated rats demonstrated a dose-dependent increase in activity, while cocaine pretreated rats showed a dose-dependent trend toward a decrease in activity up to the 0.1 ug/side dose, with no further decrease at the 0.3 ug/side. These results suggest that the effects of Dl receptor activation in the mPFC are bidirectional in regulating locomotor activity, depending upon the original state of activity. Supported by DA 11787. 360

MORPHINE

STANCE MONONUCLEAR

P

UPREGULATES AND

ITS

EXPRESSION

RECEPTOR

PHAGOCYTES

IN AND

HUMAN

OF

SUB-

BLOOD

LYMPHOCYTES

Y. Li, S. Tian, SD. Douglas, and W.Z. Ho, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA Morphine and the undecapeptide Substance P (SP, the most potent member of tachykinin family) modulate the immune system and host defense mechanisms. We have recently identified the presence of SP and its receptor mRNA in human immune cells. We investigated the interaction of morphine with cultured human immune cells on the expression of SP. We observed that morphine modulated monokines (IL-l, IL-6, TNF alpha, and IFN gamma) production by human monocytes and macrophages. SP synergistically enhanced morphine-induced TNF alpha production in these cells. We demonstrated that morphine upregulated SP expression in human mononuclear phagocytes and lymphocytes in vitro at both the mRNA and the protein level. In addition, morphine induced SP receptor (NK-1R) expression in these human immune cells. Methadone, a long acting synthetic opiate. also stimulated SP production in human monocytes. The specific morphine receptor antagonist (Naltrexone) blocked morphine or methadone-induced SP expression in hu-

s121

man mononuclear phagocytes, supporting the concept of authentic morphine receptor-mediated regulation. Since: SP modulates neurogenic inflammation and immunologic events, these data suggest that morphine-induced SP expression in cells of the immune system is of importance in the pathogenesis of immune-mediated diseases, including neuroimmunologic diseases and AIDS. Supported by MH-4998 1 and DA-l 1887. 361

DOES

MODULATE

AN ENDOCANNABINOID

SYSTEM

TONICALLY

NOCICEPTION?

A.H. Lichtman and B.R. Martin, Virginia wea1l.h University, Richmond, VA

Common-

Whereas some laboratories have found that the CBl receptor antagonist SR 141716A elicits hyperalgesia, others have failed to observe this phenomenon. In the present study, we examined the pharmacological effects of SR 141716A in various models of pain. Mice were administered SR 141716A (1, 3, or 10 mg/kg) and evaluated in the tail-flick, hotplate, or formalin tests, as well as in the chronic constrictive injury of the sciatic nerve (CCI) model of chronic pain. In the formalin test, 10 mg/kg of SR 141716A elicited some hyperalgesic responses under certain circumstances. In the hotplate and tail-flick assays, however, the drug was completely without effect regardless of the dose, route of systemic administration, or mouse strain (i.e. ICR, Swiss, and C57/B16 mice). Similarly, intrathecal administration of SR 141716A (0.001 fmol to 10 nmol) failed to produce any significant effects in either ICR or Swiss mice in the hotplate test. Finally, the drug also failed to elicit hyperalgesic responses to a radiant heat stimulus in the CC1 model. Taken together these findings do not support the assertion that an endogenous cannabinoid system tonically modulates nociception to noxious heat stimuli in normal or nerve injured mice. Although SR 141716 did produce an increase to inflammatory pain, the effect only occurred during certain circumstances and at an excessively high dose. Supported by NIDA grants DA-08387 and DA-03672. 362 STANCE

EXPOSURE USE,

AND

TO

COMMUNITY

CRIMINALITY

VIOLENCE,

SUB-

IN COURT-ADJUDICATED

ADOILESCENTS

V. Lidz, M.L. O’Neill, J.E. Folk, and L. Korein, Institute for Addictive Disorders, MCP Hahnemann University, Philadelphia, PA Assessment data for 51 court-adjudicated, substance abusing adolescents in a 3 month partial hospital treatment program were analyzed to determine the relationships of exposure to community violence with substance

Abstracts

S128

use and criminal activity. Community violence was assessed by the Post-traumatic Stress Diagnostic Scale (PDS; Foa, 1995) while substance use and criminal activity were assessed by the Comprehensive Adolescent Severity Index (CASI; Myers, McLellan, Jaeger, and Pettinati, 1995). We hypothesized that exposure to violent trauma would be positively related to substance use and criminality, while exposure to non-violent traumas would be unrelated. The trauma categories in the PDS were divided into violent and non-violent. All adolescents reported experiencing at least one trauma. Eightysix percent of the adolescents experienced at least one violent trauma, 82% experienced at least one non-violent trauma, and 69% experienced both types of trauma. Consistent with our hypothesis, the violent trauma category was related to criminal versatility (r = 0.34, P < 0.05), first age of substance use (r = - 0.32, P < 0.05) number of different substances used (r = 0.33, P < 0.05), and months of drug and alcohol use (r = 0.36, P < 0.01). Contrary to our hypotheses, the non-violent trauma category was associated with first age of substance use (r = - 0.33, P < 0.05). Consistent with our hypotheses, non-violent traumas were unrelated to criminal versatility, number of different substances used, and months of drug and alcohol use. Overall, the frequency of traumatic experiences was strikingly high in this sample of adjudicated youth. Our findings suggest that being exposed to and experiencing trauma, particularly violent trauma deserves careful evaluation in research with delinquent and substance abusing adolescents. Clinicians may wish to evaluate traumatic experiences and post-traumatic stress disorder as a routine element of work with troubled youth. 363 SUICIDAL DRUG ADDICTS

IDEATION

IN HIV-INFECTED

364 EFFECTS OF Zg-PROPANOYL-3@(2-NAPHTHYL)TROPANE (HD-23) ON COCAINE-MAINTAINED RESPONDINGINRATSANDRHESUSMONKEYS

FEMALE

J.M. Liebschutz, C.L. Kerner, and J.H. Samet, Boston University Schools of Medicine and Public Health, Boston, MA Hypotheses: We analyzed qualitative

as compared to 6/27 at the time of the interview. All had some periods in recovery since testing positive. Testing positive for HIV interrupted a long-standing drug lifestyle and shifted their awareness from the next ‘high’ to a sense of past, present and foreshortened future. A motivation to decrease drug use was the belief that using drugs would worsen their HIV status, either directly through drug effects on the immune system or indirectly through poor adherence to lifesaving medications. Increased suicidal ideation among women diminished motivation for recovery. Half of the women expressed serious suicidal desires or behaviors, compared to 2 of 17 men. Two women intentionally contracted HIV from their infected partners. Another woman who described suicidal thoughts later died of a drug overdose. After receiving the HIV diagnosis, 6 of 10 women compared to 2 of 17 men increased drug use as a suicidal gesture. Only women planned future suicide as a means to avoid suffering from end-stage illness or to protect family members from watching them suffer. Learning about HIV through engagement with medical and social service providers diminished suicidal ideation, Importance of$ndings: Compared to men, drug dependent women are more likely to express suicidal ideation after testing HIV positive, which may undermine attempts at decreasing drug use. Linkage to mental health evaluation and treatment as a routine part of post-test counseling for newly diagnosed HIVinfected women should be studied. (NIDA # DAlOOl9-0281)

research data of drug dependent persons to explore gender differences in reactions to diagnosis of HIV. Subjects: 27 (10 women, 17 men). Procedures: HIV-infected people with prior heroin or cocaine use were recruited from medical clinics. Transcriptions of open-ended individual interviews were analyzed via multiple readings, coded, and evaluated by a group of HIV-infected drug addicts, substance use counselors and healthcare providers. Grounded Theory methods were used to develop the conclusions. Results: Subject characteristics included: 77% minority ethnicity; mean age 42; mean years of illicit drug use 13; drug of choice heroin 50%, cocaine 50%; median years since initial HIV test 1.3. At the time of HIV testing 20/27 were using illicit drugs daily

J. Lile, D. Roberts, D. Morgan, R. Phelan, H. Davies, and M. Nader, Wake Forest University School of Medicine, Winston-Salem, NC, and SUNY Buffalo, Buffalo, NY 2p-propanoyl-3p-(2-naphthyl)-tropane (HD-23) is a non-selective, high-affinity tropane analog that binds to dopamine, serotonin and norepinephrine transporters, preventing reuptake of these monoamines. Previous research has demonstrated that HD-23 is self-administered by rats, but maintains low rates of responding in monkeys. The purpose of the present study was to evaluate the effect of pretreatments with HD-23 on cocaine-maintained responding in both rats and monkeys and to compare these effects between the two species. Rats (n = 6) were trained to respond under a progressive ratio schedule of cocaine (0.1% 1.5 mg/kg per infusion, i.v.) presentation; break point was defined as the final ratio completed when no injections were received for 1 h. HD-23 (1 .O mg/kg) was then administered 2 h prior to the session. Pretreatment with HD-23

Abstracts

resulted in a shift to the left in the cocaine dose-effect curve, suggesting potentiation of cocaine’s reinforcing effects. Rhesus monkeys (n = 3) were trained to respond on a multiple food, cocaine fixed-ratio 30 (FR30) schedule of reinforcement. Sessions consisted of a 15 min food component, a 10 min TO and a 3 h cocaine (0.001-0.3 mg/kg per infusion) component. HD-23 (0.003, 0.01 mg/kg) was given 10 min prior to the session. In rhesus monkeys, HD-23 administration resulted in leftward shifts in the cocaine dose-effect curve, without affecting food-maintained performance. These results indicate that while there may be differences in the reinforcing effects of HD-23 between rats and monkeys, the effects on cocaine self-administration appear to be similar. Supported by grant DA-06634. 365

SELF-REPORTED ADHERENCE TO ANTIRETROVIRALTHERAPIES AMONG HIV SERO-POSITIVEINJECTION DRUG USERSINBALTIMORE,MARYLAND

M.K. Lin, D.D. Celentano, S.A. Strathdee, and D. Vlahov, Johns Hopkins School of Public Health, Baltimore, MD, and Center for Urban Epidemiologic Studies, New York Academy of Medicine, New York, NY Objective: To evaluate the validity of self-report as a method for determining adherence to antiretroviral therapies. Background: Few studies have described the factors determining adherence for injecting drug users (IDU) with HIV, a disease requiring strict medicationtaking behaviors, as well as social and health care system support. Methods: HIV-infected IDU were recruited from an inner city, community-based clinic. The study population was 94% African-American and 73% male with a median age of 43 years. Participants were administered a survey regarding barriers and facilitators to antiretroviral therapies (ART) use. Ordinal logistical regression identified factors associated with the outcome variable of adherence, measured per dose for all ART. Results: This cross-sectional study found that only 26% of all participants (n = 137) received optimal ART and 22% received suboptimal regimens; the remainder received no ART regimens. 45% were on NRTIs, 14% on NNRTIs, and only 25% on at least one protease inhibitor. More than half (58%) of the participants reported 100% adherence to every pill. Between participants with strict and partial adherence, no significant differences were found for selected demographic characteristics; drug use and sexual behaviors; and virologic and immunologic measures. Viral load was not significantly lower in strict than in partially adherent participants (mean of 4684 vs. 4889 copies/ml, respectively). Conclusions: Current self-reported measures of adherence to medications in HIV sero-positive IDUs are limited in their ability to discriminate re-

S129

sponses to ART therapy. We cannot discern with the data whether this reflects viral resistance or responses based on social desirability. Longitudinal studies are ongoing. 366 ATTENUATION OF COCAINE SELF-ADMINISTRATION BY RTI-113: RELATION TO DOPAMINE TRANSPORTER OCCUPANCY DETERMINED BY PET IN RHESUS MONKEYS K.P. Lindsey, M.M. Goodman, J. Votaw, L. Martarello, K.M. Wilcox, F.I. Carroll, and L.L. Howell, Yerkes Regional Primate Research Center and Emory University, Atlanta, GA, and Research Triangle Institute, Research Triangle Park, NC The reinforcing effects of cocaine are thought to be due to its blockade of the dopamine transporter. Recent medication development efforts have targeted the dopamine transporter as a molecular site of action. This study evaluated the ability of pretreatments with the selective dopamine uptake inhibitor, RTI-113, to attenuate cocaine self-administration behavior under a second order schedule of cocaine reinforced responding in rhesus macaques. When given 30 min prior to the self-administration session a dose of 0.3 mg/kg RTI-113 reduced both the rate of cocaine-reinforced responding and the number of cocaine infusions self-administered per session by approximately 50%. Positron emission tomography (PET) was used to assess the degree of doparnine transporter occupancy by RTI-113 with the reductions in cocaine self-administration behavior. Dopamine transporter occupancy was determined by displacement of the high affinity dopamine transporter ligand, 8-(2-[ 18F] fluoroethyl)2B-carbomethoxy-3p-(4chloro-phenyl) nortro-pane (FECNT), from the striaturn. ,4 dose of 0.3 mg/kg RTI-113 was administered 1 h after administration of the radioligand tracer and was found to occupy approximately 50% of dopamine transporters. These data suggest that pharmacotherapies for cocaine addiction that target the dopamine transporter may require significant levels of dopamine transporter occupancy in order to be effective. Supported by USPHS grants DA10344 and RR00165. 367 TREATMENT SETTINGS IN EVALUATION OF BUPRENORPHINE/NALOXONE COMBINATION TABLET FORTHETREATMENT OFOPIATEDEPENDENCE W. Ling, J. Cunningham-Rathner, K. Miotto, C.L. Cantu, V. Pearce, S. Maya, J. Fradis, and D. Sena, Friends Research Institute, Easton, MD, Long Beach VA Medication Development and Research Unit, Long Beach, and UCLA, Los Angeles, CA

s130

Abstracts

Buprenorphine is a ‘mu’ opiate receptor partial agonist nearing approval for use in the treatment of opiate dependence. A recent question of interest is the influence of treatment setting on suboxone treatment. Parwere randomized ticipants and inducted onto open-label buprenorphine. The treatment settings under investigation are (1) an relapse prevention treatment; (2) a private physician’s office (with a standardized psychosocial component); or (3) a standard narcotic treatment program. To date, 24 males with a mean age of 37 years and 18 females with a mean age of 39 years have been enrolled. The mean duration of heroin use was 13 years. Sixty-six percent reported using heroin intravenously, 17% smoked heroin, 12% snorted heroin and 5% used other oral opiates. The induction schedule for suboxone was 8 mg (Day l), 12 mg (Day 2) 16 mg (Day 3) and 24 mg (Day 4). Participants were instructed to abstain from opiates for 12-24 h before buprenorphine treatment. All participants took half of the first dose (4 mg) in clinic and were monitored for 1 h for adverse effects. Prior to receiving medication, participants reported sweats (47%), aches/pains (35%) runny nose (47%) and anxiety/irritability (44%). Improvement was generally noted after the first full day of medication. Reports included: sweats (24%) aches/ pains (IS%), runny nose (21%) and anxiety/irritability (29%). Trends in this small sample indicate early drop out rates and are attributed to two main factors: participants either failed to return to clinic (N= 13, 38%), or they lacked transportation to their assigned treatment setting (N= 4, 12”/0). Over half of the participants dropped out by the 3-day of treatment. These findings indicate that special attention needs to be paid to early engagement and retention. Further data will clarify the efficacy of site-specific treatment. Upon completion of study on 120 participants, results and findings will be presented. 368

FUNCTIONAL MAGNETIC RESONANCE IMAGING OF TWO TEMPORALLY DISTINCT PROCEDURES FOR CUE-INDUCED COCAINE CRAVING

(FMRI)

J. Listerud, J. Maldjian, D. Langleben, J. Monterosso, R. Ehrman, T. Franklin, C.P. O’Brien, and A.R. Childress, Addiction Treatment Research Center, University of Pennsylvania School of Medicine, and VA Medical Center, Philadelphia, PA Previous reports of functional imaging during cue-induced cocaine craving states have yielded both consistencies (e.g. amygdala, when visualizable) and discrepancies (e.g. dorsolateral prefrontal cortex, DLPFC) in the regions of activation. As the studies have varied both in their respective methods of imaging (PET O-15, PET FDG, fMR1) and of craving induction (continuous vs. interrupted/repeated video segments),

the current study tests both methods of craving induction within a single imaging methodology, fMR1. Treatment-seeking cocaine patients and demographically-matched controls (sample goal, n = 15 per group) each undergo two separate imaging sessions by BOLD fMR1 during exposure to two distinct cocaine craving induction (non-drug vs. cocaine video) protocols. One protocol features continuous narratives; the other features alternating short segments of 90 s each. Imaging data is analyzed by motion correction, registration with Talairach space, and calculation of T2 statistical maps (SPM 96 software). fiypothesis: Differential activation of the DLPFC, a ‘working memory’ region, will occur only during the ‘alternating’ video induction. fMRI’s temporal resolution makes it useful for sorting out brain activations related to the pattern of stimulus presentation from those uniquely related to the cue-induced state. NIDA ROl DA10241-04 369 PARENTAL INFLUENCE WITH DRUG-USING PEERS

ON YOUTH

AFFILIATION

J.J. Lloyd, J.C. Anthony, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD Hypothesis: Peers sharing drugs may represent the most studied causal determinant of drug involvement; deficient supervision and monitoring of children by their parents is a more recently studied suspected cause. In this longitudinal epidemiological study, we test whether and by how much increased levels of parental monitoring and supervision might cause reductions in later affiliation with drug-using peers. Methods: The majority African-American sample originated in first-grade classrooms of 19 primary schools within an urban public school system. The analytical dataset included 2128 youth who were initially interviewed in 1989 (grades 334) followed, then assessed annually from 1990 through 1994 to evaluate a range of characteristics including affiliation with drug-using peers and parental monitoring and supervision. Results: With GEE models providing statistical control for baseline levels of affiliation with drug-using peers, age, sex, race, and neighborhood characteristics, there was a statistically significant but modest inverse association between earlier level of parental monitoring and later affiliation with drug-using peers (b = - 0.04; 95% CI = ( - 0.05, - 0.03); P < 0.001). Discussion: The balance of evidence from this study is in favor of a causal model in which parental monitoring and supervision might affect youthful drugtaking via an intermediate influence upon affiliation with drug-using peers. This causal model extends other conceptual models in which parental and peer influence compete but fail to allow for the possibility that parents control peer influence - at least to some extent. One

Abstracts

implication for NIDA prevention research might be that affiliation with drug-using peers could serve as a proximal endpoint in trials to evaluate parenting programs. ACKNOWLEDGEMENTS: Supported by NIDA Grants T32DA07292 and DA09897 370

EFFECTSOFTOLUENEON N-METHYL-D-ASPARTIC ACID- (NMDA) AND PENTYLENETETRAZOL(PTZ) INDUCEDCONVULSIONSINMICE

C. Lopez-Rubalcava, C. Camacho, N. Paez-Martinez, and S.L. Cruz, Mexican Institute on Psychiatry and Centro de Investigation y Estudios Avanzados, IPN, Mexico City Toluene is an abused inhalant with behavioral actions similar to those produced by central nervous system (CNS) depressants, and a non-competitive NMDA receptor antagonist. Since several CNS depressants and NMDA antagonists have anticonvulsant actions, the purpose of the present study was to analyze the effects of toluene on the convulsions induced by NMDA (120 or 240 mg/kg) or PTZ (80 and 100 mg/kg). Male Swiss-Webster mice (25-30 g) were i.p. injected with the pro-convulsive drugs, placed in static exposure chambers and observed for 30 min during air or toluene exposure. The parameters registered were the percentage of animals that presented clonic-(C), clonic-tonic seizures (CT) and death, and the latencies to these responses. NMDA at 120 mg/kg produced hyperactivity (running and jumping), followed by C and CT seizures in control animals. In addition, NMDA at 240 mg/kg produced 90% of mortality. Toluene dose-dependently decreased the percentage of animals showing C and CT seizures and increased the latency to death. PTZ, at 80 mg/kg, resulted in CT seizures and 50% of mortality in control animals. With the highest dose of PTZ, all mice presented CT seizures and died. Toluene exposure prevented the lethal effects of PTZ and decreased the percentage of animals showing CT seizures. Therefore, toluene was able to decrease the intensity of both NMDA- and PTZ-induced convulsions and protected against death produced by a high dose of PTZ. Research supported by CONACyT grant 30571-M. 371 GENDER DIFFERENCES IN THE CARDIOVASCULAR RESPONSES To OPIATES INTHE SPINAL RAT S.L. Cruz and G. Rodriguez-Manzo, Centro de Investigacion y Estudios Avanzados, IPN, Mexico Mexican Institute on Psychiatry, Mexico City, Mexico Gender differences in several acute opiate responses are well documented. Although less explored, there are also reports on gender differences in chronic effects of opiates. The aim of this work was to study the cardiovas-

s131

cular effects of morphine and naloxone in male and female rats in a model of acute opiate dependence. Animals underwent a spinal transection at the level of C 1. .4fter a recovery period, they received a single dose of morphine (30 mg/kg i.v.). Four hours later, abstinence was precipitated by naloxone (0.3, 1, or 3.1 mg/kg, i.v., n = 10 each). The parameters registered were heart rate (HR) and mean arterial pressure (MAP). Morphine produced a similar decrease in HR in both genders. Although this bradycardic effect lasted longer in males than in females, the difference did not reach statistical significance. Morphine also produced an initial brief increase in MAP that was similar in both sexes. Thereafter, a mild but constant decrease in blood pressure was seen in both genders, but males showed a more rapid decrease than females. Naloxone precipitated a gender-dependent increase in blood pressure. Although this increase was important and long lasting in both genders, a phasic response with several major pressure peaks was seen in males but not in females. A HR increase similar in both sexes was also seen after naloxone administration. Our results, together with previously published observations highlight the need to comider gender as a factor when studying opioid effects. 372 HIV RISK BEHAVIOR DURING TREATMENT FOR OPIATE DEPENDENCE: A COMPARISON OF LAAM, BUPRENORPHINE,ANDMETHADONE D. Lott, R.K. Brooner, G.E. Bigelow, E.C. Strain, and R.E. Johnson, Johns Hopkins University School of Medicine, Baltimore, MD The relative efficacy of three opioid substitution medications for reducing HIV risk behavior in opiate dependenl. patients was assessed using data from a randomized double blind clinical trial comparing LAAM (L), buprenorphine (B), high-dose methadone (HDM), and low-dose methadone (LDM). Individually optimized flexible dosing was used for all groups except LDM, with weekly possible doses of: L, 2555391 mg; B, 56- 112 mg; HDM, 420-700 mg; and LDM, 140 mg. Rescue procedures permitted patients with poor study performance to switch to HDM. The groups did not significantly differ on demographic variables. A questionnaire regarding specific HIV risk behaviors including injecting, equipment sharing, and sexual activity was completed at weeks 3 and 18 of treatment, yielding data for pretreatment, week 3, and week 18 for 181 patients. Because baseline values were expected to correlate with outcomes, pretreatment rates of risk behavior were used as covariates. Declines in risk behavior during treatment were evident in all groups for most measures of injecting and equipment sharing. Only the HDM group showed consistent declines in measures of

Abstracts

S132

sexual behavior. Patients in the LDM group had nonsignificantly greater rates of any risk behavior at week 3 (compared to the other three groups). These results demonstrate that all three medications can be highly effective in decreasing HIV risk behavior when dose is optimized. Reductions in sexual behavior for the HDM group are consistent with known methadone side effects. Supported by P50 DA05273, K02 DA00332, and K05 DA00050.

313 A REPORT OF 18 BUPRENORPHINE-TREATEDWOMEN

PREGNANCIES

AMONG

A. Loustauneau, M. Auriacombe, P. Franques, J.P. Daulouede, and J. Tignol, Universite Victor Segalen Bordeaux, Bordeaux, France Within a systematic follow-up cohort study of subjects admitted into buprenorphine treatment a network of general practitioners and addiction specialists in Bordeaux and Bayonne (Aquitaine, France, Europe), all pregnancies were specifically studied. Over a 3 year period (1996699) among a total of 415 subjects/year in buprenorphine treatment, of whom 103 where females, 18 pregnancies where reported. Average age of mothers at delivery was 29 years, and duration of buprenorphine treatment was 1.2 years. The outcome of these pregnancies where 14 newborns, 2 voluntary interruptions, and 2 involuntary interruptions. The newborns, were delivered between 37 and 41 weeks gestation and the average weight was 2999 g. Eight presented with opiate withdrawal syndrome as measured by the Finnegan scale on average 2 days after delivery, of whom five received treatment. The duration of inpatient stay for the newborns was 15 days. Compared to methadone-treated mothers during the same time frame, newborn opiate withdrawal with buprenorphine was less frequent, less sever, and of shorter duration.

374 CO-EXISTINGPSYCHIATRICPROBLEMSANDDRUG DEPENDENCE:ACOMPARISONUSINGTHEDRUGEVALUATION NETWORK SYSTEM M. Love, D. Carise, D. Festinger, A.T. McLellan, and H.D. Kleber, Treatment Research Institute at the University of Pennsylvania, Philadelphia, PA, and the National Center for Addiction and Substance Abuse at Columbia, MD Substance abuse treatment programs are challenged on a daily basis to provide appropriate and effective services to clients presenting with both drug dependence and psychiatric problems. Previous research has demonstrated that these clients often experience additional problems, such as medical and social problems,

are more vulnerable to relapse, and therefore are more difficult to treat. Forty two percent of clients providing data to the Drug Evaluation Network System (DENS) report having had one or more of the following serious psychiatric symptoms 30 days prior to treatment admission: serious depression, trouble controlling violent behavior, serious thoughts of suicide, and attempted suicide. DENS, funded by ONDCP and CSAT, has gathered Addiction Severity Index (ASI) data on over 12 000 clients in 40 treatment programs from six cities since its inception in 1996, across the following treatment modalities: methadone maintenance, inpatient/ residential, outpatient and intensive outpatient programs. This presentation compares clients reporting serious recent psychiatric symptoms with clients not reporting these symptoms. Results indicate that ‘psychiatrically severe substance abusers’ present to treatment with greater medical, employment, family/social, and drug and alcohol problems. They also place more importance on obtaining treatment in these areas, which could indicate greater motivation for treatment, and corresponds with clinician’s ratings of these issues.

375 THE~HINESEHERB,KUDZU,DIFFERENTIALLYALTERS BRAIN AND PLASMA ETHANOL LEVELS IN HUMAN SUBJECTS SE. Lukas, M. Lachance, Y. Ke, L.H. Lundahl, D.Y. Lee, and P.F. Renshaw, McLean Hospital/Harvard Medical School, Belmont, MA The Chinese herb, kudzu, has been used for centuries to treat a variety of disorders. An i.v. preparation of puerarin, one of the main isoflavones in kudzu, is also used in China to alter blood flow. We hypothesized that kudzu might be useful in treating alcohol-related problems by altering alcohol kinetics. After providing informed consent, 5 female light drinkers were given pre-packaged envelopes and instructed to take one packet of 15 capsules (each containing 0.5 g crushed kudzu root or placebo) t.i.d. for 2 consecutive days (0.30-0.35 g/kg per day). On the third day subjects participated in a challenge experiment during which subjective effects, physiologic activity and plasma and brain ethanol levels were measured before and for 2 h after drinking either placebo or 0.56 g/kg ethanol. Brain ethanol levels were measured and corrected for creatine levels using proton magnetic resonance spectroscopy (MRS). After kudzu treatment, plasma ethanol levels were elevated slightly and certain mood states such as ‘high’ were lower. In addition, brain ethanol levels in 4 of the subjects either achieved lower peaks or the appearance of ethanol in brain was delayed in the kudzu-treated subjects. Thus, the slower entry of ethanol into the brain may contribute to its usefulness in treating alcohol-related problems. This finding demon-

Abstracts

strates the usefulness of MRS technology as a tool to explore brain mechanisms of ethanol’s effects. 376 GENDERANDCOCAINEEFFECTEXPECTANCIESINTERACT ON RECREATIONAL COCAINE USERS' DRUG RESPONSES L.H. Lundahl, S. Whalen, and SE. Lukas, McLean Hospital/ Harvard Medical School, Belmont, MA Although many studies have shown that cognitive expectancies of drug effects may play important roles in drug use patterns and drug treatment outcomes, few studies have directly compared subjects’ effect expectancies with actual drug response following a drug challenge. Healthy male and female volunteers (n = 35, ages 21-35) who reported using cocaine l-2 times per month provided informed consent to participate in this study. The Cocaine Effect Expectancy Questionnaire (CEEQ: Schafer and Brown, 1991) was used to assign subjects to one of two groups: negative or positive cocaine effect expectancies. To date, 20 subjects have returned for cocaine (0.9 mg/kg, i.n.) challenge and completed a series of visual analog scales and the Addiction Research Center Inventory (ARCI) at 15 min intervals for 3 h following cocaine administration. Analyses revealed a significant gender difference in CEEQ scores, with females reporting greater negative effect expectancies than males. Preliminary analyses also indicate that males with negative effect expectancies experience greater dysphoria following cocaine challenge compared to males with positive effect expectancies, as evidenced by their scores on the item ‘Bad’ and on the ‘LSD’ scale of the ARCI. Males with negative expectancies also report feeling more ‘Anxious’ and experience greater dysphoria than females with negative expectancies. These data suggest that for males, cognitive expectancies of drug effects more accurately reflect actual drug response than for females. Additionally, for males, negative effect expectancies appear to be associated with negative drug responses. Supported by Grants DA03994 and DA00343. 377 USERS,ABUSERS,ANDTHERHETORICOFNEEDLE EXCHANGEPOLICYDEBATES H. Lune, Medical and Health Research Association of New York City, NY The intent of this study is to trace the effect of contrasting definitions of drug users’ identities on policy development processes regarding needle exchange programs (NEPs) in the US, with particular attention to New York City. I hypothesize that competing positions on the role of needle exchange in drug policy stem from incompatible notions of the identities of drug users

s133

rather than simple disagreement over the outcomes of such policies. Whereas NEP supporters often view drug users as marginal citizens who need to be reintegrated into society, opponents are more likely to identify users as criminals and threats to social order who need to be monitored and controlled. While proponents and opponents of NEPs use similar terms, meaningful debate is thwarted by this incompatibility, I therefore examine the rhetoric invoked by those who either formulate or oppose current US policies on needle exchange, paying particular attention to the relationship between representations of drug users and justifications of predictive models. I draw upon qualitative analysis of the texts (N> 100) of drug law initiatives, speeches and public pronouncements of those who administer drug laws, and published statements by advocates on both sides of the needle exchange question from the invention of the form in 1984 to the present. The analysis is enhanced by in-depth interviews conducted with staff and volunteers at four NEPs in New York City. This work seeks to clarify existing debates on drug laws and harm reduction 378 INTERPERSONAL MALADJUSTMENT AS A PREDICTOROFMETHADONEMAINTAINEDMOTHERS'RESPONSE TO THE RELATIONAL PSYCHOTHERAPY MOTHERS' GROIJP S. Luthar and N. Suchman, Teachers College Columbia University, New York, NY, and Yale University School of Medicine, New Haven, CT In previous work, Luthar and Suchman (Relational Psychotherapy Mothers’ Group: A developmentally informed intervention for at-risk mothers. Development & Psychopathology, in press) reported results of a randomized clinical trial testing the efficacy of the Relational Psychotherapy Mothers’ Group (RPMG), a 24 week parenting intervention for methadone-maintained (MM) mothers. Compared with standard drug counseling (DC) alone, the RPMG supplement led to greater reduction in child maltreatment and improvement in parental involvement, with results largely sustained at 6-month follow-up. In this extension, we examined interpersonal maladjustment (IM) as a predictor of differential response to RPMG vs. DC. We predicted that, as IM increased, RPMG would be increasngly more effective than DC. Women in the sample were predominantly Caucasian (65%) low SES (70%‘), averaging 35 years of age (SD = 5) and 2 children (SD = 1) in their custody. The Social Adjustment Scale (Weissman & Bothwell, 1976) was used to measure IM. The Parent Acceptance-Rejection Questionnaire (Rohner, 1991) measured child maltreatment (CM>, and the Parent-Child Relationship Inventory (Gerard, 1994) measured 3 positive parenting (PP) do-

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Abstracts

mains (Involvement, Limit Setting, and Autonomy). In hierarchical regressions, moderate interaction (IM x Treatment) effects were found for CM (R- = 0.06) and all 3 PP domains (R_ = 0.05, 0.05, and 0.06) at posttreatment, and for CM (R_ = 0.06) and 1 PP domain (R- = 0.11) at follow-up. Plotted interactions confirmed predictions that, as IM increased, CM and PP improved for RPMG mothers and declined for DC mothers. Results indicate that (1) drug counseling alone is not a sufficient deterrent for negative parenting practices among interpersonally maladjusted mothers; (2) further examination of interpersonal interventions for populations known to be at risk for interpersonal dysfunction is warranted. Supported by NIDA Grants ROlDA11498 and P50DA0924 1 379

FENTANYL

PATCH FOR OPIOID

DETOXIFICATION

I. Maany, A. Soliman, V. Dhopesh, C. O’Brien, University of Pennsylvania/VAMC, Philadelphia, PA We conducted an open clinical trial to assess the clinical efficacy of fentanyl patch for out-patient heroin detox. Twelve male veterans, 26-50 years old, with DSM IV diagnosis of opioid dependence were detoxed. All were IV heroin abuser (4-10 bags/d). Subjects were referred for out-patient opioid detox, due to the lack of availability of in-patient beds. They all refused clonidine, but agreed to participate in 7 days detox, which involved application of fentanyl 1 patch for q 72 h. Those using 6 bags or less of heroin received Fentanyl patch 25 mcg/h, while heavy heroin abusers(6 bags or more daily) prescribed 50 mcg/h. UDS, severity of opioid withdrawal, and retention rate were used as the outcome measures. All subjects completed the outpatient detox within 7- 10 days. All received only 2-3 patches during the detox. All UDS were negative for heroin. The severity of the opioid withdrawal was low and tolerable specifically in GI system, sleep, and dysphoria. Based on this observation we are currently conducting a double blind study comparing the fentanyl patch efficacy against clonidine patch in an outpatient setting. Methods: Twenty opiate dependent patients will be detoxed on outpatient basis in a double blind study design. Each patient will be randomized to receive either fentanyl patch or clonidine patch for a period of 7-10 days by an addiction psychiatrist. The study will be conducted at an outpatient service, the Addiction Recovery unit (ARU) at Philadelphia Veterans Affairs Medical Center (PVAMC). Outcome measures: Objective scale: OOWS Subjective scale: SOWSQ, WOWS UDS measure Attendance/ retention measures Results: Will be presented at the conference. Background:

380 ASSESSING THE REINFORCING EFFECTS OF METHYLPHENIDATE IN CHILDREN DIAGNOSED WITH ADHD USINGACHOICEPROCEDURE

E.K. MacDonald and S.H. Kollins, Western Michigan University, Kalamazoo, MI The reinforcing effects of a drug are typically highly correlated with its potential for misuse and abuse. Methylphenidate (MPH), a stimulant commonly used to treat Attention Deficit Hyperactivity Disorder (ADHD) in children and adults has been shown to exert reinforcing effects in nonhumans and, under some conditions, in human participants. The present study was designed to further assess the reinforcing effects of MPH in children diagnosed with ADHD using a multiple drug free-choice procedure. Participants will include 6 children (ages 8-14) diagnosed with ADHD who are currently receiving MPH. The reinforcing effects of MPH will be assessed using a double-blind choice procedure, with 6 sampling sessions and 6 choice sessions. Subjective effects will be measured using several self-report questionnaires. Results will be discussed in terms of the relationship between the reinforcing and subjective effects of MPH and the treatment of ADHD. Also, we will discuss issues pertaining to the abuse potential of MPH. 381 ISSUESINTHEDESIGNOFA TION STUDY:THEPERSISTENT STUDY

LONG-TERMEVALUAEFFECTS OFTREATMENT

C.L. Macken, G. Moran, and K.P. Mulvey, Center for Substance Abuse Treatment, Rockville, MD The Persistent Effects of Treatment Study (PETS) is a multi-year evaluation of long-term treatment outcomes among recipients of publicly funded substance abuse treatment in various treatment modalities, geographic settings, and among certain target populations, such as women and adolescents. Funded by the Center for Substance Abuse Treatment (CSAT), PETS includes studies that seek to understand the long-term trajectories in client outcomes over multiple data collection points rather than short-term outcomes after a single episode of treatment. PETS is unique in its approach in that it augments existing services research efforts (also funded by CSAT) and focuses upon outcomes two or more years after treatment has ended. While this approach presents economies by funding existing studies rather than mounting new efforts, it also poses interesting challenges in terms of evaluating internal and external validity and the ultimate effect that these have upon the resulting data. This paper discusses two of the studies, one currently underway in Cuyahoga County, Ohio, and one in Chicago, Illinois. The design of each

Abstracts

study will be described to illustrate how each controls threats to validity. Suggestions will be made regarding appropriate mechanisms to control for differences between the study designs to allow for comparative analysis. 382

OUTCOMES

OF

INDIVIDUALS

LEMS:

AN

ANALYSIS

OF

DRUG

USE

SEVERITY

AND

THE

WITH

AOD

RELATIONSHIP

TREATMENT

PROB-

BETWEEN

MODALITY

L. MacPherson, K.C. Kirby, A.T. McLellan, J. McNellis, and H. Eshelman, Treatment Research Institute at the University of Pennsylvania, and Temple University, Philadelphia, PA In the current climate of reductions in substance abuse treatment costs, there has been a shift from residential to outpatient care. We are examining intake and 6 month follow-up ASI results from two groups of an adult substance abusing population: those individuals with low drug use severity (25th quartile) and those with high drug use severity (75th quartile). These two groups were then further divided, in terms of treatment placement: high severity/residential treatment, high severity/outpatient treatment, low severity/residential treatment, and low severity/outpatient treatment. It was expected that individuals with a high drug severity who attended residential treatment would show greater improvement than those who attended outpatient treatment. However, it was expected that there would be no difference in improvement between those individuals with low severity of AOD problems who attended outpatient treatment and those who attended residential treatment. Repeated measures analyses showed, as hypothesized, that individuals with high drug use severity who had attended residential treatment demonstrated better outcomes (P = 0.00) at follow-up than those who had attended outpatient treatment. Also, there were no differences in outcome (P = 0.60) among those with low drug use severity, regardless of treatment. Other outcomes are also analyzed, and length of stay is examined. Results seem to indicate a greater necessity to match an individual with more severe drug and psychiatric problems than an individual with less severe drug and psychiatric problems to the appropriate treatment. 383

ASSOCIATION

DOPAMINE LAR

EVIDENCE

OF

PSYCHOSTIMULANTS

TRANSPORTER: FOR

MULTIPLE

BIOCHEMICAL BINDING

ON AND

THE

MOLECU-

DOMAINS

B.K. Madras, M.A. Fahey, P.C. Meltzer, and G.M. Miller, Harvard Medical School, New England Regional Primate Research Center, Southborough, and Organix, Inc., Woburn, MA

s135

An unfulfilled challenge in cocaine medications development is the design of a cocaine antagonist that blocks cocaine binding to the dopamine transporter while permitting the transport of dopamine. To develop compounds that fulfill this requirement, it is instructive to determine whether all transport inhibitors and dopamine bind to similar domains on the transporter. Accumulating biochemical and molecular evidence suggests that transport inhibitors and substrates may associate differently with the dopamine transporter: (1) If the transporter is radiolabeled with tropanes (e.g. cocaine), the relative potencies of cocaine congeners for binding to these sites is higher than if the transporter is labeled with structurally dissimilar drugs; (2) An aspartate counterion on the transporter appears essential for binding of monoamine inhibitors, but it is not necessary for the binding of a non-amine, a transport inhibitor devoid of an amine nitrogen. In hDAT-HEK cells, dopamine transporter affinity of the non-amine [3H]Tropoxene (IC50: 1 nM) was comparable to that of the monoamine, [3H]WIN 35428 (CFT, IC50: 8 nM), but a. mutant form of the dopamine transporter that lacked a putative aspartic acid counterion for the amine nitrogen, retained high affinity binding of [3H]Tropoxene but not [3H]WIN 35428; (3) While investigating whether cocaine binding and dopamine transport sites are distinguishable, we discovered a compound that reduced [3H]cocaine binding but affected [3H]dopamine transport minimally. In summary, dopamine transport inhibitors of various chemical classes and dopamine appear to bind differently to the transporter, findings that support the feasibility of developing an antagonist of cocaine at monoamine transporters. 384

A

FACILE

SYNTHETIC

ROUTE

TO

4-HYDROXYIN-

DOLOMORPHINANS

D.Y. Maeda and A. Coop, University Baltimore, MD

of Maryland,

In an effort to develop selective delta opioid antagonists based on indolomorphinans, Coop et al. (J. Med. Chem. 1999, 42, 1673-1679) prepared 4-hydroxy analogues of antagonists related to naltrindole. From this study, the analog AC 673 exhibited excellent delta opioid affinity and selectivity (AKi = 7 nM; u/A 1900). To further study the 4-hydroxy analogues of related indolomorphinans, a milder and more facile synthetic route was developed which directly opens the 4,5-epoxy bridge of naltrindole and oxycodone indole. The reaction (conditions used to effect this ring opening included NaB.H, in trifluoroacetic acid and catalytic transfer hydrogenation in an acidic environment. Of the two methods, catalytic transfer hydrogenation was more effici’ent in opening the 4,5-epoxy bridge. This method

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S136

provides a rapid and direct route to the ring-opened indolomorphinans, and represents a methodology which is useful for the development of indolomorphinan analogues. 385

DUAL RECOVERY ONE-YEARFOLLOW-UP

SELF-HELP

PARTICIPATION:

S. Magura, A. Laudet, H. Vogel, and E. Knight, National Development and Research Institutes, Inc., New York and Mental Health Empowerment Project, Inc., Albany, NY Presents follow-up data (N= 278) from an ongoing longitudinal study of the effectiveness of self-help for dually-diagnosed persons. Ss are members of Double Trouble in Recovery (DTR), a dual-recovery self-help program, recruited at 25 meeting sites in NYC. Ss are mostly members of under-served minority groups with long histories of substance abuse and mental health disorders. At baseline, most Ss attended outpatient treatment (for drug use, mental health or dual-diagnosis-93%) and took psychotropic medications (92%). Ss were interviewed 12 months after baseline; 70% were still attending DTR; 75% also attended traditional self-help groups (e.g. AA). Ss. who reported more mental health symptoms and those who reported less substance use at baseline were significantly more likely to continue attending DTR at follow-up. Self-reported mental health in the month preceding the follow-up interview was significantly better than at baseline, and substance use decreased significantly: 28% in the past year at follow-up, compared to 42% at baseline (P = 0.00). There was a significant association between longer DTR attendance and lower substance use: (1) total clean time was significantly correlated with total length of DTR attendance and (2) number of months of DTR attendance in the past year with no substance use in that period. Substance use was not significantly associated with outpatient treatment enrollment or attendance at other 12-step fellowship meetings. Neither formal treatment nor DTR attendance was significantly associated with mental health status. However, DTR attendance in the past year was significantly associated with better medication compliance, a correlate of better mental health. Overall, results indicate that dual-recovery self-help group succeed in engaging and retaining members over time; further, present data show that continued attendance at such meetings is associated with lower levels of substance use and better compliance with medication. ACKNOWLEDGMENTS: Funded by NIDA Grant ROl DA11240.

386 PREDICTORS OFDRUG CENTSFOLLOWINGTREATMENT

RELAPSE AMONG

ADOLES-

S.A. Maisto, J.R. Cornelius, N.K. Pollock, C.S. Martin, D.B. Clark, K.G. Lynch, and R.T. Ammerman, University of Pittsburgh, Pittsburgh Adolescent Alcohol Research Center, Pittsburgh, PA Relapse following alcohol and drug treatment in adolescents has received little research attention. The purpose of this study was to investigate the course predictors of relapse to drug use among adolescents following addictions treatment. It was predicted that both first drug use and relapse to drug use would typically occur within a short period of time following treatment, and that the presence of major depressive disorder would predict the occurrence of relapse. Subjects were 67 boys and girls ages 14-18 recruited from outpatient drug and alcohol treatment programs. Subjects were assessed while still in or shortly after completing treatment. Their daily substance use, continuing treatment participation, and relapse precipitants were then assessed monthly by telephone for 6 months. The total sample was included in analyses of first drug use, and individuals with at least 2 months of follow-up data were included in the relapse analyses. Survival functions for first drug use (n = 62) showed that 41 individuals reported at least one occasion of drug use within 6 months; the median time to first use was 0.8 months. A drug use relapse (defined as any use bounded by 4 days of abstinence from drugs; n = 41) occurred in 24 subjects, and the median time to first relapse was 1.33 months. No gender differences were found in the survival curves for first use or relapse. However, the presence of lifetime major depression increased the likelihood of relapse. The results were interpreted as supporting the implication for matching drug use patterns to drug treatment in adolescents. 387 A COMPARISONOFTHEEFFECTSOFALPRAZOLAM AND GENDER ON FOODINTAKE IN YOUNG AND SENIOR ADULTS

A.P. Makris, T.H. Kelly, and J.F. Wilson, Graduate Center for Nutritional Sciences and University of Kentucky, Lexington, KY This study evaluated the influence of gender and age on the effects of alprazolam on food intake. Following written consent and both medical and psychological evaluations, 6 female and 7 male healthy adults between the ages of 20 and 45 and 8 female and 6 male healthy adults between the ages of 46 and 6.5, blind to the study drug, participated on 3 consecutive days per week over 8 consecutive weeks. Three doses of alprazolam (0,0.4, and 0.8 mg/70 kg) were administered orally 1 day each week in random order. On test days, subjects consumed

Abstracts

a standard meal at 17:30 h, received drug at l&30 h, completed performance tasks and visual-analog ratings of drug effect, and ordered snacks from a computer generated list of assorted food items at 22:45 h. Snacks were consumed between 23:00 and 23~30 h. Breakfast was ordered from the list shortly upon waking. Study participants recorded food intake in a diary while they were away from the research laboratory. Data were analyzed using mixed model repeated measures ANOVA, with gender and age as between subject factors, and dose and week as within subject factors. Alprazolam did not significantly alter total kilocalorie intake during snack, breakfast, or the period between breakfast and dinner while participants were away from the residential laboratory. Although intake of snack protein, fat, and carbohydrate increased following drug administration, the’ effect approached significance only for carbohydrate. Both doses of alprazolam significantly increased snack sugar intake. Alprazolam did not significantly alter consumption of macronutrients the morning or afternoon following drug administration. There were no significant differences in food intake following drug administration as a function of age or gender. Alprazolam had no effect on ratings of hunger. These findings suggest that (1) alprazolam has minimal to no effects on hunger and food intake during scheduled eating occasions; (2) the effects of alprazolam are similar in males and females, despite differences in baseline intake; and (3) age does not influence the effects of alprazolam on food intake. 388

SYSTEMIC

AMLODIPINE

AND

CEREBROVASCULAR

IN COCAINE-DEPENDENT

EFFECTS

OF

PATIENTS

R. Malcolm, J. Herron, J. Liao, P. Halushka, and K.T. Brad, Medical University of South Carolina, Charleston, SC Imaging techniques have consistently demonstrated cerebral ischemia in cocaine abusers. Neurocognitive dysfunction has also been found in some populations of heavy cocaine users. We reasoned that amlodipine, an L-type calcium channel antagonist and potent systemic and cerebrovasodilator will produce vasodilatation in cocaine dependent patients as measured by serial blood pressures. We studied DSM IV defined treatment seeking cocaine dependent patients (N = 139) participating in a 12 week trial of cognitive behavior therapy plus amlodipine 5 or 10 mg or placebo. We excluded the patients with: any drug dependence (other than nicotine and cocaine), and major axis I psychiatric disorders. Patients with hypertension, neurologic disease including migraine, trauma and stroke were also excluded. Blood pressures were measured over the course of the study and analyzed using a mixed regression model. The population was 60% African-American, 40% Caucasian, 18% female, mean

s137

age 33, mean years of cocaine use 8.5, days of cocaine use in the last month was 9. Patients on amlodipine had all measures of blood pressure significantly lower than the placebo group. The seated diastolic pressures averaged 6.8 mmHg lower in the amlodipine group compared to the placebo group (F( 1,496) = 3.96, P-value = 0.047) after adjusting for age, gender and initial blood pressure level. Gender and race had no effect. To evaluate side effects, we fitted a Poisson regression. The incidence rate of headache in the placebo group was 2.7 times that in the amlodipine group (x = 8.21, P-value = 0.004). Amlodipine produced significant systemic vasodilatation in normotensive cocaine patients. Headache frequency was reduced in amlodipine patients; possibly blocking cocaine induced vascular headaches. The effects of amlodipine on cerebral ischemia and neurocognitive functions are under study. 389 VOLVED CROS,E

THE

CHOLINERGIC IN

THE

ON NICOTINE

S. Mandillo ford, MA

AND

ENHANCING

OPIOID EFFECTS

ANTINOCICEPTION

SYSTEMS OF

CHRONIC

IN FEMALE

ARE

INSU-

RATS

and R.B. Kanarek, Tufts University, Med-

Chronic sucrose intake enhances the antinociceptive effect of nicotine in female rats. The objective of this study was to evaluate what neurotransmitter systems are involved in this effect. Female Long Evans rats were given continuous access to water and chow (CONTROL). Half of these rats were also given a 32% (w/v) sucrose solution (SUCROSE). After 3 weeks, the animals were injected with nicotine (1 mg/kg, s.c.) preceded by administration of the nicotinic and opioid receptor antagonists mecamylamine (1 mg/kg s.c.) and naltrexone (0.3-3 mg/kg s.c.) and tested using the tail flick test. The rats that had access to sucrose showed significantly higher levels of nicotine-induced antinociception than animals fed chow only. The antinociceptive effect of nicotine was blocked by mecamylamine in both diet groups. Naltrexone reduced the effect of nicotine in the sucrose group only at the lower dose and actually potentiated nicotine antinociception in the control group in a dose dependent fashion. These results show that the enhancing effect of a palatable solution on the antinociceptive properties of nicotine in rats is mediated by the cholinergic and opioid systems. We also speculate that other systems are probably involved (i.e. serotoninergic, noradrenergic). It can be hypothesized that a similar mechanism may be involved in the increase of sweet food intake observed in humans during withdrawal from nicotine. This study was supported by Grant # ROl DA04132 from NIDA.

Sl38

390

THERAPEUTIC POTENTIAL RECEPTOR ANTAGONISM IN ALCOHOLISM

Abstracts

OF CANNABINOID THE TREATMENT

CBi OF

R.S. Mansbach, C.C. Rovetti, R.E. O’Connor, P.A. Iredale, KM. Ward, Central Research Division, Pfizer Inc., Groton, CT The discovery and characterization of cannabinoid receptors and, in particular, the identification of the CBl-selective antagonist SR 141716A (SR), has facilitated many studies that have helped to reveal behavioral processes that may be governed or modified by endogenous cannabinoid tone. Recent data has suggested that CBl receptors can be regulated by sustained exposure to ethanol, and that ethanol drinking is decreased by treatment with SR. In order to further evaluate the promise of CBl antagonism for the treatment of alcoholism, the present study had three purposes: (1) to examine effects of SR in rats voluntarily consuming pharmacologically significant doses of ethanol; (2) to evaluate the effects of acute combinations of SR and ethanol on a variety of neurobehavioral functions; and (3) to further characterize effects of alcohol treatment on CBl receptor populations in brain. In rats with choice between 10% ethanol and water, SR (1.75.6 mg/kg) significantly decreased ethanol consumption without decreasing concurrent water consumption. In mice treated with ethanol-SR combinations, there were few interactions on several indices of behavioral and physiological function as measured by the functional observational battery (FOB). Finally, in rats with exclusive access to 10% ethanol for 2 weeks, there were no changes in Bmax for CBl receptors in cerebellum or hippocampus. Characterization of additional brain regions and ethanol regimens is underway. Overall, these data support suggestions that CBl antagonism may have a selective effect on alcohol drinking, perhaps by modifying ethanol’s effect on mesolimbic dopamine function. 391 EFFECTS OF COCAINE SELF-ADMINISTRATION PLASMACORTICOSTERONEANDPROLACTININRATS

ON

J.R. Mantsch, S.D. Schlussman, A. Ho, and M.J. Kreek, The Rockefeller University, New York, NY The effects of i.v. cocaine self-administration under ‘naturalistic’ conditions on plasma corticosterone (CORT) and prolactin (PRL) were investigated in male Sprague-Dawley rats surgically implanted with chronic indwelling jugular catheters. Following the determination of plasma CORT and PRL under basal conditions, rats were allowed to self-administer cocaine by pressing a response lever under a continuous fixed-ratio 1 schedule of reinforcement during five consecutive daily unre-

stricted 10 h sessions. Plasma CORT was significantly increased and plasma PRL was significantly reduced following each of the five self-administration sessions. Effects of cocaine on CORT were intake-dependent, as demonstrated by significant positive correlations between post-session CORT and total cocaine intake within the preceding sessions. Effects of cocaine on PRL were also intake dependent, but only on the first day of testing, at which time a significant negative correlation between intake and post-session PRL was observed. Significant correlations between PRL and cocaine intake were not observed during any subsequent session. Alterations in neuroendocrine homeostasis emerged over time. Reductions in pre-session CORT values, as well as a blunting of the diurnal CORT peak, were observed. Additionally, plasma PRL was significantly attenuated when measured 4 days after the termination of cocaine self-administration. Disturbances in neuroendocrine homeostasis as a result of cocaine self-administration may contribute to the development of cocaine dependence and the high susceptibility of abstinent cocaine users to relapse. 392 FAMILY NETWORK EFFICACY AND DRUG TREATMENTOUTCOMES:EVIDENCEFROMLOSANGELES

ABUSE

E.A. Marcelli, R. Fiorentine, Drug Abuse Research Center, and Lewis Center for Regional Policy Analysis, UCLA, Los Angeles, CA We investigate the influence of family network quality on drug abuse treatment completion and outcome among 356 clients aged 18-55 who entered one of Los Angeles County’s 25 outpatient substance abuse treatment facilities between July and September 1994 and who completed an 8 month follow-up survey. Controlling for treatment involvement, individual attitudes toward addiction and recovery, drug and alcohol use, criminal justice system involvement, employment-related factors, extra-familial network quality, and health status, results show that familial network quality estimated using the Family Environmental Scale developed by Moos and Moos (1994) - has a positive effect on both drug abuse treatment completion (drop out, complete, or continue) and outcome (abstinence or relapse). Treatment and policy implications of these findings are discussed.393 BREAKING THE CYCLE OF DRUGS AND CRIME IN THREE U.S. CITIES

D.B. Marlowe, J.C. Merrill, A.V. Harrell, D.S. Festinger, P.A. Lee, J. McNellis, and A.T. McLellan, Treatment Research Institute at the University of Pennsylvania, Philadelphia, PA, and The Urban Institute, Washington, DC

Abstracts

‘Breaking the Cycle’ (BTC) adult demonstration projects were implemented in Birmingham, AL, Tacoma, WA, and Jacksonville, FL. BTC is designed to divert many substance-abusing felons to pretrial community supervision with treatment, case management, and urinalysis monitoring. Comparison samples were recruited in each city prior to initiation of BTC, and all subjects are being followed 9 months post-arrest. Inclusion criteria are: (1) > 18 years old; (2) charged with a felony (not limited to drug offenses); (3) resident of the target County; and (4) evidence of substance abuse via drug charge, positive UA, or self-report. Baseline data from all three cities (Birmingham N= 566, Tacoma N = 407, Jacksonville N = 527) revealed high rates of positive urinalyses at arrest (70-80%), significant criminal and substance use histories, and significant psychosocial impairments. Rates of amphetamine abuse were substantially higher in Tacoma (39% by UA, 59% by self-report). In Birmingham, where outcome data are now available, BTC participants had significantly less severe substance abuse problems, criminal histories, and psychosocial impairments at baseline than comparison subjects. All subjects in Birmingham reported substantial improvements at 9 month follow-up (70% follow-up rate), irrespective of service utilization or exposure to BTC. There were few significant differences in outcomes when controlling for these large baseline differences. These results confirm high rates of substance abuse and related dysfunction among felony offenders. It appears that BTC in Birmingham may not have reached a representative sample of these targeted offenders. Moreover, regression to the mean or a perceived demand characteristic to under-report problems at follow-up may have masked possible effects of the BTC intervention. 394

NINE-YEAR POSTNATAL NEUROPSYCHOLOGICAL PROFILES OF CHILDREN PRENATALLY EXPOSED TO COCAINE

P.R. Marques, E. Danseco, D. Branch, J. Pokorni, H. Kirk, L. Teti, and T. Long, Public Services Research Institute, Pacific Institute for Research and Evaluation, Landover, MD, and Georgetown University Child Development Center, Washington, DC There continues to be uncertainty about how much, if any, variance in the developmental trajectory of children with prenatal cocaine exposure can be attributed to that exposure. This study has been re-contacting families of 60 children on whom quantitative cocaine exposure information was compiled during an earlier NIDA supported perinatal investigation. A cohort of non-exposed contrast children are also undergoing concurrent evaluation. Children in both samples were born in Maryland suburbs adjacent to Washington DC live

s139

in the same neighborhoods and go to the same schools. Mothers of the groups differ strongiy on prior drug use and on Millon Axis II scales but not on SES, income, employment and life stress measures. (However, some mother measures are not yet calculated and sample size is still small). Children in the exposed cohort as a group were 36% low birth weight, 97% of the mothers were cocaine positive at delivery and 92% of the infants had positive hair cocaine. The contrast non-exposed sample has been formed retrospectively. As of mid year 2000 data from only one fourth of the age 9 assessments is compl.ete so no conclusions are yet possible. Child measures include: WISC, WAIT, CELF-3, Connors, GATSB, CBCL, several visual-motor tasks and physical development. Mother measures include: SES, ASI, KBIT, Millon MCMI-II, BDI, HOME, and several measures of parenting beliefs and life stresses. Two categories of outcomes are reported: (1) correlation of test scores with exposure (mother hair, child hair, mother urine, mother report) within prenatal cocaine exposed group; and (2) score differences between exposed and non-exposed cohorts. Among 31 child outcome measures calculated so far, correlation stronger than - 0.5 with exposure levels was found only for WISC verbal comprehension. Effect size differences (Cohen = s.d. > 0.9) of interest between cohorts were only j?ound for WISC verbal comprehension also. Exposed children show no remarkable trends toward lower functioning than the non-exposed. Supported Field-Initiated Award Dept Education H324C980092. 395 ANATOMY OF RISK: A QUANTITATIVE INVESTIGATION INTO INJECTION DRUG USERS' RISK ATTITUDES AND PERCEPTIONS L.A. Marsch and W.K. Bickel, University of Vermont, Burlington, VT We examined the multivariate nature of injection drug users’ (or IDUs) risk perceptions and attitudes. Fifty opioid-dependent IDUs in outpatient buprenorphine treatment and 50 control individuals, matched to the IDUs on employment status, education, gender, age, SES and IQ participated in the study. Participants completed a series of measures based on a well-established methodology that uses psychometric scaling procedures to provide quantitative representations of risk attitudes and perceptions about 53 risk-laden items (activities, substances, technologies and diseases). Results indicated that IDUs’ and controls’ risk perceptions were highly correlated on most items assessed; however, IDUs perceived several items, such as alcohol, handguns, unprotected sex, hepatitis, HIV and prescription drugs as markedly more risky than controls. IDUs wanted significantly reduced regulation of prescription drugs, heroin, Valium, and barbiturates relative to con-

Abstracts

s140

trols. IDUs also perceived themselves, as well as residents in the state, heroin users in the state and U.S. residents as a whole as having much greater risk of contracting hepatitis and HIV than controls. Factor analyses conducted to understand how various risk characteristics related to one another revealed three factors accounting for about 80% of the variance in risk perception across both groups: (1) the number of persons affected by a risk item; (2) the extent to which the risks are known or unknown; and (3) the extent to which the risks are immediate or delayed. However, risk perceptions for IDUs were more strongly influenced by: (1) the extent to which they were personally affected by a risk item; and (2) whether the risk associated with an item was immediate or delayed. Understanding the risk perceptions of IDUs may be of considerable utility in understanding their risk behavior. 396

DSM-IV

DERS

IN

CRITERIA

ADOLESCENT

FOR

SUBSTANCE

USE

DISOR-

DRINKERS

C. Martin, S. Maisto, N. Pollock, T. Chung, and J. Cornelius, Pittsburgh Adolescent Alcohol Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA This study characterized the performance and validity of DSM-IV diagnostic criteria for Substance Use Disorders (SUDS) in adolescents for 7 drug classes: cannabis, hallucinogens, inhalants, cocaine, opiates, sedatives and stimulants. Subjects were 503 male and female regular drinkers age 14-18 who were recruited from addictions treatment (n = 297) and community sources (n = 206). SUDS were diagnosed using a modified version of the SCID, and lifetime patterns of drug use were assessed with a structured interview. The rate of drug use on 5 or more lifetime occasions was 87% for cannabis and 14-32X for other drugs. The proportion of lifetime SUDS among 5 + users ranged from 70% for cannabis to 29% for sedatives. Adolescents with dependence, abuse, and no diagnosis for a drug class tended to differ in lifetime and current use patterns for that drug. Similar to adolescent alcohol disorders, abuse was less common than dependence for cannabis (abuse to dependence ratio = 0.5:1) and cocaine (0.7:1). In contrast, abuse was far more common than dependence for other drugs (abuse to dependence ratios ranged from 3.1:1 to 6.3:1). For all drugs, the most common criterion was the abuse symptom of frequent intoxication leading to a failure to fulfill major role obligations. In contrast, the prevalence of tolerance relative to other symptoms varied widely across drugs. Among adolescents, the DSM-IV criteria for SUDS show some validity but perform differently across drugs.

397

THE

GEOGRAPHIC

PHETAMINE-

AND

CHARGES

IN

SPATIAL

DISTRIBUTION

OF

COCAINE-RELATED

CALIFORNIA

INTERDEPENDENCE

METHAM-

HOSPITAL

ZIP

CODES:

AND

GENDER

DIS-

EFFECTS

OF

J. Martin and P. Gruenewald, Prevention Research Center, Pacific Institute for Research & Evaluation, Berkeley, CA Determinants of geographic variation in methamphetamine- and cocaine-related hospital inpatient discharges in California are studied, taking into account the lack of independence among the geographic units of analysis. Hypotheses: (1) Significant correlation of error (spatial autocorrelation) exists between contiguous zip codes in predictive models, leading to biased estimates; (2) After correcting for such spatial correlations, there are significant differences in the geographic distribution of methamphetamine-related hospital discharges; (3) This distribution is significantly different from that of cocaine-related hospital discharges; (4) The distributions of both methamphetamine and cocaine-related hospital discharges are significantly different for males and females. Procedures: Analyses were based on hospital inpatient discharge data from residents of 766 zip codes, selected to maximize contrast between urban and rural areas. Statistical Analyses: S3, a software package designed for spatial statistical analyses, was used to confirm the existence of spatial autocorrelation in the data, correct for it, and produce GLS estimates from regression models. Re.wZts: Spatially autocorrelated error was found to exist. The rate of methamphetamineand cocaine-related discharges, after correcting for spatial autocorrelation, was 4.6 and 15.7 per 10 000 population, respectively. Statistically significant differences in geographic distributions of both drugs were observed, suggesting the presence of factors not accounted for by population density alone. Overall, the ratio of male to female discharges was 2.0 for methamphetamines and 1.5 for cocaine. Again, significant differences in the geographic distribution of these ratios were observed. Importance of Findings: The current study demonstrates that the application of suitable geostatistical methods to surveillance data can account for problems inherent in geographic analyses and lead future research toward a better understanding of the etiology of illicit drug use. 398

THE

EFFECTS

OF

COCAINE,

CAINE/HEROIN

COMBINATIONS

TAINED

A SHOCK-TITRATION

UNDER

HEROIN, ON

RESPONDING

AND

coMAIN-

PROCEDURE

T.J. Martin, G.M. Sizemore, D.G. Cannon, and J.E. Smith, Wake Forest University School of Medicine, Winston-Salem, NC

s141

Abstracts

Although investigations of the effects of opiates on the shock level maintained under shock titration procedures (procedures in which shock intensity increases as a function of time and in which responding serves to lower the shock intensity) are relatively common, utilization of drugs of other classes are uncommon. In the experiment reported here, Fischer 344 rats were exposed to a procedure in which foot-shock intensity increased every 15 s. Completion of a fixed-ratio (FR) 5 schedule resulted in the termination of shock for 15 s, at the end of which shock was resumed at the level below that which was occurring when the escape requirement was met. Shock intensity could range from 0.01-1.0 ma. Under non-drug conditions subjects allowed the shock intensity to rise to between 0.3 and 0.6 ma and then maintained it at these levels for the duration of the session. Cocaine (10.0-42.0 mg/kg) tended to decrease shock level in a dose dependent fashion (3 of 5 rats) whereas heroin (1.0-4.2 mg/kg) tended to increase it. Heroin administration could sometimes eliminate lever-pressing at doses which, at other times, produced only small increases in shock level. For both heroin and cocaine the changes in shock level produced by moderate doses were not accompanied by substantial changes in response rate. The effects of cocaine/heroin combinations were complex; high doses of cocaine mixed with low doses of heroin tended to produce decreases in shock level even in the subjects where cocaine alone did not. High doses of cocaine mixed with high doses of heroin tended to produce no effect on shock level for subjects where the doses produced decreases and increases when administered separately. Supported in part by NINDS grant 38231. 399 ONSET AND

DRUG IN

USE, EARLY

AGE-MATCHED

IMPULSIVITY, AND

AND

EARLY

MID-ADOLESCENTS PEDIATRIC

PUBERTAL WITH

ADHD

CONTROLS

C.A. Martin, D.B. Broglia, H. Omar, T. Past, K. Himelreich, T. Kelly, and C. Leukefeld, The Center for Drug and Alcohol Research, University of Kentucky, Lexington, KY This study examined the relationship between drug use, levels of impulsivity, and early pubertal onset in early and middle adolescent males and females with Attention Deficit Hyperactivity Disorder (ADHD) (n = 64) and age-matched controls (n = 98). Impulsivity was measured using the Sensation Seeking Scale for Children (SSSC) as well as a DSM-IV based self-report questionnaire assessing ADHD, Oppositional Defiant Disorder (ODD), and Conduct Disorder (CD). Puberty was measured using a modified Pubertal Development Scale. Self-reports of nicotine, alcohol, and marijuana use were also obtained. Males endorsed more ADHD

symptoms and items on the Thrill and Adventure Seeking subscale of the SSSC than females and ADHD youth scored higher on the ADHD and ODD scales than age-matched controls. Cigarette, smokeless tobacco, and marijuana use correlated with ODD and CD symptoms, and Sensation Seeking. Sensation Seeking correlated with alcohol use (P < 0.01). For males, early pubertal onset correlated with cigarette and alcohol use and Sensation Seeking (P < 0.01). For females, early pubertal onset was associated with higher Sensation Seeking (P < 0.05). The DSM-IV, SSSC, and drug use self-report measures were easy to use in pediatric and psychiatric clinic settings and appeared to identify variables in youth at greatest risk for drug use in early and middle adolescence. 400 PAMINE TUM

PET

IMAGING

RELEASE

OF IN

THE

AMPHETAMINE-INDUCED VENTRAL

AND

DORSAL

DOSTRIA-

IN HUMANS

D. Martinez, D.R. Hwang, A. Broft, 0. Mawlawi, N. Simpson, K. Ngo, J. Pidcock, R. Van Heertum, and M. Laruelle, Columbia University, New York, NY While animal studies suggest that chronic psychostimulant Iexposure is associated with an increased amphetamine-induced DA release in the striatum, this has not been replicated in human studies. However, the respective contribution of meso-limbic versus nigro-striatal DA systems has not been investigated. The objective of this study was to assess amphetamine-induced DA release in subregions of the striatum (dorsal caudate, DC, dorsal putamen, DP, and ventral striatum, VST), using a high resolution PET camera and a dual bolus plus constant infusion with [l lC]raclopride. First, six normal controls were scanned twice and given amphetamine (0.3 mg/kg i.v.) two min prior to the second injection. Amphetamine resulted in decreased V3” in all subregions of the striatum. The amphetamine effect was significantly smaller in DC ( - 7 _+ 5%) compared to DP (-16’f5%)andVST(-18f9%). Supported by NIMH and NIDA.

1 ADOLESCENT SERVICE UTILIZATION IN RELATION TOSEVERITYOFSUBSTANCEINVOLVEMENT 401 FROMCRIMINALITYTOHEALTH:THEFAMILYEFFECTINDRUGTREATMENTFORUSERSWITHCRIMINAL JUSTICE HISTORY P. Mateu-Gelabert, Medical and Health Research Association of New York City, Inc., NY

Abstracts

s142

This study, an evaluation of La Bodega de La Familia, examines the effects that family involvement has on intervention for drug users with a criminal history. La Bodega is a demonstration project on Manhattan’s Lower East Side that seeks to reduce relapse and criminal involvement of drug users by providing support to them and their families. The qualitative evaluation of La Bodega involves a component quasi-experimental research design that compares seven drug users (African-American and Latino) and their families served by La Bodega with a similar sample not served by the program. There were two separate waves of interviews one prior to intervention and a second, six to eight month later. In both waves, a 1 h tape-recorded interview was conducted separately with the drug users and with a family member attending the family case management sessions at La Bodega. Similarly in the comparison sample the drug users and a supportive family member were interviewed before and after they attended a treatment program without Bodega’ family component. This study examines risk and protective factors that family provides in drug use and crime involvement. It also explores the distinct role of different members within a family: some are triggers for drug use (e.g. as co-user) whereas others function as a deterrent (e.g. encouraging treatment). The study will also document changes in these roles over time.

402

OPIOID

BRAIN

AFTER

PEPTIDE ‘BINGE’

MRNA NICOTINE

LEVELS

IN

THE

RAT

ADMINISTRATION

A.M. Mathieu-Kia, S.D. Schulssman, V. Yuferov, A. Ho, and M.J. Kreek, The Rockefeller University, New York, NY We have previously shown that opioid peptide gene expression was differentially altered after ‘binge’ pattern administration of cocaine. In this study, we have investigated the subacute effect of another psychostimulant, nicotine, on mRNAs encoding preproenkephalin (ppEnk), preprodynorphin (ppDyn) and preproopioimelanocortin (POMC) in various brain regions. Young adult male F344 rats received 3 daily intraperitoneal injections of nicotine (0.4 mg/kg) 1 h apart beginning at the start of their light cycle for 3 days. Elevated plasma levels of nicotine and cotinine were achieved. Levels of mRNA from brain extracts were quantified by a RNase protection/solution hybridization assay. After nicotine administration, ppEnk and ppDyn mRNAs remained unchanged in the dorsal striatum, nucleus accumbens, amygdala, hippocampus, frontal cortex and the hypothalamus. Levels of ppEnk mRNA were also unaltered in the anterior olfactory complex and the cerebellum. Levels of POMC mRNA in the hypothalamus, the anterior pituitary and the neurointermediate pituitary as well as circulating levels

of plasma ACTH and corticosterone were also unchanged by this drug regimen. Thus, in terms of effect on opioid peptide gene regulation and on neuroendocrine function, nicotine in subacute treatment can be clearly distinguished from cocaine. Supported by NIH-DA-PSO-05 130 and NIH-DAK0500049.

403

EVALUATION

COCAINE-INDUCED

OF

RIMCAZOLE

BEHAVIORAL

ANALOGS

AGAINST

TOXICITY

R.R. Matsumoto, K. Hewett, J. Cao, and A.H. Newman, University of Oklahoma Health Sciences Center, Oklahoma City, OK, and NIDA-IRP, Baltimore, MD Although rimcazole attenuates cocaine-induced locomotor activity and sensitization, it is unclear whether this effect is attributable to actions through the dopamine transporter or sigma receptor. To further characterize the mechanism(s) underlying the anti-cocaine actions of this compound, rimcazole and three analogs (SH3/24, SH2/21, SHl/57) with a range of affinities for the dopamine transporter and sigma receptor were tested for their ability to attenuate cocaine-induced convulsions and lethality. Based on competition binding studies, the rank order of the compounds at the dopamine transporter, going from highest to lowest affinity, is: SH3/24 > rimcazole > SH2/21 > SH1/57. The rank order of binding of the compounds at sigma receptors is: SH3/24 > SH2/21 > SH1/57 > rimcazole. In behavioral studies, male Swiss Webster mice were pre-treated with rimcazole or one of its analogs (0.1-30 mg/kg, i.p.), then challenged 15 min later with either an ED/LD97 convulsive (60 mg/kg, i.p.) or lethal (125 mg/kg, i.p.) dose of cocaine. When the compounds were ranked according to their peak protective effect, there was a significant correlation between their anticonvulsant actions and their affinity for sigma receptors, but not the dopamine transporter. Comparisons involving the lethal endpoint are in progress. The present data are consistent with earlier reports that sigma receptors are involved in the behavioral actions of cocaine.

404 OR

ARE

PUPS

THE

REINFORCING

GREATER

TO

MATERNAL

PROPERTIES

OF COCAINE

DAMS?

B.J. Mattson, 0. Norstrom, S. Williams, X.X. Guo, J.S. Rosenblatt, and J.I. Morrell, Rutgers University, Newark, NJ The use of cocaine by pregnant women remains an important societal problem, as there are correlations between cocaine abuse and maternal neglect. Maternal behavior in the rat is well characterized and provides a basis for determining the neural substrates of cocaine’s effects on maternal behavior in a model with minimal

Abstracts

confounds. Previous work in our laboratory has demonstrated that systemic cocaine impairs maternal behavior only when present in the bloodstream (Vernotica et al., Behavioral Neuroscience, 1996: 110; 3155 323); CNS site-specific injections of cocaine into the medial preoptic area and the nucleus accumbens also impair maternal behavior (Vernotica et al., Behavioral Neuroscience, 1999: 113, 377-390). In contrast to these behavioral observations made following drug administration (i.e. stimulus-response paradigm), we adapted the place preference conditioning paradigm to investigate the relative reinforcing properties of cocaine and pups for maternal dams. This allowed us to determine the stimulus that had the strongest reinforcing value. Seventy-seven percent of the dams preferred the chamber paired with the cocaine stimulus compared to the chamber paired with the pup stimulus (z = 1.99, P < 0.05). Overall, female Sprague-Dawley dams (n = 13) spent significantly more time (three-fold difference) in the cocaine chamber than in the pup chamber, when the pups were 12-16 days old (t= 6.40, PC 0.05). Further investigation will determine whether the hormonal status of the dam or the interaction time between dams and pups may influence the rewarding qualities of these stimuli.

405 MATERNALRISKFACTORSASSOCIATEDWITHTHE PREVALENCE OF FETAL ALCOHOL SYNDROME WESTERN CAPE OFSOUTHAFRICA

IN THE

P.A. May, J.P. Gossage, and J.S. Tonigan, Center on Alcoholism, Substance Abuse, and Addictions, The University of New Mexico, Albuquerque, NM For decades, women and men have worked in the vineyards of South Africa. Under the former ‘Dop’ system, part of their pay was wine. Also, in recent years, de-tribalization and rapid urbanization have resulted in very high rates of alcohol abuse in a number of South African populations. The result is a substantial rate of Fetal Alcohol Syndrome (FAS) in certain subsegments of the South African population. This pilot study was funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA). The study was initiated in 1997 and is ongoing. The situs of this research was a community in the heart of the grape growing and wine producing region of South Africa. Data will be presented on approximately 40 mothers of FAS children and 40 matched controls. Included in this presentation will be prevalence data and a descriptive assessment of risk factors found in women who have given birth to children with FAS. Specific maternal risk factors for FAS will be analyzed and explained via inferential analysis including discriminant and functional analysis of: socioeconomic, geographic, and family variables: maternal age and gravidity; drinking

Sl43

patterns during pregnancy; and a variety of other measures of quantity, frequency, and variability of drinking.

406 USE OF PREVENTIVE CHRONIC DRUGUSERS

HEALTH

SERVICES

BY

C. McCoy, L. Metsch, D. Chitwood, and M. Pereyra, Comprehensive Drug Research Center, and University of Miami, FL This study examined the relationship between chronic substance abuse and the utilization of preventive health care. In order to examine this relationship, date were collected from a tri-ethnic (Black, White and Hispanic) sample of 1479 men and women, of whom 384 were chronic injectors of opiates and/or cocaine, 542 were chronic users of opiates and/or cocaine and 553 were non-users. Use of preventive services was defined as having had a physical, eye and/or dental exam in the absence of symptoms in the past 12 months. The multivariate model showed that drug users were about half as likely as non-users to have used preventive services. Inject’ors were the least likely to have used services (OR ==0.4, 95% C.I. 0.3, 0.6). Similarly, other chronic drug users were 0.6 times as likely to have used services (OR ==0.6, 95% C.I. 0.4, 0.7). Respondents reporting a usual source of care and having some insurance coverage in the past 12 months were 2.0 (95% C.I. 1.5,2.6) and 2.2 (95% C.I. 1.5,2.6) times more likely to have used preventive services than those who did not have those resources. Respondents reporting one of more health problems in the past 12 months were also more likely to have used preventive health services (OR = 1.4,95% C.I. 1.1, 1.S). Men were less likely than women to have used services (OR = 0.8, 95% C.I. 0.6,0.97). Findings suggest that drug use is an important barrier to utilization of preventive health services even after controlling for need and enabling resources. An important policy implication of the study is the need for targeted health promotion activities to improve use of preventive services among chronic drug users.

407 PERPETRATOR&VICTIMS OLENCE: OUT-OF-TREATMENT VERSIJS NON-DRUG USERS

AND OBSERVERS CHRONIC DRUG

OF VIUSERS

H.V. McCoy, SE. Messiah, Z. Yu, P. Shapshak, and J. Gasana, Florida International University, North Miami, ,and University of Miami School of Medicine, Miami, FL IntroAction: Violence and drug use have been identified as major public health problems demanding appropriate intervention efforts. The purposes of this analysis were IO: (1) compare the prevalence of violence among

Abstracts

s144

a sample of out-of-treatment chronic drug users (CDUs) and non-chronic drug users (NCDUs) in Miami-Dade County, Florida; and (2) determine the level of risk of becoming a victim, perpetrator, or observer of violence if one uses drugs. Methods: A sample of 1479 NCDUs and NDUs were interviewed as part of a NIDA-funded health services research study. A stratified sampling technique assured an equal amount of subjects across gender, ethnic and drug using variables. Subjects provided information pertaining to their exposure to violence as a victim, perpetrator, or observer. Specific violent acts included assault, shooting/ stabbing, robbery, killing, and sexual assault. Results: CDUs were significantly more likely than NCDUs to have perpetrated all violent acts. However, CDUs were also significantly more likely than NCDUs to have been the victim or observer of all violent acts as well. Conclusion: Violence plays a significant role in the lives of street CDUs. Because CDUs were more likely than NCDUs to be not only perpetrators, but victims and observers of violence as well should shift our views of CDUs to include these new roles. Specific intervention strategies that take into consideration these multifaceted roles are recommended to facilitate violence reduction in this population.

408

DIFFERENCES

STANCE PREFERENCE

USE

IN

FAMILY

DISORDERS

ARE

OF STUDY

SUBJECTS

HISTORIES

RELATED

TO

OF THE

SUBDRUG

P.F. McHugh, KS. LaForge, K. Bell, S.H. Kellogg, A. Ho, and M.J. Kreek, The Rockefeller University, New York, NY Four hundred and fifty consecutive human volunteers taking part in a genetics study of the addictions were interviewed and given detailed questionnaires. In a preliminary study of 400 of these subjects, DSM-IV criteria were used to establish past or current diagnoses of drug abuse and/or dependence. Detailed standardized family histories were taken, obtaining information including medical background and drug histories for individual family members. Subjects were excluded from analysis if a diagnosis could not be made because of incomplete information, confounding variables, or if family history could not be taken (e.g. in the case of adoption); the final number of included subjects was 360. An affected group (n = 232) as a whole was compared with a control group, then further categorized into subgroups based on the subject’s predominant drug preference. The subgroups were defined as A, or alcohol abuse/dependence alone (n = 32); C, or primarily cocaine dependence with or without other substance use (n = 60); 0, or primarily opiate addiction with or without other substance use (n = 34); and OC, or concurrent opiate and cocaine dependence with or without

other substance use (n = 106). The control group, N, contained subjects with no significant drug or alcohol history (n = 128). There were some significant demographic differences among the groups. Results show that distinctive patterns of substance abuse/dependence exist in the first- and second-degree family pedigrees of each subgroup. Of particular interest, the 0 and OC groups showed different patterns of family drug abuse disorders, including the finding that the 0 group was significantly more likely than the OC group to have three consecutive generations of drug addiction in its families. These findings suggest that different endophenotypes can be identified within groups of subjects addicted to the same type of drug. These differences do not appear to be related to the demographic differences among the groups. Future studies will attempt to associate these family-related endophenotypes with specific genotypes. Supported in part by NIH grants: NIDA PSO-DA05130, K05 DA00049, and NCRR MOI-RR00102; OASAS-NY S.

409 A TIES INITIAL

RANDOMIZED

OF CONTINUING

EVALUATION CARE

FOR

OF THREE COCAINE

INTENSI-

DEPENDENCE:

OUTCOMES

J.R. McKay, S. Ratichek, J. Koppenhaver, R. Morrison, University of Pennsylvania, Philadelphia, PA Virtually all clinicians involved in the outpatient treatment of patients with cocaine dependence believe that some form of continuing care is necessary to solidify and pre-serve the gains made in the initial phase of rehabilita-tion. However, despite wide-spread beliefs concerning the need for continuing care, this phase of treatment has received relatively little study in cocainedependent individuals, particularly within the context of outpatient treatment. This report presents initial 6 month outcome data from a study in which cocaine-dependent patients who had completed an initial phase of intensive outpatient treatment at the VA (N = 90) or a community based program (N = 144) were randomly assigned to one of three 12-week continung care interventions: 1 x per week group counseling for the first 4 weeks and and continued monitoring via brief telephone calls in all 12 weeks (TEL), 2 x per week 12-step focused group counseling (STND), or a combination of 1 individual relapse prevention session and 1 group counseling session/week (RP). Preliminary results at both sites did not support the hypothesis that cocaine use outcomes would vary as a function of intensity of continuing care, in that outcomes in STND and TEL where generally equal to or somewhat better than those in RP. However, VA patients in the TEL condition were more likely to be returned to more intensive treatment in months l-3 than those in the other two

Abstracts

conditions. Future reports will examine 2-year multidimensional outcomes, with regard to both effectiveness and cost-effectiveness. 410

INFLUENCE

OF

EXPRESSION ROLE

AND

OF

MEDIAL

5HT2A

RECEPTORS

BEHAVIOR

FOLLOWING

PREFRONTAL

CORTEX

ON

c-Fos

COCAINE: AND

DORSAL

STRIATUM

L.R. McMahon, R.P. Szucs, K.A. Cunningham, University of Texas Medical Branch, Galveston, TX We have previously shown that antagonism of serotonin2A receptors (5-HT2AR) with MDL 100,907 attenuated the locomotor and discriminative stimulus effects of cocaine in rats. The present study employed both c-Fos immunocytochemistry (ICC) and intracranial microinjection studies to identify brain regions in which 5-HT2AR may modulate the in vivo effects of cocaine. For ICC studies, male rats were given ip injections of vehicle or MDL 100907 (0.2 mg/kg) followed by saline or cocaine (10 mg/kg). Standard ICC procedures were then used to determine the level of c-Fos expression in different brain regions. Cocaine treatment increased c-Fos immunostaining in both the mPFC and DS (P < 0.05). Pretreatment with MDL 100 907 attenuated cocaine-induced c-Fos expression in the DS (P < 0.05) but not the mPFC. For behavioral studies, rats were implanted with bilateral guide cannulae aimed at the mPFC (AP = 2.7; ML = + 0.75; DV = - 4.7) or nucleus accumbens (NAc) shell (AP = 1.6; ML = + 0.75; DV = - 8). Locomotor activity was measured after microinjection of saline (0.2 ml/side) or MDL 100907 (0.1 or 0.3 mg/side) followed by ip injection of saline or cocaine (10 mg/kg). Intra-NAc shell MDL 100907 did not significantly alter basal or cocaine-evoked hyperactivity. Intra-mPFC MDL 100907 (0.3 mg/side) produced a moderate enhancement of cocaine-induced hyperactivity (P < 0.05) but did not alter basal activity. These results suggest that cocaine-induced c-Fos expression in the DS, but not mPFC, is mediated by 5-HT2AR, and that cocaine-induced hyperactivity is not modulated by 5-HT2AR in the mPFC. Future studies will investigate the role of 5-HT2AR in the nigrostriatal dopamine system in cocaine-evoked hyperactivity. Supported by NIDA DA 05879 (LRM) and NIDA 06511 & 00260 (KAC). 411 AND LOWING

CONCURRENT LEGAL

ITEMS

VALIDITY AMONG

OF FELONY

AS1

SUBSTANCE

OFFENDERS

USE FOL-

ARREST

J. McNellis, D.B. Marlowe, J.C. Merrill, A.V. Harrell, D.S. Festinger, P.A. Lee, and A.T. McLellan, Treatment Research Institute at the University of Pennsylva-

s145

nia, Philadelphia, Washington, DC

PA

and

The

Urban

Institute,

There is conflicting evidence concerning the validity of self-reported use among substance abusers in criminal justice contexts. Several studies conducted in the 1970s and 1980s (e.g. DARP, TOPS) suggested that substance abuse clients may accurately report their substance use relative to biological assays. Recent studies using more sensitive urinalysis methods have revealed, however, that offenders may systematically under-report such information (e.g. Wish, 1997). The present study is investigating the validity of self-report AS1 data in the context of NIJ-sponsored ‘Breaking the Cycle’ (BTC) initiatives in Tacoma, WA and Jacksonville, FL. Felony offenders in the target communities are screened for substance abuse following booking based on their current charges, structured interviews, and urinalysis testing (using the Roche test cup). Analyses on baseline data from the two cities reveal fairly high concordance between subjects’ self-reported substance use in the preceding 30 days and their urinalysis results. In Tacoma (N= 385), sensitivity ranged from 89 to 95% for substances with adequate base rates in the sample (cocame, THC, amphetamine, opiates). Sensitivity was somewhat lower in Jacksonville (N = 405), ranging from 74 for THC to 80% for cocaine. These data lend confidence to the self-report information for evaluating these large-scale criminal justice studies and show that high concordance can be achieved when an interview is preceded by a urinalysis test. ACKNOWLEDGEMENTS: Supported by NIJ grant # 97-IJ-CX-00131 and ONDCP. 412

THE

PERSISTENT

USE

OF BUSPIRONE ANXIETY

IN

FOR

THE

TREATMENT

OF

METHADONE-MAINTAINED

PATIE:NTS

A.L. McRae, S.C. Sonne, and K.T. Brady, Medical University of South Carolina, Charleston, SC Numerous studies have been conducted on the treatment of depression in methadone-maintained patients. However, very little research has been performed on the treatment of anxiety in this population. This 12 week, double-blind, placebo-controlled trial was designed to evaluate the efficacy of buspirone for the treatment of persistent anxiety in methadone-maintained patients. Assessments for psychiatric illness include the Mini International Neuropsychiatric Interview Plus, the Hamilton Anxiety Scale (HAM-A), and the Beck Anxiety Inventory (BAI). Substance use assessments include weekly craving indices and urine drug screens as well as the timeline followback. To date, 32 subjects have been enrolled in this flexible dose study. A preliminary A/B analysis shows greater reductions in BAI scores ( - 8.30

S146

Abstracts

vs. - 19.38, P < 0.05) and craving measurements (0.143 vs. - 5.88, P < 0.05) as well as a lower percentage of positive urine drug screens (54.7 vs. 31.8%, P < 0.01) for one group as compared to the other. These results indicate that one treatment group had a greater reduction in anxiety symptoms and improved substance use outcomes compared to the other. This study is on-going; data from additional subjects will be included. The blind will be broken prior to presentation.

413 EFFECTS OF COCAINE ON RESPONDING PROGRESSIVE-RATIO SCHEDULE MAINTAINED IN 5-HT 1B KNOCKOUTMICE

UNDER A BY FOOD

A.N. Mead, R. Hen, and B.A. Rocha, Columbia University, New York, NY Previous work with mice lacking the serotonin 1B (5-HT 1B) receptor has shown that these mice are more sensitive to the locomotor stimulant properties of cocaine, and will respond to a higher break point under a progressive ratio (PR) schedule maintained by cocaine (Rocha et al., Nature, 1998: 393; 175). However, the interpretation of results from studies investigating responding for cocaine under a PR schedule may be complicated by effects of cocaine on levels of responding per s, since cocaine also increases break points for sucrose and saccharin. These studies raise the possibility that the increase in responding observed in 5-HT 1B KO mice is not due to an increase in the reinforcing efficacy of cocaine. Therefore, we investigated the effects of systemic cocaine on responding for a food reinforcer under a PR schedule in 5-HT 1B KO mice. WT (n = 5) and KO (n = 7) mice were pretreated with cocaine (O&40 mg/kg) and allowed to self-administer condensed milk solution on a PR schedule. As in previous studies with rats, cocaine dose dependently increased responding in both KO and WT mice (mean 5 sem number of reinforcers, KO: saline 15.0 f 1.2, 20 mg/kg cocaine 26.7 f 1.4; WT: saline 13.8 f 0.5, 20 mg/kg cocaine 24.0 + 1.4). The magnitude of this effect did not differ between KO and WT mice, suggesting that the increase in responding under a PR schedule for cocaine, was due to differences in the motivation to work for cocaine infusions. 414 APPROPRIATE COMPARISON OUTPATIENT ADDICTIONTREATMENT

OF INPATIENT

AND

K.Y.H. Mechanic, V. Dhopesh, E. Yu, T. McLellan, C. O’Brien, Philadelphia Veterans Affairs Medical Center, University of Pennsylvania, Philadelphia, PA Previous studies of inpatient and outpatient addiction treatments have made direct comparisons of the out-

comes and costs between these two forms of care-under the assumption that both were designed to perform the same rehabilitation function. Results have uniformly shown no significant outcome differences between the two. Suppose the underlying assumptions are wrong that in fact, inpatient care is not an alternative to outpatient - but is supposed to prepare a patient for outpatient care? In the present project we have randomly assigned two groups of cocaine dependent veterans to receive either direct admission to day hospital rehabilitation treatment or brief (3 day) inpatient stabilization prior to day hospital rehabilitation. This study is unlike prior cost effectiveness comparisons in two important ways. First, the subject population is much less restrictive, including virtually all the types of conditions that are typically seen in ‘real world’ rehabilitation programs. Second, the study specifically does not assume that inpatient and outpatient treatments should be evaluated on common outcome criteria. Instead, the study assumes that the appropriate function of inpatient care is to remove the barriers to, and prepare the patient for outpatient care. The study used an intent-totreat design with random assignment. Patients were evaluated at the start of the study, throughout the course of inpatient and day hospital treatment and at 6 month follow-up using validated instruments and procedures. Results will compare outcomes between the two groups including costs of care, engagement and retention in day hospital care, psychiatric signs and symptoms, and substance use. 415

THE EFFECTS OF COCAINE ON BASAL OVARIAN STEROID HORMONESIN FEMALERHESUS MONKEYS

N.K. Mello, J.H. Mendelson, M. Kelly, and C.A. Bowen, McLean Hospital, Harvard Medical School, Belmont, MA Cocaine stimulates anterior pituitary hormones in humans, rhesus monkeys and rodents, but its effects on ovarian steroid hormones in rhesus monkeys are unknown. The acute effects of cocaine and placebo on estradiol (E2) and progesterone (Prog) were studied in drug naive female rhesus monkeys during the mid follicular phase of the menstrual cycle (days 8- 10). Samples were collected at 15 min intervals for 300 min after cocaine (0.8 mg/kg, i.v.) or placebo administration. Basal progesterone levels were less than 1 rig/ml and did not change after cocaine or placebo administration. Basal estradiol levels averaged 198 and 167 pg/ml before placebo and cocaine administration, respectively. Estradiol levels increased significantly after cocaine administration (P < 0.01) and remained significantly above baseline for 45 min. Peak estradiol increases ranged between 45 and 59% above baseline in individual monkeys. Cocaine-induced increases in estradiol

Abstracts

during the follicular phase could disrupt folliculogenesis and contribute to the menstrual cycle abnormalities observed during chronic cocaine self-administration (Mello et al., J. Pharmacol. Exp. Ther., 1997). Studies of cocaine’s effects on ovarian steroid hormones during the mid-luteal phase of the menstrual cycle are now ongoing. ACKNOWLEDGMENTS: This research was supported in part by K05-DAOOlOl, K05-DA00064 and P50-DA04059 from the National Institute on Drug Abuse, NIH. 416

FORMATION

CAETHYLENE VENOUS

AND FOLLOWING

COCAINE

AND

ELIMINATION ORAL,

ORAL

OF

SMOKED,

AND

coINTRA-

ETHANOL

J. Mendelson, E. Herbs& B. Heifets, M. Baggott, P. Jacob III, E.T. Everhart, and R.T. Jones, Drug Dependence Research Center, Langley Porter Psychiatric Institute, University of California, San Francisco, CA Ethanol alters the hepatic biotransformation of cocaine, resulting in transesterification to a novel active metabolite, cocaethylene (CE). Because oral (in contrast to inhaled) drug administration exposes the liver to large relative concentrations, we compared the effects of route of cocaine administration on the formation and elimination of CE. Six experienced cocaine users were tested in 6 sessions, approximately 1 week apart. The treatment groups were: (1) and (2) oral ethanol 1.0 g/kg (or placebo) with oral cocaine-d5 2.0 mg/kg; (3) and (4) oral ethanol 1.0 g/kg (or placebo) with IV cocaine-d5 1.0 mg/kg; (5) and (6) oral ethanol 1.0 g/kg (or placebo) with smoked cocaine-d5 (two 100 mg pipes). Deuter-ium-labeled cocaine (d5) with a small, nonpharmacologically active IV dose of deuterated CE (d3) was administered with all conditions. Physiologic and subjective effects were recorded and plasma cocaine-d5, CE-d5 and CE-d3 were measured by GC-MS. Compared within each route of administration, heart rate and rate pressure product were higher after cocaine and ethanol than after cocaine alone. Percent of CE-d5 formed from cocaine-d5 (measured by AUCO- > 31 ratios) was greater after oral (45 f 11%) than after IV (29 f 21%) or smoked (23 Ifr 7%) routes. Quantitative pharmacokinetics for cocaine, benzoyl-ecgonine, and CE will be presented. Supported by NIDA grant DA01696 and NIH RR-00079 (GCRC, UCSF). 417

SOCIODEMOGRAPHIC

TERISTICS WITH LOW-UP

OF

RETENTION

INJECTION AND

AND

BEHAVIORAL

DRUG

USERS

TIMELINESS

OF

CHARACASSOCIATED

VISIT

IN

A FOL-

STUDY

A. Messiah, D. Metzger, A. Davis-Vogel, H. Navaline, D. Tobin-Fiore, and G. Woody, Center for Studies of

SI41

Addjction, PA

University

of Pennsylvania,

Philadelphia,

Background: Retention and timeliness of follow-up (FU:I are critical issues for the validity of follow-up studies of intravenous drug users (IDUs). Assessment of any associations between retention/timeliness and subject characteristics allows for the evaluation of study biases and flaws. Objective 6; methods: Timeliness (defined as the delay between targeted and actual 6 month visit) and retention at 6 months were analyzed by subjects baseline characteristics, in a follow-up study of 263 seronegative IDUs at high risk of HIV-infection. Subjlects were recruited from September 1997 to June 1998 in community settings in Philadelphia. Results: As of December 1999, 93% of the subjects completed a 6 month visit: 11% early (up to 24 days), 38% on time, 32% within 1 month of targeted visit, and 12% beyond 1 month (up to 191 days). Subjects lost to FU were more likely than those retained to have a high-school degree and to have moved at least once during past year. By contrast, timeliness was not associated with those variables; subjects returning late to FU were more likely to be young and living far away from study center, and less likely to have stayed in a welfare residence during past year. Neither retention nor timeliness were significantly correlated with drug habits. Conclusion: Socio-demographic but not behavioral characteristics were correlated with adherence to FU. Characteristics associated with timeliness were not the same as those for retention, suggesting that late completers are not potential drop-outs. This study indicates that results on behavioral variables obtained using only those retained might be minimally biased, but this may differ for studies with lower retention rates 418

SYMMETRICAL

THE

DISCRIMINATIVE

GAMMA-HYDROXYBUTYRATE TONE

IN

TESTS

OF

STIMULUS AND

GENERALIZATION PROPERTIES

TO OF

GAMMA-BUTYROLAC-

RATS

B.R. Metcalf, J.M. Stahl, P.L. Soto, M. Sanchez, and L.L. Jones, Morris Brown College and Spelman College, Atlanta, GA Gamma-hydroxybutyrate (GHB) is a naturally occurring metabolite of gamma-aminobutyrate (GABA) meeting definitions of a neurotransmitter. Banned in the 1JS in 1990, GHB continues to be used legally in other parts of the world as a treatment for sleep disturbances and substance addiction, and is widely used illicitly in the US, particularly for its alcohol-like, hangover-free euphoric feelings. Gamma-butyrolactone (GBIL), a precursor to GHB, is metabolized to GHB and is widely available in unregulated forms and is increasingly being used as a substitute for the more

S148

Abstracts

regulated GHB. Few DD studies have been done with GHB- or GBL-trained animals, it has not previously been determined if the stimulus properties of these substances can be discriminated in animals. Thirty-six rats trained on a fixed ratio 10 (FRlO) schedule of food reinforcement began daily drug training sessions. Rats were divided into three training groups. In the on-going study, rats are injected on a semi-random alternating basis with either 300 mg/kg GHB or 110 mg/kg GBL, respectively or an equal volume of vehicle. The third group of rats is what is sometimes referred to as an AND group. These rats are trained following injections on a semi-alternating basis with either 300 mg/kg GHB or 110 mg/kg GBL. Upon mastering the training criteria of eight consecutive sessions with correct lever selection, test sessions with other doses and drugs will commence. In addition to cross-generalization tests with several doses of GHB and GBL, all rats will be tested with several doses of: (1) ethanol; (2) the opioid, morphine sulfate; and (3) the benzodiazepine, flunitrazepam (Rohypnol). Since GBL is metabolized to GHB, we hypothesize that the AND group will be unable to discriminate these drugs from each other during training and that GHB- and GBL-trained rats will be unable to discriminate doses of the other during cross-generalization tests. Dose response, generalization, and response rate curves will be generated and presented for all three groups for all drugs trained and tested. This research is supported by NIDA/MIRD grant 5R24DA07256. 419

ALTERNATIVE STRATEGIES DUCTIONUSEDBYACTIVEDRUGUSERS

FOR SEXUAL

RISKRE-

L. Metsch, C. McCoy, J. Wingerd, and C. Miles, Comprehensive Drug Research Center, University of Miami, FL Failure by active drug users to use condoms consistently is not equivalent to failure to adopt any personal risk reduction strategies. In this study, data from qualitative interviews with 92 active users of crack and injection drugs illustrate risk reduction strategies employed either in addition to, or instead of condom usage. Findings are based on respondentsi narrative accounts of methods used to reduce personal risk of contracting HIV during sexual acts. Pre-coital strategies focused on partner selection techniques based on the belief that isafei partners can be selected. Coital strategies included the selection of specific sex acts that were presumed to be safe or safer than other and/or cleanliness rituals. Post-coital strategies included techniques such as washing sex organs with bleach or lemon juice. These data suggest that active drug users may be able to ignore recommended practices without conflict or

cognitive dissonance because they believe that they are doing other things which are presumed to be equally effective. Interventions must take into account the notion that drug users have their own subculture and that misconceptions may be passed along within this subculture. 420 INCIDENCE OF HIV INFECTION AMONG JECTION DRUG USING WOMEN IN PHILADELPHIA

NON-IN-

D. Metzger, A. Davis-Vogel, H. Navaline, J. Meyers, G. Wilson. J. Downey, D. Tobin-Fiore, and G.E.Woody, University of Pennsylvania/VA Medical Center, and Center for Studies of Addiction, Philadelphia, PA To examine the risk of HIV infection among non-injection drug using women, 222 uninfected crack smoking women from Philadelphia were enrolled in a 1 year seroincidence study. Sexually active women who used crack cocaine on at least 12 days during the prior 3 months were eligible. All subjects completed behavioral assessments via audio-assisted computer interviews and were tested for HIV infection at baseline, 6, and 12 months. Subjects also received extensive risk reduction counseling, referrals to drug treatment or other necessary services, and prevention supplies including female and male condoms. The subjects had an average age of 37. Seventy-nine percent were African American, 16% white, and 3% Latina. Ninety-three percent had annual incomes of less than $12000 and only 58% reported health care coverage of any type. With respect to drug use, 59% smoked crack more than once a day during the prior 6 months and 24% reported injecting at least once. The study achieved a 93% rate of follow-up. HIV incidence was found to be 2.04 per 100 person years. The findings suggest that frequent use of crack cocaine is associated with elevated risk of HIV infection. New drug treatment and prevention strategies targeting this high risk population are needed. 421 ENGAGING RESISTANT MULTICULTURAL ADOLESCENTS INTO TREATMENT USING COMMUNITY REINFORCEMENTANDFAMILYTRAINING

R.J. Meyers, H.B. Waldron, and T.R. Peterson, University of New Mexico Center for Family and Adolescent Research, Albuquerque, NM Preliminary data from a NIDA funded clinical trial evaluating the effectiveness of Community Reinforcement and Family Training (CRAFT) for engaging resistant adolescents into substance abuse treatment will be presented. The primary goal in this application of CRAFT is to work with a concerned significant other (CSO), typically a parent, to train them in techniques

Abstracts

for engaging their resistant adolescent into treatment. To date 11 Hispanic American and 8 Anglo American parents have been recruited into treatment. Of these, 71% have successfully engaged their adolescent into treatment. Most of the remaining adolescents are still within their 6 month engagement window, thus the opportunity for them to respond to ongoing engagement efforts by entering treatment remains. Updated demographic and engagement rate data will be presented and discussed. A secondary goal of parent treatment is to improve their psychological and physiological functioning with regard to depression, anxiety, self-esteem, and medical and physical symptoms. Preliminary data indicate significant improvements in all areas of functioning measured. Outcome data for parent treatment will be presented and discussed, along with any other available significant findings.

422 SIMILARITIES AND DIFFERENCES IN PROBLEM SEVERITY AND MOTIVATION FOR CHANGE BETWEEN SUBJECTS RECRUITED IN CLINICAL TRIALS VS COMMUNITY PATIENTS J. Mezinskis, F. Moskowitz, and E. Somoza, VA/ NIDA Medications Development Research Unit, Cincinnati, OH Questions have been raised about the generalizability of data collected from ‘subjects’ volunteering for clinical trials versus ‘patients’ seeking treatment in community treatment programs. External validity of data can be partly addressed by looking at pre-treatment differences between the two populations. This study aggregated baseline data from 83 patients participating in two pharmacotherapy clinical trials for the treatment of cocaine dependence. AS1 composite scores were compared to those of patients in a local treatment program as well as published normative data. In general, the trials group reported more severe drug problems and less severe alcohol problems because the trials focused on cocaine dependence while the community samples had a mixed population of alcohol and drug dependent persons. The trials group had significantly (P < 0.001) fewer medical and psychiatric problems, because strict safety criteria excluded persons with major medical and psychiatric disorders. There were no differences between the trials group and the community samples in terms of employment, legal, and family problems, which were variables not addressed in trials’ inclusion and exclusion criteria. Hierarchical tree clustering, using Ward’s method, was used to categorize the clinical trials subjects on Stage of Change scales (URICA). A three-cluster solution yielded the most interpretable solution. Plotting these three cluster groups revealed a group of ‘Pre-contemplation subjects (37% of the sam-

s149

ple), a group of ‘Decision-Making’ subjects (21%), and a group of ‘Participative’ subjects (43%). These results suggest that subjects in the clinical trials group had a wide range of motivational levels. In summary, as long as clinical trials have inclusion and exclusion criteria, the sample characteristics will be skewed for those variables. However, non-manipulated variables do not seem affected, there is a wide range in motivation for treatment, and the level of severity for the focal disorder, cocaine dependence, remains quite high. AcKNOWLEDGMENT: Supported by NIDA under agreement # YOl DA 50038-00.

423 SUBSTANCE USE SEVERITY TOYOUNGADULTHOODINFEMALES

FROM ADOLESCENCE

A.C. Mezzich, S. Lu, M. Dunn, S. Parks, University of Pittsburgh, School of Pharmacy, Pittsburgh, PA The aim of this study was to test a model that states that: (1) history of sexual abuse, psychiatric symptomatology, a poor parent-daughter relationship, and affiliation with deviant peers at adolescence (age 14-18; Tl) predict substance use severity at young adulthood (age 19923; T2) in females (n = 67) and these; (2) associations are mediated by substance use severity at Tl. The correlational analysis indicated that history of sexual abuse (Y = 0.49, P < O.OOl), psychiatric symptomatology (r = 0.44, P < O.OOl), a poor parent-daughter relationship (r = 0.42, P < O.OOl), affiliation with deviant peers (Y = 0.59, P < .OOl), and severity of substance use at Tl (r = 0.71, P < .OOl) were correlated with severity of substance use at T2. The results of the multiple regression showed that psychiatric symptomatology (p = 0.23, P < 0.05) and affiliation with deviant peers (/I = 0.45, P < 0.001) predicted substance use severity from Tl to T2. Also, the mediating analysis revealed that substance use severity at Tl explained the relation between affiliation with deviant peers and substance use problems at T2. The model explained 56% of the total variance of substance use severity at T2. These results suggest that affiliation with deviant peers predisposes females to severe substance use during adolescence which in conjunction with psychiatric symptomatology predicts increased substance use severity during young adulthood.

424

TREATMENT

ADHERENCE

IN

PHARMACOLOGIC

TRIALS

E. Midkiff and G. Galloway, Clinics, San Francisco, CA

Haight

Ashbury

Free

Adherence to treatment is an important determinant of succ~essin pharmacologic trails for substance abuse, but one which has not received enough attention. The

s150

Abstracts

present study will examine the correspondence between self-report of treatment adherence and objective measures, including capsule count and urinalysis. Subjects are 105 patients in a randomized, placebo-controlled 12-week trial of tyrosine for methamphetamine dependence. Adherence will be measured by counting returned capsules (subjects were given a lo-day dose during each weekly visit, so some capsule return was expected), and urinalysis of riboflavin (included in the medication as dispensed) at weeks 4, 8, and 12. Demographic predictors of adherence will also be examined. Sponsored by: NIDA grant DA10739. 425 AFFECT DYSREGULATION AS A MEDIATOR MALECOCAINEABUSEANDAGGRESSIVEBEHAVIOR

OF FE-

G.M. Miele and D.A. Hien, Columbia University College of Physicians and Surgeons, New York, and Derner Institute for Advanced Psychological Studies, Garden City, NY A great deal of empirical data exists implicating parental drug or alcohol use as a potential risk factor for child abuse or neglect. Parents, especially mothers, who abuse drugs are at risk for perpetrating child abuse and failing to protect their children from the abuse of others. There is also a growing body of clinical and research literature suggesting that individuals with a history of abuse are more likely to engage in violent behavior in adulthood than those without a history of abuse. This case-control study examined a sample of 279 inner-city mothers, comparing three groups of women: crack/cocaine abusers (n = 112) depressed (n = 73) and non-substance-abusing controls (n = 94). The present study focused on the risk factors of maternal aggression by examining the relative contributions of a motheris personal history of victimization in contrast to a motheris history of cocaine abuse in explaining maternal violence potential. Using hierarchical regression techniques and controlling for ethnicity, current depression and family history of psychopathology, we found that maternal cocaine abuse predicted violence, both against her own children and others. Victimization of the mother in childhood did not predict maternal aggression. Follow-up analyses indicated that affect-focused coping, an indicator of affect dysregulation, mediated the relationship between cocaine abuse and violence towards children and others; however, cocaine abuse retained unique predictive power. These results highlight the importance of focusing on affect regulation in the prevention and treatment of violence in cocaine abusing women. ACKNOWLEDGMENT: This research was supported by a NIDA FIRST Award R29DAl0863 to D. Hien.

426 ADOLESCENTSINDAYTREATMENTFORCONDUCT ANDSUBSTANCEUSEPROBLEMSzMINIMALGENDERDIFFERENCES SK. Mikulich, E.A. Whitmore, SK. Hall, and T.J. Crowley, University of Colorado School of Medicine, Denver, CO Evidence is accumulating that substance use and addiction differ for males and females. However, our previous research on delinquent adolescents found few gender differences between 285 residential males and a much smaller sample of 82-day treatment females. When examining only day treatment patients, do delinquent adolescent females have different substance use disorder (SUD) profiles than males? Hypotheses: Female adolescents referred to day treatment for comorbid conduct disorder and SUD will have at least as severe substance use and psychiatric problems as comparable males. Metho&: We used structured interviews to assess DSM-IV diagnoses and measures of substance and psychiatric disorders in 50 male and 47 female adolescents in our day treatment program. Results: Age (15.2 years), ethnicity, SES (lower middle class), and rates of psychiatric diagnoses were very similar between males and females. Prevalence of ever using or of having a DSM-IV diagnosis on each of 10 substances did not differ by gender. Males and females reported equal numbers of SUD diagnoses (2.4) and of dependence symptoms (9.1). Most females first tried tobacco (75%) whereas in males, 48% first used tobacco and 42% first tried cannabis (P < 0.02). Survival analyses indicated that across drugs, females began using a year later than males (P < 0.05) but both progressed to regular (monthly) use by 12.5 years. Females began using cannabis later and progressed to regular cocaine use earlier than males (P < 0.05). Conclusions: As shown in our earlier research comparing somewhat dissimilar samples, equated groups of day treatment male and female adolescent patients demonstrate comparable SUD profiles with minimal gender differences. Support: NIDA grants DA-l 1015 and DA-06941. 427

ABSTINENT vs. NON-ABSTINENT CONTINGENT HOUSING FOR COCAINE-DEPENDENT HOMELESS: EFFECTS

OF HOUSING

TOGETHER

OR

APART

J.B. Milby, J.E. Schumacher, C. McNamara, S. Usdan, D. Wallace, S. Frison, M.A. Plant, University of Alabama at Birmingham, Birmingham, AL, University of Kansas Medical Center, Kansas City, KS, Birmingham Healthcare for the Homeless Inc., Birmingham, AL In a 3 group randomized controlled study of housing conditions as an adjunct to behavioral day treatment for cocaine use disorders, this study explores the impact

Abstracts

of housing together vs. apart for 2 provided housing groups (total n = 82). The abstinent contingent housing (ACH) group was hypothesized to show better abstinence outcomes when housed apart. After exposure to ACH and non-abstinent contingent housing (NACH) while residing in the same apartment unit, housed groups were assigned to separate but comparable apartments in a similar neighborhood for an equal time period (9 months). Both groups participated in the same day treatment and work therapy aftercare programs. A total of 615 urine toxicologies for the NACH group and 587 for ACH group were used for comparison of 2 distinct housing conditions (together vs. apart). Model-based estimates of prevalence of abstinence that accounted for treatment, housing structure, and their interaction were conducted. While there was no evidence of a treatment effect (x2 = 0.18, P = 0.68) or a treatment by housing structure interaction (1” < 0.01, P = 0.96), there was a significant housing structure effect (x2 = 5.23, P = 0.022). When housed together, level of abstinence was 48.4% (SE = 0.074) and 45.9% (SE = 0.062) for the ACH and the NACH groups, respectively. When housed apart, however, abstinence levels rose to 65.9% (SE = 0.085) for the ACH and 62.5% (SE = 0.064) for the NACH groups. Results suggest conditions in which an abstinence contingency for housing is implemented may also play a role in contingency effects and have implications for substance abuse programs that utilize housing in treatment. Supported by NIDA grant ROI DA08475

428

RELATIONSHIP

PROTECTIVE SEVERITY

FACTORS IN FEMALE,

BETWEEN AND DRUG

FAMILIAL

RISK

AND

ADDICTION/PSYCHIATRIC ABUSERS

D.R. Miles, J. Kulstad, R.W. Pickens, and D.L. Haller, Virginia Commonwealth University, Medical College of Virginia, Richmond, VA A number of childhood and family variables have been identified as possible risk factors for development of substance use disorders in adulthood. These include early age of onset of substance use, negative peer involvement, low religiosity, conduct and learning problems, and presence of substance abuse or psychiatric illness in family members. In addition, a poor upbringing may affect a woman’s parenting ability. We assessed the relationship between childhood environmental and psychological risk factors and family history of mental illness/substance abuse with current addiction severity and parenting stress in 111 women enrolled in a residential treatment program for pregnant substance abusers. Most were never married (680/o), African Americans (81%) with a mean age of 26 years. Two-thirds had completed high school. At time of treatment entry, only 3% were employed. All subjects

s151

had previous substance abuse treatment experiences and met substance dependence criteria. The primary substances of abuse were cocaine/crack (87%) and heroin (8%). Secondary substances of abuse were alcohol (43%) and cannabis (33%). The majority (86%) of subjects were also nicotine dependent. Step-wise regression was first applied to assess the relationship between AS1 alcohol, drug, and psychiatric severity scores and selected childhood risk factors including living situation, perceived quality of relationships with family and peers, family values (work, religiosity, education, ethnic heritage), age of onset of substance use, childhood psychopathology, and family history of mental illness and substance abuse. Similarly, the relationship between these risk factors and current parenting stress was examined. The most highly significant variables were then included in a path analysis to examine the relationship between each risk factor, AS1 severity, and parenting stress. These models lead us to a further understanding in the relationship between early childhood family influences, self-perceived parenting ability, psyc.hopathology and substance abuse in adulthood.

429 AND

EFFECTS

OF

LOBELINE

NICOTINE-INDUCED

ON

METHAMPHETAMINE

HYPERACTIVITY

AND

SENSITIZATION

D.K. Miller, T.A. Green, S.B. Harrod, M.T. Bardo, P.A. Crooks, and L.P. Dwoskin, University of Kentucky, Lexington, KY Lobeline (LOB) potently inhibits dopamine (DA) uptake and promotes DA release from synaptic vesicles within the DA terminal, thereby perturbing mechanisms of presynaptic DA storage and release. Because locomotor sensitization has been attributed at least in part to adaptations within DA neuronal pathways, we determined whether LOB would attenuate the sensitization to repeated methamphetamine (METH) or nicotine (NIC). Adult male rats were administered (SC) 3 mg/kg LOB or saline (SAL) and locomotor activity was monitored for 10 min. Subsequently, animals were injected (SC) with METH (1 mg/kg, HCl salt), NIC (0.8 mg/kg, free base) or SAL, and activity was measured for an additional 50 min. On day lof drug treatment, LOB pretreatment attenuated METH-induced hyperactivity and completely blocked NICevoked hyperactivity. Following either acute or repeated treatment, LOB alone did not induce a significant change in locomotor activity. The drug treatment regimen continued for an additional 11 days, and locomotor sensitization was induced in animals repeatedly administered METH or NIC. However, on each day, locomotor activity following METH or NIC was greater in SAL-pretreated than in LOB-pretreated groups. On the next day, all rats were pretreated with

s152

Abstracts

SAL rather than LOB, and subsequently were administered METH, NIC, or SAL. No attenuation of the response to METH was apparent. In contrast, attenuation of the response to NIC persisted despite termination of LOB pretreatment. Thus, LOB attenuated both the induction and expression of locomotor sensitization to NIC, but only attenuated the induction of sensitization to METH. These results are consistent with the observed LOB-induced inhibition of METH-evoked and NIC-evoked DA release in vitro and suggest that LOB has potential as a pharmacotherapy for METH and NIC abuse. Supported by the Tobacco and Health Research Institute, Lexington, KY. 430 CLONING OF VARIANTS OF THE DOPAMINE TRANSPORTER,APRlNCIPALTARGETOFCOCAINE,FROM THREESPECIESOFMONKEY BRAIN

G.M. Miller, R. De La Garza, M. Goulet, SM. Yatin, B.K. Madras, Harvard Medical School, New England Regional Primate Research Center, Southborough, MA Monkeys are widely used in models of drug addiction and medications development. Although monoamine transporters (MATS) have been cloned from human and several other species, none have been cloned from brain of monkey. We used RT-PCR to clone MATS from Macaca mulatta, Macaca fasicularis and Saimiri sciureus (dopamine transporter; DAT) and Macaca mulatta (norepinephrine transporter; NET and serotonin transporter; SERT). Monkey MAT proteins were > 98% homologous to human, and displayed drug affinities and uptake kinetics that were highly correlated with monkey brain or human MATS, when expressed in HEK-293 cells. In contrast to reports of other species, we discovered double (leucine for phenylalanine 143 and arginine for glutamine 509; 143L/ 509R) and single (proline for leucine 355; 355P) amino acid variants of DAT that exist with wild-type (wt) DAT and were detected across and are invariant between species of monkey. 143L/509P displayed dopamine transport kinetics and binding affinities for various DAT blockers (including cocaine) vs [3H]CFT that were identical to wtDAT (n = 7 drugs; R2 = 0.991). However, we detected a six-fold difference in the affinity of cocaine vs [3H]cocaine between 143L/509P (IC50: 488 + 102 nM, C fs.e., n= 3) and wtDAT (IC50: 79 + 8.2 nM, n = 3, P < 0.05), suggesting the value of this assay to study cocaine binding and potential cocaine antagonists. 355P displayed an intracellular distribution in HEK-293 cells, as detected by confocal microscopy, and had very low levels of binding and dopamine transport. Also discovered was a novel exon 5 splice variant of NET that displayed very low levels of transport and did not bind cocaine (vs

[3H]cocaine:wtNET:IC50: 193 * 53 nM vs > 10 mM). The detection of novel transporter variants in monkey with varying cocaine affinities warrants investigation of their function and their expression in human brain. The homology and functional similarity of human and monkey MATS further support the value of primates in investigating the role of monoamine transporters in substance abuse and neuropsychiatric disorders. Support:DA06303, DA11558, DA00304, RRO0168. 431 NETWORKS, RESOURCES WOMENWHOUSEDRUGS

AND

RISK

AMONG

M. Miller and A. Neaigus, National Development and Research Institutes, Inc, Center for Drug Use and HIV Research, Raleigh, NC The public health tradition of intervening at the environmental level has not been fully exploited in terms of HIV prevention efforts among drug users. Women who use drugs are at particularly high risk of acquiring HIV and other blood borne and sexually transmitted infections, such as hepatitis B (HBV) and hepatitis C (HCV). In order to prevent infection with HIV, as well as with HBV and HCV, among women who use drugs, we need to examine the factors, at different causal levels, that increase women’s risk of acquiring these infections. In a review of the existing literature, we examine the extent to which the linkages among multiple causal levels may contribute to the disease transmission risk experienced by women who use drugs. The multiple causal levels of risk potentially involved in the transmission dynamics of infectious pathogens include biological, behavioral, dyadic relationship, network, and structural levels. Biological and behavioral risk factors have already been examined in depth; yet, little empirical research currently exists for other causal levels. Increasingly, investigators have suggested that the character and dynamics of relationships with sex partners may be an important determinant of risk, both for engaging in risk behaviors and for doing so with high risk partners. The influence of other causal level factors, specifically of network and social and economic structural factors, are the least well documented among women who use drugs, but are posited to be a principal underlying cause of the current differential HIV incidence rates between men and women. Future research should focus on higher order causal levels, in order to better understand disease transmission dynamics, to develop interventions that improve and supplement current HIV prevention efforts among women who use drugs, to inform public policy debate, and to better evaluate the limits, as well as the opportunities, of current intervention efforts, especially since recent evidence suggests that interventions implemented at higher order causal levels can be effective in preventing disease transmission to women.

s153

Abstructs

432

PSYCHOLOGICAL FANT PLACEMENT IN WOMEN

DISTRESS, VIOLENCE, AND INCOCAINE-USING POST-PARTUM

S. Minnes, L.T. Singer, K. Farkas, Case Western Reserve University School of Medicine and School of Applied Social Science, Cleveland, OH Negative behavioral and psychological consequences of prenatal cocaine use may impact a woman’s ability to parent effectively. In a prospective study of 415 post partum women and their infants, 218 cocaine using women (C + ) (66 with infant placed in foster care (FC); 134 whose infants were not placed in foster care (NFC)) and 218 control subjects (C - ) of similar socio-economic status and race were assessed after infant birth. Hypotheses were: (1) cocaine using women would report more violence over the past year and lifetime than control subjects; and (2) cocaine using women with children in FC would report higher levels of psychological distress and violence than women whose children were NFC. Mothers were assessed for levels of experienced violence, as well as use of violence, drug use during pregnancy and, for psychological distress post-partum using the Conflict Tactics Scale (CTS), the Post-Partum Interview and the Brief Symptom Inventory (BSI). x2- and t-test analyses compared group differences. Stepwise forward regression analyses assessed significant predictors of maternal violence. C + women reported higher levels of violence by partners, but not violent behavior toward a partner than C - women. C + women whose children were in FC used more marijuana and cocaine, had more children and fewer prenatal visits than NFC women. Other maternal factors including age at infant birth, alcohol and cigarette use and measures of intellectual functioning were not different. Reported psychological distress symptoms, ‘% of women with symptoms in the clinical range (47 NFC vs 68% FC), and maternal report of overall and severe (maternal OV and SV) violence toward her partner was higher for C + women with children in FC than those NFC. Lifetime experience of overall violence toward the women was also higher for women with children in FC. Maternal OV, SV and partner violence were all predicted by levels of paranoid ideation. Additionally maternal OV and partner violence were predicted by the amount of alcohol use and maternal SV was predicted by marijuana use. Complete, ongoing assessment of psychological distress and concomitant use of other drugs in addition to cocaine is necessary to assess predisposition to violence and to offer effective drug treatment.

433

METHADONE TO BUPRENORPHINE CRO!B-OVER PROTOCOL

OUT-PATIENT,

K. Miotto, D. Wesson, J. Cunningham-Rathner, C. Charuvastra, C.L. Cantu, K. Garrison, J. Basch, J. Fradis, and W. Ling, Friends Research Institute, Easton, MD, Long Beach VA Medication Development and Research Unit, Long Beach, and UCLA, Los Angeles, CA Buprenorphine is being developed for office-based treatment of opiate dependence. Effective outpatient protocols for transition from methadone to buprenorphine are necessary. Previous studies have examined inpatient protocols to transition from methadone to buprenorphine. Common findings were that rapid taper from methadone with a transition to varying doses of buprenorphine produced moderate withdrawal symptoms occurring after initiation of buprenorphine treatment. Twenty-seven heroin-dependent individuals enrolled in this open-label, 14-day crossover pilot. Twenty four patients completed the protocol. Participants were stabilized on 40 mg of methadone for 7 days, followed by a transition to buprenorphine, liquid form, for 6 days. The dose of buprenorphine was increased over 3 days (2,4, and 8 mg). Withdrawal symptoms were measured using the Short Opiate Withdrawal Scale (SOWS). Prior to induction on buprenorphine, participants reported minimal withdrawal symptoms. The SOWS score doubled 60 min after infestion of 2 mg of Buprenorphine. The highest SOWS scores were reported pre-buprenorphine dose on the second day of induction. Eight five used heroin while on percent of participants buprlenorphine. Use of heroin during buprenorphine induction may impact the time period for stabilization. These findings suggest that abrupt transition from 40 mg of methadone to buprenorphine in an outpatient clinic is associated with a high rate of heroin use and withdrawal symptoms during induction. It is difficult to determine if these results are due to the antagonist effects of buprenorphine, insufficient buprenorphine dose, or confounding factors associated with continued street drug use. This data will guide future studies in developing protocols to crossover from methadone to buprenorphine in selected participants. 434 AFRICAN AMERICAN TEEN SMOKERS: TERISTICS TO CONSIDER FOR TREATMENT

CHARAC-

E.T. Moolchan, M.L. Robinson, I. Berlin, and J.L. Cadet, NIH, NIDA Intramural Research Program, Teen Tobacco Addiction Treatment Research Clinic, Baltimore, MD

Abstracts

s154

Previous reports have indicated ethnic differences in both tobacco-related morbidity and treatment outcome for smoking cessation in adults. We assessed several smoking-related characteristics in African American (AA) and non-African American (non-AA) teenagers applying to a cessation program. Seventy-nine teens (15.9 f 1.8 years, 68% females, 17% AA) responded via phone to media ads. Self-reported sociodemographic, medical and smoking-related data were obtained to determine eligibilAA teen applicants reported ity for participation. (ANOVA controlling for gender) fewer cigarettes smoked per day (10.6 + 5.8 vs. 20.0 + 9.0; P = 0.014), lower FTND scores (3.4 f 2.4 vs. 6.4 f 1.8; P = 0.001) longer time to first cigarette of the day and were more likely not to smoke if they were ill (P = 0.001) than non-AA teens. AA teens reported similar duration of smoking (3.2 _+ 1.6 vs. 3.2 _+ 1.5 years) and time elapsed between first cigarette ever smoked and daily smoking (0.5 + 0.8 vs. 0.8 4 0.9 years). AA teens had comparable motivation to quit scores (7.8 _+2.2 vs. 8.2 _+ 1.6) and similar frequency of disease conditions (e.g. asthma) to non-AA teens. If further confirmed in larger samples, these data suggest that study designs for cessation treatment aimed at African American youth should target lower levels of tobacco dependence. Supported by NIDA Intramural funds. 435 DEVELOPMENT OF A PROCEDURE TO CIGARETTECRAVINGINAFUNCTIONALMAGNETICRESONANCEIMAGING SCANNERUSINGVERBALSTIMULI

INDUCE

G. Moore, R. Aranas, J.M. Roll, S. Tiffany, and C.E. Johanson, Wayne State University, Detroit, MI Craving, when assessed via neural imaging technology, is generally induced by exposing participants to cues associated with their drug taking. However, Tiffany and colleagues have developed verbal scripts for the induction of craving episodes that may allow investigators to make more fine grained manipulations of variables that might be related to craving. The primary purpose of the present study was to ascertain whether we could induce craving for cigarettes using the verbally presented scripts designed by Tiffany and his colleagues in the functional magnetic resonance imagining (fMR1) environment. The fMR1 scan takes place in a confined, noisy setting and the participants are required to be very still. We were concerned that this environment might not be conducive to the subtle Tiffany craving induction procedures. To date, six regular cigarette smokers have participated in the study. During 1 h sessions participants were presented with 12 of the Tiffany scripts during fMR1 scans. Half of these scripts were designed to induce craving for cigarettes while the other half were neutral in content and served as controls. Results show that all but one partic-

ipant experienced robust craving following scripts relative to the neutral scripts. 436 REINFORCING EFFICACY PHETAMINE AND THE TROPANE DENTSANDRHESUSMONKEYS

the craving

OF COCAINE, D-AMANALOG PTT IN RO-

D. Morgan, D. Roberts, J. Lile, T. Moore, S. Nader, H. Davies, and M. Nader, Wake Forest University School of Medicine, Winston-Salem, NC The tropane analog PTT functions as a reinforcer in rodents, but only under certain experimental situations in monkeys. In the present study, the reinforcing efficacy of PTT relative to cocaine and D-amphetamine was examined in monkeys and compared to previously published data in rats (Roberts et al., Psychopharmacology 144: 1999). In that study, rodents trained to self-administer i.v. cocaine under a progressive-ratio schedule, had similar break points for cocaine, D-amphetamine and PTT, suggesting equal reinforcing efficacy. In the present study, rhesus monkeys chose between i.v. injections of cocaine and either saline, PTT or D-amphetamine. Cocaine preference decreased from - 90 to - 50% when the alternative was either PTT or D-amphetamine, indicating equal reinforcing strength of the three compounds. These data indicate that despite differences in measures of reinforcing effects with long-acting DA agonists in rodents and monkeys, measures of reinforcing strength provide concordant information. Supported by grant DA-06634. 437

SURVEY QUESTIONS INCORPORATING LOCAL STREET TERMS FOR DRUGS YIELD SUBSTANTIALLY INCREASED ACKNOWLEDGMENT OF USE AMONG ADOLESCENTS

A.R. Morral, T.M. Ryan, P. Ebener, and KM. Becker, Drug Policy Research Center, RAND, Santa Monica, CA Adolescents’ drug use reports are among the most closely observed indicators of the nation’s drug use problems. There is evidence, however, that these self reports suffer from considerable underreporting. A portion of this underreporting could result from the use in surveys of drug terms and classifications (e.g. Psilocybin, Hallucinogens, or Psychedelics) that are unfamiliar to youths who refer to drugs using street terms (e.g. Shrooms). We conducted three ethnically homogenous focus groups with Latino, Black and White adolescents in drug treatment to establish current Los Angeles street terminology. The collected terms were used to supplement a survey of adolescent probationer’s drug use. Conventional drug use questions were followed by items using street terms. Preliminary results from over 100 completed surveys

s155

Abstracts

indicate that the use of street terms increases reports of lifetime use by as much as 100% for some drug classes. These results suggest that a portion of adolescents’ drug-use underreporting may result from unfamiliar, abstract, or confusing drug terminology on surveys, rather than from adolescents’ intentions to conceal their drug use. ACKNOWLEDGMENT: This research was supported by grant KDl T111433 (Morral) from the SubHealth Services stance Abuse and Mental Administration, Center for Substance Abuse Treatment (SAMHSACSAT). 438

SEX

SPONSES

DIFFERENCES TO

IN

ANTICIPATORY

DRUG-DEPENDENT

SALIVARY STRESS

CORTISOL IN

CHILDREN

REOF

FATHERS

H.B. Moss, T.L. Hardie, M.M. Vanyukov, and J.K. Yao, Temple University School of Medicine, Philadelphia, and University of Pittsburgh, PA We previously reported that in anticipation of a modest stressor, preadolescent sons of fathers with a drug dependence disorder (DD + ) demonstrated a diminished salivary cortisol response compared to control boys. In addition, lower pre-adolescent anticipatory cortisol responses were associated with subsequent regular monthly cigarette smoking and regular monthly marijuana use during adolescence. However, no data was available concerning salivary cortisol responses in preadolescent daughters of DD + fathers. Consequently, in this study. we have examined the hypothesis that pre-adolescent DD + daughters show a similar salivary cortisol response to an anticipatory stressor as DD + sons. Salivary cortisol responses pre and post an anticipated stressor were determined in 15 daughters of drug dependent fathers and 19 daughters of control fathers, and compared to responses from 111 sons of drug dependent fathers and 172 sons of control fathers. Multivariate repeated measures analyses revealed an interaction of group x time such that DD + subjects had diminished anticipatory cortisol responses compared to controls. However, there were also significant between-subjects effects of sex such that daughters had consistently higher salivary cortisol concentrations than sons both before and after the stressor. The results may have etiological significance for both substance use disorders (over-represented among males) and mood disorders (over-represented in females). 439 ABUSE AND

PERFORMANCE TREATMENT: RESULTS

ACT

THE

MONITORING GOVERNMENT

OF SUBSTANCE PERFORMANCE

OF 1993

K.P. Mulvey, Center for Substance Abuse Treatment, Rockville, MD

The Government Performance Results Act (Public Law-103-62) (GPRA) of 1993, was enacted to improve stewardship in the federal government, linking resources and management decisions to program performance. This act requires all federal departments and agencies to: (1) Develop strategic plans that specify what they will accomplish over a 3-5 year period; (2) Annually set performance targets related to their strategic plan, and to annually report the degree to which the targets set in the previous year were met; and (3) Regularly conduct evaluations of their programs and use those results to ‘explain’ their success and failures based on the performance monitoring data. This paper addresses the process and current thinking about how GPRA is being implemented within the Center for Subsl:ance Abuse Treatment. One of the major activities of CSAT with regards to GPRA is the development of alcohol and drug abuse Core Client Outcome Indicators. The decision to use standard indicators of treatment improvement is mainly justified by wanting to promote comparability of outcome assessment across all c.lients, and the need for clear readily explained indicators of program performance. The primary use of the core indicators will be part of an assessment of outcomes to include the following three activities: Knowledge Development, Knowledge Application, and Targeted Capacity Expansion. This paper further discusses the potential this should have on program impact on substance abusing clients who receive treatment or prevention services. 440 SQUIRREL

ESTABLISHMENT MONKEYS

OF

M

SELF-ADMINISTRATION

P. Munzar, G.H. Redhi, and S.R. Goldberg, IRP, Baltimore, MD

IN

NIDA,

Although benzodiazepines are frequently abused by humans, in most preclinical studies with experimental anim,als they maintain only low rates of self-administration behavior. In the present study, self-administration of the short acting benzodiazepine midazolam was evaluated in squirrel monkeys originally trained to self-administer methohexital (0.1 mg/kg per injection), a short acting barbiturate. Monkeys (n = 3) had an opportunity to self-administer a range of midazolam doses i.v. (0.0003-0.003 mg/kg per injection) during daily 1 h sessions under a fixed-ratio 10 schedule of reinforcement with a 60 s time-out following each injection. Each dose of midazolam was tested for 5 consecutive sessions (Monday through Friday) with 5 intervening vehicle-extinction sessions between each dosage condition. Midazolam maintained high rates of responding in all subjects. The midazolam dose-effect curve was an inver:ed U-shape curve with maximal rates of responding averaging 1.01 responses/s at 0.001 mg/kg per injec-

S156

Abstracts

tion. This resulted in a mean of 48 injections/h. Subsequently, the effects of 5 consecutive daily treatments with flumazenil (3.0 mg/kg, i.m.), a benzodiazepine receptor antagonist, on midazolam (0.001 mg/kg per infusion), methohexital (0.03 mg/kg per infusion) and vehicle (saline) self-administration were evaluated. Flumazenil reduced self-administration of midazolam but not methohexital and transiently reinstated drugtaking behavior during vehicle extinction. The present data demonstrate that low doses of midazolam, well below doses producing sedation, can maintain high rates of self-administration in squirrel monkeys. 441

EFFECTS

SMOKING CAINE

IN AND

OF MEN

BUPRENORPHINE CONCURRENTLY

ON DEPENDENT

CIGARETTE ON

CO-

OPIATES

N.H. Mutschler, B.J. Stephen, N.K. Mello, J.H. Mendelson, Harvard Medical School, Southborough, and McLean Hospital, Belmont, MA Opioid drugs (heroin, methadone, buprenorphine) appear to increase cigarette smoking in opioid dependent men under several conditions. Buprenorphine is currently under FDA review as a possible treatment for opioid addiction. The present study was undertaken to examine the effect of buprenorphine on cigarette smoking in men that were concurrently dependent on both opioids and cocaine. Subjects were 23 adult men with a DSM-III-R Axis I diagnosis of concurrent opioid and cocaine dependence. Subjects were first detoxified with methadone (lo-50 mg per day) then maintained drug free for 6 days before random assignment to daily sublingual administration of either 4 or 8 mg of buprenorphine. Each subjects preferred brand of cigarettes was available ad libitum throughout the study. Subjects were required to press a button five times to receive one cigarette (FR 5). The number of cigarettes smoked during drug free, buprenorphine induction, and buprenorphine maintenance phases was analyzed. Subjects smoked significantly more cigarettes during the buprenorphine induction and maintenance phases than during the drug free phase (P < 0.05). Specifically, within a 24 h period, subjects smoked more cigarettes between 8 and 2 h. during buprenorphine induction and maintenance in comparison to the drug free period. Furthermore, the rate of smoking, defined by inter-cigarette intervals, was shorter during the buprenorphine induction and maintenance phases than during the drug free phase. The present findings suggest that the partial agonist, buprenorphine, increases smoking in subjects concurrently dependent on opiates and cocaine. Supported by Grants DA 07252, R18-DA06116, P50DA 04059, K05DA00101, K05-DA00064 from the NIDA, NIH.

442 TRIAL

A

DOUBLE-BLIND OF

RANDOMIZED

CONTROLLED

BUPRENORPHINE/NALOXONE

VERSUS

METHADONE/LOFEXIDINE

CATION

OF

(SUBOXONE) FOR

OPIATE-DEPENDENT

THE

DETOXIFI-

ADDICTS

J. Myles, F. Law, T. Raybould, S. Singh, E. Cockerill, and D. Nutt, Bristol Specialist Drug Service, Avon and Western Wiltshire Healthcare NHS Trust,University of Bristol, Bristol, UK Buprenorphine and lofexidine (an a2adrenergic agonist) are two relatively new medications with potential utility in opiate withdrawal. We tested the idea that the opiate withdrawal syndromes using these drugs will be mild and of about equal severity. Buprenorphine is the form of Suboxone was used, which is a combination product containing naloxone (4:l ratio), designed to limit misuse by injection. Outline of study: Two short-term intensive outpatient psychological and pharmacological opiate detoxification packages were compared. Pharmacological treatments included opiate stabilisation on fixed dose methadone 30 mg or Suboxone 4 mg/l mg, followed by lofexidine assisted methadone withdrawal or by a gradual Suboxone reduction (1 mg reduction twice a week). Psychological treatments included relapse prevention, motivational interviewing, problem solving, and low value contingent voucher reinforcement. Inclusion/Exclusion Criteria: 80 opiate dependent (DSM-IV) patients aged 1665 years with &3 years of opiate dependence using the equivalent of lo-30 mg methadone daily or &0.25 g heroin IV or &0.5 g heroin chased, without other drug or serious psychiatric comorbidity, were recruited over an 18 month period. Procedure: Patients attended daily for 5-9 weeks (except Sundays), for supervised consumption of medication, completion of opiate withdrawal scales, weekly counselling, thrice weekly on-the-spot opiates urine tests tied to low value voucher reinforcement. Patients had to provide 3 consecutively clean urine samples to progress to the detoxification phase. Those that failed to do this within 6 weeks were discharged. Results: The withdrawal curves and outcomes of both groups will be presented, which confirm that withdrawal severity was generally mild or very mild. ACKNOWLEDGEMENTS: This study was supported by Reckitt and Colman Products Ltd. Introduction:

443 CORTEX WORKING

INVOLVEMENT IN THE

0F EFFECTS

THE OF

MEDIAL

ABUSED

DRUGS

PREFRONTAL ON

SPATIAL

MEMORY

E.M. Nakamura-Palacios, R.W.D. Oliveira, J.T.C. Ferreira, L.C.S. Melo, L.R. Laranja, M.B. Lugon, and E.F. Curi, Federal University of Espirito Santo, Vitoria, ES, Brazil

Abstracts

The prefrontal cortex (PFC) is considered a site for working memory. The medial portion of the PFC (mPFC) is also part of a brain reward circuit. Our current studies have examined the involvement of the mPFC in the effects of abused drugs such as alcohol (ETOH), cocaine (COC) or D9-tetrahydrocannabinol (D9-THC) on 5 s, 1 or 4 h delayed tasks in an 8 arm radial maze. Male Wistar rats (250-300 g) trained in the radial maze and with bilateral cannulas implanted in the mPFC (B: 2,5 mm A, Ifr 1 mm L, 2,7 mm V) received intraperitoneal (IP) or intracortical (IC) drug administration. ETOH IC (32-180 mg, 5 min before session, n = 6 - 8) disrupted 5 s and 1 h delay performance in a dose-dependent manner, whereas ETOH IP (0.1X-1.8 g/kg, 5 min before session, 12= 6-13) tended to impair only the 1 h delayed task. The disruptive effect of ETOH IC (100 mg) on 1 h delayed task was blocked by naltrexone IC (56 mg, 15 min before session, n = 8). COC IP (1- 18 mg/kg, 5 min before session, n = 10-14) impaired 5 and 1 h delay performance in a dose-dependent manner whereas COC IC (lo- 100 mg, 5 min before session, IZ= ll13) tended to decrease the number of errors in the 1 h delay task, especially in the lower doses. The facilitating effect of COC IC (32 mg, n = 13) was particularly evident in the performance of a 4 h delay task and was attenuated by haloperidol IC (32 mg, 15 min before session, y1= 6). Both IP (0.32- 1.8 mg/kg, 30 min before session, 12= 7-8) or IC (32-180 mg, 5 min before session, n = 5) administration of D9-THC impaired the performance of 1 h delay task in a dosedependent manner. These results suggest that the disruptive effects of alcohol or D9-tetrahydrocannabinol, or the facilitating effects of cocaine on spatial working memory are, at least in part, mediated by the mPFC. This cortical area might also be important in the mediation of therapeutic effects of substances used in the treatment of drug abuse or dependence such as naltrexone for alcohol or haloperidol for cocaine abuse. 444 AND

HEPATITIS METHAMPHETAMINE

C

VIRAL

LOAD

FOLLOWING

COCAINE

ADMINISTRATION

R.P. Nath, D.S. Harris, R.T. Jones, A.K. Melby, and J. Mendelson, Drug Dependence Research Center, Langley Porter Psychiatric Institute, University of California, San Francisco, CA Hepatitis C virus (HCV) is a common cause of chronic blood-borne infection and liver disease. Injection drug use is the single most important risk factor for acquiring HCV infection. Reports suggest that high plasma levels of HCV RNA (viral load) may predict poor treatment response, correlate with advanced stage of disease, and be a risk factor for hep-

s157

ato-cellular carcinoma in patients with cirrhosis. Measures of viral load are commonly obtained to monitor viral activity. In a recent experiment assessing the effect of cocaine infusions on development of tolerance and sensitization to cocaine, one HCV + subject received either placebo or 6 mg/kg body weight cocaine as a 12 or 24 h infusion. Forty-eight hours after cocaine exposure, baseline HCV RNA increas’ed from 0.81 x lo6 to 6.37 x lo6 copies/ml in one session and from 0.64 x lo6 to 4.28 x lo6 copies/ ml in another (sensitivity 2 x lo3 copies/ml). It is unlikely that these 7-8 fold increases were spontaneous fluctuations. The data suggest illicit drug use by HCV + patients may lead to fluctuating viral loads and an increased risk of disease progression. HCV RNA levels are being measured in a similar experiment with d- and I-meth-amphet-amine. Since the study blind remains in place, results will be available by approximately April 2000. Supported by NIDA grants DA10939 and DA12521. 445

THE

METABOLISM ACETYLMETHADOL

EFFECT AND

OF

KETOCONAZOLE

PHARMACODYNAMICS IN

OPIATE-NAIVE

ON OF

THE

L-ALPHA-

INDIVIDUALS

J.A. Neff, D.E. Moody, W. Huang, D.E. Rollins, and S.L. Walsh, University of Utah, Salt Lake City, UT, Johns Hopkins University School of Medicine, Baltimore, MD The effects of ketoconazole (K) on the in vivo metabolism and pharmacodynamics of LAAM (L) were investigated. Subjects were given an oral dose of L (5 mg/70 kg) plus K (400 mg) in one session and L alone in another in random order (N= 8 to date). Pupil diameter and subjective measures were recorded and plasma and urine samples were collected over time. Concentrations of L and its active metabolites, norLAAM (NL) and dinorLAAM (DL), were measured in urine samples using GC/MS. The metabolic ratio of L/(NL + DL) was significantly increased 7.7 times (P= 0.005) by K, while the metabolic ratio (L + NL)/DL was significantly increased 11.1 times (P = 0.003). K increased both the time to maximum pupil constriction (3.1 times) and the AUC pupil values (2.3 times). The effect on time to maximum constriction was significant (P = 0.05). These results are consistent with a decreased rate of formation of NL and DL associated with coadministration of K. The pupil findings may be attributed to K having a greater inhibitory effect on the conversion of NL to DL than it does on L to NL. The resulting build up of NIL may lead to a higher level and prolonged duration of pharmacological activity following L administration. Supported by ROl-DAlOlOO.

Abstracts

S158

446 AND KEYS:

EFFECTS

OF

MU

FOOD-MAINTAINED THE

ROLE

OPIOID

AGONISTS

RESPONDING OF MU

AGONIST

ON IN

COCAINE-

RHESUS

MON-

EFFICACY

S.S. Negus and N.K. Mello, McLean vard Medical School, Belmont, MA

Hospital,

Har-

Both preclinical and clinical studies suggest that opioid agonists may alter the abuse-related effects of cocaine. To further examine the interactions between opioids and cocaine, the purpose of the present study was to compare the effects of chronic treatment with high, intermediate and low efficacy mu agonists on cocaine self-administration in rhesus monkeys. Monkeys were trained to self-administer cocaine (0.032 mg/kg per injection) and 1 g food pellets under a second-order schedule during multiple daily sessions of cocaine and food availability. Subsequently, the effects of chronic treatment with saline on cocaine- and food-maintained responding were compared with the effects of chronic treatment with the high efficacy mu agonist fentanyl (0.001-0.01 mg/kg per h), the intermediate efficacy mu agonist morphine (0.032-0.32 mg/kg per h) or the low efficacy mu agonist nalbuphine (0. I - 1.O mg/kg per h). Saline and each dose of the mu agonists were administered by repeated infusions (3 infusions/h) for 7 consecutive days. All three mu agonists produced dose-dependent and sustained decreases in responding maintained by cocaine and downward shifts in the cocaine self-administration dose-effect curve. However, these compounds differed in the degree to which they also decreased rates of food-maintined responding. Fentanyl produced the greatest suppression of foodmaintained responding at doses that also decreased cocaine self-administration, whereas nalbuphine produced the least suppression of food-maintained responding. These results suggest that low efficacy mu agonists may decrease cocaine self-administration more selectively than high efficacy mu agonists. Supported by grants P50-DA04059, ROl -DA025 19 and K05-DA00101 from NIDA, NIH. 447 HEALTH

WOMEN

RESPONSES

TO

ONLINE

DRUG

PROBLEM/

SCREEN

S. Nemes, J. Hoffman, R. Landis, K. Holtz, and C. Zeiler, Danya International, Inc., Silver Spring, MD Hypothesis: As part of a study of the Drug and Alcohol Problem Assessment for Primary Care (DAPA-PC), a separate Health and Safety Screen was administered to patients in a primary care setting. It was hypothesized that although women are less likely to report drug use, they will be more likely to report other health and safety problems on a brief computerized screening assessment. DAPA-PC is a self-administered (via com-

puter), Internet-based screening instrument which features automatic scoring, generation of a patient profile for medical reference, and presentation of unique motivational messages and advice. Methodology: One hundred and eighty-one women and 140 men were administered the Health and Safety Screen along with the DAPA-PC. Hair and urine specimens were also, as objective measures of drug use. The Health and Safety Screen asks several questions about trauma, physical/emotional abuse, depression, drug and alcohol use. Results and importance: Men and women differed in their responses on 6 out of 12 on the Health and Safety Screen. More men reported having been in a physical fight, having used drugs, having drunk alcohol, and having smoked or chewed tobacco in the past five years. In addition, men reported drinking a greater number of drinks on a typical occasion than women did. A larger percent of men also responded positively to drug use when compared to women on the Drug and Alcohol Problem Screen. There was also a difference between the average total score for men and the average total score for women. Men had higher scores, indicating greater risk for drug problems in this sample. Our findings suggest that it may be appropriate to have different screening criteria for women and men, particularly in terms of drinking habits. 448 AND

A

COMPARISON

OF

PHARMACOKINETICS

IN MAINTENANCE

THE OF

PHARMACODYNAMICS

METHADONE

AND

LAAM

PATIENTS

D.A.L. Newcombe, J.M. White, A. Menelaou, M.-L. Brixen, B. Christensen, S. Mikhail, and A.A. Somogyi, University of Adelaide, Australia and Drug and Alcohol Services Council of South Australia, and Royal Danish School of Pharmacy, Australia It has been reported that up to one third of patients on methadone maintenance complain of withdrawal (nonholding) during the interdosing interval (Dyer et al., 1999). Dyer reported that ‘non-holders’ had a higher maximum rate of decline in racemic methadone concentration than ‘holders’. Therefore there was a very steepconcentration effect relationship for withdrawal. LAAM is a promising alternative to methadone as its more stable plasma profile and longer duration of action promises to help methadone ‘non-holders’. Patients participating in this study were at steady state plasma concentrations of both methadone and LAAM and underwent two testing sessions (24 h for methadone: 48 h for LAAM), at least 6 weeks apart, in an inpatient facility. Blood was sampled on 13 occasions throughout the methadone session and on 15 occasions throughout the LAAM session. A number of measures of opioid effect and withdrawal were also made. Drug

Abstracts

free controls (age and sex matched) underwent a similar testing session over a 48 h period, but did not have blood sampled. The temporal pattern for each measure was consistent with maximal opiate effect and suppression of withdrawal occurring at peak plasma level of LAAM and metabolites and methadone. LAAM produced a more prolonged and persistent opiate effect, as measured by pupil diameter and respiratory rate, than methadone, which is consistent with its more stable plasma profile. Results show that LAAM ameliorates withdrawal and improves the mood of methadone ‘nonholders’. 449

CORTICAL

CAINE-DEPENDENT PHOTON METHOD

BLOOD

FLOW

INDIVIDUALS

EMISSION

COMPUTED

ABNORMALITIES EVALUATED

IN

co-

BY SINGLE

TOMOGRAPHY:

A

OF QUANTIFICATION

S. Nicastri, V.D. Calhoun, G.D. Pearlson, CA. Buchpiguel, A.S. Tanaka, M.C. Leite, and A.G. Andrade, University of Sao Paulo, Sao Paulo, Brazil, and Johns Hopkins University, Baltimore, MD The objective of this study was to quantitatively examine a pattern of cerebral perfusion abnormalities in cocaine-dependent individuals described as ‘patchiness’ or inhomogeneity in previous qualitative emission tomographic imaging studies. We applied a quantitative measure of inhomogeneity in cocaine-dependent individuals. High-frequency variance in cortical profiles served to indicate inhomogeneity in the distribution of radiotracer in the cerebral cortex. For this reason, the study analysis focused upon variance frequencies in cortical profiles. This method originally was developed for evaluation of HIV-infected individuals, who show a pattern of cerebral perfusion abnormalities somewhat similar to that of cocaine-dependent subjects. Regional cerebral blood flow was examined in 14 neurologically asymptomatic cocaine-dependent individuals and 14 normal controls using single photon emission computed tomography with radiotracer [99m-Tc]-L, L-ethyl cyteinate dimer (ECD). Quantitative analysis was performed using circumferential profiles of cerebral cortical perfusion. Fourier transform power spectra of the profiles were examined indices of patchiness in tracer distribution. Normal controls were characterized by strong low-frequency and weak high-frequency power. Cocaine dependence was associated with a power shift from low to high frequencies (P < 0.05). Increased high-frequency variations in cocaine-dependent subjects indicate diffuse cortical perfusion changes compared with normal controls. This quantitative method may have some utility in evaluation of treatment of cocaineinduced cerebral blood flow abnormalities.

s159

450

RELATIONSHIPS

DRUG-TAKING OPIOID

BETWEEN

AND

SYSTEMS

VULNERABILITY

IMBALANCE STUDIED

IN IN

ENDOGENOUS

DIFFERENT

RAT

TO

CCK/ STRAINS

F. Noble, P. Coric, J.L. Wilson, and B.P. Roques, UniversitC RenC Descartes, Paris, France Drug-preferring Lewis rats and drug non-preferring Fischer rats can serve to study genetically-determined differences in behaviour to drugs of abuse. We investigated the differences between Lewis, Fischer and Sprague-Dawley (SD) rats to the analgesic effects induced by endogenous and exogenous opioids, associated or not with CCKB antagonists. In the tail-flick test, morphine administration produced an equally potent peak antinociceptive effect in all three strains but was longer lasting in Lewis rats. Administration of the enkephalin-degrading enzymes inhibitor RB 101 produced an antinociceptive effect in Lewis and SD but not in Fischer rats in the tail-flick test. However, RB 101 could produce an antinociceptive effect in all three strains of rats in the tail-pinch test. Administration of the CCKB antagonist PD-134,308 alone had no effect in Lewis or SD rats but produced a long-lasting antinociception in Fischer rats in the tail-flick test. However, although PD-134,308 potentiated the antinociceptive response of RB 101 in Lewis and SD, it had no effect in Fischer rats. In conclusion, these results seem to indicate that the counteracting effect of CCK on opioid analgesia is stronger in Fischer than in Lewis or SD rats. This imbalance in endogenous CCK/opioid systems could be at the basis of individual differences in vulnerability to drug-taking. 451

A

INCREASES

COCAINE-SELECTIVE THE

COCAINE

MONOCLONAL PRIMING

THRESHOLD

ANTIBODY IN RATS

A.B. Norman, W.J. Ball, M.K. Norman, M.R. Tabet, and V.L. Tsibulsky, University of Cincinnati College of Medicine, Cincinnati, OH The cocaine-induced priming of cocaine self-administration in rats represents a useful model of relapse. The minirnum level of cocaine required to reinstate maintained self-administration (the priming threshold) is hypothesized to represent a quantitative measure of the susceptibility to cocaine-induced relapse. We measured the effect of the cocaine-selective monoclonal antibody B4ElO on the priming threshold in rats. Cocaine priming threshold was measured in individual rats for at least 5 consecutive days. Rats (n = 5) were then injected with B4ElO (40 mg/kg i.v.) and the cocaine priming threshold was measured for up to 8 days following the injection. In another study increasing daily doses of B4ElO were administered i.v. to provide cumulative total doses of 1, 3 and 10 mg/kg. Cocaine priming

Abstracts

S160

thresholds were significantly increased by approximately 400-500% following the injection of the higher doses of B4ElO. Priming thresholds were not significantly different from baseline levels after 3-5 days. Passive immunotherapy with anti-cocaine antibodies may be useful for the prevention of cocaine induced relapse. Supported by DA 12043.

452 MULTIPLE VENOUS ROUTES OF COCAINE ERY DURING LONG-TERM SELF-ADMINISTRATION IES IN RATS

DELIVSTUD-

M.K. Norman, V.L. Tsibulsky, A. Warner, and A.B. Norman, University of Cincinnati College of Medicine, Cincinnati, OH The pharmacokinetics of cocaine fundamentally determines the rate of cocaine self-administration. Cocaine disappearance from the vascular system is consistent with a rapid distribution from a central compartment (including the brain) to peripheral tissues, followed by a slower elimination. We investigated whether drug distribution rates within the central compartment were also a significant factor in the rate of cocaine self-administration. Rats were cannulated in both jugular veins and one or both femoral veins. There were no differences in the inter-injection intervals of cocaine self-administration, at any unit dose, via any of the veins. Furthermore, the induction times of methohexital anesthesia were not different via the femoral or the jugular veins. Therefore, distribution times of these drugs within the central compartment appear negligible. The occlusion of the jugular veins has no apparent effect on the distribution of cocaine to and from the brain. Consequently, if the jugular catheters become occluded, other veins can be sequentially cannulated during long-term experiments with no change in self-administration, thereby increasing the between assay reliability and decreasing the use of animals. Supported by DA 12043.

453 DESIPRAMINE TREATMENT FOR COCAINE-DEPENDENT PATIENTS WITH DEPRESSION E.V. Nunes, D. McDowell, J. Rothenberg, A. Seracini, and H. Kleber, Columbia University, New York State Psychiatric Institute, New York, NY Various antidepressant medications have been tested as treatments for cocaine dependence with little evidence of efficacy. In these trials cocaine dependence was conceptualized as a unitary syndrome, and medications were tested in unselected samples. This study pursued an alternative model - that cocaine dependence is heterogenous with subtypes which respond to different treatment approaches. Depression is considered a promising target because it is the most common comor-

bid psychiatric disorder in substance-dependent samples, and is associated with poor outcome. Subgroup analyses of prior antidepressant trials (desipramine, bupropion, imipramine) have suggested efficacy against cocaine abuse in the depressed subgroup. A 12-week randomized, placebo-controlled trial was therefore conducted to determine whether desipramine is superior to placebo in reducing depressive symptoms and cocaine use in cocaine dependent patients with current DSM-III-R depressive disorders. Patients were selected by SCID interview and followed with the Hamilton Depression Scale, self-report cocaine use, and urine toxicology. The study has been completed with N = 121 patients randomized. An analysis of the efficacy of desipramine in this sample will be presented.

454 A

NEWLOOKATTHEASSOCIATIONBETWEENCOCAINE USE AND HIV/STDs AMONG INNER-CITY KITCHEN ATTENDEES

SOUP

L. Nuttbrock, A. Rosenblum, S. Magura, H. McQuistion, and H. Joseph, NDRI, .Project Renewal, OASAS, New York, NY We examined the associations of cocaine use with HIV/ STDs in a sample of 184 soup-kitchen attendees using a medical van in Manhattan (male = 66O/o;black or Hispanic = 81%; cocaine use = 75%; ever injected = 22%). Controlling for injection history. (Years of regular cocaine use (coded as 0; l-3; 3 + ) was significantly associated with HIV antibodies (odds ratio of 2.11, P = 0.05) and a pattern of associations with STDs indicative of heterosexual transmission: syphilis exposure (odds ratio = 2.07, P = 0.05) hepatitis B core antibodies (odds ratio = 1.50, P = 0.05) and hepatitis C antibodies (odds ratio = 1.48, P = ns). The unique contribution of cocaine use to the heterosexual transmission of HIV/ STDs was further indicated by correlations of biological (hair assays) and self-reported measurements of cocaine use (but not opiates) with self-reports of high risk sexual behavior among the women (number of partners and selling sex) and men (number of partners and buying sex). The high prevalence of cocaine use in this sample and the strong evidence linking it to heterosexual transmission of HIV/STDs underscores the need for effective cocaine treatment and HIV interventions tailored to the large numbers of cocaine users in inner cities. This study was supported by NIDA Grant No. 5 ROl DA 10432-03.

455 CLINICALTRIAL OUTCOMES OF ENHANCED MANAGEMENTFORDRUGUSERSINASOUPKITCHEN

CASE

P. Nwakeze, S. Magura, A. Rosenblum, H. Joseph, National Development and Research Institutes, NYS Office of Alcoholism and Substance Abuse Services, New York, NY

Abstracts

This study determined client outcomes for two ‘linkage and coordination’ models of case management - an individual case manager model and an enhanced model consisting of a case manager and a peer helper - in an inner-city meal program. Soup kitchen guests seeking social services were voluntarily randomly assigned to one of two conditions - Linkage and Coordination (L/C) plus Peer Consumer Advocacy (PCA) [N = 571 or Linkage and Coordination (L/C) only [N = 531. The PCAs provided guests with social and instrumental support to help them implement their case plans. Almost all study participants were unemployed and reported drug or alcohol misuse. Participants who received L/C plus PCA, compared with those receiving L/C only, met more often with the case manager, kept more service referral appointments and received more entitlements and community services. Other significant predictors of appointments kept were older age and limitations in activities of daily living. The L/C plus PCA participants also showed better outcomes for cocaine/crack use, but not for heavy alcohol or other drug use. NIDA Grant No. ROlDA10188. 456 STUDIES OFSUBSTANCE P, ITS CONVERTINGENZYMES AND ITS N-TERMINAL FRAGMENT SUBSTANCE Pl-7 DURING OPIOID WITHDRAWAL IN MALE RATS F. Nyberg, Q. Zhou, K. Karlsson, and P. Le Greves, Uppsala University, Uppsala, Sweden Previous studies have demonstrated that the undecapeptide substance P (SP) may modulate the abstinence reaction to opioid withdrawal. Moreover, its N-terminal fragment SPl-7 was shown to inhibit the intensity of withdrawal reactions in morphine dependent mice. We have recently shown that the level of this fragment is increased following naloxone-precipitated withdrawal in rats 1. The level of SPl-7 is regulated by several endopeptidases, one of which is named SP endopeptidase (SPE). In this presentation we describe a study where an SPE-like activity was measured in CNS tissues of male rats during morphine tolerance and withdrawal. The results indicated that the enzyme activity was significantly increased in periacqueductal grey, spinal cord, substantia nigra and in the ventral tegmental area (VTA) during withdrawal. The observed enhancement in enzyme activity in these areas is in agreement with our previous finding that the level of the SPl-7 fragment is elevated in these brain areas during naloxone-precipitated withdrawal. Furthermore, in some tissues including VTA a correlation between the SPE-like activity and the intensity of the abstinence reaction was observed. The present work also includes studies where i.c.v. injections of SPl-7 was shown to inhibit signs of opioid withdrawal in the male rat.

S161

Studies on the expression of the gene transcript of NMDA receptor subunits after i.c.v. injections of SPl-7 indicated that these transcripts were affected by the heptapaptide. This observation suggests that glutamate transmission is involved in the effects mediated by the N-terminal SP fragment. 457 MMPI

RASCH INTERVALSCALINGOFANXIETY-RELATED SCALES AS PREDICTORS IN DRUG ADDICTION

H. lYyborg and H. Albeck, International Research Center for Psychoneuroendocrinology, Institute of Psychology, University of Aarhus, Denmark MMPI (Minnesota Multiphasic Personality Inventory) scales have traditionally been used in psychiatric diagnosing. Though the validity of these scales has been demonstrated, it has been suggested in the statistical literature, that the additive raw score method of calculation is not optimal for scale construction, because of the rank categorical structure of the employed items, this leads to scales with uncertain interval properties. The Rasch interval scales of measurement are designed to obtain interval properties of the scales extracted from the underlying items. In this study we specifically looked at the MMPI inventories concerned with anxiety namely ‘Acute Anxiety State’ (AAS) and ‘Anxiety and Tension’ (AT) and their involvement in drug using behavior. At our disposal we had a database with the full .MMPI battery of items for 4462 American men (mean age = 38.4 year, SD = 2.5 year). The Rasch scale showed a high Spearman rank correlation with the MMPI raw score based scales R(AAS) = 0.999; t(4460) = 1321.8; P < 0.0001 and R(AT) = 0.990; t(4460) = 466.8; P < 0.0001, as expected. Alcohol and general drug abusers (DSM-III) both showed a significantly elevated level of AAS and AT over non-abusers. We have previously demonstrated, that testosterone is a factor in drug addiction; when testosterone was factored out, the AAS and AT still showed an independent effecl: on drug addiction behavior. 458 EVALUATING TREATMENT ADOLESCENT SUBSTANCE-ABUSERS: DER VERSUSPSYCHOPATHY

OUTCOME CONDUCT

AMONG DISOR-

M.L. O’Neill, L. Korein, and V. Lidz, Institute for Addictive Disorders, MCP Hahnemann University, Philadelphia, PA Assessment and clinical progress data for 67 court-adjudicated, substance abusing adolescents in a 3-month partial hospital treatment program were analyzed to evaluate the value of conduct disorder (CD) and psychopathic characteristics as predictors of treatment out-

Sl62

Abstracts

comes. Diagnoses of CD were based on personal interviews using the Structured Clinical Interview for DSM IV (SCID) section for CD conducted by graduate students in clinical psychology. Psychopathic characteristics were based on reviews of extensive assessment and intake data using the Psychopathy Checklist:Youth Version (PCL:YV; Forth, Kosson, & Hare, in press) conducted by two independent graduate student raters blind to treatment outcome and study objectives. For purposes of comparison with the adult literature, PCL:YV total scores of 30 or higher indicated psychopathy. Both CD and psychopathy were hypothesized to be negatively associated with key measures of treatment engagement and progress. Contrary to our hypothesis, a diagnosis of CD did not differentiate clients on rate of attendance (t = -- 0.58, P = 0.57) quality of participation (t = 0.18, P = 0.86), number of consecutively clean urines (t = 1.48, P = 0.15), and overall clinical improvement (t = 0.73, P = 0.47). Consistent with our hypothesis, psychopathic characteristics significantly differentiated clients on rate of attendance (t = 2.33, P < 0.05) quality of participation (t = 2.06, P < 0.05), number of consecutively clean urines (t = 2.97, P < 0.01) and overall clinical improvement (t = 3.99, P < 0.001). Our findings suggest that psychopathic characteristics, as measured by the PCL:YV, deserve further evaluation in clinical research with delinquent and substance abusing adolescents. 459 EARLY ONSET DRUG USE AMONG CHILDREN OF PARENTS WITH ALCOHOL PROBLEMS: DATA FROM THE NATIONALHOUSEHOLDSURVEYONDRUGABUSE I.S. Obot, F.A. Wagner, and J.C. Anthony, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, MD Aim: There is good evidence that children of parents with alcohol problems have more drug involvement, plus related mental health and behavioral problems. In this study, we sought to estimate the degree to which these children might be more likely to initiate drug use precociously. Method: A national sample of 3229 parent-child pairs was identified within public data files of the National Household Surveys on Drug Abuse (NHSDA), 1995-97. Alcohol dependence of one parent (AD + vs AD - ) was assessed by that parent’s report of three or more dependence manifestations. Independently, the 12-17 year old children answered standardized survey questions on age at first use. Results: In analyses contrasting 127 AD + pairs with 3102 AD pairs, AD + children were more likely to have used tobacco (estimated odds ratio, OR = 2.0, 95% CI = 1.442.8) alcohol (OR = 1.6, 95% CI = l.l-2.3), and marijuana (OR = 2.1, 95% CI = 1.4-3.2). Survival analyses clarified excess risk of early-onset drug use:

e.g. by age 17, an estimated 70% of AD + children had smoked tobacco, 72% had started drinking, and 38% had smoked marijuana, versus 45, 57, and 26% of AD - children. Importance: This new evidence helps consolidate a case that children of parents with alcohol problems experience precocious drug use. Additional studies, now underway, will clarify sources of the association, such as whether it might be traced back to illicit drug use by AD + parents, or through markers of individual, household, and neighborhood vulnerability. ACKNOWLEDGMENTS: NIDA T32DA07292 and the NHSDA research group at SAMHSA and RTI 460 CHARACTERISTICS OF DRUG ABUSE: A QUALITATIVEMULTICENTERSTUDYINTURKEY K. Ogel, Ruh de Sinir Hastaliklari ATEM, Bakirkoy, Istanbol

Hastanesi,

AM-

The first phase of the study is qualitative research based on key informant interviews conducted in 10 different regions of Turkey and Cyprus. One hundred and fourty nine males and 37 females, totalling 186 informants, were interviewed. Seventy-two of them were drug abusers. Drug abusers were described as persons who have problems with their families and society. Informants defined drug abusers in two dimensions as sick and criminal. Abusers who use pills were described as more aggressive, criminal, self-mutilating and psychopathic. Cannabis was stated as the most frequently used drug. Pills and solvent use were also high. It was found that heroin is frequently used by sniffing and inhalation; intravenous use is rare. Solvents are common in small children who have no families and live in streets. In every region, specific districts were found for drug use and sale. Older parts of the city and low socioeconomic status are the common characteristics of these districts. Production and dealing of drugs in a region was found as an important predicting factor for drug use in a region. Generally, a relationship was found between drug use and immigration. Drug use was frequent among Turkish people who lived in Europe. Most of the drug users are male and a small proportion of them are female. Abusers who use pills and cannabis have a lower level of education, in contrast to heroin and cocaine users. Most of the users do not work. Work impairment could not be found among cannabis users, despite long-term use. 461

POST-TRANSPLANT SUBSTANCE ABUSE OTHEROUTCOMESINPATIENTSWITH ALD

AND

M.E. Olbrisch, K. Ashe, D.L. Haller, M. Shiffman, R.A. Fisher, and A.M. Best, Medical College of Virginia of Virginia Commonwealth University, Richmond, VA

Abstructs

Subjects: Outcomes for 32 patients with alcoholic liver

disease (ALD) who underwent orthotopic liver transplant (OLT) were compared to those for 32 non-ALD controls matched for age, gender, and date of transplant. Each group contained 25 males and 7 females with a mean age of 51. Procedure: Survivors (N = 50) were interviewed by phone regarding current symptoms, substance use, work status, leisure and marital satisfaction, and quality of life. Collateral reports were obtained from significant others. Minimum time from transplant to interview was 1 year. Results: Survival curves were identical for the two groups and there were no differences in recent physical, cognitive, or emotional symptoms except ALD subjects had more tremors. Only half of the subjects in each groups were working and the majority (75%) were dissatisfied with their job performance. Barriers to optimal job performance included concentration difficulties (72%), fatigue (30%) difficulty coping with stress (60%) and needing to take frequent sick days (65%). Most subjects (71%) enjoyed their leisure time, although fatigue (78%), medical restrictions on activity (35%), boredom (30%), and loss of friends since surgery (13%) interfered to some extent. Controls reported greater variability in quality of partner relationship, with more ALD patients (95%) describing good relations; 75% of both groups reported being closer to their partner since transplant. Only 17% of subjects reported having a drink since transplant and no between groups differences were observed. Self-reports were verified by collaterals. One ALD subject relapsed to regular alcohol use. No subject admitted use of illicit drugs, although one control was later found to be benzodiazepine dependent. Interestingly. 28% of the ALD group expressed never having had a problem with ETOH, while a lower percent of collaterals (11%) agreed. The majority of ALD subjects (63%) had never participated in drug treatment or attended AA (62%) and 81% were out-of-treatment at time of interview. QOL for both groups was rated 7.75/10. Discussion: Overall, ALD subjects were doing as well or slightly better than controls. These finding suggest that addictions treatment may not be necessary for all transplant patients with ALD. Rather, careful evaluation, patient education, behavioral contracting, a documented (drug screens and family corroboration) period of sobriety, and case management resulted in excellent outcomes. 462

NUTRITION THERAPY IN LAAM-MAINTAINED TIENTS: A RANDOMIZED, SINGLE BLIND, PILOT

PASTUDY

A. Oliveto, K. Sevarino, S. Baker, F. DePourcq, G. Onofrio, K. Gonsai, A. Feingold, and T.R. Kosten, Yale University, New Haven, and VA CT Healthcare System, West Haven, CT

S163

This study examined the effects of a nutritional supplement plus a healthy lifestyle-oriented therapeutic approach on treatment response and health status in an opioid-dependent population maintained on LAAM. In this 24-week, single-blind, randomized clinical trial, participants were maintained on LAAM and randomly assigned to one of two cells: placebo nutritional supplemerrt with standard relapse prevention group therapy or nutritional supplement with a healthy lifestyle-oriented group therapy focusing on relapse prevention, nutr:ction/fitness education and lifestyle changes. Participants attended weekly group sessions and monthly individual sessions. Assessments included drug use, as measured by thrice-weekly urinalyses and self-reports, nutrj tion status, health behaviors, and treatment retention. Data collection is in progress. Thus far, 49 participarrts (35M/14F; 37C, 8AA, 4H) have been entered into the study. Groups did not differ on baseline characteristics or retention. Preliminary analyses based on hierarchical linear modeling indicate that opioid-positive urines decreased more rapidly in the standard group relative to the lifestyle group. The standard group decreased while the lifestyle group increased their intake of nutrients B2, B6, D, and zinc as well as the frequency of relaxation behaviors. These preliminary results suggest that a treatment package focusing on healthy lifestyle changes may facilitate health-promoting behaviors to a greater degree than standard relapse prevention treatment. Supported by NIDA grants DA50853 and DA05626. 463 HAVE MALE

FEMALE METHADONE-MAINTENANCE MORE COCAINE-POSITIVE URINES COUNTERPARTS

THAN

CLIENTS THEIR

K.P. Olshausen, D. Epstein, A. Umbricht, and K.L. Preston, NIDA Intramural Research Program, Baltimore, MD In the past, gender differences in substance use disorders have been scrutinized and possible implications for treatment have been suggested. Conflicting reports exist concerning the sex differences in treatment outcome. We evaluated the effects of sex and a number of other patient characteristics on outcome in 122 men and 90 wornlen participating in two treatment studies conducted in our clinic from 1994 to 1999. Both studies compared voucher-based abstinence reinforcement therapy and different forms of counseling for treatment of cocaine abuse in methadone-maintenance patients. An initial ANOVA showed a main effect of sex on mean% cocaine-positive urine specimens, with women having more positive urines than men (overall mean% positive A: SD was 80.4 + 25.7% for women, 68.3 f 29.3% for men). This remained significant in an ANCOVA controlling for age, ethnicity, education, income, em-

s164

Abstracts

ployment, and experimental group. Significant effects were also found for contingency condition (those getting vouchers contingent on cocaine-negative urines had more negative urines) and income (those with higher incomes had fewer negative urines). There was no significant interaction between sex and these factors. Opiate-positive urines were not more frequent in women than in men; the trend was in the opposite direction. Response to contingency management treatment was similar across sexes, although women continued to have higher rates of cocaine-positive urines. Further psychiatric, psychological and social variables will be analyzed for possible explanations for the discovered sex difference. 464

HIV RISK AMONG YOUNG FEMALE INJECTION DRUG USERS WHO HAVE SEX WITH WOMEN IN BALTIMORE,MARYLAND

D.C. Ompad, CM. Fuller, C. Latkin, D. Vlahov, and S.A. Strathdee, Johns Hopkins School of Public Health, Baltimore, MD, and Center for Urban Epidemiologic Studies, New York Academy of Medicine, New York, NY Objective: Previous studies have reported that bisexual women have higher rates of both sexual and drug use behaviors as compared to heterosexual women. This study investigated drug use and sexual risk factors among female bisexual injection drug users (IDU) in Baltimore, Maryland. Methods: Adolescent and young adult (age 15-30) female IDU who initiated injection drug use I 5 years prior were prospectively studied (n = 137). Drug and sexual risk behaviors were assessed through interviewer-administered questionnaires. Participants were tested for HCV and HIV antibodies. Logistic regression was used to identify risk behaviors reported at baseline among females who identified as bisexual compared to those who did not. Results: At baseline, 75.2% were African American. Median age was 25 (range 16-30). Age at initiation of injection was 22 (range 13-30). Prevalence of HCV and HIV was 59.5 and 13.2%, respectively. Of the young female IDU, 82.4% self-identified as heterosexual, 13.2% as bisexual, and 4.4% as lesbian. Self-identified bisexual women were more likely to be HIV prevalent [OR = 3.21, 95% CI: 0.97, 10.56)], have been raped (OR = 5.93, 95% CI: 2.03, 17.28) have traded sex for money or drugs (OR=4.15, 95% CI: 1.14, 15.11), have >two sex partners of any gender in past 6 months (OR = 10.96, 95% CI: 2.40, 50.00) and report shooting gallery use (OR = 2.81, 95% CI: 0.87, 9.04) compared to women who did not self-identify as bisexual. Conclusions: Female IDUs self-identifying as bisexual have multiple risk factors for HIV and sexually transmitted diseases. Further prospective investigation is warranted to investigate causal associations.

465 BASELINEDRUGANDALCOHOLUSEPATTERNSIN PATIENTS SEEKING TREATMENT FOR COCAINE COHOLDEPENDENCE

AND AL-

D.W. Oslin, K.M. Kampman, J. Betteridge, K.A. Hovan, J.R. Volpicelli, and H.M. Pettinati, University of Pennsylvania and Veterans Affairs Medical Center, Philadelphia, PA Background: Treatment outcome in patients dependent upon both alcohol and cocaine may be affected by baseline patterns of drug use. For instance, clinical observations suggest that cocaine dependence severity is better than alcohol dependence severity in predicting successful detoxification (detox) from cocaine and alcohol, This study compared the relative severity of cocaine and alcohol dependence among cocaine and alcohol dependent subjects undergoing detox from cocaine and alcohol. Methods: Subjects included 84 alcohol and cocaine dependent subjects admitted for outpatient detox prior to entering a clinical trial with naltrexone. Fifty-three subjects completed detox and randomized into the clinical trial and 31 failed to complete detox. Outcome measures included the Addiction Severity Index, cocaine and alcohol craving measured by a visual analog scale, cocaine withdrawal measured by the Cocaine Selective Severity Assessment (CSSA), and alcohol withdrawal measured by the 15 item CIWA scale. Results: Baseline drug use severity but not alcohol use severity predicted detox outcome. Cocaine craving, but not alcohol craving predicted detox outcome. Cocaine withdrawal symptom severity but not alcohol withdrawal symptom severity predicted detox outcome. When all variables were entered into a logistic regression equation only days of cocaine use and cocaine withdrawal symptom severity were significant predictors of detox outcome. Conclusions: Cocaine dependence severity but not alcohol dependence severity is predictive of outcome in detoxification from cocaine and alcohol. 466

BENZODIAZEPINE SENSITIVITY OF SELF-MEDICATION BEHAVIOR

AS A PREDICTOR

L.M. Oswald and J.D. Roache, University Health Science Center at San Antonio, TX

of Texas

In order to expand our knowledge about factors that may place anxious patients at risk for benzodiazepine (BZ) dependence, we are evaluating medication sensitivity as a potential predictor of alprazolam (Alz) selfmedication. In this ongoing study, a 3-week outpatient Choice Procedure is conducted to determine how individual patients choose to use Alz when they take it ‘as needed.’ Self-medication behavior is assessed for 1 week of placebo, 1 week of Alz, and 1 week of concurrent

Abstracts

access to both. Patients are classified as either HIGH or LOW users based on observed patterns of use. Preliminary findings suggest that patients can be differentiated into two groups on the basis of medication use patterns. LOW users consumed an average of about 1 mg Alz per day on less than 20% of the days that medication was available. HIGH users consumed an average of 2.5 mg Alz per day on more than 85% of the days. The Choice Procedure is followed by 4 weeks of Prescribed Dosing in which patients receive scheduled doses of medication (placebo, 0.25, 0.5, and lmg of Alz), each taken TID for 1 week. During this phase of the study, HIGH users reported liking all doses of Alz better than placebo; LOW users reported liking placebo better than the 1 mg TID dose of Alz. This may be related to the greater sedation and disability that LOW users experienced with that dose. HIGH users also showed greater escalation in anxiety than LOW users during a procedural dose reduction at the end of the 4 weeks of Prescribed Dosing. The group differences suggest that medication sensitivity plays a role in determining patterns of BZ self-administration in anxious patients. Findings also showed that differences may be at least partially related to differential Alz blood levels in the two groups; levels tended to be higher in LOW users than in the HIGH users. These findings are consistent with prior evidence showing that persons who experience less impairment with sedative drugs may be at greater risk of dependence on these drugs than those who experience less. ACKNOWLEDGEMENT: Supported by NIDA Grants DA05962 and DA08220 467

IBOCAINE

WITHDRAWAL

IS

EFFECTIVE

SYMPTOMS:

IN ROLE

OF

BLOCKING THE

OPIATE METABOLITE

NORIBOGAINE

D.C. Mash, J. Pablo, and C.A. Kovera, University of Miami School of Medicine, Miami, FL Ibogaine (IBO) a naturally occurring indole alkaloid derived from the roots of the rainforest shrub Tabernanthe iboga, has been demonstrated to have efficacy for the blockade of opiate withdrawal. However, it is likely that IBO’s purported efficacy may be due to the long-acting metabolite, because IBO has a rapid clearance from blood. IBO is O-demethylated to noribogaine (norIB0) in both animals and humans. We have obtained observational data on the effects of a singledose administration of ibogaine on mood, craving and withdrawal symptoms in treatment-seeking patients with chemical dependency on opiates (N = 32). We observed significant reductions in negative health symptoms, as well as improvements in mood and energy/ vigor for the post-ibogaine time points. Mean scores from category scales of the HCQ-NOW29 showed significantly reduced craving for opiates post treatment.

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Physician-rated assessments and subjective reports of opiaid-dependent patient volunteers demonstrated an alleviation of withdrawal symptoms during detoxification with IBO. While these observations suggest treatment efficacy, the precise mechanism(s) accounting for these effects remain uncertain. Radioligand binding screens demonstrated that norIB has affinity for the 5-I-IT transporter (SERT) and u- and K-opioid receptors. norIB elevates extracellular levels of 5-HT and acts as a full u-agonist. Kinetic analysis of [3H]norIBO gave t,,, values for biphasic dissociation with rapid and slow rate constants of 9.0 + 0.4 min and 3123.4 + 21.1 min ( - 2.2 days), respectively. Kinetic assays performed in the presence and absence of SERT occluders resulted in the loss of the fast dissociate rate, suggesting pseudoirreversible binding at a second target. The slowrate of dissociation was blocked by the addition of a u-agonist. The multitarget actions of norIB may explain how a single dose of IBO in humans blocks the opiate withdrawal syndrome. 468

A

DRUG

SELF-ADMINISTRATION

FORMAL

ANALYSIS

OF

THE

REGULARITY

OF

IN RATS

L.V. Panlilio, J.L. Katz, R.W. Pickens, and C.W. Schindler, NIH/NIDA Division of Intramural Research, Baltimore, MD, and Virginia Commonwealth University, Richmond, VA It is widely accepted that temporal patterns of drug self-administration in animals tend to be highly regular at a particular dose. When the dose is manipulated, the average inter-infusion interval varies as a direct function of dose. These phenomena are consistent with suggestions that inter-infusion intervals are regulated to maintain a specific level of drug or magnitude of drug effect. However, even with a fixed dose these intervals are n.ot perfectly constant. Given that variability exists, a fine-grain analysis of the patterns of responding might provide insight into the mechanisms that control drug self-a.dministration. For example, if moment-to moment regulation of drug effect occurs, a relatively short interinfusion interval should be followed by a relatively long interval. Similarly, once a short interval occurs, the prob.sbility of the next interval being long should increase. To determine whether this type of regulation occurs, sequential inter-infusion intervals were analyzed under stable baselines of cocaine self-administration. Rats were trained under a continuous-reinforcement schedule (time-out 5 s). Sessions lasted 2.5 h, and data were analyzed from the last hour of each session. Each of several doses (O.Ol- 1.0 mg/kg) was made available for a number of sessions until stable performances were obtained. Autocorrelations of sequential inter-infusion intervals for each rat indicated that there was no dependence between sequential intervals (up to a lag of 3

Abstracts

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intervals). These results suggest that moment-to-moment regulation is not a mechanism generally operating in cocaine self-administration. 469

VOUCHER PURCHASES COCAINE-DEPENDENT WOMEN

AND DRUG

USE AMONG

M.V. Pantalon, D.M. LaPaglia, J.P. Pakes, M.C. Chawarski, and R.S. Schottenfeld, Yale University School of Medicine and The APT Foundation, New Haven, CT Contingency management (CM) has been shown to be effective in treating cocaine dependence, but it is unclear whether encouraging voucher purchases of certain types over others is a useful component of the intervention. In this study, we evaluated whether certain purchases are more likely to be associated with drug use than others in a sample of 78 cocaine dependent pregnant women or women who have a school-age child. These women were enrolled in a 24week trial comparing CM to a yoked voucher control. Each woman was classified based on whether or not she made at least one voucher purchase in each of seven categories. Purchases in each category ranged in value from several dollars to several hundred dollars, and all of the women earned enough in vouchers to allow at least one purchase in each category. Women who made purchases in each category were compared to those who did not on their proportion of cocaine-positive urine toxicology results. Preliminary results indicate that 47% of the women made at least one purchase for their children, 39% for food, 37”/0 for entertainment, 32% for household items, 30% for housing, 28% for transportation, and 22% for clothing. No differences in cocaine-positive urine toxicology tests were found between women who did or did not use vouchers for entertainment, food, or transportation. However, women who used vouchers on their children had significantly lower rates of cocaine-positive urine toxicology results than those who did not (48 vs 67%; t = 2.89, df = 76, P < O.OOS),as did those who spent on housing (40 vs 66%; t = 3.63, df = 76, P < 0.001) and household items (40 vs 67%; t = 4.02. df = 76, P < 0.001). Additional analyses will compare abstinent to non-abstinent women on the proportion of purchases made in each category and evaluate the impact of making purchases that are consistent with treatment plans on drug use. Findings suggest the importance of monitoring voucher use and that encouraging purchases most associated with abstinence could improve the efficacy of CM. AcKNOWLEDGMENTS: Supported by NIDA Grant ROl DA096 15

470 SEXUAL HIV-RELATED

ABUSE, PSYCHOLOGICAL RISK

DISTRESS

AND

D. Paone, V. Catan, S. Titus, and D. Des Jarlais, Beth Israel Medical Center, Chemical Dependency Institute, New York, NY Objective: To examine the association between early childhood sexual abuse (ab), current psychological distress and HIV-related risk behavior(s) among New York City (NYC) drug users in Methadone Maintenance Treatment Programs (MMTP). Procedure: Baseline data were collected from 27 1 MMTP clients (5 1%)female) who were randomly recruited from three clinics in NYC from October 1998 to April 1999. Participants were administered a face-to-face structured questionnaire which included self-reported HIV-related sex and drug risk behavior(s) in the prior 6 months, histories (hx) of sexual ab, current depression, post-traumatic stress disorder (PTSD), and dissociation. Analyses: Data were compared for those with a sexual ab hx to those without reported abuse. Data were analyzed using x2 tests and independent sample t-tests. Results: Participants had a mean age of 43 (S.D. = 8.6) and were racially diverse (37% African American, 28% Latino, and 28% White). Eleven percent reported being homeless in the last year. Thirty-seven percent reported hx of sexual ab; 25% of the males and 50% of the females. Participants were, on average, 10 years of age when the ab began. There were no significant differences observed with regard to injecting drugs, risky injection, or using crack/cocaine during the prior 6 months. Both groups were similar when comparing rates of unprotected sex during the last episode of intercourse (37% reported abstinence in the prior 6 months.) Those with sexual abuse hx were more likely to report physical ab as a child, current depression, PTSD, and dissociation (all significant at P < 0.001.) Those abused were also more likely to be psychologically abused by his/her current sexual partners (P = 0.05). Conclusion: A reported hx of sexual ab was not found to be associated with current HIV-related sex and drug risk behavior(s). Strong associations were observed, however, between an ab hx and all three psychological distress variables, i.e. depression, PTSD, and dissociation. These affective components should be represented in all HIV-related risk reduction counseling and intervention programs. Drug treatment programs should also provide comprehensive staff training or referral provision for clients. 471 NALTREXONE-PRECIPITATED WITHDRAWAL BUPRENORPHINE-TREATEDFEMALEMONKEYS

IN

C. Paronis and J. Bergman, Harvard Medical School/ McLean Hospital ADARC, Belmont, MA The discontinuation of chronic treatment with the longacting mixed-action opioid buprenorphine (BUP) has

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Ahstructs

been reported to produce a mild abstinence syndrome with delayed onset, probably indicative of mu-opioid dependence. In the present experiments, buprenorphine dependence was further evaluated by examining the behavioral effects of mu and kappa opioids during a regimen of daily buprenorphine administration. A group of four female rhesus monkeys performed under a 30-response fixed-ratio schedule of food delivery in daily sessions designed for rapid dose-effect determination. Using cumulative i.m. dosing procedures, the effects of the mu agonist heroin (0.01-3.0 mg/kg), the kappa agonist U50488 (0.01-3.2 mg/kg) and the nonselective opioid receptor blocker naltrexone (O.Ol- 1.O mg/kg) were determined prior to and during a regimen of daily i.m. administration of 0.3 mg/kg buprenorphine. Prior to daily treatment, food-maintained performance was decreased in a dose-related manner by heroin (0.01-0.3 mg/kg), U50 488 (0.03-0.3 mg/kg) and not altered by naltrexone (O.Ol- 1.O mg/kg). Daily buprenorphine resulted in an approximately 1O-fold rightward shift in the heroin dose-effect function and inconsistent changes in the effects of the kappa agonist U50488. Daily treatment also produced a time-dependent sensitivity to the effects of naltrexone in all monkeys. A dose of 1.0 mg/kg naltrexone nearly completely suppressed responding 24 h following buprenorphine whereas a IO-fold lower dose (0.1 mg/kg) had similar effects 48 h following buprenorphine. The behavioral suppressant effects of naltrexone coupled with decreased sensitivity to the behavioral suppressant effects of heroin suggest that daily injections of buprenorphine produces mu-opioid dependence. Supported by USPHS DA10566, DA11453, and DA03774. 472

INTERACTION METABOLITES WITH

OF DIETHYLPROPION AND ITS BIOGENIC AMINE TRANSPORTERS

J.S. Partilla, M.H. Baumann, H. Yu, K.C. Rice, and R.B. Rothman, IRP, NIDA, NIH, Baltimore, and NIDDK, NIH, Bethesda, MD Introduction: Diethylpropion (DEP) is a clinically available anorectic agent. In animals, i.v. DEP is self-administered and i.p. DEP is discriminated as cocaine. The present study examined the ability of DEP and its two major metabolites to block the reuptake of [3H]DA, [3H]5-HT and [3H]NE in vitro and to release [3H]DA, [3H]5-HT and [3H]NE in vitro. In addition, the effect of DEP on extracellular DA (ECDA) in rat n. accumbens was determined. Methods: DEP and its metabolites ethylaminopropiophenone (HY-159) and ( + )-diethylnorpseudoephedrine (HY- 160 and HY- 161) were synthesized in LMC. Uptake, release and in vivo microdialysis assays followed published procedures. Results: Administration of DEP via the microdialysis

probe increased ECDA only at supraphysiological concentrations. Iv. administration of DEP, a dose which stimulated motoric activity (10 mg/kg), produced a delayed and minimal effect on ECDA. Results with the metabolites are pending. DEP was inactive (IC50 values :> 10 000 nM) in the uptake and release assays. HY-159 acted as a substrate at the NE transporters (IC50 = 99 f 7 nM) and 5-HT (IC50 = 2118 + 98 nM) transporters and an uptake inhibitor at the DA transporter (IC50 = 1014 nM). HY-160 and HY-161 were in active in the release and uptake assays. Conclusions: These results suggest that DEP is a prodrug, its Ndealklyated metabolite (HY-159) mediating its pharmacological effects. The delayed effects of iv. DEP on ECDA are consistent with a slow formation of the active metabolite. Although the DA uptake blocking effects of metabolite HY-159 could explain the fact that iv. DEP is self-administered, the delayed nature of its appearance suggest that other factors might also contribute to the ability of DEP to support i.v. selfadministration.

473 ARE THERE NEUROLOGICAL CORRELATES UTEROCOCAINE EXPOSUREATAGE6YEARS?

OF IN

T. Plelham, J.M. Giannetta, E. Malmud, N.L. Brodsky, and H. Hurt, Albert Einstein Medical Center, Philadelphia, PA More than a decade ago in utero cocaine exposure was reported as causing irreparable neurologic deficits in exposed infants. Since that time a number of investigators have not found such devastating effects; there are, however, few data regarding the neurologic status of children with in utero cocaine exposure at school age. Objective: To determine if children with in utero cocaine exposure (COC) exhibit neurologic abnormalities in comparison with unexposed control (CON) children at age 6 years. Design/Methods: Children enrolled at birth and followed prospectively, were given a standard pediatric neurologic examination (cranial nerves, optic fundus, deep tendon reflexes, tone, gross motor strength, range of motion, gait, plantar responses, fine motor skills, sensation, a communication/articulation screen, and soft signs [finger to nose, rapid pronationsupination, heel to toe walking, balance on one foot with eyes closed, and hop]) by a developmental pediatrician masked to child exposure status. Results: One hundred and sixteen (52 COC [median in utero cocaine exposure 99 days] and 64 CON) children were examined. COC and CON did not differ (COC first) in age (80.4 f 2.2 months vs 81.2 + 2.6) weight (23.7 + 5.5 kg vs 25.0 f 6.0) length (123.5 f 5.2 ems vs 124.3 + 6.8) or head circumference (51.7 f 1.4 cm vs 52.0 + 1.6); all P 2 0.06. There was no difference in any aspect of the neurologic examination between COC and CON (all

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Abstracts

P 2 0.29). Results of soft signs showed percent normal as follows (COC first): finger to nose 98 vs loo%, P = 0.45; pronation-supination 98 vs lOO%, P = 0.45; heel to toe walking 94 vs 94%, P = 0.54; balance 98 vs 94%, P = 0.39; hop 100 vs 98%, P = 1.0. The overall impression of the masked evaluator of the neurologic status of COC vs CON (COC first) was as follows: Normal: 82 vs 82%; Questionable: 18 vs 16%; Abnormal 0 vs 2% (P = 0.65). Conclusion: At age 6 years COC and CON do not differ on a standard pediatric neurologic examination. While this finding is at variance with earlier predictions of significant neurologic impairment in COC, subtle deficits in COC cannot be excluded. 474

FACTORS INVOLVED IN THE ACQUISITION ETHANOL SELF-ADMINISTRATION IN RATS

OF IV

R.L. Peltier and N.E. Goeders, LSU Health Sciences Center, Shreveport, LA Despite reports in the literature indicating that rats will self-administer ethanol intravenously, there continues to be very little research using this method. Consequently, there is a very small database of knowledge related to this behavioral technique. The current study was designed to examine the optimal doses and environmental factors for establishing intravenous ethanol self-administration in rats. Male Wistar rats (n = 12) were trained on a multiple-alternating schedule of food reinforcement and intravenous ethanol self-administration (5.0 or 20.0 or 100 mg/kg per infusion). The schedule consisted of a 2-h session containing eight 15 min alternating bins with either food or ethanol serving as the reinforcer. Ethanol infusions were initially delivered over 5.6 s. Rats trained with 5.0 mg/kg/infusion of ethanol acquired self-administration faster and this behavior was more stable than in rats trained with 20 mg/kg/infusion. In addition, rats trained with the lower dose were able to successfully track a lever reversal and decreased the number of ratios completed when saline was substituted for ethanol, while neither of these significantly affected responding in rats trained with the higher dose of ethanol. A 5-fold increase in the infusion duration and dose, as well as the addition of a secondary reinforcer, facilitated the acquisition of ethanol self-administration (100 mg/kg/infusion) in two rats. The effects of increasing the infusion duration and including a secondary reinforcer were also examined independently in separate groups of rats. Increasing the infusion duration from 5.6 to 18.7 s increased the acquisition rate, although pairing a tone/house-light combination with each drug delivery did not alter rates of acquisition. In conclusion, it is possible to train rats to reliably self-administer ethanol by the intravenous route. However, dose, infusion duration and condi-

tioned cues all affect the rate at which rats acquire this behavior. Supported by USPHS grant DA06013 from the National Institute on Drug Abuse and the State of LouisiEdward P. Stiles Trust Fund Grant ana ‘Neurobiological Determinants of Alcohol Dependence’. 475 MORPHINE INHIBITS MURINE CHOLERA TOXINSPECIFIC IcA AND IGG PRODUCTIONFROMINTESTINAL LYMPHOID TISSUES

X. Peng, J.J. Meissler Jr., M.W. Adler, J.J. Cebra, and T.K. Eisenstein, Temple University School of Medicine, and University of Pennsylvania, Philadelphia, PA Morphine has been shown to suppress a variety of immune functions including natural killer cell activity, antibody formation, and response to mitogens. In this study, we investigated the effect of morphine on the mucosal immune system using fragment cultures of small intestine (SI), Peyer’s Patches (PPs), or mesenteric lymph nodes (MLNs). Mice were anesthetized with Metofane@ and implanted subcutaneously with a 75 mg morphine slow-release pellet. Control groups received either a 30 mg naltrexone pellet, a placebo pellet, or a both a morphine and a naltrexone pellet. After 48 h mice were deprived of food for 2 h and then given 0.25 ml of a solution containing eight parts Hanks’ balanced salt solution and two parts 7.5% sodium bicarbonate by gastric intubation to neutralize stomach acidity. After 30 min, mice were orally immunized by intubation with 0.25 ml cholera toxin (CT) in PBS (10 mg/mouse). The mice were boosted 1 week later. Mice were sacrificed 1 week after the booster immunization, and PPs, MLNs and SIs were harvested, washed and cultured in 24 well-plates in 1.0 ml of Kennett’s complete medium for 12 days in an atmosphere of 90% 0, and 10% CO, at 37°C. Culture supernatants were harvested and frozen at - 70°C prior to assay for antibody production by ELISA. It was found that IgA and IgG antibodies specific for CT were detected in MLN and SI fragment culture supernatants taken from placebo and naltrexone pelleted mice, but not in those of PPs. Morphine dramatically inhibited CT-specific IgA and IgG production in both the MLNs and SIs compared with placebo. Naltrexone blocked the reduction in antibody levels induced by morphine, indicating that the effect is opioid receptor mediated. CT-specific IgM was not detected in any of the tissue culture supernatants. Total IgA production was also analyzed. Morphine did not significantly alter total IgA levels in any of the tissue culture supernatants. These results indicate that morphine inhibits antigen specific mucosal IgA and IgG antibody responses in the gastrointestinal tract. This work was supported by NIDA grants DA06650 and DA1 1134.

Abstracts

476

APPLICATION OF A PROCESS MODELINDUALDIAGNOSISTREATMENTRESEARCH

EVALUATION

P.E. Penn and A.J. Brooks, La Frontera Center, Inc., Tucson, AZ A process evaluation was conducted for a study that compared two intensive day treatment approaches for clients with dual diagnosis (persistent mental illness plus chemical dependency). The two approaches were 12-Step (e.g. AA, NA) and Self-Management and Recovery Training (SMART), a cognitive therapy based self-help modality. A model-guided process evaluation framework was applied to the presentation of process evaluation results to organize the findings and assess the usefulness of the framework. The framework assessed treatment model specification, implementation, monitoring implementation integrity, exposure to the treatment model, and treatment absorption. The framework proved useful not only for organizing the results into coherent domains, but also for identifying whether each area had been adequately assessed in the process evaluation. Extensive evaluation in the area of monitoring implementation integrity enabled us to identify, monitor, and remedy a persistent client-counselor interaction style difference between the two treatment approaches. Lack of adequate measures in the area of model absorption was noted with recommendations for future studies. Through the process evaluation, program and counselor characteristics beneficial for working with this difficult-to-treat population were also identified. Recommendations for future interventions with this population based on the process evaluation are also discussed. Supported by a grant from NIDA, ROI-DA08537 to Penn, and by La Frontera Center, Inc. 477

THRESHOLD DOSES FOR NICOTINE TION INSMOKERSANDNONSMOKERS

DISCRIMINA-

K.A. Perkins, C. Fonte, M. Sanders, A. Wilson, University of Pittsburgh School of Medicine and Children’s Hospital, Pittsburgh, PA Threshold doses for nicotine discrimination in nonsmokers may be relevant to understanding the onset of nicotine dependence. Moreover, threshold dose differences between smokers and non-smokers may indicate whether chronic nicotine use leads to tolerance or sensitization of nicotine discrimination. During each session of this study, men and women smokers (n = 18) and nonsmokers (n = 17) were initially trained to discriminate the designated dose of nasal spray nicotine from placebo, followed by discrimination testing in up to 10 trials per session. All subjects first learned to discriminate 20 ug/kg (approximately

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-cig) from placebo before proceeding to threshold determination sessions, which involved discrimination of progressively lower doses below 20 ug/kg (Adescending order@ subgroup) or higher doses above 1 ug/kg (Aascending order@ subgroup). Threshold was determined by the lowest dose reliably discriminated and by failure to discriminate the next lowest dose. Reliable discrimination was indicated by correct identification on at least 80% of testing trials. Smokers and non-smokers reliably discriminated very low doses (med.ian thresholds of 3 vs. 2 ug/kg, respectively; no significant difference between groups). Thresholds were similar between descending and ascending order subgroups. Few subjective responses differentiated threshold dose from the dose just below threshold. In sum, threshold doses for nicotine discrimination in humans are low, even among smokers. Supported by NIDA Grant DA08578 (KAP). 478 ASSESSING READINESS TO ENTER DRUG ABUSE TREATMENT AMONG PARTICIPANTS AT A SYRINGE EXCHANGEPROGRAM D.C. Perlman, C. Trinh, L. Horn, A. Nugent, P. Friedmann, N. Salomon, D.C. Des Jarlais, Beth Israel Medical Center, New York, NY Intmduction: Syringe exchange programs (SEPs) are used to promote HIV risk reduction among active intravenous drug users (IDUs). The extent to which SEPs can serve as sites to recruit individuals into substance abuse treatment is less clear. We sought to assess the readiness for substance abuse treatment among participants at a NYC SEP. Methods: As part of an ongoing study of TB screening at an SEP, participants were given a staff-administered interview, including questions to assess their readiness for drug treatment according to a standardized instrument based on Prochaska’s Transtheoretical Stages of Change Model. Results: For the period August-December 1999, 69 active drug users were interviewed. Twenty-four/sixty-nine (35%) were females, 42 median age, 39% non-Hispanic Black, 32% White, 19% Hispanic, 3% American Indian/Alaskan Native and 7% Other. Thirty/sixty-nine (43%) and 8/69 (11%) reporte’d 2 once daily injections heroin or cocaine, respectively. Fifty-five/sixty-nine (80%) reported ever being in drug treatment and 17/69 (25%) were currently in drug treatment. Sixty-nine/sixty-nine (100%) agreed that their ‘drug use was a problem.’ Fourtyfive/sixty-nine (65%) agreed that ‘being in drug treatment is the only way to get off drugs, and 50/69 (72%) agreed that ‘being in drug treatment would help you with a lot of your problems.’ Fourty-

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Abstracts

three/sixty-nine (62%) agreed that they ‘would like to get into drug treatment.’ However, 47/69 (68%) agreed that they ‘wanted to make changes in their drug use but feel they cannot right now.’ Summary measures revealed that 49/69 (61%) participants were in the contemplation stage. Conclusion: While SEPs are valuable ways of reducing HIV risk among IDUs and to deliver a variety of health care services, their potential for engaging users in substance abuse treatment is less well characterized. Approximately one-quarter of participants were in drug treatment but still using drugs. The majority of participants were in the contemplation stage, suggesting that attempts to engage SEP participants in drug abuse treatment may need to consider their individual stage of drug treatment readiness and employ strategies to move individuals along the stages of change continuum. 479 ESTROGEN AFFECTS IORAL SENSITIZATION

COCAINE-INDUCED

BEHAV-

L.1. Perrotti, T. Webb, S. Russo, H. Fletcher, J. Chin, S.J. Fabian, S. Jenab, and V. Quifiones-Jenab, Hunter College of the City, University of New York, New York, NY The present study investigates the effect of chronic estrogen treatment (administered via S.C. silastic implants) on the behavioral effects of chronic cocaine administration (15 mg/kg per day i.p. for 14 days) in ovariectomized (OVX) female Fischer rats. OVX rats were randomly assigned to estrogen or cholesterol treatment groups and then, further subdivided into one of two drug-treatment groups, cocaine or saline. Cocaine administration increased both stereotypic and locomotor activities in OVX female rats. Overall, estrogen treated rats had higher scores of stereotypy than cholesterol-treated animals’. However, we did not observe sensitization of stereotypic behavior over the course of cocaine treatment. Interestingly, estrogentreated rats exhibited behavioral sensitization of locomotor activity in response to cocaine. Estrogen-treated rats given chronic cocaine displayed more rearing behavior than cholesterol-treated cocaine animals. Plasma levels of the cocaine metabolite benzoylecgonine did not differ between estrogen and cholesterol-treated animals. Thus, suggesting that the observed effects of estrogen on cocaine-induced behavioral activity may not be related to cocaine metabolism. However, corticosterone levels for estrogen treated animals given chronic cocaine were higher than those for cholesteroltreated animals. Thus, suggesting that estrogen treatment may affect cocaine-induced HPA activity. This may be one of the mechanisms underlying hormonallyinduced differences in response to cocaine. In summary, these data suggest that there are interactions between

ovarian hormones on cocaine-induced behavioral and neuroendocrinological alterations in female rats. AcKNOWLEDGEMENTS: Supported by the Altman Foundation Fellowship, RR-03037, NARSAD Young Investigator Award, and MIDARP DA12136. 480 MOTOR

EFFECTS OF INTRAVENOUS HEROIN ON PSYCHOAND COGNITIVE FUNCTIONING IN HUMANS

S. Petitjean, Switzerland

D.

Ladewig,

University

of

Basel,

The objective of this study was to compare the shortterm effects of intravenous heroin (range: 90-290 mg) with those of oral methadone (range: 30-130 mg) on psychomotor performance. Ten heroin maintained patients (mean age: 31.4 f 3.9) were compared with 13 age matched healthy controls (mean age: 29.8 + 6.4) and 11 methadone maintained patients (mean age: 29.9 + 5.2). Opioid-dependent subjects without concomitant drug use were recruited from an outpatient heroin maintenance and a methadone maintenance program in Basel. Psychomotor effects and cognitive functioning were assessed using a standardized and computerized test battery at baseline, before and immediately after the application of their prescribed IV heroin doses. Methadone maintained patients received their usual methadone treatment. There were no significant differences between groups on demographic variables. Before heroin injection the three groups differed only in one of seven variables in their driving test performance. Intravenous heroin produced a rapid and significant decrease of psychomotor and cognitive functioning in five of seven test variables. This marked decrease of performance in the heroin group could still be observed 35 min after the injection (ANOVA; F(2, 32) = 5.64, P = 0.009). Oral methadone had no negative effects. These preliminary findings are important for the medical monitoring of outpatient heroin maintenance treatment programs and especially the judgement of driving abilities of heroin maintained persons. 481

COGNITIVE-BEHAVIORAL PATHOLOGICALGAMBLING:

TREATMENT A RANDOMIZEDTRIAL

FOR

N.M. Petry, J. Kelley, J. Boccuzzi, J. Tedford, C. Armentano, University of CT Health Center, Farmington, and Mental Health and Addiction Services, Middletown, CT Pathological gambling is a growing mental health concern, and estimates indicate that up to 30% of substance abusers have a gambling problem. However, few studies have evaluated treatments for this condition. This study describes preliminary results from a study

Abstracts

evaluating treatment interventions for pathological gamblers. Pathological gamblers (n = 85) were randomly assigned to one of three, 8-week treatment conditions: (1) referral to Gamblers Anonymous (GA); (2) referral to GA plus a cognitive-behavioral self-help manual; or (3) referral to GA plus professionally-delivered cognitive-behavioral therapy. Subjects and collateral informants were interviewed regarding the subjects’ gambling at intake, week 4 and week 8. Thirty percent of the subjects had a history of drug or alcohol use disorders. Approximately 25% of subjects in each group attended GA during the 8-week treatment period. Beneficial effects of the professionally-delivered cognitive-behavioral therapy were noted with respect to percent of subjects achieving gambling abstinence, days gambled, and amount spent gambling. Subjects in the GA-referral only group did not change on any of the outcome measures, and intermediary effects were found among those assigned to the cognitive-behavioral manual condition. These results suggest preliminary evidence of the efficacy of cognitive-behavioral therapy in treating pathological gamblers. 482 SEVERITY OF ALCOHOL MENT ATTRITION IN PATIENTS ANDCOCAINE

PROBLEMS AND TREATADDICTED TO ALCOHOL

H.M. Pettinati, KM. Kampman, D.W. Oslin, K. Hedtke, K. Decker, J.A. Insua, and J.R. Volpicelli, University of Pennsylvania Treatment Research Center, Philadelphia, PA Background: Concurrent use of alcohol and cocaine is common. Patients suffering from both disorders have poor treatment outcomes compared to patients suffering from alcohol dependence alone. This study examined the severity of both alcohol problems and alcohol withdrawal symptoms as a predictor of outcome among subjects undergoing outpatient detoxification (detox). Methods: Subjects included 71 alcohol dependent (ale) and 67 alcohol and cocaine dependent subjects (alc/coc) admitted to treatment at a university-affiliated treatment research center during a 1Zmonth period. Baseline demographics, alcohol and drug use history, 15item CIWA-A scale, and total mg of oxazepam prescribed over the first 4 visits were used to predict completed detox. Results: 70% of ale patients completed detox compared to 45% of alc/coc patients. Although CIWA-A scores were similar between groups, ale patients reported more signs of autonomic instability than alc/coc patients. More autonomic instability was associated with higher oxazepam doses. Oxazepam dose predicted completion of detox among ale patients but not among alc/coc patients. Conclusions: Alcohol withdrawal symptoms and oxazepam treatment are more predictive of detox outcome among ale patients compared to alc/coc patients.

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483

PREVALENCE OF HCV AND HIV-I INFECTION IN FORMER OPIATE ADDICTS IN METHADONE MAINTENANCETREATMENT

P. Piccolo, L. Borg, A. Lin, E.T. Khuri, A. Wells, D. Melia, and M.J. Kreek, The Rockefeller University, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, NY, University of Rome ‘Tor Vergata’, Rome, Italy We investigated the prevalence of HCV and HIV-I infections in a population of former predominantly heroin addicts currently in methadone maintenance treatment (MMT) in New York City. All persons currently in MMT (n = 327) at the end of 1999 at two clinics affiliated with New York Presbyterian Hospital (Adolescent Development Program or ADP, n = 102; Adult Clinic or AC, y1= 225) are to be included in this study. Age, year of admission, HCV status, and HIV-l status are being collated from active medical records. Serology results for HCV and HIV-l have been collated to date for 270 and 220 patients, respectively. Median age was 41 years (ADP, 30 years; AC, 45 years). Overall prevalence of HCV infection was 65% (ADP, 46%; AC, 77%); overall prevalence of HIV-l infection was 24% (ADP, 13%, AC, 31%). Prevalence of HCV increased with age, from a minimum of 25”/0 in patients under 30 years (n = 51) to a maximum of 93% in patients in the 50-59 year group (n = 35). Maximum HIV-,1 prevalence (37%) was in the 30-39 year group. Infection prevalence in subgroups based on year of admission into MMT ranged from 45 to 73% for HCV and from 10 to 39% for HIV-l. Data for both HCV and HIV-I was available for 189 subjects; co-infection was present in 20% (ADP, 13%; AC, 26%). We conclude that patients in MMT have a high prevalence of HCV infection and HIV-l co-infection. and prevalence patterns differ with age. These patients are at high risk for HCV-related chronic liver disease, and therefore need education and treatment. ACKNOWLEDGEMENTS: NIH-NIDA Grants P50 DA05130, K05 DA00049 484 ANTINOCICEPTIVE EFFECTS OFOPIOIDSI: IMPORTANCE OF GENOTYPE, NOCICEPTIVE STIMULUS INTENSITY AND ACTIVITY AT THE p-OPIOID RECEPTOR

M.J. Picker, C.D. Cook, E.L. Roach, and A.C. Barrett, University of North Carolina, Chapel Hill, NC The influence of sex, nociceptive stimulus intensity and an opioid’s relative efficacy on opioid-induced antinociception was examined in F344 and Lewis rats using a warm-water tail-withdrawal procedure. At the nociceptive stimulus intensities tested, the high efficacy mu opioids morphine, etorphine and levorphanol were equally effective in both sexes, but on average 2.5-fold

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Abstracts

more potent in males. With the lower efficacy opioids, marked sex differences in potency and effectiveness (maximal effect) were observed. The low efficacy mu opioid buprenorphine was approximately lo-fold more potent in males at moderate stimulus intensities, and more potent and effective in males at a high intensity stimulus. At low stimulus intensities, the low efficacy mu opioid dezocine and the mu/kappa opioid butorphanol were greater than lo-fold more potent in males, and at a moderate stimulus intensity were more potent and effective in males. Even at a low stimulus intensity, the mu/kappa opioid nalbuphine was more potent and effective in males. At stimulus intensities in which buprenorphine, dezocine, butorphanol and nalbuphine produced maximal effects in males but not females, they antagonized the effects of morphine in females. Genotype-related differences were noted as opioids were generally more potent in F344 than Lewis males, whereas no consistent differences were observed between females. That sex differences in the potency and effectiveness of opioids increased with decreases in the opioid’s relative efficacy and with increases in the nociceptive stimulus intensity, suggests that the relative efficacy of opioids as antinociceptive agents is greater in male than female rats. Supported by NIDA grants DA10277 and DA05888 485 COMPOSITION AND EFFECTS ROLLED INDIAN CIGARETTES

OF BIDIS,

W.B. Pickworth, J.L. Malson, E.T.Moolchan, Murty, NIDA, Intramural Research Program Murty Pharmaceutical, Baltimore, MD

HAND-

R. and

About 80% of adult smokers began smoking as teenagers. Alternative tobacco products such as smokeless tobacco, ‘non-additive cigarettes’ and bidis are often the first tobacco products that are used. In a recent survey, 40% of urban adolescents had smoked bidis and 16% were current users. Adolescents smoke bidis because they are cheaper, more trendy and are regarded as safer than commercial cigarettes. In the present study, physical characteristics, subjective and physiologic effects of bidis, commercial filtered and non-filtered were compared. The nicotine concentration of tobacco in 12 brands of bidi cigarettes averaged 71% higher than in commercial filtered cigarettes and 27% higher than in the unfiltered cigarette. After smoking bidi cigarettes, participants showed significant increases in exhaled CO, heart rate and blood pressure that were similar to increases after smoking commercial cigarettes. These data indicate that smoking bidi cigarettes exposes one to substantial levels of nicotine and other components of tobacco smoke that may lead to tobacco dependence and its consequent health risks.

486 COCAINE-DEPENDENT SCHIZOPHRENICS MORE CRAVING THAN NON-SCHIZOPHRENIC ADDICTS

DISPLAY COCAINE

I. Pinsky, G. Carol, D. Smelson, C. Gerigk, C. Kilker, and D. Ziedonis, Robert Wood Johnson Medical School, Piscataway, and VA New Jersey Health Care System, Lyons, NJ Hypothesis: The dopamine system is involved in the rewarding effects of cocaine and the etiology of schizophrenia. Therefore, given the shared neurobiological abnormalities, we were interested in examining whether individuals with schizophrenia and cocaine dependence have a heightened craving state as compared to cocaine addicts without schizophrenia. Procedures: Non-hospitalized veterans were asked to rate their craving at baseline and again 72 h after the initial assessment. This design was used to examine group differences in addition to ensuring the reliability of the ratings among these subjects. Results: Preliminary results suggest that individuals with cocaine dependence and schizophrenia had significantly higher scores in craving intensity (0.02) mood (0.008), energy (0.007) and health (0.02) compared to cocaine addicts without schizophrenia (N = 40’). Test-retest reliability over the 72 h period was high for Depression 0.73, Energy 0.64 and Feeling 0.68, with craving intensity being slightly lower 0.53. Importance of jindings: This research suggests that individuals with schizophrenia and cocaine dependence display a heightened craving state which warrants psychosocial and pharmacological interventions. 487 DISCRIMINATIVE STIMULUS VENOUSHEROININRHESUSMONKEYS

EFFECTS

OF INTRA-

D.M. Platt, J.K. Rowlett, and R.D. Spealman, Harvard Medical School, New England Regional Primate Research Center, Southborough, MA Heroin is the most widely abused opioid among injecting drug users and is associated with the highest mortality of all illegal drugs. Surprisingly few studies have assessed the discriminative stimulus (DS) effects of heroin, especially when administered by the i.v. route. The present study characterized the DS effects of intravenously-administered heroin in rhesus monkeys. Monkeys were trained to discriminate heroin (0.03 or 0.1 mg/kg) from saline under a lo-response fixed-ratio schedule of food delivery. Under test conditions, heroin (0.001-o. 1 mg/kg) engendered a dose-dependent increase in drug-lever responding, reaching an average maximum of 2 80%. The mu-selective agonist fentanyl also engendered 2 80% heroin-lever responding. However, the delta-selective agonist SNC 80, the kappa-se-

Abstracts

lective agonist spiradoline and the barbiturate amobarbital engendered maximums of only 8850% drug-lever responding up to doses that markedly reduced response rate. These results suggest that the DS effects of heroin are pharmacologically specific and mediated via p-, rather than 6- or k-opioid receptor mechanisms. Both centrally and peripherally, heroin is converted to metabolites that may contribute to its behavioral effects. To assess the role of these metabolites, 6 monoacetylmorphine morphine, (6MAW, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) were tested for their ability to engender heroin-like responding. All of the metabolites substituted fully for heroin in at least 3 of 4 subjects. The finding that M3G fully substituted for the heroin DS was surprising since it has been found either to be inactive or to have low efficacy in other in vivo preparations. The rank order of potency for heroin and its metabolites to engender heroin-lever responding was heroin > 6MAM > morphine > M6G > M3G. Together with reported affinities for the y-opioid receptor and reported ability to penetrate the CNS, these findings show that the acetylated and glucuronide metabolites of heroin may play significant roles in the p-receptor mediated DS effects heroin. Supported by DA1 1928 and RRO0168. 488

INHIB~TIONOFMORPHINETOLERANCEBYSELECTIVEAGONISTOFGRC~UPIIGLUTAMATEMETABOTROPIC RECEPTORS, LY354740 IN MICE

P. Popik, E. Kozela, Institute of Pharmacology, Academy of Sciences, Krakow, Poland

Polish

The development of tolerance to antinociceptive effects of opioids is inhibited by N-methyl-D-aspartate (NMDA) subtype receptor antagonists. Another way to inhibit the function of glutamate receptors is the stimulation of presynaptic metabotropic group II (mGluRI1) receptors. Because LY354740 (( + ) - 2-aminobicyclo [3,1,0]-hexane-2,6-dicarboxylic acid) is the first systemically active agonist of mGluRsI1, we investigated if this compound might inhibit the development of antinociceptive morphine tolerance. Male Albino Swiss mice were tested twice in the tail-flick test and the antinociceptive tolerance was assessed by constructing morphine cumulative dose-response curves, calculating morphine ED50 and resulting fold shifts. Between the tests, mice received for 6 days b.i.d. 10 mg/kg morphine and either placebo, 1, or 10 mg/kg of LY354740. Control mice received placebo injections between the two tests. Such a schedule of morphine injections shifted morphine EDSOs 4.03 f 0.72 times to the right, while the fold shift in control mice was 1.29 + 0.21. Co-administration of LY354740 at 1 and 10 mg/kg inhibited morphine tolerance, since the fold shifts were 2.05 +

s113

0.46 and 2.00 * 0.26, respectively. The present results are the first to suggest an involvement of metabotropic group II receptors in the development of antinociceptive morphine tolerance. 489 DETERMINING BEST ORGANIZATIONAL PRACTICE!i AMONG COMMUNITY-BASED TREATMENT PROVIDERS: A TWO-STAGE DATA ENVELOPMENT ANALYSIS J.V. Porto and P.M. Flynn, School of Public Health, University of North Carolina, Chapel Hill, and National Development and Research Institutes, Raleigh, NC Using data from 40 treatment programs participating in NIDA’s Drug Abuse Treatment Outcome Studies (DATOS), program treatment efficiency and effectiveness frontiers were established to identify the ‘best organizationally performing’ community-based treatment programs. Substance abuse treatment was modeled as a two-stage service delivery process and a two-stage data envelopment analysis (DEA) was conducted to estimate this model. The first stage examined the r,atio of outputs (e.g. treatment services provided by prog:rams) to inputs (e.g. programs resources), and the second stage examined the ratio of outcomes (e.g. reduced substance use, decreased unemployment, reduced illegal acts, etc.) to outputs while controlling for between program variances in patient-level problem severity. Outcomes were case-mix adjusted with a problem severity index that produced a percentage of client problems present in each program: alcohol use, lack of health insurance, depression/anxiety, hostility, anti-social personality, and criminality. Programs were classrfied into one of four performance groups: low efficiency/low effectiveness; high efficiency/low effectiveness; low efficiency/high effectiveness; and high efficiency/high effectiveness. Using these categories or DEA. measurement scores, characteristics of performance groups may be identified through standard analytic techniques. This methodology provides the capability of conducting a comparative evaluation across a large number of programs that determines both organizational efficiency and effectiveness and has the potential to produce important policy-relevant information. States and other regulatory entities could use this methodology to improve treatment practices and (outcomes in public behavioral health systems. 490 CHARACTERISTICS OF INDIVIDUALS WITH DISORDERE:DGAMBLINGREPORTINGEXCESSIVETOBACCOUSE M.N. Potenza, M.A. Steinberg, S. McLaughlin, D. Hemstock, R. Wu, E.T. LaVelle, B.J. Rounsaville, and

Abstracts

s114

S.S. O’Malley, Yale University, New Haven, and Connecticut Council on Problem Gambling, Guilford, CT Nicotine dependence (ND) is commonly observed in individuals with pathological gambling (PG), with comorbidity rates approximating 70%. Despite significant morbidity and mortality associated singly with both PG and ND, the relationship between the disorders remains incompletely understood. We hypothesized that individuals with disordered gambling reporting excessive tobacco use would represent a group more susceptible to addictive disorders and therefore experience more severe gambling problems. To investigate, we analyzed data from a gambling helpline serving the Southern New England region of the United States. Gamblingproblem-related calls received from 2/98-2/99 were analyzed with regard to reports of excessive tobacco use. Differences were observed with regard to education level, income, gambling patterns, legal problems, lifetime money lost to gambling, financial problems, interpersonal problems, drug and alcohol problems, suicidality, and patterns of mental health care treatment. These results have implications for both the provision of care to individuals with gambling disorders and the theoretical framework within which PG is conceptualized. 491 SUBSTANCE ABUSE IN ADULTHOOD: HISTORY OVER A 25YEAR PERIOD

NATURAL

R.K. Price and N.K. Risk, Washington School of Medicine, St. Louis, MO

University

The 25-year follow-up data from the Washington University Vietnam Era Study Phase III (VES-III) was utilized to examine the natural history, encompassing the lifespan from early 20s to late 40s of substance abuse including alcohol, marijuana, cocaine and opiates. The original VES study cohort consisted of two samples of Vietnam War soldiers ascertained at their departure from Vietnam in September 1971, and an additional sample of comparison civilians ascertained in 1974. Using the year-to-year measures obtained from the interviews conducted in 1996-7 and the information collected in earlier waves, the current study (N= 841) (a) examined time trends of use, abuse and cessation over the 25-year period; (b) tested the hypotheses on over-time transitions from abuse of one drug to another, with use of the latent transition analysis (LTA); (c) estimated the effects of psychiatric and socio-environmental predictors of abuse of each substance using the general estimation equation (GEE) modeling; and (d) estimated their effects on the timing of cessation using Cox proportional hazard models. The results show that (1) over time, heavy use of each class of substances declined steadily and largely

monotonically, while the rates of abuse and dependence were stable except for marijuana; (2) asymmetry of transition was observed over time, in which marijuana abuse was switched to alcohol abuse and opiate to cocaine abuse, but not vice versa; (3) psychiatric and socio-environmental factors were equally important predictors over time; (4) predictors were similar across the four classes of substances, although those for alcohol and marijuana abuse were somewhat different from others; and (5) comorbid substance abuse was more detrimental to continuous cessation, than were psychiatric conditions. The Anarrowing of repertoire@ of substance abuse occurs gradually but in a systematic direction over time in the context of polydrug use. Simultaneous treatment of multiple substance abuse, while improving socio-environmental conditions surrounding abusers, would facilitate successful cessation from substance abuse Supported by NIDA, ROl DA0928 1, K02DA00221. 492 NEUROPSYCHOLOGICAL DEPENDENTSUBJECTS

PROFILE

OF COCAINE-

L.S. Prichep, K. Alper, M. Tom, H. Merkin, B. Howard, S. Kowalik, and M.S. Rosenthal, Brain Research Laboratories, NYU School of Medicine, New York, Nathan Kline Institute, Orangeburg, and Phoenix House Foundation, New York, NY While the literature reports the presence of neuropsychological abnormalities in crack cocaine dependent subjects, there are many inconsistencies in the findings. In this study, 148 subjects (98 M, 50 F), with a mean age of 32.7 years, and mean exposure to cocaine of 10.3 years, were studied. Initial evaluations were done 5-14 days after last drug use and repeated after 1 month of abstinence. The test battery included measures of verbal and visual memory, visual perception, psychomotor performance, visuomotor coordination, sustained attention; short term recall, perseveration and abstract reasoning ability, cognitive ‘flexibility’, visual search, attention and mental flexibility. Overall IQ estimates were found to be average, although, digit symbol substitution (DSST) and digit span (DS), were borderline. Buschke Selective Retention Test (BSRT), Benton Visual Recall Test (BVRT), Trails B and Stroop Test all fell below expected normal values. Many of the measures for the Wisconsin Card Sort Test were within normal limits, although number of errors was below normal. Gender differences were found for IQ (fullscale estimate), BVRT and Trails B. One month evaluations supported these findings, and suggest that the BL did not reflect withdrawal. In the presence of normal IQ, baseline evaluations suggest global impairment in memory, visual motor coordination, attention and cognitive ‘flexibility’. However, normal performance on WCST

Abstructs

measures implies that some aspect of frontal lobe function is intact. Gender differences were seen in visual but not verbal memory tasks and in visual search and attention. Emerging evidence of brain dysfunction from the imaging literature is consistent with such functional impairment. It is of note that there were no significant relationships found between BL neuropsychological scores and subsequent length of stay in treatment (period of sustained abstinence) as reflected in our longitudinal follow-up of this population. This work was supported by NIDA Grant number ROl DA # -07707. 493 COCAINE AFFECTS TESTOSTERONE TERONE PLASMALEVELS IN MALE RATS

AND PROGES-

V. Quiiiones-Jenab, Y. Zhou, S. Jenab, A. Ho, and M.J. Kreek, The Rockefeller University and Hunter College, CUNY, New York, NY In male Fischer rats cocaine in a ‘binge’ pattern (15 mg/kg, i.p., three times a day, at 1 h intervals) significantly decreases plasma levels of testosterone [Saline: 453.33 A 60.46 vs. Cocaine: 162.50 A 28.35 rig/ml; P < O.OOOOl].Testosterone plasma levels were also decreased after a single dose of cocaine (15 mg/kg) when compared to controls [Saline: 391.40 A 50.73 vs. Cocaine: 95.25 A 43.87, P < O.OOl]. However, 3 h post injection testosterone plasma levels had returned to normal [Saline: 210.10 A 90.25 vs. Cocaine: 254 A 91.411. Thus, cocaine modulation of testosterone plasma levels appears to be an acute and transient effect. Similar to our previous observations intact female rats, ‘binge’ pattern cocaine administration significantly increased levels of progesterone in male rats when compared to saline-treated controls [0.20 A 0.04 and 0.53 A 0.04; saline vs. cocaine, respectively; P < O.OOOl]. However, progesterone plasma levels were not significantly increased after a single dose of cocaine (15 mg/kg) or 3 h post cocaine injection. Due to the profound effects of both steroids in the modulation of CNS plasticity, the modulation of progesterone and testosterone plasma level by cocaine may have implications for reproductive processes and neuronal functions of males. This work was supported by NIH-NIDA P50-DA05130 NIH-NIDA K05-DA0049 (M.J.K.); and The Altman Foundation, PSC-CUNY, and RCMI RR-0307, MIDARP DA-, NARSAD Young Investigator Award, (V.Q.J.). 494

MEASURES ADOLESCENTS

OF

NICOTINE

DEPENDENCE

IN

A. Radzius, J.E. Henningfield, and E.T. Moolchan, NIH, NIDA Intramural Research Program, Teen To-

5.175

bacco Addiction Treatment Research Clinic, Baltimore, and Pinney Associates, Bethesda, MD At least two reports have suggested that adolescent-specific (questionnaires are needed to assess nicotine dependence among teens, yet no studies have assessed the concordance of the various methods used for assessing nicotine dependence among teen smokers. We administered questionnaires to adolescents from which conventional nicotine addiction scores or criteria could be derived (i.e. FTQ, FTND, DSM-III-R and DSM-IV nicotine dependence section) as well as FTQ questionnaires modified for adolescents. Preliminary analyses (pairled ‘t’ test, II = 21) suggest a lack of statistically significant difference between scores obtained on FTND, PTQ and FTQ questionnaires modified for adolescents. Results from a larger sample of teens comparing the conventional questionnaires to the FTQ modified for adolescents and DSM criteria for nicotine dependence will be presented. Supported by NIDA Intramural funds 495 DIFFERENTIALROLEOF DARPP-32 INACUTEAND CHRONIC MODELSOFOPIOIDANTINOCICEPTIVETOLERANCE:ANDPHYSlCAL DEPENDENCE

K. Raehal, E. Castro, F. Porreca, W. Sadee, A. Fienberg, P. Greengard, and E. Bilsky, University of Northern (Colorado, Greeley, CO, University of Arizona, Tucson, AZ, UCSF, San Francisco, CA, and The Rock.efeller University, New York, NY Previous work from our laboratories and others have suggested that phosphorylation of intracellular proteins may regulate the development of opioid tolerance and/ or physical dependence in vitro and in vivo. DARPP-32 (dopamine- and CAMP-regulated phosphoprotein, Mr 32000) is a potent inhibitor of protein phosphatase-1 (PP-1). We hypothesized that DARPP-32 regulates the development of opioid tolerance and physical dependence in vivo. The current studies tested this hypothesis using DARPP-32 wild-type (WT) and knock-out (KO) mice. Single injections of morphine were used for the acute models of tolerance (40 nmol, i.c.v., - 4 h) and physical dependence (100 mg/kg, s.c., - 4 h). For chronic studies, mice received either repeated S.C. injections of morphine or a 75 mg S.C.morphine pellet for 3 days. Tolerance was assessed by comparing calculated antinociceptive A50 values (55°C tail-flick) in naive and morphine treated DARPP-32 WT and KO mice. Physical dlependence was assessed by measuring naloxone (10 mg/kg, i.p.) precipitated jumping. Compared to the WT mice. DARPP-32 KO mice developed less antinociceptive tolerance and physical dependence in the acute models. In a chronic model of tolerance, the DARPP32 WT and KO developed similar degrees of tolerance.

Abstracts

S176

Interestingly, DARPP-32 KO mice showed significantly greater withdrawal jumping than WT control mice following chronic exposure to morphine. These results suggest that DARPP-32 plays a critical role in the development of acute morphine antinociceptive tolerance and physical dependence. In contrast, it appears that DARPP-32 is not critical to the development of antinociceptive tolerance following sustained exposure to morphine. Furthermore, lack of the DARPP-32 protein may enhance the development of physical dependence to sustained morphine exposure. 496 PROGRESS REPORT ON THE DEVELOPMENT HIV/STD RISK-OF-FUTURE-EXPOSURE SCREEN DRUG-USING

OF FOR

ADOLESCENTS

E. Rahdert, National Bethesda, MD

Institute

on

Drug

Abuse,

Approximately 25% of AIDS cases, age 20-29 years, become HIV positive as teenagers, highlighting importance of identifying youth at risk of future HIV/STD exposure. To date, no valid HIVjSTD risk screen appropriate for adolescents is available. In response, the self-report, easy-to-administer 139-item Problem Oriented Screening Instrument for Teenagers (POSIT), designed specifically for adolescents age 12-19 years, was selected as the tool upon which to configure a brief HIVjSTD risk-of-future-exposure scale (HIV-risk scale). Clinical experts in adolescent HIV/STDs contributed 180 potential screening items related to risk of proximal and distal exposure, classified the 180 items into 20 behavioral risk categories, selected items from the 180-item pool to represent the top 10 behavioral categories and 30 related items thought to best predict current or future risk of HIVjSTD exposure in young (12- 15 years) and older (16-19 years) boys and girls, to produce a 30-item HIV-risk scale. Based on focus group feedback from high-risk drug abusing youths (13- 18 years) in outpatient AOD treatment, the 30 items were reduced to 27. Pilot study # 1: The 27-item HIV-risk scale was administered to drug abusing juvenile offenders (N = 65; 70% male; mean 15.8 years) determined to be at medium to high risk of HIV/STD. Results indicate frequent endorsement of two item-subsets: sex-related behaviors (e.g. Did you have sex . . . before your 15th birthday?) and behaviors related to family (e.g. If you get into trouble, can you go to your family for help?). Pilot study # 2: The 27-item HIVrisk scale, POSIT and Kelly Sex Risk Survey were administered to youths (N = 53; 75% male; mean 15.4 years) admitted to AOD treatment. Results indicate a 9-item sex-risk subscale from the 27-item HIV-risk scale predicts self-report of protected sex and number of sex partners prior to treatment; POSIT Family Relations problem area scores predict HIV-risk scale total scores.

Future studies include administering via audio-CASI the 27-item HIV-risk scale, POSIT, CDC youth risk survey and family measures to youths at high-, medium- and low-risk sites, to produce a 15-20 item HIVjSTD risk-of-future-exposure scale valid for use with young and older, male and female adolescents. 497 THEEFFECTS OFWITHDRAWALFROM ONIMMUNERESPONSESINMICE

MORPHINE

R.T. Rahim, J.J. Meissler Jr., A. Cowan, T.J. Rogers, E.B. Geller, M.W. Adler, and T.K. Eisenstein, Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA Our laboratory has shown that morphine administered by a 75-mg slow-release pellet leads to profound suppression of antibody responses to sheep red blood cells by murine splenocytes, which is blocked by a naltrexone pellet. Suppression is maximal at 48 h after pellet implantation, but immune responses return to normal levels by 96 h, due to development of tolerance. The present studies used tolerant, female, C3HeB/FeJ mice to test the effect of withdrawal on the antibody response. Two different paradigms were used to induce an abstinence (withdrawal) syndrome at 96 h after morphine pellet implantation: (1) Precipitated withdrawal: morphine pellets were removed and mice were given either a S.C. injection of naloxone (1 mg/kg) or implanted S.C. with either a naloxone osmotic minipump (1 mg/kg per day) or a naltrexone pellet (30 mg); (2) Abrupt withdrawal: morphine pellets were removed. After precipitated or abrupt withdrawal, splenocytes were harvested at various time points, and the number of antibody-forming cells was determined using a plaque-forming cell assay. The results show that initiation of withdrawal from morphine by these two paradigms has different effects on the immune system. Precipitated withdrawal led to an initial immunopotentiation followed by immunosuppression, whereas abrupt withdrawal resulted in progressive immunosuppression. Both paradigms led to profound immunosuppression by 24 h after pellet removal. These studies suggest that addicts undergoing episodes of withdrawal may experience immunosuppression that provides periods of enhanced sensitization to infection. 498 CLINICAL WOMEN WITH SUBSTANCES

CHARACTERISTICS OF 3,549 MEN AND DEPENDENCE ON ONE OR MULTIPLE

E.B. Raimo, T.L. Smith, N.L. Stephany, T.L. Wall, and M.A. Schuckit, University of California, San Diego, CA

s177

Abstracts

The literature and clinical lore have suggested that a small proportion of individuals are dependent on one substance only. There is an implication that people with one substance dependence might have a less severe clinical course than those with multiple dependencies. This report presents data from personal interviews of 3,549 men and women with one or more substance dependencies from the COGA project. Placing an emphasis on the three most commonly used substances (besides nicotine), relevant individuals were divided into 4 groups: marijuana dependence only (n = 167, 5%); dependence on stimulants (amphetamines and cocaine) alone (n = 134, 4%); alcohol dependence only (n = 1,773, 50%); and a combination of these dependencies (n = 1,475, 41%). The subjects were administered the SSAGA interview that gathers data on demography, substance use patterns, and associated diagnoses. More than half (56%) of the alcoholics had no other substance dependencies, while fewer marijuana dependent (14%) and stimulant dependent (11%) subjects had a single dependence. Men and women with one dependence had fewer general life problems (e.g. marital instability), lower rates of antisocial personality disorder (ASPD) and substanceinduced depression, a later age of onset of dependence, and a lower proportion with a history of substance-related treatment. A logistic regression indicated that people with single dependencies were more likely to be older, Caucasian, non-ASPD, to have an older age of onset of dependence, were less likely to have a substance-induced depression, and were less often treated (overall 2 = 1,095.7; P < 0.001; explaining 18.6% of the variance). Each of the final predictors remained robust after controlling for ASPD and gender. These data are consistent with the hypothesis that people with one substance dependence have a less severe clinical course than those dependent on more than one drug.

499

THE RELATIONSHIP BETWEEN GENDER AND PHYSIOLOGICALDEPENDENCETO OPIOIDSINGENERAL POPULATIONANDTREATMENTSAMPLES

E. Rasmussen, L.Cottler, W. Compton, and A.B. Abdallah, Washington University, St. Louis, MO Previous research has determined that the presence of tolerance and withdrawal in alcoholism is associated with an earlier age of onset, more severe problems and greater consumption of alcohol as compared to cases without physiological dependence (Shuckitt et al., 1999). The goal of the work presented here is to replicate this finding with opioids. Data were collected on 192 (64 female, 128 male) opioid users from both treatment and community-based samples as part

of an ongoing reliability and validity study of DSM/ ICD Substance Use Disorders. There was no gender difference in lifetime DSM-IV diagnosis of opioid abuse or dependence in either sample, and the mean number of abuse and dependence symptoms across samples was generally comparable. There was no gender difference in opioid users reporting both tolerance and withdrawal (36% of total users), withdrawal only (5%) tolerance only (9%) or neither (50%). In cases where tolerance, withdrawal or both were present (50% of the sample), a diagnosis of abuse or dependence and frequent use of opioids ( > 3 days/week) did .not differentiate between female and male users. However, in cases where both tolerance and withdrawal were absent, females were significantly less likely to report opioid abuse or dependence (c2 = 3.7; P = 0.05), and less likely to use opioids frequently (c2 ==5.8; P = 0.02). These preliminary findings appear congruent with data from recent animal studies (Cicero et al., 1999) which have demonstrated a significant gender effect in the reinforcing properties of morphine. Additional multivariate analyses will more closely examine the issue of physiological dependence as it relates to type of symptoms, other drugs used, onset of use and other issues. 500

REINFORCING EFFECT 0~ 3,4-METHYLENEDIOXYMETHAMPHETAMINE (MDMA, GE~~~~~~9) IN RATS: REINFORCING STRENGTH, DRUG HISTORY, AND SENSITIZATION

E. R.atzenboeck, A. Saria, and G. Zernig, University of Innsbruck, Innsbruck, Austria The reinforcing effect of 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’) was determined in an FR 1 TO150 s operant conditioning schedule of i.v. self-administration in male Long-Evans. MDMA (0.032-3.2 mg/(kg.injection)) proved to be a reinforcer (i.e. engendered responding significantly above operant level) in 12 of 19 (i.e. 63%) of the tested animals, while cocaine (0.75 mg/(kg injection)) served as a reinforcer in 14 of 19 (i.e. 74%) of the animals. Drug-naive rats did not differ from rats that had been previously trained with cocaine. Maximum responding for MDMA upon the second dose response curve determination was significantly higher than upon the first determination. This sensitization to MDMA’s rate-increasing effect did not extend to MDMA’s potency (dose engendering maximum responding, 0.8 vs. 1 mg/(kg.injection)). Even when MDMA was tested immediately after cocaine, there was no carryover of the reinforcing effect from cocaine: to MDMA.

Abstracts

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501

REBOXETINE,

A HIGHLY

NOREPINEPHRINE NICOTINE

POTENT

TRANSPORT

AND

INHIBITOR,

SELF-ADMINISTRATION

SELECTIVE REDUCES

IN RATS

AS. Rauhut, M.D. Chesnut, M.T. Bardo, and L.P. Dwoskin, University of Kentucky, Lexington, KY The potency and relative selectivity of reboxetine as a transport inhibitor were determined in in vitro experiments using rat brain synaptosomal preparations. The ability of reboxetine to inhibit nicotine self-administration (SA) in rats was also determined. Comparison of Ki values revealed that reboxetine is a highly selective inhibitor of [3H]norepinephrine uptake into hippocampal synaptosomes (Ki= 4 nM, n = 8), and has a markedly lower potency for inhibition of [3H]dopamine uptake into striatal synaptosomes (K, = 30 PM, IZ = 5) and for [3H]serotonin uptake into hippocampal synaptosomes (K, = 3 PM, n = 8). Following repeated in vivo pretreatment with reboxetine (10 mg/kg, two times daily for 14 days), tolerance did not develop to the reboxetine-induced inhibition of neurotransmitter uptake. In a separate experiment, rats (n = 7) were trained to self-administer intravenous nicotine (0.03 mg/kg per infusion) and then received a subcutaneous injection of reboxetine (1 .O, 3.0, or 5.6 mg/kg) 15 min prior to the start of the session. One-way within-subject ANOVAs followed by correlated t-tests revealed that 1.0 mg/kg reboxetine failed to suppress nicotine SA. However, 3.0 mg/kg reboxetine suppressed responding during the first 15 min of the session and 5.6 mg/kg reboxetine suppressed responding throughout the 60 min session. These results demonstrate that reboxetine, a highly potent and selective norepinephrine transport inhibitor, suppressed nicotine SA in a dose-dependent manner and suggest that reboxetine may serve as an effective smoking-cessation treatment. Supported by Pharmacia and Upjohn. 502 AGEMENT CAINE

RELAPSE

PREVENTION

APPROACHES ABUSE

FOR

AND

CONTINGENCY

THE

TREATMENT

MANOF

CO-

DISORDERS

R.A. Rawson, M. McCann, and W. Ling, L.A. Addiction Research Consortium; West Los Angeles Matrix Center; Los Angeles, CA Cocaine abuse is a serious and widespread problem. The development of empirically supported behavioral and cognitive behavioral strategies for the treatment of cocaine abuse disorders is an important addiction research priority. The present study evaluated two promising approaches, relapse prevention (RP) and contingency management (CM), for treatment of cocaine abuse in 162 primary cocaine dependant subjects. Subjects were randomly assigned into one of three

conditions, RP (n = 54); CM (n = 54); or a combination of both RP + CM (n = 54). The RP condition consists of 90 min group sessions three times a week for 16 weeks. The CM procedures consisted of a 16-week positive reinforcement voucher system in which subjects earned vouchers exchangeable for goods and services based upon their ability to produce urine samples negative for cocaine metabolite. Subjects in the RP + CM condition received both the RP and CM procedures. A battery of measures was collected at baseline, weekly during treatment, and at 4, 6, and 12 months post admission. Final data analysis will compare the relative effectiveness of each procedure alone and in combination in producing short and longer term changes in drug use and HIV risk behaviors. Preliminary findings suggest that during treatment subjects in the ‘CM only’ condition responded more rapidly to the intervention than subjects in the ‘RP only’ and combined condition. However, at follow-up, there appears to be a reversal in this trend, whereas subjects in the ‘RP only’ condition show a marked improvement over that of the CM subjects. 503 HIV GAY

A

QUALITATIVE

ANALYSIS

RISKS AS AN OUTCOME MALE METHAMPHETAMINE

OF DRUG OF

TREATMENT USERS

AND

SEXUAL AMONG

C.J. Reback, S. Larkins, and S. Shoptaw, Friends Research Institute, Van Ness Recovery House, Los Angeles, CA Methamphetamine is the most frequently used drug among gay and bisexual males in Los Angeles and is associated with high-risk behaviors for HIV transmission. This presentation describes a qualitative study on 34 gay and bisexual men in a gay-specific behavioral treatment/research program for methamphetamine use. Clients are randomly assigned to one of four behavioral treatment conditions and participate in treatment for 16 weeks. Clients participated in in-depth, semi-structured interviews at baseline, 16 weeks, and 52 weeks. Ages ranged from 20 to 47 years, with a mean age of 36.4 years. Eighty-five percent were Caucasian/white, 12% were Hispanic/Latino, and 3% were Native American. Sixty-five percent of the clients were HIV infected. Qualitative data from baseline and 52-week follow-up interviews have been analyzed using grounded theory. Themes examined include the connection between sexual identity and drug use, sexual-related HIV risks, and perceptions of HIV risk. Clients demonstrated marked differences in their substance use, HIV risks, and perceptions of risk before and after drug treatment. Most reduced or eliminated methamphetamine use and began to identify a relationship between their drug use and high-risk sexual behaviors. Preliminary findings indicate that drug treatment is an effective HIV risk-reduction strategy

Abstracts

504

INFLUENCE OF ALCOHOL PROBLEMS ON HIVRISKBEHAVIORAMONGA COHORTOFINJECTIONDRUG USERS

V.W. Rees, R. Saitz, J. Savetsky, and J.H. Samet, Boston University Schools of Medicine and Public Health, Boston, MA Hypothesis: A substantial research effort has been devoted to understanding the relationship between injection drug use and HIV infection. The role of alcohol abuse in mediating HIV risk behavior in IDUs is less well documented. We hypothesized that injection drug users who also abuse alcohol would be more likely to engage in HIV risk-taking behavior. Procedures: Participants were derived from the Health Evaluation and Linkage to Primary Care (HELP) study of IDUs identified in a cohort of subjects undergoing detoxification. Interviewers collected data on demographics, drug use histories including heroin, cocaine and alcohol abuse (Addiction Severity Index), HIV risk behavior (Risk Assessment Battery), and motivational stage of change (SOCRATES). The study cohort was stratified according to the presence or absence of a current problem with alcohol (defined according to evidence of both lifetime and recent alcohol abuse). Bivariate analyses were employed to compare alcohol abusers with nonabusers on measures of sexual and injection drug use HIV risk behavior. Results: Participants were 170 injection drug users, of whom 71% (n = 120) had alcohol problems. Current alcohol abusers were significantly more likely to engage in greater unsafe sexual behavior than non-alcohol abusers (P = 0.02), as well as engage in greater unsafe needle-use behavior (P = 0.01). Further analyses aim to explore the role of motivational stage of change on this worse outcome among injection drug users who abuse alcohol. Importance of jindings: Addressing alcohol problems among IDUs may provide an important, though poorly utilized, opportunity for tailoring interventions designed to reduce HIV risk behavior among this high risk population. Further conceptual and clinical implications, including the role of motivational stage of change in HIV risk behavior and alcohol abuse, will be discussed. Supported by NIDA Grant # DA 10019 & NIDA/INVEST International Research Fellowship Program.

505 A CONTROLLED TRIAL OF OLANZAPINE, VALPROATE OR COENZYME QIo/L-CARNITINE VERSUS PLACEBO THE TREATMENT OF COCAINE FOR DEPENDENCE M.S. Reid, D. Leiderman, P. Casadonte, A. Montgomery, D. Majewska, M. Sanfilipo, S. Baker, D. Braunstein, E. Conner, J. Robinson, and J. Rotrosen, New York NlDAjVA MDRU, Medical Center, New

s119

York, NY and NIDA sion. Bethesda, MD

Medications

Development

Divi-

This placebo-controlled, modified double blind, clinical trial evaluated the safety and efficacy of three separate pharmacotherapies for the treatment of cocaine addiction in primary cocaine abusers. Following a 2-week prospective baseline, subjects (N = 63) were randomly assigned to an 8-week treatment period with placebo or one of three drug treatments: Olanzapine 10 mg per day, Valproate 1500 mg per day, or Coenzyme QlO 200 mg per day + L-Carnitine 500 mg per day (Olanzapine and Valproate were dose titrated). In addition, participants received weekly individual substance abuse behavioral therapy. Safety measures included adverse event monitoring, vital signs, electrocardiograms, extrapyramidal side effects tests and standard laboratory tests. Cocaine addiction treatment efficacy measures included quantitative urine benzoylecgonine (BE) assays, self-and observer-rated clinical global impressions (CGl) scales, craving measures, self-report of substance use, and the Addiction Severity Index (ASI). Secondary measures included study retention, Hamilton Depression (HAM-D) and Anxiety (HAM-A) scales, and the Risk Assessment Battery (RAB). Preliminary analyses indicate no significant improvement in cocaine abstinence, cocaine craving, CGI-Observer or CGI-Self scores, or AS1 composite drug scores for any treatment group versus placebo. Study retention was similar across all treatment groups. Further analyses of the primary and secondary outcome measures will be presented. Supported by NIDA contract: YOI DA 50038-05. 506 MDMA

GENDER DFFERENCES IN SUSCEPTIBILITY NEUROTOXIC EFFECTS: A SPECT STUDY

TO

L. Reneman, G.J. den Heeten, and J. Booij, Graduate School of Neuroscience, Academic Medical Center, University of Amsterdam, The Netherlands 3,4-Methylenedioxymethamphetamine (MDMA) or ‘Ecstasy’, is a popular drug of abuse that selectively damages brain serotonin (5-HT) neurons in animals, and as recently shown, also in humans. Since there is accumulating evidence indicating that the causes and consequences of drug abuse may be different for women and men, we performed the present study to investigate whether gender differences in the susceptibility to the neurotoxic effects of MDMA exist. Methods: Direct visualization of 5-HT transporters using [I123]b-CIT single photon emission computed tomography (SPECT) allows detection and quantification of MDMA-induced 5-HT damage in the living human brain. 23 regular MDMA users (male/female: 12 ill, average time since last dose: 2.3 months, lifetime no of tablets: 530 [55-20161, average age: 26.1 years) and 15

Abstracts

S180

controls (7/8, average age: 26.1 years) underwent [I123]b-CIT SPECT imaging. Participants agreed to abstain from all recreational drugs for at least 3 weeks, and undergo drug screening. Imaging was performed 4 h after intravenous injection of the radiotracer, using a 12 headed dedicated brain SPECT camera (SME 810). ROIs were positioned over the midbrain, thalamus, frontal, parietal, occipital cortex, and cerebellum (a region free from 5-HT transporters). Binding ratios of brain areas versus cerebellum were calculated. Results: Male MDMA users used, on average, four times as many MDMA tablets compared to female MDMA users. MDMA users showed significantly lower binding ratios compared with controls (P = 0.01, MANOVA). No differences in binding ratios were found between male controls and male MDMA users (P = 0.31). However, binding ratios were significantly lower in female MDMA users compared to female controls (P = 0.03). Conclusions: Consistent with previous reports, we observed reduced in vivo binding to the 5-HT transporter in abstinent MDMA users, suggesting 5-HT neurotoxicity of MDMA in humans. Interestingly, the present study provides suggestive evidence that sex differences in the effects of MDMA exposure may exist. These preliminary results suggest that women may be more susceptible to the neurotoxic effects of MDMA. 507

CHRONIC

TRATION IMPROVES

CITICOLINE

ALTERS

BRAIN

COGNITIVE

(CDP-CHOLINE) PHOSPHOLIPID PERFORMANCE,

ADMINISMETABOLITES, AND

TREATS

DEPRESSION

P.F. Renshaw, S.M. Babb, D.A. Yurgelun-Todd, M.E. Henry, L.L. Wald, C.M. Moore, R.A. Villafuerte, S.A. Gruber, B.M. Cohen, and S.E. Lukas, Harvard Medical School, Boston, MA We have recently suggested that citicoline (CDPcholine), which increases the synthesis of dopamine and brain phospholipids in animals, may be of benefit for the treatment of stimulant dependent individuals. As citicoline has not been approved for clinical use in the United States, we have been conducting industrysponsored studies in healthy and depressed subjects. We have assessed whether chronic citicoline (CDPcholine) administration leads to detectable changes in lipid metabolite resonances in phosphorus-3 1 MR spectra. Eighteen healthy subjects (mean age 70) received 500 mg of citicoline daily for a 6-week period. Treatment was associated with increases in brain phosphodiesters (P = O.OOS),a finding which is consistent with increased phospholipid synthesis. From weeks 6 to 12, half of the subjects continued to receive citicoline and half received placebo in a double

blind fashion. Neuropsychological testing revealed increases in verbal fluency (P = 0.07) verbal learning (P = 0.003) and visuospatial learning (P = 0.0001) across all subjects at week 12. In a separate cohort of 12 depressed adults (mean age 40) treatment with citicoline at a dose of 500 mg BID was associated with a reduction in Hamilton Depression Inventory scores from 21 + 3 to 10 4 7 at week 8 (P < 0.0001). Comparable data from depressed subjects participating in imaging trials and treated with fluoxetine, 20 mg per day, (N=41) are 21f4 and 11 +6 (PC O.OOOl), respectively. These data represent the first demonstration that human brain lipid metabolism can be modified using pharmacological strategies and, in older adults, treatment was associated with improved cognitive performance on some measures. In depressed adults, the antidepressant effects of citicoline were similar to those of fluoxetine. These findings are encouraging for the future use of citicoline in cocaine dependent populations. Supported by NIDA grants DA09448, DA00343, and Interneuron Pharmaceuticals. 508 IN AND

LONGITUDINAL THE

AND

CORRESPONDENCE

SELF-REPORTED

INDIVIDUAL OF

DRUG

URINE

DIFFERENCES DRUG

SCREEN

USE

H. Rhoades and J. Grabowski, University Medical School at Houston, Houston, TX

of Texas

There is continuing interest in the correspondence between a patients self reported drug use and biological evidence of drug use, usually urine screens. Most estimates of reliability are based on one-time assessment. Even if longitudinal data are available (e.g. Ehrman et al., 1997) most analyses reduce measures to a single dichotomous point. No individual differences can be assessed under these methods. As part of a 12week, double-blind, randomized, placebo-controlled trial of fluoxetine for the treatment of cocaine use (Grabowski et al., 1995) patients were asked during their weekly therapy visit if they had used any drugs during the prior week. Patients also provided two urine samples per week as part of the study protocol. Self-reported drug use and urine screen data from the N = 155 patients (70 of whom completed the 12-week study) will be presented having been analyzed with special attention paid to change in reliability as a function of time. For the sub-set of patients completing (or nearly completing) the study, individual reliablility estimates will be calculated and modeled as a function of demographic and drug history information, as well as treatment related components (e.g. treatment condition, counselor).

S181

Abstracts

COMPARISON OF FIXED VERSUS VARIABLE REINFORCEMENT SCHEDULES IN A CONTINGENCY MANAGEMENT INTERVENTION TO PROMOTE ON-TIME COUNSELING ATTENDANCE IN A METHADONE MAINTENANCETREATMENTPROGRAM

510 PERCEPTIONS ABOUT PRENATAL CARE AMONG AFRICAN AMERICAN WOMEN WHO ABUSE ILLEGAL DRU~GS IN WASHINGTON, DC: A CASE STUDY

G.R. Rhodes, T. Helmus, K.K. Downey, D. Ledgerwood, and C.R. Schuster, Wayne State University, Research Division on Substance Abuse, Detroit, MI

Women who abuse illegal drugs often do not get consistent health care. This is of special concern during pregnancy, which generally requires consistent monitoring by healthcare professionals, to improve the overall chances of healthy fetal outcomes. Washington, D.C. has ;ihe nations’ highest infant mortality rate. Congress mandated that NIH look into the causes of the District’s high infant mortality rate, and NIH established the NIH/D.C. Initiative. Infants delivered by drug dependent women are a significant contributor to Washington’s high infant mortality and poor infant health rates In this aspect of the study, four focus groups were conducted from 1996697 among pregnant women and women of child bearing age identified by the courts or themselves as abusers of illegal drugs. The aim of the research was to determine their perceptions about what motivated or deterred their use of professional health care. in order to increase the use of prenatal care among drug dependent women. Preliminary results indicate feelings of inferiority engendered by interactions with healthcare professionals serve as a major deterrent. Many of the women also have misperceptions about the interactions of drugs and drug maintenance programs. Additionally, women use medications and ‘medical advise’ from fellow drug abusers. These feelings of inferiority and misperceptions result in their failure to seek and adhere to medical supervision during pregnancy.

509

Two studies were conducted to investigate the effectiveness of contingency management techniques in promoting punctual counseling attendance among those with a history of poor compliance. In Study One, 50 participants were recruited from an inner-city methadone maintenance program. Study One utilized an A-B-A design with baseline, intervention and return-to baseline phases. On-time attendance was reinforced during intervention with a voucher, which was redeemable for a draw out of a box containing 100 tokens with values varying from $0.00 to $100.00. Methadone maintenance patients who exhibited poor attendance during baseline showed a significant positive response during the contingency management intervention phase. Good attenders, however, evidenced a significant decrease in attendance during intervention. In Study One, Poor Attenders also submitted a significantly higher proportion of opiate positive drug screens and dropped out of treatment at a significantly higher rate than Good Attenders. Study Two was conducted for four reasons: (1) to replicate the encouraging results obtained in Study One among Poor Attenders; (2) to improve categorization of participants into Attender group and further investigate the effect of reinforcement among the Good Attender group; (3) to investigate the efficacy of an alternative low-cost fixed-rate reinforcement procedure; and (4) to investigate the cost-effectiveness of monetary contingency management procedures. Study Two utitlized the same design as Study One with one exception; the 52 participants were also randomized into reinforcement groups of receiving either the variable reinforcement as in Study One or a fixed value of $3.25. As in Study One, Poor Attenders significantly improved counseling attendance during baseline, but Good Attenders significantly dropped in attendance during the return-to-baseline phase. There were no differences between the variable and fixed reinforcement groups. In Study Two, Poor Attenders again dropped out of treatment at a significantly higher rate than Good Attenders. The overall results suggest that targeting poor attenders with contingency management techniques is a cost-effective method of improving counseling attendance.

L. Richards, Medical and Health Research Association, New York, NY, and NIH, Washington, DC

511

SELF-RATED METHAMPHETAMINE TREATMENTCOURT

TREATMENT MOTIVATION ABUSERS INVOLVED

SCALE OF IN DRUG

K. Richardsonl, S. Simon, T. Sim, J. Dacey, and W. Ling, Los Angeles Addiction Research Consortium, Los Angeles, and, Long Beach VA Medical Center, Long Beach, CA The influx of methamphetamine (MA) users entering Drug Treatment Court programs has increased as MA use has spread and as drug court programs have multiplied. This study presents the results of a treatment motivation self-rating scale (TCU TMS) administered to MA abusers mandated for treatment in a Drug Treatment Court program compared with MA abusers participating in voluntary outpatient treatment. Preliminary analysis suggests that MA abusers in Drug Treatmen: Court exemplify many positive motivational characteristics considered to be essential to a successful treatment outcome. The information provided from this

Abstructs

S182

study, along with other demographical data specific to MA abusers in Drug Treatment Court, can assist researchers in improving existing treatment models. 512

UNIQUE INTERVENTION-MATCHING TOREDUCECRACKUSE

STRATEGIES

T.A. Ridenour, L.B. Cottler, W.M. Compton, and E.L. Spitznagel, Washington University School of Medicine, St. Louis, MO Studies attempting to identify types of patients with substance use disorders whose outcomes are best when given a particular type of intervention (for interventionmatching) have generally failed to produce replicable results. It has been argued that alternative analytical techniques might more accurately estimate the associations between pretreatment characteristics and outcomes, which could also inform clinical decision making regarding intervention matching. Artificial neural network analysis (ANN) was compared to OLS regression for the potential usefulness in intervention matching research in 955 cocaine users. Out-of-treatment crack users were randomly-assigned to one of two interventions designed in part to reduce crack use. At the 3-month follow-up, the observed number of days that participants used crack during the preceding month was reduced by 6.0 days (C.I. = 5.39-6.84) compared to baseline crack use. Using regression models for intervention matching was estimated to reduce days of crack use by 6.8 days (C.I. = 6.66.-6.97) a non-significant 13.3% improvement over random assignment. Using ANN models for intervention matching was estimated to reduce days of crack use by 7.4 days (C.I. = 7.22-7.53) a significant 23.3% improvement over random assignment. ANN was slightly better than OLS regression in terms outcome prediction accuracy and demonstrated better generalization to new data. ANN, the allocation average, and the bootstrap are statistical tools that may be useful to drug use treatment researchers. 513 GENDER DIFFERENCES IN HOW INTIMATE NERSINFLUENCEDRUGTREATMENTMOTIVATION

PART-

KS. Riehman, Y. Hser, Drug Abuse Research Center, University of California, Los Angeles, and RAND Drug Policy Research Center, Santa Monica, CA We examine the association between partner-related variables, (i.e. partner’s economic support, drug use, treatment experience, and recent partner conflict), and treatment motivation (i.e. drug use problem recognition, desire for help and treatment readiness) for men and women. Participants were 266 cohabiting or married individuals recruited from STD clinics, emergency rooms, and jails in Los Angeles County between 1992

and 1994, who reported recent drug use. Multivariate analyses show that none of the partner-related variables is associated with motivation for men; however, for women, having a partner who has been in treatment, having a non drug-using partner, and deriving greater income from self-sources than from a partner, are associated with high treatment motivation. 514 NUCLEUSACCUMBENSNEURALACTIVITYDURING REPEATEDCOCAINESELF-ADMINISTRATION INHUMANS

R.C. Risinger, T. Ross, B.J. Salmeron, H. Garavan, C. Rainey, A.S. Bloom, and E.A. Stein, Medical College of Wisconsin, Milwaukee, WI Animal models have demonstrated that, when compared to passive drug injection, cocaine self-administration (SA) produces distinct patterns of biochemical and electrophysiological changes in reward-related structures, particularly the NAcc. Human neuroimaging studies to date have demonstrated activation of a variety of mesocorticolimbic and striatal structures associated with passive stimulant administration. Based upon preclinical literature describing changes in NAcc phasic and tonic firing patterns during cocaine SA, we sought to characterize neural activity in the NAcc during human cocaine SA. Six healthy male cocaine dependent subjects underwent BOLD fMR1 while repeatedly self-administering (FRl) 20 mg/70 kg cocaine and performing continuous on-line ratings of subjective effects. Injection event-related analysis of the NAcc ROI revealed two patterns of change related to drug injections. Initial injections were followed by BOLD signal decrease that was apparent within 100 s post-injection and did not return to baseline within 5 min. After the third SA, a different pattern emerged where MR signal began to increase prior to injection, peaking at a time when subjects reported maximal High, and then decreasing. This biphasic effect was apparently specific to the NAcc as it was not seen in parietal or cingulate cortex, and supports the hypothesis that an increase in neural activity in the NAcc proximal to drug injection is related to the motivational properties of reinforcers. Supported by grant DA09465 and MO1 RR00058. 515

DOSE-RELATEDALPRAZOLAMREINFORCEMENTIN ANXIOUS OUTPATIENTS

J.D. Roache and L.M. Oswald, University of Texas Health Science Center at San Antonio, San Antonio, TX The present study examined whether alprazolam selfmedication behavior was dose related in nine patients with generalized anxiety or panic disorder. Under double-blind conditions, outpatients could self-administer color-coded capsules containing placebo (PL) or alprazo-

S183

Abstracts

lam, ad libitum, 7 days per week. A 3-week Choice Trial consisted of a ‘Sample Period’ in which two different medication doses were individually available for 1 week each before both medication doses were concurrently available during a third ‘Choice Week’. Over three different and independent Choice Trials, dose comparisons were 0.25 mg vs. PL; 0.5 mg vs. PL, and 0.25 mg vs. 0.5 mg alprazolam. Color codes and dose sequences were counter-balanced across subjects. Dose comparisons during the Sample Periods of the Choice Trials showed that drug and PL capsules were self-administered at similar rates so that there was no dose relationship. However, during the drug vs. PL Choice Periods, 0.5 mg, but not 0.25 mg alprazolam was self-administered at higher rates than PL and during the dose choice, 0.5 mg was self-administered at higher rates than 0.25 mg. Five of eight patients completing the trial showed a significant (binomial P < 0.05) preference for 0.5 mg vs. PL whereas only two of eight did the same for 0.25 mg vs. PL. There were three patients who did not show alprazolam vs. PL preference at either dose although two of them consumed 2-3 capsules per day on more than 60% of available days. Positive alprazolam dose relationships also were observed with measures of anxiety reduction, perceived drug effects, and sedative side effects. Thus, the reinforcing effects of alprazolam are dose-related as are the anxiolytic and subjective effects. The outpatient choice procedure is therefore sensitive to detect drug/dose differences. ACKNOWLEDGEMENT: Supported by NIDA Grant DA-08220. 516

USING

COGNITIVE

THE

TRAIL-MAKING

IMPAIRMENT

IN A DRUG

TEST

TO

ABUSE

SCREEN

FOR

TREATMENT

SAMPLE

C. Roberts, A. Horton, Center for Substance Abuse Treatment, Rockville, MD The Trail-Making test (TMT) is a brief paper and pencil neuropsychological test often used for screening for cognitive impairment. The value of the TMT is examined in a sample of 5619 males and 2902 females was drawn from electronic files of data from the Drug Abuse Treatment outcome Study (DATOS), a naturalistic, prospective cohort study that collected data from 199 l1993 in 96 programs in 11 cities in the United States. Data were analyzed to determine the effects of specific drugs of abuse on parts A and B of the TMT in this large sample of patients in drug abuse treatment programs. Most subjects, regardless of type of drug abused, on TMT parts A and B appeared to fall within normal limits relative to commonly accepted cutoff scores. These results suggest that the TMT parts A and B would have great value as a screening measures for cognitive impairment in a drug abuse treatment population.

517

CHAOTIC

ASSOCIATED TREATMENT

LIVES: WITH

RISK

AFRICAN

HOW

CONTEXTUAL

BEHAVIORS AMERICAN

ISSUES AMONG

ARE

OUT-OF-

CRACK-ABUSING

WOhIEN

A.C. Roberts, W. Wechsberg, W. Zule, K. Perritt, University of North Carolina-Chapel Hill, WinstonSalem, NC HIV infection has been steadily increasing among women in the Southeast through heterosexual transmission, particularly among crack abusing African American wonen. This NIDA funded HIV prevention intervention study was designed specifically to attract out-of-treatmen: African American crack abusing women. We hypothesized that historical abuse, co-morbid conditions and contextual factors would be associated with levels of crack use and HIV risk. This paper will explore the current contextual dimensions and complexities of these women’s lives in addition to examining issues of historical abuse. Variables studied include drug use, sexual risk, multiple risks, violence, criminal justice, health and mental health, family status, living arrangements, social support, and economic independent. Baseline findings from over 352 women indicate that 32% were homeless; 24% used crack 2-4 days at a time, 21% reported their first sexual contact was forced; 13% had multiple sexual contacts with an injecting drug using partner; 52% did not use condoms during vaginal sex; 78% had multiple partners and did not use condoms; 63”/0 used crack during sex; 37% traded sex for drugs; 43% traded sex for monl:y and food; and, 71% had been physically abused and 37% sexually abused this past year. Identifying histories of abuse, current co-morbid conditions and environmental supports, and disentangling them as mediating factors will be explored in relationship to drug and sexual risk behaviors. These findings reinforce the need for personalized interventions which address larger issues for these women. 518

IS

THE

PREADOLESCENT

PSYCHIATRIC

DIAGNOSIS INITIATION

ASSOCIATED OF

WITH CIGARETTE

SMOIKING?

M.L Robinson, D.J. Jackson, D.H. Epstein, D.A. Gorelick, J.L. Cadet, G.R. Uhl, and E.T. Moolchan, Teen Tobacco Addiction Treatment Research Clinic, NIDA/IRP/NIH, Baltimore, MD Age of onset of smoking is likely influenced by psychosocial, environmental and genetic factors. Psychiatric comorbidities may interact with nicotine use and dependence in several ways, including self-medication attempts. One hypothesis is that smokers with DSM-IIIR axis 1 nonsubstance use psychiatric diagnoses would start cigarette use at younger ages than those without such

S184

Abstracts

diagnoses. We examined data for DSM-IIIR current and lifetime psychiatric diagnoses and smoking data obtained from Diagnostic Interview Schedule-III-R and drug use survey for 390 research volunteers admitted to different studies at the NIDA/IRP. Eighty-three preadolescent initiators who started smoking at < 12 years of age were compared to 307 ‘older initiators’ who began smoking at later ages. Preadolescent initiators displayed trends toward higher frequencies of current (0.80 f 1.38 vs. 0.52 + 0.85, t = 1.5, P = 0.14) and lifetime (0.98 + 1.43 vs. 0.72 f 1.04, t = 1.75, P = 0.08) nonsubstance use psychiatric diagnoses than the ‘older initiators’. Preadolescent initiators had significantly fewer years of education than the ‘older initiators’ (11.7 + 1.9 vs. 12.2 + 1.8; t = 4.04, P < 0.0001). Multiple logistic regression analyses (controlled for differences in education) failed to find significant differences in psychiatric diagnosis frequency. These data fail to support any sizable effect of subsequent psychiatric diagnoses on age of smoking onset. Further analyses will be conducted to determine whether age of smoking onset is associated with subsequent psychiatric symptomatology that may not reach the threshold for diagnosis. Supported by NIDA intramural funds. 519

SUBSTANCE ABUSEAMONGWELFARE RECIPIENTS PARTICIPATING IN STATE-MANDATED JOB READINESS PROGRAMS

L.K. Robison, V. Lidz, A.M. Follis, Institute for Addictive Disorders, MCP Hahnemann University, Philadelphia, PA Substance abuse is widely recognized as one of the barriers to the employment of women and men on welfare. However, estimates of the incidence of drug use among welfare recipients vary between 8 and 40%, leaving public officials who plan services for people leaving welfare for work without essential information on the type and extent of needs for substance abuse treatment services. A series of interviews with 250 Temporary Assistance for Needy Families (TANF) beneficiaries taking part in state mandated job readiness training programs illustrates how difficult obtaining accurate information is. In response to baseline interview questions asking about any drug and/or alcohol use, 10.8% self reported current use. In addition, 7.6% self-reported only past use of drugs and alcohol. To date, 125 of the 250 subjects have been re-interviewed for the 3-month follow-up, with 10.4% disclosed past use and 8.8% reported current use. During the 3-month follow-up, an additional 6% reported current use for the first time and 6.4% reported no longer using. At the 6-month followup, 12.8% reported past use and 6.4% reported current use. Significant inconsistencies in self-reports about drug and alcohol use and personal demographics, suggest that

the data are not reliable. Efforts to validate self-reports with testing of hair samples failed because subjects refused to provide hair samples. Urine screens have been started to improve reliability. Interview instruments are being adjusted to remove wording, typical of clinical instruments, that implies the respondent has a substance abuse problem. Standard terms, such as ‘any use of-‘, are being clarified because respondents seen to understand them as asking only about abuse or dependence rather than including occasional use. 520 IMPLEMENTATION OF A CLINIC-WIDE CLIENT-SELECTEDMETHADONEDOSAGE

POLICY

OF

E. Robles, F.B. Miller, K. Gilmore-Thomas, and D.E. McMillan, University of Arkansas for Medical Sciences, Little Rock, AR A 6-month interval (baseline) during which methadone doses above 99 mg required individual approval by the clinic’s physician was compared with the succeeding 16-month period in which a policy of patient-regulated methadone dosing with no preset upper limit was implemented. During the patient-selected dosage period, the initial 30-35 mg methadone dose was raised by 5- 10 mg per week under medical supervision, until patients reported no withdrawal symptoms. Subsequently, patient requests for dose changes were implemented by the nursing staff in l-5 mg steps within 24 h of the request. Patients were required to remain at the selected dose for a minimum of 4 days before a new dose increase would be effective. Take-home policy remained unchanged, with patients receiving l-6 take-home doses per week depending on abstinence from drugs of abuse, overall time in treatment, and compliance with counseling requirements and clinic regulations. The clinic’s maximum daily methadone dose increased from 165 mg during baseline to 300 mg during the self-regulation period, while the average daily methadone dose increased from 76.84-80.04 mg ( W = 473, N = 57, P = 0.01). Monthly percent of opiate-positive urine specimens decreased significantly from 5.26% during baseline to 1.64% during the self-regulated dose period ( W = 169, N = 57, P < 0.01) and use of other drugs remained unchanged. No patient failed to show possession of recalled take-home doses, and no instances of liquid methadone diversion were reported by law enforcement agencies in the area. 521 RURAL AND URBAN DIFFERENCES IN HIV RISK BEHAVlORS,HEALTHSTATUSANDPATTERNSOFHEALTH CARE UTILIZATION AMONG DRUG USERS IN PUERTO RICO

R.R. Robles, C.A. Marrero, H.M. Colon, T.D. Matos, and J.C. Reyes, Universidad Central de1 Caribe, Bayaman, PR

Abstracts

Recent research on the prevalence of HIV risk behaviors and comorbidity among drug users indicate that the alarming upward trend identified during the late 70s is stabilizing. However, there is disagreement concerning whether the same pattern holds for rural populations. The aim of this study is to compare prevalence of HIV risk behaviors, HIV seroprevalence and changes in risk behaviors among drug users residing in urban and rural communities in Puerto Rico. The sample of the study comprised of 286 participants recruited in copping areas in rural communities and in urban communities. Participants received serum tests for HIV antibody and HIV pre- and posttest counseling. Subjects were interviewed at baseline and 6 months follow-up by trained interviewers. Results: Drug users residing in rural communities were more likely to be drug injectors, have a history of incarceration and episodes of depression than their peers residing in urban communities. No significant differences between the two groups were reported in HIV seropositivity and access to drug treatment. Subjects in rural communities were more likely to inject drugs and to continue injecting at 6 months followup. However, there was a significant reduction in the use of shooting galleries, the sharing of needles and unprotected sex at 6-month follow-up in both sites. Conclusions: The high rate of drug use cronicity (years of injecting; number of episodes of incarceration) and comorbidity (episodes of depression) among drug users residing in rural communities was not expected. However, changes in HIV risk behavior demonstrate the willingness of drug users to alter their HIV risk behaviors. 522

INITIAL

SELF-ADMINISTRATION BUPHINE

UNDER

RESPONSE

REQUIREMENTS OF

ALFENTANIL

A PROGRESSIVE-RATIO

DELINEATE AND

NAL-

SCHEDULE

J.S. Rodefer, J.K. Rowlett, and R.D. Spealman, Harvard Medical School, and New England Regional Primate Research Center, Southborough, MA Previous research has suggested that self-administration of drugs, which differ with respect to intrinsic efficacy, can be distinguished quantitatively by using procedures that vary response requirements [e.g. progressive-ratio (PR) procedures]. To assess the relationship of response requirement and self-administration of opioid agonists differing in intrinsic efficacy, the present study compared the high-efficacy m-agonist alfentanil to the low-efficacy agonist nalbuphine in rhesus monkeys responding under a PR schedule of i.v. drug delivery. The initial fixed-ratio (IFR) response requirement was 25, 100, or 400 and doubled across successive components to produce a maximum response requirements of 400, 1600, or 6400, respec-

S185

tively. Increasing the IFR generally shifted dose-response functions for drug deliveries downward for both alfentanil and nalbuphine. Alfentanil (0.03- 10.0 mg/b:g per infusion) was self-administered across all IFRs and produced dose-dependent increases in drug deliveries that reached an asymptote at the higher doses in most monkeys. In contrast, nalbuphine (0.001-0.3 mg/kg per infusion) maintained behavior at IIPR 25 and 100, but not at IFR 400. Furthermore, increasing doses of nalbuphine typically resulted in inverted-U shaped dose-response curves. Therefore, by varying IFR, self-administration of a high-efficacy agonist could be characterized by a monophasic dose-response curve over a wide range of response costs. In contrast, self-administration of a low-efficacy agonist was characterized by biphasic dose-response curve over a narrower range of response costs. These data suggest that PR schedules utilizing a range of IFRs may be useful for delineating the relationships between intrinsic efficacy and the reinforcing effectiveness of drugs. 523 IN

ESTABLISHMENT

HUMAN

CONDITIONING AZEF’AM

OF

VOLUNTEERS HISTORY

A

DIAZEPAM

FOLLOWING OF

PLACEBO

PREFERENCE A DIFFERENTIAL VERSUS

DI-

CHOICE

J.M. Roll, SM. Alessi, M.P. Reilly, and C.E. Johanson, Wayne State University, Detroit, MI Seven participants took part in this 2-phase study. During the first four sessions of phase 1, they were administered 5 mg diazepam or placebo (drug A and B) under double blind conditions such that the drug they received alternated between sessions. During the remaining 5 sessions of phase 1, they were allowed to select which of the drugs (A or B) they wished to receive. Phase 2 was a replication of phase 1 with the following exceptions: during the first four sessions parti’cipants completed a computer task that resulted in their earning money after ingestion of the drug (still 5 mg diazepam and placebo, but labeled drug C and D). Payment for the computer task was highest following the drug they had avoided in their last five sessions of phase 1 and lowest following the drug they had preferred from phase 1. During the last five sessions of phase 2, preference was reassessed by allowing participants to choose the drug (C or D) they wished to receive. Six of the seven participants preferred placebo to diazepam in phase 1. In phase 2, however, this preference was reversed for these six partil;ipants who now selected diazepam over placebo. Subjective responses to placebo and diazepam also chan,ged across the two phases.

S186

524

MONEY MANAGEMENT PSYCHIATRIC INPATIENTS

Abstracts

HABITS

AND

NEEDS

OF

MI. Rosen, A. Shaner, SM. Harman, and R.A. Rosenheck, Yale University School of Medicine-VA Connecticut Healthcare System, New Haven, CT Attempts have been made to operationalize the term ‘incapable of managing funds’ which is frequently the criterion used for appointment of payees such as representative payees, VA fiduciaries, and conservators. We applied an algorithm for ‘incapable’ to a questionnaire around money management completed by, 83 veterans hospitalized on a general psychiatry inpatient unit in an ongoing study. Only nine of the 83 had been assigned any kind of payee. For the 43 who received benefits from the VA or SSA, we applied our criteria to patient questionnaires, inpatient clinician questionnaires (n = 37) outpatient clinicians (n = 25). Fifty-eight percent of beneficiaries were eligible for payees based on self-reported failure to meet basic needs or harm caused by substance use. Sensitivity and specificity for both types of clinician ratings ranged from 50 to 70%. Patient self-reports were correlated with outpatient clinicians willingness to assign a representative payee if the patient agreed (0.47, P < 0.01). Beneficiary and outpatient clinician ratings of whether funds were currently managed appropriately were not correlated, although opinions around need for someone to control the patients’ funds were correlated (0.48, P = 0.01). Sixty-eight percent of those eligible for payee assignment endorsed ‘want’ for some type of money management help but only 13% wanted someone to manage and control their funds. Preliminary conclusions are that the proposed criteria for ‘incapable of managing funds’ show moderate agreement with each other, and that many veterans who are ‘incapable’ of managing funds have not been assigned a payee. 525

TIME FROM USE TO PROBLEMS IN A PROSPECTIVELY STUDIED COMMUNITY SAMPLE OF CANNABIS USERS

M.F. Rosenberg and J.C. Anthony, University, Baltimore, MD

Johns Hopkins

Aim: In this epidemiological study of almost 600 untreated community-dwelling cannabis users, we sought clinical features of DSM cannabis dependence that occur distinctively earlier in its natural history. Methods: The Baltimore Epidemiologic Catchment Area research group sampled, recruited, and assessed 3481 adults age 18 + years in 1981. Almost 3/4th of the survivors were traced and re-assessed roughly 13.5 years later, when they completed an assessment of age at each drug-associated problem (adapted from the

National Comorbidity Survey methods). In the re-assessed sample, 37 cannabis users were identified as cases of cannabis dependence during the follow-up interval; 41 as cases of nondependent cannabis abuse; 521 had suffered no problems or insufficient problems to qualify as cases. Survival analysis methods were used to plot and study the cumulative occurrence of these problems in a contrast of the 37 dependence cases and 521 never-cases (CD + vs CD - ). Results: We show graphs for cumulative incidence of each DSM CD symptom group (Al -A9), plotted in years since 1st use, for CD + vs CD - users. For example, within 5 years of 1st use, for an estimated 35% of CD + cases but only 20% of CD - users, there had been failed efforts or sustained hopes to cut back on cannabis use (criterion A3). In contrast, within 5 years after starting use, 80% of non-cases had experienced socially maladaptive or physically hazardous bouts of cannabis intoxication, as compared to 55% of the CD + cases (criterion A9). Discussion: The 5000 + person-years of followup experience provided by the cannabis users in this study give an unprecedented look at the natural history of cannabis dependence, as well as the experience of 521 users who did not become cannabis dependent. Continuing work to identify distinctive features of early cannabis dependence may promote earlier differentiation of cannabis users who will or will not progress to clinically significant dependence. ACKNOWLEDGMENT: NIDA DA05960, DA08199, NIMH MH47447. 526 LINKING FEMALE STANCEABUSETREATMENT

SEX

WORKERS

WITH

SUB-

A. Rosenblum, L. Nuttbrock, J. Wallace, S. Magura, M. Marthol, and D. Tucker, National Development and Research Institutes, Inc., FROST’D, Project Return, New York, NY This randomized clinical trial is implementing and evaluating an organizational linkage model for delivering substance abuse treatment to female street-based sex workers in New York City. FROST’D (From Our Streets with Dignity) is a well-established communitybased organization, which provides outreach services (including referrals for substance abuse treatment) to sex workers. These services are delivered from a mobile unit, which parks in areas where these women congregate. The study is experimentally enhancing this outreach modality by establishing a separate mobile unit from which Project Return, a large substance abuse treatment organization with many specialized services for women, will provide front-line counseling for substance abuse with the aim of linking clients to appropriately matched longer-term treatment within Project Return’s established array of programs. The alliance between FROST’D and Project Return includes NDRI

Abstracts

to administer/coordinate the overall project and design/ conduct the evaluative research. The primary outcome variables are participation in substance abuse treatment and reduction in substance use. Preliminary data (N = 39) show 87% use cocaine, 46% use heroin and 36% inject drugs. Mean number of paying male customers in past month was 49. Condom use with paying partners is high: condom use in last episode of vaginal and oral sex was 100 and 890/b, respectively. This research was supported by Grant 4 KDl TI 12049-lo- 1 from CSAT. 527 BUPRENORPHINE/NALOXONE FOR OPIATE TION:POTENTlAL ECONOMIC IMPACT

ADDIC-

R. Rosenheck and T.R. Kosten, Yale University School of Medicine and VA Connecticut Healthcare System, New Haven, CT Buprenorphine combined with naloxone (Suboxone) may soon be approved for office practice, thereby improving the accessibility, convenience and acceptability of opiate substitution therapy compared to clinic based methadone maintenance. Methods: The potential economic impact of office based Suboxone was assessed by estimating: (1) direct treatment cost compared to clinic based methadone; (2) relative effectiveness in reducing heroin addiction, health service use, crime and unemployment; and (3) ability to increase the number of treated addicts. Results: In comparison to methadone clinics, Suboxone in office practice is likely to increase medication, physician, and nursing costs, but reduce toxicology screens, medication dispensing, administrative oversight, counseling and travel costs for patients. Costs may be equivalent in year 1 treatment, but generate savings in year 2 ($400-600/year/patient). Since at comparable doses Suboxone efficacy is equivalent to methadone, Suboxone may be more cost-effective in similar patients. Because of the convenience of officebased treatment, Suboxone may increase access to opiate substitution. To the extent that Suboxone is provided to previously unsuccessfully treated high-cost patients who typically receive 3-4 inpatient detoxifications each year, net cost savings could exceed several thousand dollars/year/patient. To the extent that Suboxone is extended to employed heroin abusers who endure their dependency and have avoided treatment, costs could increase. Conclusion: The total cost impact will depend on which addict sub-populations make greatest use of the treatment opportunity presented by Suboxone. While it is potentially more cost-effective than methadone maintenance, high cost-efficacy depends on targeting high cost recidivists rather than low cost, higher functioning opiate users.

Sl87

528

NICOTINE EFFECTS IN THE HUMAN ANTERIOR CINGULATE ASSESSED BY lH-MAGNETIC RESONANCE SPECTROSCOPY

T.J. Ross, E. Schneider, R. Prost, S.J. Li, R.C. Risinger, B.J. Salmeron, A.S. Bloom and E.A. Stein, Me&al College of Wisconsin, Milwaukee, WI, and Pfizer Central Research, Groton, CT Nicotine is generally considered the addictive and reinforcing agent responsible for continued cigarette smoking behavior, and is thought to interact with the mesacorticolimbic dopamine (DA) system in a manner simil,sr to other abused drugs. Nicotine-induced changes in human brain chemistry are poorly understood. As such, to quantify nicotine’s acute actions, effecls of tolerance and the ability to pharmacologically block these effects, lH-MRS in the anterior cingulate (AC) was employed in nine healthy, cigarette smokers. The AC is involved in attentional processes and has prominent DA afferent terminals. Nicotine is thought to enhance attention, modulate DA release, and can increase AC neuronal activity. MRS was acquired before and 30 min after an acute IV nicotine challenge (0.75 mg/70 kg in 30 s) on three separate occasions, the first being the baseline condition. Two 21 mg nicotine transdermal patches were applied 2 h before visits 2 and 3; 3 mg oral mecamylamine (MEC), was also administered 2 h prior to visit 3. A significant 1 l”/o decrease in the ratio of Choline to Creatine signal was seen after nicotine patches (with or without MEC) relative to the baseline. This decrease was reversed by acute nicotine. A similar trend (P < 0.08) was observed in Myoinositol/Creatine ratio. No change in NAA/Creatine ratio was seen. Changes in Choline/Creatine may reflect changes in drug-induced receptor-membrane interactions and turnover. Supported by NIDA grant DA09465 and Pfizer Central Research, Inc. 529 THE EFFECT OF ESTROGEN OF COCAINE SELF-ADMINISTRATION

ON THE ACQUISITION IN FEMALE RATS

M.E. Roth, W.J. Lynch, J.L. Mickelberg, and M.E. Carroll, University of Minnesota, Minneapolis, MN Previous research indicates that female rats acquire cocaine self-administration more rapidly, stabilize with greater cocaine intake (Lynch and Carroll, 1999), and show greater reinstatement of extinguished cocaine selfadministration (Lynch and Carroll, 2000) than males. It has been suggested that these differences may be related to phases of the estrous cycle (Roberts et al., 1989). Therefore, to examine the importance of the role of the ovarian hormone estrogen in the acquisition of cocaine reinforced behavior, intact and ovariectomized (OVX)

S188

Abstructs

rats were treated with estrodial benzoate (EB), the estrogen antagonist tamoxifen (TAM), or equal volume vehicle. Four groups of female rats were compared: (1) OVX + EB (n = lo), (2) OVX + vehicle (n = IO), (3) intact + TAM (n = 10) and (4) intact + vehicle (n = 5). Rats had access to i.v. cocaine (0.2 mg/kg) during daily 6 h self-administration sessions. The criterion for cocaine acquisition was a total of 500 infusions over 5 consecutive days. Preliminary results indicate 88.9% of OVX + E rats and 80% of intact + vehicle rats acquired cocaine self-administration, while only 37.5% of OVX + vehicle rats and 37.5% of intact + TAM rats acquired cocaine self-administration. In a previous study examining sex differences in acquisition of cocaine self-administration, 70% of intact female rats acquired drug self-administration, while only 30% of intact male rats acquired (Lynch and Carroll, 1999). The present results for the intact + vehicle rats are similar to those previously presented. Furthermore, group differences suggest that the female sex hormone estrogen may be a critical factor that influences drugseeking behavior in female rats. Supported by grants T32DA07097 (M.E.R.), F31DA05915 (W.J.L.), and R37DA03240 (M.E.C.).

530 BEHAVIORAL NALTREXONE THERAPY: GRATEDTREATMENTFOROPIATEADDICTIONANDNALTREXONE MAINTENANCE

AN INTE-

J.L. Rothenberg, M.A. Sullivan, S.H. Church, A. Seracini, and E.V. Nunes, Columbia University College of Physicians and Surgeons/NY State Psychiatric Institute, New York, NY Treating opiate dependence with long-term maintenance on naltrexone, although effective has faced several clinical limitations. The aim of this NIDA-funded Stage I Behavioral Therapies development project is to develop and test Behavioral Naltrexone Therapy (BNT), a novel psychotherapy designed to promote abstinence from opiates, adherence to naltrexone maintenance, and lifestyle changes in opiate-dependent individuals. BNT is a 6-month therapy approach incorporating components from various empirically tested treatments for drug dependence. These therapies include Network Therapy, in which a significant other is involved to monitor and support medication compliance, the Community Reinforcement Approach (CRA), voucher-based contingency management, cognitive-behavioral Relapse Prevention Therapy, and Motivational Enhancement techniques. A working treatment manual for BNT was constructed, therapist training procedures and a therapist competency measure were developed, and a therapist adherence measure was developed and tested for inter-rater reliability. Initially, an uncontrolled pilot trial was conducted with 47 opiate-

dependent participants and provided a preliminary evaluation of the efficacy of BNT. Based on our findings, BNT was modified to better address severe depressive symptoms and methadone use at baseline, two significant predictors of premature attrition in our pilot sample. Currently, we are conducting a small, randomized controlled trial to test the refined BNT vs. a standard compliance enhancement approach. To date, 10 subjects have entered the randomized trial. In this presentation, an overview of BNT will be provided and its preliminary efficacy for the treatment of opiate dependence based on the progress of the randomized trial will be reported.

531 COGNITIVE TASK PERFORMANCE AS A FUNCTION OFILLICITSUBSTANCE USE AND OF TOBACCO USE E. Rotheram-Fuller, E.D. London, S. Shoptaw, and S. Burman, Friends Research Institute, Los Angeles, Intramural Research Program, NIDA, Baltimore, MD, UCLA, Long Beach Research Foundation /VAMDRU, Long Beach, CA While substance abuse might produce cognitive deficits, such deficits could in turn also affect vulnerability to drug dependence and sustained addiction. The current study evaluates whether performance on a cognitive task that reflects function of the orbitofrontal gyrus (Gambling Task) correlates with illicit substance use (Opiate-Dependent Group versus Control Group) and/ or tobacco smoking (smokers versus non-smokers). A total of 19 methadone maintained and 19 non-substance using matched controls (each group comprised of 9 smokers and 10 non-smokers) will complete tests designed to assess deficits in both the ventromedial prefrontal cortex (Gambling Task) and the dorsolateral prefrontal cortex (Wisconsin Card Sorting Task) to identify specific or generalized prefrontal lobe damage. Illicit drug use and tobacco smoking status is verified using both self-report and biological samples (urine analysis and expired carbon monoxide) collected on 5 consecutive days for the Opiate Dependence Group, and 2 days for the Control Group. Preliminary findings suggest a trend for better performance by individuals in the non-smoking Control Group on the Gambling Task than the Opiate Dependent Smokers, with equal performance from the two groups on the Wisconsin Card Sorting Task. Opiate-dependent smokers are significantly more depressed (15.7 (2.5)) as measured by the Beck Depression Inventory, than non-smoking controls (5.5 (4.2); t(9) = 3.83; P < 0.05). This ongoing research will likely produce more significant differences in cognitive performance between groups with an increased number of participants. ACKNOWLEDGEMENTS: NIDA Grants 1 ROl DA 09992 and 1 YOl DA 50038

Abstracts

532

IN

THAT

NOREPINEPHRINE

INDUCED

VITRO

PROFILING

SUBJECTIVE

OF

STIMULANTS

CONTRIBUTES EFFECTS

SUGGESTS TO

STIMULANT-

IN HUMANS

R.B. Rothman, M.H. Baumann, C.M. Dersch, D.V. Romero, K.C. Rice, F.I. Carroll and J.S. Partilla, IRP, NIDA NIH, Baltimore, MD, NIDDK, NIH, Bethesda, MD, Research Triangle Institute, Research Triangle Park, NC Much evidence supports the hypothesis that mesolimbic dopamine (DA) mediates the rewarding/reinforcing effects of central nervous system stimulants such as cocaine and amphetamine. Although it is tempting to assume that DA also mediates the euphoric effects of these medications in humans, the role DA plays in mediating the subjective effects of stimulants in humans remains to be established. Amphetamine and cocaine increase norepinephrine (NE) via stimulation of release and inhibition of reuptake, respectively. If increases in NE mediate the positive subjective effects of stimulants, then one would predict that stimulant medications which produce positive subjective effects in humans should share the ability to increase NE. To test this hypothesis, we determined, using in vitro methods, the neurochemical mechanism of action of well-studied stimulants such as amphetamine, MDMA, methamphetamine, ephedrine, phentermine, chlorphentermine, and aminorex. The results for the release assays are tabulated as IC.50 values (nM) for NE, 5HT and DA release. ( + )-Amphetamine (6.97, 1765, 24.8); ( f )-MDMA (64.2, 55.7, 376); Phentermine (28.8,2575, 262); ( - )-Ephedrine (34.5, > 10 000, 1350); ( + )-Methamphetamine (14.3, 740,40.4); Aminorex (26.4, 193,44.8). In humans, doses of MDMA, amphetamine and methamphetamine which produce autonomic (NE-mediated) and subjective effects do not decrease plasma prolactin (DA-mediated). This, and the fact that the most potent effect of these stimulants is to release NE, suggests that NE plays an important role in mediating stimulant-induced subjective effects. 533

THE

IMPACT

OF SEXUAL

TREATMENT SUBSTANCE USE CENT SUBSTANCE ABUSERS

ABUSE AMONG

HISTORY FEMALE

J. Rounds-Bryant, National Development Institutes, Inc., Raleigh, NC

ON POSTADOLES-

and Research

Various studies have found a relationship between childhood sexual abuse and problematic alcohol and drug use in a variety of samples. For example, there is evidence that female adolescent substance abusers tend to have relatively high rates of sexual abuse history. Yet, little is known about the impact of historical sexual abuse on treatment outcomes for adolescent girls with substance

S189

use problems who seek substance abuse treatment. This study will test the hypothesis that girls with a pre-treatment history of sexual abuse will engage in problematic marijuana and/or alcohol use following treatment at a greater rate than girls without a history of sexual abuse. Human subjects were 885 girls who were treated in community-based treatment programs that participated in the NIDA-sponsored Drug Abuse Treatment Outcome Studies (DATOS), from 1993 to 1995. Subjects were interviewed before and 12 months following treatment, using a comprehensive psychosocial and behavioral assessment battery. Some 58% of subjects were diagnosed with Marijuana Dependence (DSM-III-R), 33% were diagnosed with Alcohol Dependence (DSMIII-R), and 42% reported a history of sexual abuse. Multivariate regression analysis (which will also include depression, time in treatment, and treatment modality as important predictor variables) will be used to evaluate the impact of historical sexual abuse on post-treatment marijuana and alcohol use. The results will have treatment implications for this population. 534

CONTINGENCY

ENGAGEMENT DONE:

MANAGEMENT

IN A SAMPLE

AND

OF COCAINE-USING

TREATMENT METHA-

PATIENTS

G.A. Rowan-Szal and D.D. Simpson, Institute of Behavioral Research, Texas Christian University, Fort Worth, TX Behavioral treatments such as contingency management (CM) have shown promise in engaging and retaining patients in outpatient methadone treatment. Patients in these programs who also use cocaine are especially difficult to engage and retain. This study compares the effectiveness of CM in increasing treatment engagement among cocaine and non-cocaine using methadone patients using a 2 x 2 design consisting of cocaine admission status (cocaine or non-cocaine) and CM intervention (reward or non-reward). Based on indicators of cocaine use at admission, 114 patients were randomly assigned to treatment conditions. Patients participated in their assigned intervention for 2 months and progress was followed for the 3 months post-intervention. Analysis of variance (ANOVA) was used to examine differences in treatment participation, engagement, and retention. Patients participating in CM had significantly greater session attendance and treatment engagement (increased rapport with counselor) 3 months after the intervention. The CM results were more pronounced for non-cocaine admissions, although there were interactions between the CM and cocaine groups. That is, cocaine admissions receiving CM (rewards) had increased engagement. In summary, CM appears to be an effective intervention for cocaine-using patients in methadone maintenance.

Abstracts

s190

535

COMBINED

TION

UNDER

VARYING

COCAINE-HEROIN

SELF-ADMINISTRA-

PROGRESSIVERATIO

INITIAL

RESPONSE

SCHEDULES

WITH

REQUIREMENTS

J.K. Rowlett and R.D. Spealman, Harvard Medical School, New England Regional Primate Research Center, Southborough, MA Previous studies have shown that under a progressiveratio (PR) schedule, monkeys self-administer low-dose combinations of cocaine and heroin (i.e. ‘speedballs’) to a greater extent than either drug individually. The present study assessed the effects of varying the initial fixed-ratio (IFR) response requirement of a PR schedule on self-administration of cocaine-heroin combinations. Rhesus monkeys were implanted with indwelling intravenous catheters and trained to self-administer cocaine under PR schedules with IFRs of 25 or 100. Consistent with previous findings, combination of low, inactive doses of heroin with cocaine resulted in a shift to the left in the cocaine dose-response function under the IFR 100 condition. However, the ability of a particular dose of heroin to enhance the reinforcing effects of cocaine at IFR 100 was related to the effect of the heroin alone at IFR 25. Specifically, doses of heroin that were inactive at IFR 100 but that enhanced the reinforcing effects of cocaine were self-administered consistently at IFR 25. Furthermore, doses of heroin that were inactive at IFR 25 did not enhance the reinforcing effects of cocaine at IFR 100. These findings show that inactive doses of heroin, which enhance self-administration of cocaine at a relatively high response cost, have reinforcing effects at a relatively low response cost. The results are interpretable either in terms of an increase in the reinforcer value of cocaine when combined with heroin or an unmasking of reinforcing effects of heroin at high response costs by low doses of cocaine. Supported by DA11928 and RROO168. 536 ING

RAPID

PROGRESSION

IN TEENAGERS

REQUESTING

TO

DAILY

TOBACCO

SMOK-

TREATMENT

S. Rucke, M.L. Robinson, A. Radzius, J.E. Henningfield, and E.T. Moolchan, NIH, NIDA Intramural Research Program, Baltimore, and Pinney Associates, Bethesda, MD Previous reports have suggested that age of smoking onset is related to both subsequent dependence level and quitting success. We are assessing these relationships in teen smokers seeking treatment and have hypothesized that age of onset of smoking would predict time to daily smoking and time to formal request for assistance with quitting. We collected demographic and smoking-related (smoking rates, measures of depen-

dence, motivation to quit, self-quit attempts) and demographic data from 72 male and female adolescents interested in a currently-accruing treatment protocol. Preliminary results obtained via Pearson’s correlation suggest a relationship between age started smoking (12.5 + 1.9, mean f SD) and age of onset of daily smoking (13.1 f 1.4) r =0.83, P
BEHAVIORAL

PHARMACOLOGICAL

BETWEEN METHYLPHENIDATE CAINE ABUSERS

AND

SIMILARITIES COCAINE

IN

CO-

C.R. Rush and R.W. Baker, University of Mississippi Medical Center, Jackson, MS Six human volunteers with recent histories of cocaine use were trained to discriminate 200 mg oral cocaine HCL. After meeting a predetermined discrimination criteria (i.e. 2 80% correct responding on 4 consecutive days), a range of doses of oral cocaine (50, 100,200 and 300 mg), methylphenidate (15, 30, 60 and 90 mg) and triazolam (0.125, 0.25, 0.5 and 0.75 mg), and placebo were then tested to determine if they shared discriminative-stimulus and subject-rated effects with 200 mg cocaine. Cocaine and methylphenidate dose-dependently increased cocaine-appropriate responding. The highest doses of cocaine (i.e. 200 and 300 mg) and methylphenidate (60 and 90 mg) produced at least 80% drug-appropriate responding. Cocaine and methylphenidate produced prototypical stimulant-like subject-rated drug effects (e.g. increased subject ratings of Drug Liking, Good Effects, Willing to Pay For and Willing to Take Again), and increased heart rate and blood pressure. Across the range of doses tested, the effects of cocaine and methylphenidate did not differ significantly. Triazolam occasioned low levels of cocaine-appropriate responding (i.e. < 20% drug-appropriate responding) and did not produce stimulant-like subject-rated drug effects. Across the range of doses tested, the effects of cocaine and triazolam differed significantly. The results of this experiment demonstrate that humans can reliably discriminate oral cocaine, which is concordant with previous studies. Consistent with in vivo behavioral neuropharmacological data, the discriminative-stimulus, subject-rated and physiological effects of oral cocaine and methylphenidate did not differ. Supported by N.I.D..4. Grant DA 10325.

s191

Abstracts

538

HIV

INCIDENCE AND PREVALENCE SONSADMITTEDTODRUGTREATMENTCENTERS,

AMONG

PER-

1994-

1997

KM. Sabin, K.A. Bordelon, and MS. Miller, Centers for Disease Control and Prevention, Atlanta, GA Injection drug users (IDUs) admitted to treatment have high prevalence of HIV infection but HIV incidence is this population is less well understood. Anonymous unlinked HIV testing was performed on residual blood collected for routine medical purposes in 12 drug treatment centers in 4 metropolitan areas. Recent HIV infections were determined by testing with the STARHS assay and used to calculate incidence rates. Demographic and risk data were abstracted from medical records and intake forms. Data were collected from 18 837 drug treatment recipients. Nearly 14% of admissions were HIV-infected (25% in New York City (NY), 12% in Newark (NJ), 1% in Los Angeles (LA), 1% in Seattle (WA)). Annualized incidence was 1.7% in NY, 1.3% in NJ, 0.2% in LA and 0.2% in WA. Fifteen percent of men and 13% of women were HIV infected; incidence was 1.1“XI in both sexes. Persons injecting in the previous 12 months were 4.4 times more likely to be infected in NJ (95% CI: 3.5, 5.6) and 2.9 (2.3, 3.6) times in NY compared to LA and WA. Recent history of injecting was not associated with infection in WA. Prevalence among IDUs was 22% compared to 8% among non-IDUs. incidence among IDUs was the same as non-IDUs (1.1%); however, rates varied among sites. Incidence among IDUs in NJ (2.6%) and NY (2.4%) were much higher than in LA (0.2%) and WA (0.3%). Among non-IDUs, incidence in NY (2.9%) was much higher than NJ (0.9%) LA and WA (both 0.0%). Among non-IDUs in NJ, incident infections reported heroin use only; in NY, 57% reported crack use and 43% heroin. Blacks (32%) had twice the prevalence of Hispanics (18%) but a lower incidence (3.5 vs. 4.3%). Blacks and Hispanics were more likely to be IDUs in NY and NJ. Incidence remains high in these two east coast settings among IDUs, emphasizing the need for more prevention work. Variability in HIV incidence among different sites suggests that prevention programs in drug treatment centers should be tailored to local epidemiology and should not focus exclusively on IDUs. 539

FAILURE OF LINKAGE WITH CARE:A PROSPECTIVECOHORTSTUDY

PRIMARY

MEDICAL

R. Saitz, M.J. Larson, L. Jacobson, M. Winter, L.M. Sullivan, and J.H. Samet, Boston University Schools of Medicine and Public Health and Boston Medical Center, Boston, and New England Research Institutes, Watertown, MA

We hypothesized that we could identify factors associated with a failure to link with primary medical care. We studied a prospective cohort of subjects in a randomized trial of an intervention, the Health Evaluation and Linkage to Primary care (HELP) study. Eligible subjects were admitted for detoxification from heroin, cocaine or alcohol and had no primary medical care. Linkage was defined as one or more primary care clinician visits in 2 years. Subject characteristics were: 76% male; mean age 36; 46% black, 37% white, 11% Hispanic; and 47% had a chronic medical illness. Most (81%) reported addictions or mental health utilization or episodic medical visits in the past 6 months. Most (87%) had polysubstance problems; 86% alcohol, 75% cocaine, 69% marijuana, and 38% heroin problems. Of 470 subjects, 348 (74%) completed a follow-up interview; 144/348 (41%) did not link with primary medical care. Insurance, psychiatric illness, addiction severity and addictions and mental health utilization were not signifcant bivariate predictors. In a multivariable model adjusting for age and randomization assignment, the following were associated with a failure of linkage: male (Odds Ratio 2.6, 95% Confidence Interval 1.54.5), white (OR 1.7, CI l.ll2.8), friends and family that do not support abstinence (OR 2.1, CI 1.3-3.5), no recent medical visits (OR 1.7, CI l.O-2.9), and absence of chronic illness (OR 1.8, CI 1.1-2.8). This cohort of young addicted patients without primary care had very high health care utilization but many failed to link with primary medical care. Characteristics and experiences identified in this study suggest that linkage with primary medical care will require aggressive strategies I.hat make use of episodic health care encounters and address patients’ perceptions of need for primary care. Supported by NIDA Grant DA 10019. 540

AGE AND GENDER PREDICT DEPRESSIVE AND MANIC SYMPTOMS AMONG BIPOLAR DISORDER PATIENTS WITH COMORBID ALCOHOLDEPENDENCE

I. Salloum, J. Cornelius, L. Kirisci, and D. Daley, University of Pittsburgh School of Medicine, Pittsburgh, PA The aim of this study is to examine predictors of mood symptomatology among patients with comorbid bipolar disorder and alcohol dependence. Thirty-seven patients with DSM-IV/SCID comorbid diagnoses of bipolar disorder and alcohol dependence were assessed using the Hamilton Rating Scale for Depression (HAMD-25), and the Beth-Rafaelsen Rating Scale for Mania (BRM). These two objective rating scales measure the

Abstracts

S192

presence and intensity of depressive and manic symptoms. Multiple regression analysis was employed to examine predictors of depressive and manic symptoms at presentation. Independent variables included demographic and baseline alcohol-related variables. Age significantly predicted depressive and anxiety symptoms on the HAMD-25 (B = 0.49, t = 2.742, P = 0.01). On the other hand, male gender predicted manic symptoms on the BRM scale (B = - 0.41, t = - 2.636, P = 0.01). Our findings highlight the importance of age and gender in predicting the manifestation of the bipolar episode. 541 DURING

NEURAL HUMAN

CORRELATES COCAINE

OF

HIGH

AND

CRAVING

SELF-ADMINISTRATION

B.J. Salmeron, R.C. Risinger, T. Ross, H. Garavan, C. Rainey, A. Bloom, and E.A. Stein, Medical College of Wisconsin, Milwaukee, WI Animal models have demonstrated that self-administration (SA) of abused substances produces distinct patterns of activity in mesocorticolimbic (MCL) regions compared to passive drug injection. Human neuroimaging studies of passive stimulant administration have begun to relate function of MCL and striatal structures to subjective drug effects. As such, six healthy male cocaine dependent subjects underwent BOLD fMRI while repeatedly self-administering (FRl) 20 mg/70 kg cocaine and performing continuous on-line ratings of High, Rush, and Craving. Each question was asked every min during the 60 min session. Using the High ratings as a canonical, robust, positive correlations were seen in middle frontal cortex, anterior cingulum, thalamus, caudate, anterior insula, entorhinal and ventral tegmental area. Negative correlations were seen in superior frontal, anterior cingulate, and nucleus accumbens. This topography also encompassed that of Rush. In contrast, Craving was associated with a more heterogeneous topography including middle, medial and inferior frontal, anterior cingulum, anterior cingulate, superior temporal, occipital and parietal cortex. While preliminary, these results suggest that the hedonic effects of SA are associated with activity in discrete brain regions, including MCL DA projection fields, and support the hypothesis that feelings of euphoria and craving during cocaine SA are related to alteration of neural activity in human brain reward and reinforcement pathways. Supported by grant and DA09465 and MO1 RR00058. 542

METHADONE

MARY

REPORT

MEDICAL

MAINTENANCE:

A

SUM-

E.A. Salsitz, H. Joseph, B. Frank, J. Perez, B.L. Richman, N. Salomon, M.F. Kalin, and D.M. Novick, Beth Israel Medical Center, NY State OASAS, and Wright State University School of Medicine, New York, NY

Methadone medical maintenance (MMM) has been used since 1983 to provide continuing care for patients who require methadone maintenance but no longer need the services and structure of traditional methadone clinics. MMM is provided to socially rehabilitated patients in the offices of hospital-based physicians. To evaluate our hypothesis that MMM can be sustained and perpetuated on a long-term basis, we evaluated our experience of over 15 years. We treated 158 patients, of whom 132 (83.5%) complied with the program; the other 26 were discharged. The cumulative proportion of patients remaining in MMM at 5 (n = 94) 10 (n = 48) and I5 (n = 10) years was 72, 59 and 45%, respectively. The anticipated median time in treatment would be 13.8 years (life table analysis). The 132 compliant patients included 12 (9%) who withdrew from methadone after 17.7 ) 4.8 year in methadone treatment and 20 (13%) who died (4 lung cancer, 3 heart disease, 1 emphysema, 4 hepatitis C, 3 AIDS, 5 other causes). Tobacco-related illnesses comprised 40% of the deaths. Non-compliance was associated with cocaine use in 15 (58%) of 26. We conclude that MMM is a viable long-term alternative to treatment in the traditional methadone maintenance clinic system for socially rehabilitated patients. 543 MEDICAL A

LINKAGE CARE:

OF

SUBSTANCE

A RANDOMIZED

MULTIDISCIPLINARY

DETOXIFICATION

HEALTH

ABUSERS

TO

CONTROLLED

PRIMARY TRIAL

EVALUATION

OF IN

A

UNIT

J.H. Samet, M.J. Larson, J.B. Savetsky, M. L.M. Sullivan, and R. Saitz, Boston University of Medicine and Public Health, Boston Medical Boston, and New England Research Institutes, town, MA

Winter, Schools Center, Water-

Hypothesis: Development of a novel multidisciplinary medical clinic for linking patients in a residential detoxification program to primary care will significantly increase linkage of substance abusers to primary care. Procedures: We enrolled 470 subjects undergoing inpatient detoxification from heroin, cocaine, or alcohol in a randomized controlled trial. The intervention consisted of a health evaluation at the detoxification unit by a nurse, social worker and physician trained in motivational interviewing and a specific referral to primary care. Prior to randomization all subjects were interviewed by a research associate concerning demographics, substance abuse, mental health, medical problems, social support, utilization, and HIV risk behaviors. The primary outcome of interest was a visit with a primary care physician after discharge from the detoxification unit. Results: Of the 470 subjects enrolled, 235 were randomized to the intervention. Baseline characteristics included the following: 76% male; 46% black; 37%

Abstracts

white; 15% Hispanic; mean age 36 years. Comparison of control and intervention subjects revealed no differences in terms of demographic, substance use and medical severity. Heroin or cocaine were identified as the first or second drug of choice by 354/470 (75%). Thus far, among all subjects with follow-up within two years of the start of the study (348/470,74%), linkage was achieved in 65% of the intervention group and 52% of the control group (P = 0.01). Results among those with follow-up at 6 months, found 61 and 36% linkage in the intervention and control groups respectively (P < 0.001). Examination of the 269 subjects with heroin or cocaine problems found similar linkage results (64 vs. 53% at 2 years; 59 vs. 36% at 6 months). Importance of Findings: Linkage of addicted patients to primary medical care occurs and can be enhanced by a multidisciplinary medical clinic within a detoxification unit. Effective linkage of drug dependent patients to primary care can utilize the efforts of medical providers to address these individuals’ health and addiction issues. Supported by NIDA grant DA10019. 544 CURRENT CLUB DRUG REVIEWS REPORTED BY THE DRUG ENFORCEMENT ADMINISTRATION 1999-2000 CA. Sannerud, D.V. Gauvin, and F. Sapienza, Drug Enforcement Administration, Washington, DC In an effort to determine the appropriate control status of drugs and other substances under federal law, the DEA collects and evaluates data regarding the abuse and dependence liability, pattern, history and significance of its actual abuse, trafficking and diversion, pharmacology, chemistry and legitimate medical use. Gamma hydroxybutyric acid (GHB) is a CNS depressant that is not approved for medical use in the US, but is abused to produce euphoric and hallucinatory states, and as a idate-rapei drug. It is abused primarily by bodybuilders, young adults, and rave party attendees. Its simple illicit synthesis and the availability of information on the Internet have contributed to the increasing abuse of GHB. To date, the DEA has documented over 5700 overdoses and law enforcement encounters with GHB and 58 GHB-related deaths. Other structurally related substances such as gamma butyrolactone (GBL) and 1, 4 butanediol have also grown in popularity among young adults. Currently, there is legislation pending in Congress to place GHB in CI under federal law. Ketamine, a PCP-like drug, was placed into CIII effective August 12, 1999. Other iclub drugsi including methylenedioxymethamphetamine (MDMA) (CI) have also grown in popularity and use in contemporary iravei clubs and parties across the US. Adverse events, overdoses, and deaths attributed to these iclub drugsi have sharply risen over the last few years. The DEA will provide an update on these iclub drugsi including

s193

the most typical dosage, logos, and qualities of the drugs currently found across the US. The illicit productlon, distribution and abuse of these substances pose yet an additional public health and safety threat to the youth of America. 545 A CHARTFORTHECLINICALCOURSEINTHESUBSTANCEABUSETREATMENT R. Santis, J. Perez de 10s Cobos, F. Bathe, S.Valero, and M. Casas, Hospital de Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain The multiple clinical problems that clinicians must address in the short and long-term substance abuse treatment. might difficult the global picture of the biop:;ychosocial status of patients. A chart that visually shows this status was designed. The aim of this chart is provide an easy mechanism to maximise the information collection from the contacts of the patient with the addiction unit. Four sections are illustrated according to time (dates in columns). The first section corresponds to ‘clinical problems’ that were defined as symptoms, behaviours or situations that demand a therapeutical intervention. Thirty of the most frequent problems of the clinical practice at this unit were included. Each problem is coded as present (1) or absent (0). The second section corresponds to relevant results of assessment procedures and to results of alcohol and drug testing. The third section is a record of therapeutical indications including medications and psychosocial interventions; both professional recommendation and the final compliance are considered. The last section is a graph where the routine scale scores (Beck Depression Inventory, State-trait Anxiety Scale, Craving and Withdrawal scales) are drawn. The routine assessment procedures and therapeutical interventions of the unit were coded to be included. Examples of the use of this chart in outpatient and inpatient settings are illustrated. Supported by: &gan Tecnic de Drogodependencies, Generalitat de Catalunya. 546 IMPACT OF SEXUAL SUBSTANCE ABUSE-RELATED

AND PHYSICAL PROBLEMS

ABUSE

0~

J.B. Savetsky, R. Saitz, J.M. Liebschutz, L.M. Sullivan, C. Lloyd-Travaglini, L. Weinstein, and J.H. Samet, Boston University Schools of Medicine and Public Health Boston Medical Center, Boston, MA Hypothesis: Past interpersonal trauma is associated with worse physical and mental health; however its relationship to addiction severity is unclear. We hypothesize that a history of sexual and/or physical abuse [SPA] is associated with increased substance-related problems in a drug and alcohol-dependent population.

s194

Abstructs

Procedures: We interviewed subjects at an inpatient detoxification unit between 6197 and 4199. Interviewers collected data on SPA, demographics, physical and mental health, and administered the Inventory of Drug Use Consequences (INDUC), a validated instrument measuring lifetime substance abuse consequences. All analyses were stratified by gender. We examined the relationship between SPA and INDUC score (range l-45). Variables associated with the INDUC at P < 0.20 in bivariate analysis or deemed clinically relevant were entered into linear regression models. In multivariable analysis we adjusted for age, race, depressive symptoms, physical functioning, drug of choice, polysubstance use, homelessness, and having a partner/ spouse. Results: The 470 subjects were 24% female, 46% African American, 15% Hispanic, and had a mean age of 36 years. Drugs of choice were heroin (27%), cocaine (32%/o), and alcohol (39’S). Among women 81% (901 1 ll), and among men 69% (247/356), disclosed SPA. While women experienced predominantly both sexual and physical abuse, males reported mostly physical abuse. The median age of reported first abuse was 11 years. In bivariate analysis, INDUC scores were significantly higher in both men and women with SPA. In the multivariate model, SPA remained significantly associated with increased substance abuse consequences (male adjusted mean 36.3 vs. 34.0, P = 0.001; female adjusted mean 33.1 vs. 27.8, P = 0.006). Importance of Findings: SPA is common among persons admitted for detoxification, and this trauma is associated with greater substance abuse severity in both men and women. These findings support efforts to develop and evaluate substance abuse treatment strategies that simultaneously address SPA and addiction. Supported by NIDA grant DA10019. 547

DETERMINING

OUTPATIENT

SUBSTANCE

PREDICTORS ABUSE

OF

ATTRITION

IN

AN

PROGRAM

S. Sayre, J.M. Schmitz, A. Stotts, H. Rhoades, and J. Grabowski, Substance Abuse Research Center, University of Texas, Houston, TX Determining pre-treatment variables that predict attrition in an outpatient cocaine abuse program is critically important in efforts to enhance retention and ultimately improve client outcome. Potential predictors have been identified, such as treatment history, deviant behaviors, and level of drug use, however there is not widespread agreement on their applicability across treatments and populations. In addition, pre-treatment variables that predict early versus late attrition have yet to be identified and may be informative for effective treatment planning and development. This study examines the relationship of demographic, drug use severity, and psychosocial factors with dropping out of treatment

and the timing of dropout. One hundred sixty-five individuals from the Houston area, seeking treatment for cocaine addiction, completed a pre-treatment assessment battery (including the Addiction Severity Index) prior to starting the 12-week treatment program for cocaine abuse. Regression analyses were conducted to determine the predictive value of twenty pre-treatment variables on treatment attrition and time of dropout. Treatment dropouts were more likely to be separated from their spouse, have poorer family/social functioning, have fewer years of education, and to be female. Those participants with higher education levels and those with poorer psychiatric functioning tended to remain in treatment longer. The implications of these findings are discussed. ACKNOWLEDGEMENTS: Supported by NIDA Grant DA-09262-02. 548

IN

TENT

METABOLIC

PYROLYZATE,

VIVO

EVIDENCE

THAT

PRODUCT

ECGONIDINE OF

THE

IS A PERSISCRACK

COCAINE

METHYLECGONIDINE

K. Scheidweiler, M. Plessinger, J. Shojaie, T. Kwong, and R. Wood, University of Rochester School of Medicine, Rochester, NY A recent report detected the presence of ecgonidine (EC; anhydroecgonine) in forensic urine specimens and suggested that EC may be a better marker of crack smoking than the parent pyrolyzate, methylecgonidine (MEG). Conversion of MEG to EC has been hypothesized to result from in vivo processes similar to the conversion of cocaine to benzoylecgonine. EC is produced from MEG by liver homogenates in vitro, however we have demonstrated minimal in vitro conversion in sheep plasma. We conducted pharmacokinetic studies in sheep following intravenous MEG administration using 3.0, 5.6 and 10.0 mg/kg MEG. Plasma samples were analyzed to detect formation of EC from MEG and to characterize its kinetics. N-ethyl-N-norecgonidine was synthesized for use as an internal standard in a GC/MS assay performed following solid-phase extraction. MEG clears relatively rapidly from plasma concurrent with increasing venous plasma levels of EC. Peak MEG levels, (4085.8-8570.0 rig/ml) were achieved shortly after MEG iv administration. Peak EC levels, (3047.6-6277.0 rig/ml) occurred at approximately 40 min after injection, at which time MEG levels were 68.9--108.5 rig/ml. This provides in vivo evidence that EC is a major metabolite of MEG. Plasma levels of the pyrolyzate and its metabolite were dose-related up to 10.0 mg/kg MEG. Following 10.0 mg/kg, EC plasma levels were 462.6 and 233.6 rig/ml at 24 and 48 h. The persistent detection of EC when MEG levels were no longer detectable supports the assertion that EC may have forensic utility for differential identification of the route of cocaine self-administration. MEG contains a

Ahstructs

double bond that demonstrates irreversible covalent interaction with model nucleophilic biologic substrates. EC retains this double bond, raising the possibility that it also might covalently bind to nucleophilic biologic substrates. MEG is an irreversible non-competitive antagonist of acetylcholine and histamine in vitro at low concentrations. If EC displayed similar activity, its persistence would elevate concern about the risk of adverse effects associated with crack smoking. Support: NIDA grants DA05080 and DA07232. 549 ON

EFFECT OF THE DRUG-SEEKING

WIN

KAPPA

PRODUCED

OPIOID

AGONIST,

BY COCAINE,

U69593,

GBR

12909,

35,428 AND RTI-55

S. Schenk, Texas A&M University, College Station, TX Reinstatement of extinguished cocaine-taking behavior was measured for rats that received injections of the kappa-opioid agonist, U69593 (0.0 or 0.32 mg/kg, SC), 1.5 min prior to injections of cocaine- (0.0~-20.0 mg/kg, ip), GBR 12909- (0.0-30.0 mg/kg, ip), WIN 3542% (O.O- I .O mg/kg, ip) or RTI-55 (0.0-0.50 mg/kg, ip). All of the drugs produced a dose-dependent reinstatement of extinguished cocaine-taking behavior. However, only the effects of cocaine and RTI-55 were attenuated by prior administration of U69593 (0.32 mg/kg, SC). The failure of U69593 to attenuate GBR 12909- or WIN 35428-produced cocaine-seeking suggests that the effect of this kappa-opioid receptor agonist on cocaine-seeking is not mediated by interactions at the dopamine transporter. The ability of U69593 to attenuate RTI-55produced cocaine-seeking raises the possibility that Kopioids and cocaine may interact at common sites on the serotonin transporter. Supported by DA 10084. 550

GENDER

FECTS

OF

DIFFERENCES

IN

THE

BEHAVIORAL

EF-

C.W. Schindler, J.G. Bross, E.B. Thorndike, NIDA Intramural Research, Baltimore, MD

NIH/

METHAMPHETAMINE

Previous research has shown that female rats are more sensitive to the behavioral effects of the cocaine than are male rats. For example, following cocaine female rats show greater locomotor activity than male rats. The purpose of this experiment was to determine if similar effects could be observed for methamphetamine. Male and female Sprague-Dawley rats were adapted to a locomotor activity chamber by placing them in the chamber for 30 min per day following an IP injection of saline. Following approximately 10 days of adaptation, the rats were treated with methamphetamine (0.1, 0.3, 1.0 and 3.0 mg/kg IP) over a period of 3 weeks, with at least 2 days separating drug injections.

s195

The rats continued to be placed in the activity chamber following saline injections on intervening days. Activity in terms of distance traveled was similar for males and females following saline injections. However, higher doses of methamphetamine produced larger increases in activity in females than males. While a clear difference was observed, the effect was not as large as that seen with cocaine. Separate groups of rats were given place preference training with 1 mg/kg methamphetamine. Following 4, 1 h conditioning trails, preference for the methamphetamine paired side during a 15 min test was comparable for both males and females. These results support the finding that psychomotor stimulants have differing effects on locomotor activity in male and female rats, but these differences may not extend to other behavioral paradigms. Supported by NIDA IRP. 551

METYRAPONE

TAINED COC 41NE

FORMER

TESTING HEROIN

ADDICTS

IN

METHADONE-MAINWITH

AND

WITHOUT

ADDICTION

J.H. Schluger, G. Perrett, L. Borg, A. Ho, and M.J. Kreek, The Laboratory of the Biology of Addictive Diseases and The Rockefeller University, New York, NY The metyrapone test, a provocation of HPA axis function was performed in 39 inpatient subjects at the Rockefeller University Hospital GCRC: 10 stable methadone maintained former heroin addicts without ongoing drug or alcohol use (MM), 8 methadone maintained former heroin addicts with no ongoing heroin use, but recently abstinent from ongoing cocaine dependence (C-MM), and 21 normal volunteers. Plasma ACTH levels were determined in samples drawn at 9 h, just prior to administration of a single 2.25 g oral Metyrapone dose, and at 13 and 17 h. There was no significant difference between the three groups in ACTH levels at 9 h. Two way ANOVA of plasma ACTH levels showed a significant group effect (P < 0.011, effect over time (P < 0.000001); Group by Time interaction (P < 0.005). NewmanKeuls post hoc tests showed C-MM had greater responses than NV (P < 0.01) and MM (P < 0.05), with no significant difference between NV and MM. Examination of area under the curves yielded similar results with C-MM having the greatest HPA axis activation, and MM and NV not differing significantly. While C-MM had lower postmetyrapone levels of cortisol than MM and NV, when the magnitude of the reductions in plasma cortisol levels for each subject over time were examined, there were no significant differences between groups, nor were there significant correlations between AUC’s for cortisol and ACTH, i.e. despite lower post metyrapone cortisol AUC’s in the C-MM, amount of cortisol sup-

S196

Abstracts

pression did not predict ACTH response. These results confirm and extend the findings of normalization of HPA axis function in stabilized methadone maintained former heroin addicts, and hyper-responsivity to the removal of glucocorticoid negative feedback associated with cocaine addiction. ACKNOWLEDGEMENTS: Supported in part by NIH grants: NIDA DA-P50-05130, NIDA DA00049, and NCRR MOl-RR00102. 552 EFFECTSOFANDROGENICANABOLICSTEROIDADMINISTRATION ON THE HYPOTHALAMIC-PITUITARYADRENAL AXIS S.D. Schlussman, Y. Zhou, P. Johansson, A. Kiuru, A. Ho, F. Nyberg, and M.J. Kreek, The Rockefeller University, New York, NY, and Uppsala University, Uppsala, Sweden Androgenic anabolic steroids (AAS) are most usually associated with body-builders and athletes seeking to enhance their performance. However, there is a subgroup of non-athlete AAS abusers who use high doses of the drugs for the perceived euphoric effect. It has been estimated that 1000 000 Americans have used AAS and 4- 12% of males attending US high schools admit AAS use at least once in their lives. Additionally, AAS use has been associated with psychiatric symptoms such as mania, major depression and aggression (‘roid rage’) and the development of dependence. Little is known about the effects of AAS on HPA function or corticotropin releasing factor, which may be involved in mediating some of the psychiatric symptoms associated with AAS abuse. Methods: Male Sprague-Dawley rats received one intra-muscular injection of the AAS nandrolone deconate (ND, 5 or 15 mg/kg) or vehicle for 3 days. Animals were sacrificed either 1 or 24 h after the last injection, brain regions dissected and trunk blood collected. CRF and POMC mRNAs were measured with solution hybridization/RNase protection. Circulating levels of corticosterone and ACTH were determined using RIA. Results: One hour following the last injection, 15 mg/kg ND, but not 5 mg/kg, significantly increased circulating levels of corticosterone (P < 0.0001). Both doses of ND significantly increased ACTH levels (P < 0.0001). Circulating levels of both hormones returned to control levels 24 h after the last injection. In the amygdala, CRF mRNA was significantly reduced 24 h (P < 0.05), but not 1 h after the last injection of 15 mg/kg ND. No significant AAS effects were observed on hypothalamic CRF mRNA, POMC mRNA in the hypothalamus, amygdala or anterior pituitary, or CRFRl mRNA in the anterior pituitary. Supported by NIH- P50-DA-05130 and NIH-KOS-DA00049 to M.J.K.

553

FLUOXETINE TREATMENT OF COCAINE-DEPENDENTPATIENTSWITHMAJORDEPRESSIVEDISORDER

J.M. Schmitz, A. Stotts, P. Averill, H.M. Rhoades, and J. Grabowski, Substance Abuse Research Center, University of Texas-Houston, TX Comorbid depression in clinical samples of cocaine abusers is prevalent and consistently associated with poor outcome. The pharmacologic rational for using antidepressant medications in treating this type of dualdisorder is plausible, but empirical findings have been mixed. In this study 65 male and female individuals with both DSM-IV diagnoses of cocaine dependence and major depressive disorder were randomly assigned to one of two medication conditions (0 mg vs. 40 mg per day) as part of a double-blind, placebo-controlled clinical efficacy trial of fluoxetine for the treatment of this dual diagnosis. During the 12-week outpatient treatment phase all participants also received individual cognitive-behavioral psychotherapy targeting both cocaine use and depression. Depressive symptoms remitted as a function of time in treatment, with no significant medication effects found. An overall reduction in days of cocaine use was found along with evidence of fewer cocaine positive urines during the first 6 weeks of treatment in the 0-mg group compared to the 40 mg group. Percent cocaine-positive urines correlated significantly with improvement in depression (BDI scores). The cognitive-behavioral therapy developed for this study proved to be credible and consistent with its dual-focused objective. The findings fail to support the role of fluoxetine for treatment of cocaine use and depression in dually-diagnosed patients. ACKNOWLEDGEMENTS: Supported by NIDA grant DA08654. 554

DETECTIONOFABUSEDDRUGS

INORALFLUID

E.P. Schoener, S. Doddamane, S. Kardos, and R.S. Niedbala, Wayne State University, Detroit, MI, and STC Technologies, Bethlehem, PA While objective tests for psychotropic substances have been adopted widely as tools for treatment, forensics and workplace, those currently in use are intrusive. Tests on saliva would be more acceptable and more convenient than those based on blood, urine and hair specimens. Before we implement tests on oral fluid, however, it is necessary to determine their validity and concordance with accepted techniques under ‘real world’ conditions. The present study compared detection of cocaine, amphetamines, opiates, marijuana, PCP, barbiturates, benzodiazepines, propoxyphene, methaqualone, and methadone in saliva and urine specimens from 61 clients in a treatment program and 18 controls. The client group was comprised of 35 men

Abstracts

(Average age = 48.2 + 8.7) and 29 women (46.4 f 8.2). The control group was evenly divided between men (36.4 + 11.3) and women (37.7 + 8.3). All participants were asked confidentially to report their use.of medications and illicit substances over the past week. Specimens were provided weekly for up to 16 weeks (Avg 8.5 + 4.5). Urine was collected by conventional methods and oral fluid was obtained with an Orasurea device (Epitope, Inc., Portland, OR). Samples were tested for IgG as a control measure. Seven hundred and two matched oral/urine specimens were submitted to standard immuno-assay procedure and reported qualitatively. All urine and saliva positives were confirmed with GC/MS. Findings with both specimens were not always concordant due to differences in pharmacokinetic distribution. 555

DEPRESSION ADVERSELY AFFECTS OUTCOMEINCOCAINE-DEPENDENT WOMEN

TREATMENT

R.S. Schottenfeld, J. Pakes, M. Chawarski, M. Panatalon, and D. LaPaglia, Yale University School of Medicine, New Haven, CT We examined the prognostic significance of major depressive disorder (MDD) and depressive symptoms (DS) at 1 month in cocaine dependent women treated in a 6-month clinical trial comparing drug counseling and the community reinforcement approach and voucher based contingency management and yoked voucher controls. Subjects were cocaine dependent pregnant women or women with children less than 5 years (n = 99) and were predominantly single (76%) with an average age of 30 (SD = 5) years, 11 (SD = 3) years of education, 8 (SD = 6) years of cocaine use. Baseline assessments included SCID interview for MDD and alcohol disorders and ASI. Urine toxicology was performed twice weekly during treatment, and CES-D was assessed monthly, with a cutoff 2 23 for moderate to severe DS. At baseline, MDD was found in 32/99 and alcohol abuse or dependence in 43199 women; 38/99 had attempted suicide lifetime, including 19/32 with MDD. CES-D at month 1 was obtained on 25/32 women with MDD and 43/67 of women without MDD; 23/66 women met criteria for DS, including 13125 women with MDD. Women with vs. without MDD were less likely to complete treatment (44 vs. 57%, NS), but MDD was not associated with significant differences in proportions of cocaine positive urine tests, using random regression models (55 vs. 62%, P = 0.25). DS at month 1 was associated with significantly higher proportions of cocaine-positive urine tests (68 vs. 52%; P < 0.05) and lower proportions of 2 3 consecutive weeks abstinence (30 vs. 66%, P < 0.05). Women with MDD and persistent DS had the lowest proportions of 2 3 consecutive weeks abstinence, com-

s197

pared to all other women (23 vs. 53%, P < 0.05). These results suggest that while depressive symptoms remit for many cocaine dependent women with MDD at treatment entry, MDD and persistent DS are associated with adverse treatment outcome and may require specific targeted treatment. Supported by ROI-DA06915. 556 THE EFFECTS OF LOWERING URINE BENZOYLECGONINE EQUIVALENTS CUTOFF AND CORRECTING FOR CREATININE CONCENTRATION ON CLINICAL TR1A.L RESULTS J.R. Schroeder, A. Umbricht, K. Silverman, and K.L. Preston, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD Three recent methodological changes for assessing cocaine use have been proposed: applying new use rules to determine carryover positives, correcting urine benzoylecgonine equivalents (BZE) for creatinine, and lowering the concentration cutoff for positive urine specimens from 300 to 150 rig/ml BZE. Application of new use rules decreases the number of false positive urinalysis results, and application of the creatinine correction and lower cutoff both decrease the number of false negative results. We conducted a re-analysis of clinical trial data to determine the effect these changes woud have on the results, individually and in combination. The clinical trial was a study of contingency management to reduce cocaine use in a sample of 59 polydrug users; a significant treatment effect was found. This reanalysis determined whether the proportion of BZE-positive specimens differed by treatment group, defining BZE-positive in four ways: (1) uncorrected BZE 2 300 and 2 75% of the BZE concentration at the previous visit, (2) corrected BZE (BZE ngjml x creatinine mg/dl x 100) 2 300, (3) uncorrected BZE 2 150, and (5) corrected BZE 2 150 and 2 75% of the BZE concentration at the previous visit. The results from the five analyses were similar. Application of new use criteria resulted in the most (7.2%) reclassifications and resolved 19% of discrepancies between urinalysis and self-report, but slightly lowered the observed treatment effect. Correcting for creatinine and lowering the cutoff to 150 resulted in relatively few reclassifications (1.3 and 2.8% respectively); neither altered the treatment effect. Application of the three methods simultaneously resulted in the highest proportion of reclassifications (9%) but conclusions were unchanged. These three methods used in combination can be useful for correcting the problems of false positive and false negative urinalysis results but seem to exert a small effect of clinical trial conclusions. Their potential utility may be greatest in monitoring drug use in individuals, and in reconciling discrepancies between urinalysis and self-report.

Abstracts

S198

557 PRENATAL NLAAM EXPOSUREAND~ORPOSTNATAL WITHDRAWAL ALTER ENDOCRINE AND IMMUNE SYSTEMREACTIVITY INTHEYOUNGCHICKEN L.M. Schrott, E.B. Larson, J.A. Stanek and S.B. Sparber, University of Minnesota, Minneapolis, MN Prenatal opiate exposure and/or subsequent withdrawal may alter immune responses to a variety of challenges. Eggs with 4 day old (E4) embryos were injected with 2.5 mg NLAAMjkg or its vehicle (50% propylene glycol; PG). NLAAM marginally decreased hatching by 15% compared to PG controls (P < 0.08), while not affecting hatch weight. NLAAM-treated chicks displayed signs of mild withdrawal on posthatch day 3. They had 3.5 fold more serum corticosterone compared to PG controls following a mild stress, a saline injection 4 h prior (P < 0.03; y1= 7 per group). NLAAM treated chicks also gained 27% less weight on day 3, the first day after free access to food (P < 0.02;n = 35-43 per group). The weight gain difference disappeared by day 4 and they gained weight at an equal or greater rate than controls thereafter. Neural-immune interactions were assessed on day 5 via the fever response to a peripheral injection of lipopolysaccharide (LPS; 7.5 mg/ kg) on day 5. While not affecting basal body temperature, embryonic NLAAM exposure blunted the fever response by more than 50% compared to controls (P < 0.04; n = 6-8 per group). T-cell immunity was assessed via the cutaneous basophil hypersensitivity reaction to an intradermal foot injection of saline or phytohemagglutinin (PHA) on D17-18. NLAAM decreased the reaction to PHA by 35% compared to PG controls (P < 0.05; n = 10 per group). Thus, prenatal opiate exposure and/or postnatal withdrawal suppressed beneficial immune responses and may compromise organism health during the perinatal period and beyond. Supported in part by USPHS grants R37 DA 04979 and KOl DA 00362.

558 DISCRIMINATION FECTS OF INTRANASAL

OF INTRANASAL BENZOCAINE

COCAINE:

EF-

K.J. Schuh, H. Schubiner and C.E. Johanson, Wayne State University School of Medicine, Detroit, MI In the development of medications for the treatment of cocaine abuse, the drug discrimination paradigm can be used to identify medications that can attenuate the discriminative stimulus effects of cocaine. To ascertain that participants are basing the discrimination on the drug’s central effects, this paradigm requires that the drug and placebo administrations do not produce any peripheral effects on which the discrimination can be based. This study examined whether intranasal cocaine (50 mg) can be discriminated from placebo (46 mg

lactose + 4 mg cocaine), how quickly this discrimination can be made, and whether pre-treatment with intranasal benzocaine can affect this discrimination. Three cocaine-abusing participants were trained to discriminate intranasal cocaine from placebo. Because it was likely that participants could base the discrimination upon peripheral effects such as nasal numbing, participants then received pre-treatment with intranasal benzocaine spray to determine if this could block the discrimination. Subjective and physiological data were analyzed using ANOVA and showed cocaine-induced increases in ‘good effects’ and heart rate. Subjects were generally able to correctly discriminate the drug conditions 15 s after administration, and this was unaffected by benzocaine. Because it is unlikely that intranasal cocaine can produce central effects within 15 s, these results indicate subjects base the discrimination upon peripheral drug effects (e.g. taste) that are not affected by anesthesia of the nasal passage, and that the feasibility of using the intranasal route of cocaine administration with a drug discrimination paradigm is unlikely.

559 FLUOXETINE TREATMENT

IN

SMOKING

CESSATION

L.M. Schuh, K.K. Downey, J.A. Hopper, M. Tancer, and C.R. Schuster, Wayne State University School of Medicine, Detroit, MI Preliminary results (N = 152) are presented for a clinical trial pretreating smokers with the antidepressant fluoxetine before a smoking cessation program with cognitive-behavioral therapy and transdermal nicotine patches. The final sample will be 225 normal, healthy cigarette smokers, stratified on presence or absence of a history of Major Depressive Disorder or current depressive symptoms. Participants were randomly assigned in double-blind fashion to 0,20, or 40 mg fluoxetine daily. They had a mean age of 39.6 years; 57.9% were female and 70.4% were white, 28.3% African American, and 1.3% Native American. Fluoxetine significantly improved quit rates 1 week after the quit rate: 51.2% of those on placebo, 65.7% of those on 20 mg fluoxetine, and 80.0% of those on 40 mg fluoxetine were abstinent 1 week after the quit date. This was not maintained at the end of treatment. Fluoxetine’s effects may be attenuated by the unexpectedly low rate of depression (20.4%) in this sample to date, perhaps due in part to a relatively high proportion of African Americans. We have found significant racial differences in depression history, which have not been reported before. Caucasians (19.8%) were more likely than African Americans (5.2%) to have a depression history (Odds ratio = 1.8, 95% CL 1.0, 3.5; x’= 3.70, P=

0.05).

Sl99

Abstracts

560

How

SCRIBED AND

TO

WIHS

ANTIRETROVIRAL

HIV

+

COHORT

WOMEN:

THERAPY

IS

EXPERIENCE

BEING

OF THE

PRE-

HERS

STUDIES

P. Schuman and M. Cohen, Wayne State University, Detroit, MI, and Cook County Hospital, Chicago, IL Objective: To determine the prevalence of ART rx and study related factors among HIV + women participating in two prospective cohort studies of US women. Methods: 453 HIV + HERS or WIHS participants with a CD4 + count of 15, suggesting depression (37% vs. 23%, P = 0.004), were associated with ART d/c, but educational level and drug use were not. Crack users were less likely than others to report their decision to d/c ART to their provider. Conclusion: Race/ethnicity and drug use are impacting how ART is prescribed and taken. Nonwhite women and those reporting substance use were less likely to report receiving combination ART and PI from providers; non-whites and those with CES-D scores > 15 were more likely to d/c ART on their own decision.

561

EFFECTS

GAGEMENT

OF

GENDER

IN A HOSPITAL-BASED

ON

INITIAL

TREATMENT

ADDICTION

A. Schuster and A. King, The University Chicago, IL

EN-

CLINIC

of Chicago,

The majority of addiction treatment retention studies have been conducted in treatment research centers using group or group combined with individual counseling in relatively homogeneous (and largely male)

patient samples. The present study examined patient-related factors in initial treatment engagement in female and male patients referred for substance abuse evaluation within a medical center environment. Initial treatment engagement was defined as attending five or more ther,apy sessions. Patients met for individual weekly psychotherapy sessions based on NIDA and NIAAA treatment manuals and delivered by a Master’s or Ph.D. level clinician. The following characteristics describe the first 97 patients evaluated and deemed appropriate for treatment: 29% female, 71% male; 57% employed; 52% Caucasian, 44%, African American; mean age 41.1 + 12.0. The main primary drug of abuse was alcohol (59%), followed by cocaine (18%), heroin (7%), nicotine (12%), and other (4%). Dependence on mor’e than one substance was found in 28% of the sample. Of the women substance abusers 39% (1 l/28) were treatment engaged, which was significantly less than their male counterparts (74%; 51/69, P < 0.002). Other patient-related variables associated with treatment non-engagement, included: African American and cocaine as the primary drug of abuse (x2 > 11.26, Ps < 0.05). Lower education level showed a trend toward signjficance (P = 0.05). Patients referred from outside the medical center were less likely to engage in treatment than within-center referrals (x’(2) = 9.62, P < 0.01). Logistic regression analysis showed that the model with these variables significantly predicted treatment engagement (x2(5) = 26.5, P < O.OOOl), with female gender and African American race as significant independent predictors. Continued investigation of gender and race issues in early treatment dropout may improve retention rates and ultimately lead to better trealment outcomes for female and minority substance abmers. Supported by AA1 1133, MOl-RR00055, and the ABMRF. 562

IN

VIVO

NICOTINE-DEPENDENT

BRAIN

OPIOID MALES

RECEPTOR AND

BINDING

IN

CONTROLS

C.G. Schlitz, H.J. Wester, M. Voelk, and F. Willoch, Ludwig Maximilians University and Technical University, Munich, Germany Recently Krishnan-Sarin et al. (1999) reported preliminary evidence in humans to suggest that long-term exposure to cigarette smoke is associated with alterations in the endogenous opioid system. After presenting results from our study on opioid receptor binding in alcohol dependent patients at the last meeting, we now intent to report results from a still ongoing study on opioid receptor binding in nicotine dependent males (DSM IV) and healthy controls. Method: All individuals are being assessed using standard state and trait measurements. Opioid binding is measured using 1 lC-

s200

Abstracts

Diprenorphin PET. Arterial input function is generated. Parallel spectral analysis (pSA) will be applied on a voxel level (Cunningham, 1993) for estimation of tracer delivery (impulse response function, IRF, at 1 min) and retention (IRF at 60 min). The stereotactic transformation is based on Neurostat program package (Michigan software). For pixelwise comparisons of relative values SPM99 routines will be applied (after spatial normalization and smoothing). Results: Preliminary analysis on three nicotine dependent subjects and eight controls indicated decreased binding in the posterior part of the thalamus (P = 0.003, 170 voxels). Nicotine consume was associated with increased binding in the Brodman area (BA) 10 frontopolar left, BA 20121 left and B40 right hemisphere. Discussion: This study is to our knowledge the first attempt to demonstrate in vivo changes in opioid binding among human subjects with chronic exposure to cigarette smoke. 563 OVER WITH

A

COST-EFFECTIVE 90%

FOLLOW-UP

SUBSTANCE

ABUSE

APPROACH IN

TO

OUTCOME

TREATMENT

ACHIEVING MONITORING

CLIENTS

C.K Scott and M.L. Dennis, Chestnut tems, Chicago and Bloomington, IL

Health

Sys-

Most researchers and funding agencies would agree that essential performance elements of a successful outcome monitoring initiative include high quality data, low attrition, and minimal cost. The goals of this presentation are twofold. The first goal will focus on data that clearly indicate the need to successfully complete follow-up interviews with more than the typical 70%. Using contact data from studies in which better than 93% follow-up rates were achieved, on average, we demonstrate that settling for lower rates of follow-up would have biased by 25-75% key dependent variables such as days of alcohol use. drug use, days incarcerated, or days working. Moreover, the biases are not all in the same direction or simply linear functions that can be easily modeled. The second goal is to describe a model for follow-up that consistently produces completion rates above 90% with substance abuse treatment clients. The model was developed over a 3-year period, and has been used to locate and interview over 3000 adults and adolescents with an overall completion rate of 94%. The strategies incorporated into the model are proactive, tightly structured, and closely monitored. The combination of these three elements produces an efficient and effective method for conducting successful outcome monitoring studies that actually cost less than typical approaches used in most studies.

564

ESTROGEN

TION

TO

INFLUENCES

COCAINE

BEHAVIORAL

IN FEMALE

SENSITIZA-

RATS

S.L. Sell, M.L. Thomas, and K.A. Cunningham, University of Texas Medical Branch, Galveston, TX We have reported that the acute behavioral effects of cocaine in female rats are under the regulation of ovarian hormones. In the present study, we investigate the hypothesis that, in female rats, estrogen (E) influences the chronic effects of cocaine, such as sensitization. To this end, 32 female Sprague-Dawley rats were ovariectomized (OVX) or OVX and implanted with E-filled silastic capsules 2 weeks prior to treatment with cocaine (15 mg/kg) or saline (1 ml/kg; BID) for 5 days. During withdrawal (WD) automated and observational measures of behavior were collected following challenge injections of cocaine (5 mg/kg) at 72 h, 10 days, and 3 weeks following the last treatment injection. Although, sensitization was not evident for either OVX or OVX + E rats at the 72 h WD time, OVX + E rats expressed sensitization at 10 days WD. Both OVX and OVX + E rats exhibited sensitization to cocaine at 3 weeks WD, with OVX + E rats demonstrating a greater overall level of activity than OVX rats. These results suggest that the neural adaptations involved in cocaine sensitization in female rats are affected by interactions between E and the dynamics of withdrawal from cocaine. 565

CHARACTERIZATION

STIMULATED HETEROZYGOUS

G-PROTEIN

CBI

OF

CANNABINOID

ACTIVATION RECEPTOR

AGONIST-

IN WILD-TYPE KNOCKOUT

AND

MICE

D.E. Selley, L.J. Sim-Selley, W.K. Rorrer, C.S. Breivogel, A.M. Zimmer, A. Zimmer, and B.R. Martin, Virginia Commonwealth University Medical College of Virginia, Richmond, VA and National Institute of Mental Health, Bethesda, MD The effects of cannabinoid receptor density on Gprotein activation were examined in brain membranes from wild-type and heterozygous CBl receptor knockout C57/BL6 mice. CBl receptor density was m 50”/ lower in the heterozygous mice, as determined by Bmax values of [3H]SR-171416A binding in striatum, cerebellum and hippocampus. Although maximal stimulation (Emax) of 0.1 nM [35S]GTPgS binding by WIN 55,2122 (WIN) was 47% lower in the striatum of heterozygous compared to wild-type mice, only 20-25% decreases in WIN-stimulated [35S]GTPgS binding were observed in the cerebellum, hippocampus and cingulate cortex. [35S]GTPgS saturation binding was performed to determine whether the number of CBl receptor-activated G-proteins, or their affinity for GTPgS, was decreased in heterozygous mice. Despite the 50% reduction in receptor density, no significant decrease in the Bmax values of net WIN-stimulated [35S]GTPgS binding was observed in any region. Thus, the maximal number of

s201

Abstracts

G-proteins activated per CBl receptor was approximately 2-fold higher in heterozygotes. However, an increase in the apparent KD of WIN-stimulated [35S]GTPgS binding was observed in the striatum of heterozygous mice, suggesting that the decreased Emax value of WIN-stimulated [35S]GTPgS binding was due to a lower relative affinity of receptor-activated Gproteins for GTPgS. Supported by DA-10770, DA-00287 and DA-03672 from the NIDA. 566 AND

REGULATION

TRH

OF RAT

BY ACUTE

AND

BRAIN CHRONIC

PREPROTRH MRNA COCAINE

K.A. Sevarino, R.X. Zhang, and S.O. Griffiths, Yale University School of Medicine and CT VA Healthcare System, West Haven, CT Cocaine regulates preproTRH (ppTRH) mRNA in rat mesolimbic nuclei (J. Neurochem. 60: 115 1- 1154, 1993). We now report a more extensive characterization of ppTRH mRNA regulation, and test whether these findings correlate with changes in TRH peptide levels. Rats received cocaine (15 mg/kg, i.p.) or saline once (acute), or twice daily for 14 days (chronic), and brain regions were harvested by micro-dissection at various times following the last cocaine injection. Acute cocaine induced ppTRH mRNA in caudate, and reduced levels in nucleus accumbens, at 6 h post-cocaine. Rostra1 piriform cortex mRNA was elevated at 12 h, while caudal piriform cortex showed elevations at 3 and 6 h. Caudal, but not rostra1 medulla, demonstrated rapid induction at 45 min, which gradually declined to control levels by 12 h post-cocaine. Chronic cocaine caused induction in rostra1 and caudal piriform cortex and caudal amygdala at 45 min, and in septum at 72 h. Opposite to acute cocaine, ppTRH mRNA in caudal medulla was reduced at 45 min. For peptide, acute cocaine induced TRH in rostra1 amygdala 1 and 2 h post-cocaine, as well as in adjacent piriform cortex at 6 h. Thus, the amygdala and surrounding cortical areas demonstrate the most consistent regulation, and induction of ppTRH mRNA correlates with elevations in TRH itself. TRH was reduced in rostral, but not caudal medulla at 2 h, different than the pattern seen for ppTRH mRNA. Supported by NlDA DA10762. 567 NIST, TRATION

EFFECTS

OF THE

CP-291,952,ON

s-HTiB/iD

ETHANOL

IN CYNOMOLGUS

AND

RECEPTOR TANG

ANTAGO-

SELF-ADMINIS-

MONKEYS

K.L. Shelton, J.E. Young, R.S. Mansbach, and K.A. Grant, Wake Forest University School of Medicine, Winston-Salem, NC, and Pfizer Central Research, Groton, CT

The 5-HTlB/lD receptor has been implicated in the reinforcing and discriminative stimulus effects of ethanol. Mice lacking 5-HTlB receptors consume more ethanol than wild-type controls and 5-HTlB agonists substitute for ethanol in the drug discrimination paradigm. In present study, the selective 5-HTlB/lD antagonist, CP-291952, was examined for its effect on ethanol self-administration in four adult monkeys (2 male, 2 female). The animals were trained to drink 4% (w/v in water) ethanol and an orange flavored liquid (4% or 6% w/v sugar-free Tang) under a multiple schedule of fluid access. Sessions were 1 h in duration, consisting of four, 15 min, periods of alternating liquid availability (Tang, EtOH, Tang, EtOH). Mean ethanol intak:e under baseline conditions was 2.03 g/kg. Following training, CP-291 952 (1, 3, 5.6, 10, 17 mg/kg; i.g. gavage) was administered no more than once every 3 days, 60 min prior to the drinking session based on the PK of oral CP-291952. Each CP-291952 dose was tested twice in a random order. BEC’s were measured immediately post-session to determine if CP-291 952 affected ethanol metabolism. CP-291952 had no effect on either ethanol or Tang self-administration at any dose tested. Mean ethanol intake following the highest dose of CP-291952 (17 mg/kg) was 1.96 g/kg compared to 2.03 g/kg for the water control. These findings suggest that CP-291 952 neither attenuates nor enhances ethanol self-administration and is unlikely to have either clinical efficacy for ethanol treatment or ethanol-like abuse liability. 568

PHARMACOLOGICAL

CRIMINATIVE NICOTINE

AND IN

C57BL/6

ANTAGONISM AVERSIVE

STIMULUS

OF

THE

PROPERTIES

DISOF

MICE

M. Shoaib, J. Gommans, and I.P. Stolerman, Institute of Psychiatry, De Crespigny Park, London, UK The present experiments examined which nicotine receptor subtypes mediate the discriminative stimulus and aversive stimulus produced by nicotine in C57BL/6 mice. The competitive nicotine receptor antagonist dihydro-b-erythroidine (DHbE) that shows selectivity for several forms of high-affinity nicotine binding sites was compared against methyllycaconitine (MLA), a purportedly selective a7-nicotinic receptor antagonist. Mice were successfully trained to discriminate nicotine (1.2 mg/kg, SC) from saline in a two-lever operant drug discrimination procedure under a tandem variable interval 60 s-fixed ratio 10 schedule of reinforcement. Nicotine yielded a steep dose-response curve that could be completely antagonized by DHbE (effective doses: 3.0-5.6 mg/kg, SC), but not by MLA (up to 10 mg/kg, SC). In a two-choice conditioned taste aversion (CTA) procedure, on different days mice could drink one of two differently flavoured solutions after which they

Abstructs

s202

were injected immediately with nicotine (0.6, 1.2 or 2.0 mg/kg, SC) or saline. During tests for CTA mice were presented both flavoured solutions simultaneously and the amount consumed of each was measured. A decrease in intake of the nicotine-paired flavoured solution was indicative of a nicotine-induced CTA. C57BL/6 mice showed CTAs dependent on the dose of nicotine. This aversive effect of nicotine was weakened when DHbE (5.6 mg/kg, SC) but not MLA (up to 10 mg/kg, SC) was administered at the same time as the nicotine on conditioning trials only. It may be concluded that both the discriminative and aversive stimulus effects of nicotine are mediated via nicotine receptor subtypes blocked by DHbE, and that the a7 receptor subtype may be less important in the mediation of this effect than high-affinity receptors such as the a4b2 subtype. Supported by a European Union TMR grant. 569 LIMINARY TROLLED

DHEA

AS A COCAINE

RESULTS

OF

PHARMACOTHERAPY:

.4 RANDOMIZED

18.1% of DHEA-treated subjects completing the 12week trial compared to 75.0% of placebo-treated subjects (x2=7.43(1), P= 0.006). Plasma levels of DHEA and DHEA-S doubled compared to baseline for participants in the DHEA condition at weeks 1, 2,4, 8, and 12. These findings indicate that DHEA clearly caused significant increases in cocaine use compared to subjects treated with placebo. The reliability of findings (e.g. urine toxicology and retention) point to potential biological foundations for stress hormones in supporting cocaine dependence. This study was supported by NIDA grant # 1 YOl DA50038. 570

THE

COMMUNITY

DRUG

ABUSE

PROGRAM

NETWORKING IN

OF

NGO

IN

DELHI

S. Shridhar and S. Somnath, Institute of Human Behaviour & Allied Sciences, Delhi, India

PRE-

PLACEBO-CON-

TRIAL

S. Shoptaw, W. Ling, G. Twitchell, J. Wilkins, and M. Majewska, Friends Research Institute, Easton, National Institute of Drug Abuse, Baltimore, MD, UCLA, Los Angeles, and UCLA Long Beach, CA Stress hormone response levels at treatment entry among cocaine dependent individuals have been shown to predict clinical outcome, with subjects who show markedly higher cortisol and DHEA-S levels having better abstinence outcomes than those with blunted stress response levels. This two parallel double-blind, placebo-controlled study was grow, conducted to test whether stimulation of stress hormones in male cocaine dependent individuals using DHEA (100 mg/day) in the context of thrice-weekly group counseling would correspond with improved outcomes for cocaine dependence when compared to individuals who received placebo plus counseling. Subjects (DHEA = 11; placebo = 12) were similar demographically across groups and were predominantly African American (73.9%; 13% Caucasian, 13% Latino). The average subject was aged 39.7 years and had completed 13.8 years of education. Urine toxicology results indicated that subjects assigned to receive DHEA used significantly more cocaine than subjects treated with placebo as measured by the Treatment Effectiveness Score (3.3 vs 20.0, MWU = 19.0, P = 0.003) and by the percent of samples provided negative for cocaine metabolite (26.8% SD = 29.3 vs 70.6% SD = 39.9; MWLJ = 24.5, P = 0.009). Statistically significant differences in retention also were found with

There are several government and non-governmental organizations working in the field of drug abuse. Recently the Institute of Human Behaviour and Allied Sciences has been identified by the Government of Delhi as the Nodal Centre in de-addiction services in the National Capital ‘Territory of Delhi. As a part of its mission, it was planned to develop effective linking of services offered by various NGOs in Delhi with those available at IHBAS, as it was increasingly becoming evident that the problem of drug abuse is difficult to curb by any single organization. To overcome this problem, the networking of communitybased NGOs working in the drug abuse area was recently established in Delhi. Its primary objective is (a) to provide ongoing community-level surveillance of drug abuse through analysis of quantitative and qualitative data as produced by the NGOs with IHBAS as a Nodal Centre; (b) to develop effective linkages of available services in a drug abuse treatment program. As a first step in this direction a workshop was held. Proforma were circulated among NGOs to collect information on types of services, funding, and needs of the staff of the NGOs. During the workshop, the specific modes of collaboration and linking were discussed and agreed upon by the NGOs and IHBAS. It is further planned that the linking of services of NGOs could be done at three different levels: (a) through personal communication, by a computer networking system and by holding meetings and discussing the relevant issues. Effective networking is not common between NGOs and Government organizations and such networking will help in ongoing community-level surveillance of drug abuse and improving the drug treatment programs effectively.

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Abstracts

571

ELEVATION CAINE-DEPENDENT

OF ACUTE-PHASE PERSONS

REACTANTS

IN co-

A.J. Siegel, M. Sholar, J. Mendelson, I. Lipinska, J. Stec, P. Ridker, and G. Tofler, McLean Hospital-Harvard Medical School, Belmont, MA Elevated serum levels of acute-phase reactants including C-reactive protein (CRP), vonwillebrand Factor (vWF) and fibrinogen (FBG) are sensitive indicators of acute inflammation which mediate pro-coagulant effects. Increased serum levels of these markers have been shown to predict risk of acute myocardial infarction and mortality in unstable angina. We therefore measured acutephase reactants in occasional cocaine users (n = 10, mean age 26.2 + 4.8 SD, < 10 uses in prior year) and in cocaine-dependent subjects (n = 10, mean age 41.4 + 6.2 SD, 15.3 + 6.7 SD years of use), who were matched for body mass index. Compared to normal values in drugfree occasional users, cocaine-dependent subjects showed significant elevations in CRP (n = 7, P < 0.02), vWF (P < 0.0003) and FBG (P < 0.0001). There was no significant difference in fibrinolytic activity between the two groups. Prothrombotic effects from elevated acute-phase reactants in cocaine-dependent persons may contribute to an increase in risk for heart attack and stroke. 572 LEGALSEVERITYINCOCAINE-DEPENDENTOUTPATIENTS: DEMOGRAPHlCS, DRUG USE CHARACTERISTICS ANDTREATMENTOUTCOME S.C. Sigmon, G.J. Badger, and S.T. Higgins, Substance Abuse Treatment Center, University of Vermont, Burlington, VT Severity of legal problems and associated characteristics were assessed in 309 individuals seeking outpatient treatment for cocaine dependence. Individuals were divided into three groups: no, moderate and severe Addiction Severity Index Legal Composite Scores at the intake interview. Greater legal severity was associated with poorer pre-treatment functioning. Individuals with more legal problems at intake exhibited less full-time employment, lower weekly income, greater severity of cocaine involvement, more adverse consequences of cocaine use, were more likely to be cigarette smokers, were more likely to be alcohol, cannabis, or sedative dependent, and had higher scores on MAST, BDI, and AS1 medical and employment composite scores. Relationships between severity of legal problems and treatment outcome variables were assessed in a subset of 242 patients who received versions of the Community Reinforcement Approach + Vouchers or other drug abuse counseling. Overall, there were no statistically significant differences in treatment outcome with respect to legal severity. However, a clear trend suggested that patients with greater legal severity at intake tended to have less success

with cocaine abstinence, particularly receiving vouchers.

among those not

573 A THERAPEUTIC WORKPLACE FOR THE TREATMENTOFDRUG ABUSEzZYEARABSTINENCEOUTCOMES K. Silverman, D. Svikis, G. Bedient, M.L. Stitzer, and G.E. Bigelow, Johns Hopkins University School of Medicine, Baltimore, MD, and Virginia Commonwealth University, Richmond, VA Voucher-based abstinence reinforcement has been highly effective, but practical applications of this technology have not yet been developed. This study evaluated the efficalsy of a potential application of the abstinence reinforcement technology, a Therapeutic Workplace. This intervention integrates abstinence reinforcement into a work setting, using salary that drug abusers earn for work to reinforce drug abstinence. In the Therapeutic Workplace patients are hired and paid to work. To link salary to abstinence, patients are required to provide drug-free urine samples to gain daily access to the workplace. The Therapeutic Workplace was evaluated in heroin and cocaine abusing methadone patients (N = 40) enrolled in a treatment program for pregnant drug abusi:ng women. Patients were randomly assigned to a Therapeutic Workplace or a usual care control group. Thera.peutic Workplace participants were invited to attend the workplace 3 h every weekday for 6 months and were .repeatedly re-enrolled in the workplace in 6-month blocks. As previously reported at CPDD, the Therapeutic Workplace significantly increased abstinence from opiates and cocaine during the first 6 months of treatment relative to controls. This presentation will report long-term abstinence outcomes up to 24-months after treatment entry. Long-term abstinence outcomes for both groups were assessed through urine samples collected monthly beginning at 18 months. Data are currently available at least to 21 months for all participants. Analysis of those monthly (months 18-21) urine samples show that the Therapeutic Workplace significantly increased the mean percentage of urines that were negative for opiates and cocaine relative to controls (60 vs. 24% negative, respectively; t = 2.83, P < 0.007). This study demonstrates the effectiveness of the Therapeutic Workplace intervention in maintaining long-term drug abstinence, and suggests that employment might serve a valuable role in the treatment of drug abuse as a vehicle for funding, implementing, and sustaining long-term exposure to abstinence reinforcement contingencies. Supported by NIDA grants ROl DA09426, ROl DA12564, ROl DA13107 and K05 DA00050. 574 COGNITIVE DEFICITS IN PHETAMINEABUSERS: PATTERNS

ABSTINENT METHAMOFRECOVERY

S.L. 1Simon, K. Richardson, J. Dacey, S. Glynn, R. Raws’on, W. Ling, Los Angeles Addiction Research

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Abstracts

Consortium, Los Angeles, and Long Beach VA Medical Center, Long Beach, CA Although cognitive deficits have previously been found for abstinent methamphetamine abusers (Simon et al. under review), the patterns of recovery of different functions have not been fully examined. Seventy-five MA abusers abstinent from 2 weeks to 6 months were grouped by time abstinent and given a battery of tests tapping functions that have previously been found to be impaired in abstinent methamphetamine users. This cross sectional data is utilized to determine the duration of each deficit and slope of recovery for measures of perceptual speed, the ability to ignore irrelevant information, manipulation of information, for recall and recognition of pictures and words and mental flexibility. Deficits were found for all tests, but most striking was performance ona test of mental flexibility which declined over time until at 6 months it was approximately 55% of the mean performance of non-using participants. ACKNOWLEDGEMENTS: Supported by NIDA/DVA interagency agreement # 1 YOl DA 50038-00. 575 CIAL

AN

EVALUATION

FACTORS

TWEEN TREATMENT

THAT

CHILDHOOD IMPLICATIONS

OF A MODEL

OF BIOPSYCHOSO-

MEDIATE

THE

RELATIONSHIP

ABUSE

AND

SUBSTANCE

FOR

BEUSE:

WOMEN

L. Simons, J. Ducette, G.J. Stahler, K. Kirby, and T.E. Shipley, Temple University School of Medicine, and Diagnostic Rehabilitation Center/Hutchinson Place, Philadelphia, PA The study evaluated an hypothesized model of biopsychosocial factors that mediate the relationship between childhood abuse and substance use. Questionnaires containing items assessing biopsychosocial factors of famial alcoholism/addiction, parental mental health, childhood abuse, self-esteem, family and social support, belief systems, mood states, coping methods, and substance use were administered to 110 drug addicted subjects receiving either residential or day partial treatment. A series of path analyses were conducted to assess the theoretical model and to explore the direct and indirect relationships among childhood abuse, biopsychosocial factors, and substance use. Preliminary results support the hypotheses that childhood abuse is directly and indirectly related to substance use. Childhood abuse is indirectly linked to substance use through mediating biopsychosocial factors of low self-esteem, negative social support, and negative family support, avoidance and affective beliefs, mood states, and avoidance coping methods. An exploratory path analysis was conducted among childhood abuse, biopsychosocial factors, and alcohol

and nicotine use. The results support that childhood abuse was directly related to negative social support, negative family support, low self-esteem, and avoidance coping methods; and it is indirectly related to drinking and smoking. This. finding further supports the hypothesis that substance use is an avoidance coping method for negative psychosocial factors promoted by the different types of childhood abuse. A one-way ANOVA demonstrated significant differences between males and females in psychosocial characteristics and substance use. This finding supports that females were more likely to report a history of childhood abuse, low self-esteem, and avoidance coping than males. Females were diagnosed with co-occurring psychological disorders and given prescription medication more often compared to males. Implications from these findings suggest that a gender specific theoretical model may be necessary for the development of effective treatment programs for women. Overall, this preliminary investigation demonstrated the biopsychosocial relationships that should be addressed in treatment in order to elucidate the biological, psychological, social mechanisms precipitating substance use among women. 576 AND TWEEN

COMBINED

BEHAVIORAL

BENZODIAZEPINE FEMALE

EFFECTS

HYPNOTICS: AND

MALE

OF

ETHANOL

DIFFERENCES

BE-

VOLUNTEERS

C. Simpson and C. Rush, The University tucky, Lexington, KY

of Ken-

Women tend to be disproportionately represented among patients presenting for treatment for insomnia and related sleep disorders and to be disproportionately prescribed fast-acting benzodiazepines. Past laboratory studies that compared the behavioral effects of clinically equivalent doses of triazolam (TRZ) and temazepam (TMZ) relied on predominantly male samples, which leaves open the possibility of gender-specific differences in behavioral impairment profiles. The present study compared the acute behavioral and subject-rated effects of TRZ (0.125, and 0.25 mg), TMZ (15, and 30 mg), and placebo in 5 female and 5 male volunteers. Triazolam, but not temazepam, significantly impaired performance in the female volunteers. Neither drug significantly impaired performance in the male volunteers. Females also reported greater sedative-like subject-rated drug effects (e.g. ‘Sleepy’) following triazolam administration, but not temazepam. These data suggest the use of lower doses of triazolam, and perhaps other triazolobenzodiazepine hypnotics, in the treatment of sleep disorders in females. Supported by NIDA grant DA 09841 (C.R.R.).

Abstracts

577

ASSESSMENT OF 6-0~101~ TIONED TASTE AVERSIONDESIGN

AGONISTS

IN A CONDI-

G.R. Simpson, A.C. Hutchinson, and A.L. Riley, American University, Washington, DC Assessments of opioid-induced conditioned taste aversions (CTA) have been limited primarily to compounds with selectivity for the mu or kappa opioid receptor subtypes. The recent development of non-peptide, 6 selective opioids allows for systemic administration of these compounds and their examination within the CTA design. The present experiment, therefore, attempted to characterize CTAs produced by opioid agonists with varying degrees of selectivity for the 6 receptor. Specifically, following water deprivation 138 female LongEvans rats were given 4 pairings of a novel saccharin solution and various doses (0,0.32, 1, 3.2 and 10 mg/kg, s.c.) of the selective 6 agonists BW373U86, SNC 80 and SNC 162, listed in order of increasing selectivity for the 6 receptor. For comparison, the mu agonist morphine was assessed under identical conditions. Both the 6 compounds and the mu-selective morphine induced aversions, however, those produced by the 6 agonists were greater. more rapidly acquired and acquired at lower doses than those induced by morphine. At the highest dose, each of the 6 agonists induced aversions (relative to controls) after a single trial. These aversions were maintained with repeated conditioning (except SNC 162 on trial 5). Aversions were weakly induced by morphine, i.e. only the highest dose of morphine produced aversions and even at this dose only on conditioning trial four. In relation to the relative degree of aversions induced by the S compounds, aversions appeared to be inversely related to the degree of selectivity for the 6 receptor, i.e. BW373U86 produced stronger aversions than SNC 80 that in turn produced stronger aversions than SNC 162. This examination of 6 agonist-induced CTA suggests that while aversions produced by 6 compounds are different than those induced by morphine, this difference is less evident as selectivity for the 6 receptor increases. 578 SUBSTANCE ABUSE AND VIOLENCE WOMENENTERINGSUBSTANCEABUSETREATMENT R. Sinha and C.J. Easton, Yale University Medicine, New Haven, CT

AMONG

School of

Substance abuse and psychiatric problems are common among women with a history of trauma. The present study evaluated women who were referred to an outpatient substance abuse treatment unit for an evaluation. Forty women who met DSM-IV criteria for substance abuse participated in the study. An evaluation that utilized questions from the Conflict Tactic Scale (CTS) was completed with clients to assess lifetime prevalence

s205

of family violence and trauma. The Michigan Alcohol Screening Test (MAST), and Beck Depression Inventory (BDI) were also administered. Preliminary results indicate that women who reported being a victim of physical violence had significantly higher depressive symptoms, more alcohol related problems and shorter lengths of stay in substance abuse treatment than women without a history of physical violence. The findings illustrate the impo.rtance of assessing a history of trauma among women entering substance abuse treatment, as this may be an important indicator for treatment retention and outcome among this population. 579 THE EFFECTS OF WF-11 (PTT) AND COCAINE RESPONDINGMAINTAINEDUNDERAPROGRESSIVE-RATIO SCHEDULE OFFOOD PRESENTATION

ON

G.M. Sizemore, H. Davies, and J.E. Smith, Wake Forest University School of Medicine, Winston-Salem, NC and SUNY Buffalo, Buffalo, NY The tropane analogs are useful experimental tools for examming the pharmacology of drug self-administration and may have use as pharmacotherapies for cocaine abuse. Among these is WF-11 (PTT), a potent analogue relatively selective for the dopamine transporter. When PTT is substituted for cocaine on a progressive-ratio (PR) schedule (a schedule in which the number of responses required per infusion increases after each infusion) animals will quit responding only when the number of responses required is relatively large. This fact is thought to indicate that PTT is an efficacious reinforcer, but some responding may be due to the direct stimulating effects of the drug. In this experiment Fischer 344 rats responded under a PR schedule of food presentation in which the number of responses required increased exponentially. Sessions were terminated if no reinforcer was delivered for 1 h. The last ratio completed was termed the ‘breakpoint’. Under non-drug conditions breakpoints were relatively low (10-60). PTT (0.333.0 mg/kg) or cocaine (5.6630 mg/kg) was administered 10 min prior to the start of the session. Breakpoint was a bitonic, inverted U-shaped function of dose for both drugs and the extent of the increases in breakpoint produced by both drugs were strongly correlated. Subjects for whom PTT produced large increases also showed large increases when cocaine was administered. Maximum breakpoints observed ranged from 130 to 2000 for PTT and 50-350 for cocaine. These data suggest that the direct effects of some drugs may contribute to the high breakpoints seen when the drugs are self-administered. Supported in part by US PHS grants DA 06634 and DA 00114.

Abstructs

S206 580

RISPERIDONE

CRAVING

AND

DECREASES RELAPSES

CUE-ELICITED IN

COCAINE

INDIVIDUALS

WITH

SCHIZOPHRENIA

D.A. Smelson, J. Williams, A. Storasta, J. Williams, M.F. Losonczy, D. Ziedonis, Robert Wood Johnson Medical School, Piscataway, and VA New Jersey Health Care System, Lyons, NJ Hypothesis: Since the same neurobiological systems are involved in the etiology of schizophrenia and the rewarding effects of cocaine, we believe that individuals with the combined disorders may have a heightened craving state, which predisposes them to relapse. This suggests a need to develop effective pharmacological anti-craving interventions to prevent frequent deterioration. Procedures: We conducted a preliminary open-label trial comparing risperidone to typical neuroleptics for decreasing cue-elicited craving and relapses among withdrawn cocaine-dependent schizophrenics (N = 17). Symptom severity was rated weekly and patients completed a craving questionnaire before and after the cue-exposure procedure. Results: Patients receiving risperidone (N = 7) were less likely to drop out of the study (P = 0.05) or relapse with drugs (P = 0.02) and had lower change scores on the energy/arousal (P = 0.01) and feeling (P= 0.07) dimensions of craving compared to individuals receiving a typical neuroleptic (N = 10). Importance of findings: These results suggest that future research should include a double-blind trial comparing risperidone to another typical neuroleptic. 581 EFFECTS

PHYSIOLOGICAL, OF

ORAL

SUBJECTIVE AND

INTRAVENOUS

AND

REINFORCING COCAINE

IN

HUMANS

B.J. Smith, H.E. Jones, R.R. Griffiths, Johns Hopkins University School of Medicine, Baltimore, MD There is little comparative information on the qualitative similarity, relative potency and relative reinforcing effects of oral cocaine versus cocaine administered via other routes. The present study (n = 7) used a withinsubject, double-blind, double-dummy design to compare the physiological, subjective and reinforcing effects of placebo and oral (62.5, 125,250 mg/70 kg) and intravenous (12.5,25, 50 mg/70 kg) cocaine in volunteers with histories of cocaine abuse. Both routes produced dose-dependent increases on heart rate and blood pressure, with effects after oral cocaine lasting longer. Subjective ratings (e.g. ‘rush’, ‘drug effect’, ‘liking’) were qualitatively similar and dose-dependently increased after oral and intravenous administration, and the duration of effects was similar under both routes. On a money vs. drug choice measure of reinforcement, both routes produced significant increases in the amount of

money participants would forgo in order to receive drug. At doses that produced comparable subjective, physiological, and reinforcing effects, oral cocaine was not identified as cocaine as frequently as intravenous cocaine. Across most measures, the data suggested a IO-fold potency difference between oral and intravenous cocaine in humans. Overall, the results of this study support qualitatively similar effects of oral and intravenous cocaine. Supported by NIDA grant ROl DA 03890. 582 (PTT) HEROIN

THE ON AND

EFFECTS

OF

RESPONDING COCAINE/HEROIN

THE

TROPANE

ANALOG

MAINTAINED

BY

WF- it COCAINE,

COMBINATIONS

J.E. Smith, G.M. Sizemore, H. Davies, Wake Forest University School of Medicine, Winston-Salem, NC, and SUNY Buffalo, Buffalo, NY The tropane analogs are useful experimental tools for examining the pharmacology of drug self-administration and may have use as pharmacotherapies for cocaine abuse. Among these is WF-11 (PTT), a potent analogue relatively selective for the dopamine transporter. In the experiment reported here, the effects of PTT upon responding maintained by cocaine, heroin, or cocaine/heroin combinations were examined. Fischer 344 rats responded under a fixed-ratio two schedule in which three different doses of the maintaining drug(s) were available, in ascending order during a session. Each dose was available for 1 h and these components were separated by 10 min blackouts. The cocaine/ heroin combinations were composed of the same doses used for these drugs separately. The number of infusions/component was a decreasing function of dose of the response-maintaining drug for cocaine, heroin, and cocaine/heroin combinations. PTT (0.3-3.0 mg/kg) was administered 10 min prior to the start of the session and produced dose-dependent decreases in the rate of self-administration of both cocaine and cocaine/heroin combinations. Self-administration of the large dose or dose combinations was less affected by PTT administration than the two smaller doses or dose combinations. Though decreases in the rate of heroin self-administration were also observed, some doses of PTT could produce large increases depending on the dose maintaining responding. Thus, heroin self-administration was affected differently by PTT than cocaine or cocaine/heroin self-administration. These data suggest that self-administration of some cocaine heroin/ combinations is similar to self-administration of cocaine alone, and that heroin self-administration depends on neurotransmitter systems different from those of cocaine. Supported in part by US PHS grants DA 06634 and DA 00114.

Abstracts

583

ENGAGING THE UNMOTIVATED COMPARISONOFTWOINTERVENTIONS

DRUG ABUSER: A

J.E. Smith, R.J. Meyers, W.R. Miller, J.S. Tonigan, University of New Mexico, and The Center on Alcoholism, Substance Abuse and Addictions, Albuquerque. NM It is well known that many individuals with drug abuse problems are resistant to treatment. A randomized clinical trial investigated the effectiveness of two approaches for working with the Concerned Significant Others (CSOs) of treatment-resistant drug abusers, with the objective of engaging the resistant individual in treatment. A secondary goal was to improve the psychosocial functioning of the CSOs. One intervention, Community Reinforcement and Family Training (CRAFT), was a cognitive-behavioral skills program for the CSO. The comparison group was individual CSO counseling based on eh 12- Step model. To balance for the potential additional impact of 12-Step group attendance for the second condition, a third condition was introduced. It consisted of CRAFT and a ongoing support group. But due to lack of significant differences between the two CRAFT conditions, their data were combined for all analyses. Engagement rate for the CRA condition was significantly better than that of the 12-step group. 584 SENSITIVITY SANTS ON MOTOR TREATEDRATS

TO THE EFFECTS OF CNS DEPRESCOORDINATION IN PHENOBARBITAL-

M.A. Smith, W.W. Stoops, D. Morgan, Davidson College, Davidson, and Wake Forest School of Medicine, Winston Salem, NC The present investigation examined sensitivity to the motor-impairing effects of CNS depressants in rats treated chronically with phenobarbital. Eight rats were trained to walk on a rotorod treadmill at low (8 rpm) and high (24 rpm) rotational speeds. Prior to the chronic regimen, phenobarbital, pentobarbital, amobarbital, diazepam and clonazepam produced dose-dependent decreases in motor performance at both speeds. During chronic treatment with phenobarbital (100 mg/ kg per day), tolerance was conferred to the effects of all the drugs examined as evidenced by rightward shifts in their dose-effect curves. For all drugs, the magnitude of this tolerance was generally consistent across the two speeds. Following a 6-week washout period during which no drugs were administered, dose-effect curves for each drug shifted back toward their original (i.e. pre-chronic) positions. Under all conditions, the doses

S207

required for each drug to impair motor performance at the low speed were higher than those required to impair motor performance at the high speed. These data suggest that sensitivity to the motor impairing effects of CNS depressants is influenced by the motor requirements of the behavioral task, and that this effect is consistent before, during and after a regimen of chronic phenobarbital administration. 585 EFFECTS OF CHRONIC NICOTINE TREATMENT vs. ABSTINENCE ON THE EFFECTS OF INTRAVENOUS NICOTINE,CAFFEINE AND COCAINE B.F.X. Sobel and R.R. Griffiths, Johns Hopkins University School of Medicine, Baltimore, MD Few studies have focused on tolerance to and abstinence from chronic nicotine exposure in humans. Furthermore, nicotine is often used concurrently with other drugs. Epidemiological studies have shown strong concordance between tobacco and caffeine use and between tobacco and cocaine abuse. The present study examined the effects of chronic nicotine treatment and abstinence on the subjective and physiological effects of nicotine, caffeine and cocaine. Subjects were healthy volunteers with histories of cocaine, nicotine and caffeine use and they resided on a residential research unit. Cigarette smoking and all dietary sources of caffeine were eliminated for the duration of the study. Subjects wore skin patches throughout the study. During the experimental sessions, placebo, caffeine (200 and 400 mg/70 kg), cocaine (15 and 30 mg/70kg) and nicotine (1 and 2 mg/70kg) were administered intravenously under double-blind conditions and in a mixed order. Subjective and physiological data were collected prior to and for 30 min following drug administration. These 7 drug conditions were administered twice: once after maintaining subjects for at lease 2 weeks on chronic nicotine via skin patch (21 mg per day) and once on chronic placebo patch via skin patch (0 mg per day). The study is ongoing. Results suggest that chronic nicotine treatment produces marked decreases in the subjective effects (e.g. drug effect, rush, like the drug, high, stimulated) of nicotine. The effects of chronic nicotine treatment on caffeine and cocaine are only preliminary at the present time. ACKNOWLEDGMENT: Supported by NIDA DA-03890. 586 LOSSOFCELLULARITYANDT-CELLRESPONSIVENESS FOLLOWING ACUTE EXPOSURE TO THE ABUSED INHALANT,ISOBUTYL NITRITE L.S.F. Soderberg, G.L. Guo, J.B. Barnett, University of Arkansas for Medical Science, Little Rock, AR and

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University of West Virginia Morgantown, WV

Abstracts

College

of Medicine,

Isobutyl nitrite is an inhalant abused principally by male homosexuals. We have reported that subchronic inhalation exposure (45 min per day for 14 days) to 900 ppm isobutyl nitrite was immunosuppressive. In the present study, the effects of acute exposure to the inhalant were examined. Mice were exposed in an inhalation chamber to 900 ppm isobutyl nitrite for 45 min. One day later, spleen cellularity was reduced by 39% without selectively depleting CD4 + or CD8 + cells. The numbers of peripheral blood leukocytes and peritoneal cells were also reduced. Following acute inhalation exposure, T cell proliferative responses stimulated with allogeneic cells or anti-CD3 and antiCD28 antibodies were inhibited, while mitogen-induced responses were not affected. Purified T cells exposed to the inhalant also had compromised responses, suggesting a direct effect on T cells. However, the cumulative effects of multiple exposures were necessary to inhibit T-dependent antibody responses or T cell or macrophage cytotoxicity. 587 CARVEDILOL AFFECTS THE PHYSIOLOGICAL AND BEHAVIORAL RESPONSE TO SMOKED COCAINE IN HUMANS

M. Sofuoglu, S. Brown, P.R. Pentel, D.K. Hatsukami, University of Minnesota and Hennepin County Medical Center, Minneapolis, MN Noradrenergic system is implicated in mediating some of the physiological effects of cocaine. The purpose of this study was to investigate whether treatment with an adrenergic blocker, carvedilol, which would be expected to attenuate the physiological effects of cocaine, would also attenuate the subjective and behavioral response to cocaine in humans. Twelve crack cocaine users participated in this double-blind, placebo-controlled outpatient study. Acute treatment with 50 mg of oral carvedilol attenuated the smoked cocaine-induced increases in heart rate, systolic and diastolic blood pressure. The number of cocaine selfadministrations was lower under 25 mg carvedilol treatment condition compared with 50 mg carvedilol or placebo treatment conditions. The subjective responses to smoked cocaine deliveries were not affected by carvedilol treatment. These results suggest that acute treatment with carvedilol attenuates the physiological effects of smoked cocaine. The effects of carvedilol on cocaine self-administration need to be studied further. Supported by NIH grants P-50 DA09259 and MOlRR00400.

588 GABAPENTIN TREATMENT FOR COCAINE DENCEINMETHADONE-MAINTAINEDOPIOID-DEPENDENT PATIENTS

DEPEN-

A. Soliman, K. Kampman, J. Cornish, L. McNicholas, G. Woody, and C. O’Brien, Philadelphia VA Medical Center, Philadelphia, PA Hypothesis: (1) Subjects who take active medication, gabapentin, will become abstinent or decrease the amount or the frequency of cocaine use; (2) Subjects on active medication will have fewer positive urine drug screens than subjects on placebo. Objectives: The overall objective of this project is to evaluate the clinical efficacy and safety of Gabapentin in treatment of cocaine dependence in opioid dependent patients in early partial remission on agonist therapy (methadone). Methods: This outpatient protocol involves the provision of medications and the available standard drug counseling. Patients will continue to take their maintenance dose of methadone during the study. Twenty evaluated cocaine dependent patients will be randomized in a double blind fashion, to gabapentin or placebo for 8 weeks after a period of 2-weeks to measure base line function and use of patients. Outcome meusures: Urine Toxicology screens for benzoyglyconine(quantitative) cocaine craving 100 mm Visual analogue scale Clinical Global Impressions. 589 AN OPEN-LABELPILOT STUDY OF METHYLPHENIDATE IN THE TREATMENT OF COCAINE-DEPENDENT PATIENTS WITH ATTENTION DEFICIT HYPERACTIVITY DISORDER

E. Somoza, P. Bridge, T. Winhusen, J. Rotrosen, D. Vanderburg, J. Harrer, J. Mezinskis, A. Montgomery, D. Leiderman, J. Locastro, L. Wulsin, and J. Barrett, NIDA MDRU: Cincinnati, OH, New York, NY, Boston, MA and NIDA Division of Treatment Research and Development, Bethesda, MD This multi-site, outpatient, open-label, lo-week trial evaluated the safety and efficacy of using methylphenidate (MPD) to treat individuals with comorbid diagnoses of cocaine dependence and Attention-Deficit/Hyperactivity Disorder (ADHD). Forty-one participants were enrolled into this trial, 29 of whom completed final study measures. Participants received a maximum daily dose of 60 mg (20 mg TID) MPD. In addition, participants received weekly individual substance abuse behavioral therapy. Safety measures included adverse events, vital signs, electrocardiograms and standard laboratory tests. MPD’s efficacy in treating cocaine dependence was assessed by quantitative urine benzoylecgonine (BE), self- and observer-rated clinical global impressions scales (CGIs), craving measures, self-report of substance use, and the Addiction Severity Index. MPD’s efficacy in treating ADHD was measured by self- and observer-

S209

Abstracts

rated CGIs, the UMASS Adult Behavioral Checklist, and the CALCAP@, a computerized assessment of attention. The Risk Assessment Battery, an assessment of participation in behaviors that increase the risk of contracting HIV, was also utilized. Self-report measures indicated significant improvement for cocaine dependence and ADHD symptoms and a significant decrease in activities associated with contracting HIV. Urine BE results indicated that participants compliant with self-administering MPD as prescribed used significantly less cocaine than non-compliant participants (U= 83, P < 0.05). 590 GENDER DIFFERENCES A RANDOMIZED CLINICAL DEPENDENCE

IN SAMPLE SELECTION IN TRIAL FOR COCAINE

Y.S. Song, A.M. Washburn, J.L. Sorensen, E.E. Midkiff, and H.D. Kleber, University of California-San Francisco, CA and CASA, Columbia University, New York, NY Within substance abuse treatment research, women are often underrepresented in clinical trials. Women may experience more difficulty finding appropriate substance abuse treatment programs due to the lack of availability of key services that women often require (e.g. child-care, gender-sensitive treatments). In addition, these services are even more difficult to find within experimental treatment programs (i.e. randomized clinical trials). We analyzed screening/intake data from a randomized clinical trial of acupuncture for treatment of cocaine dependence. Linear regression analyses revealed that gender was predictive of whether a participant would be randomized to one of the three treatment arms of the study. In addition, prior substance abuse treatment was a predictive factor for women being randomized into the study. Of the 5 15 male and 3 17 female participants screened for inclusion into the treatment study, 55.6% of the female participants met the initial screening criteria and were offered intake appointments versus 66% of the male participants. In addition, 13.9% of the total sample of women met the study inclusion criteria and were randomized to treatment versus 22.4% of the men. These results suggest that women are less likely to be accepted for inclusion in clinical trials research for substance abuse. Therefore, experimental substance abuse treatment programs may not be adequately addressing the specific recruitment needs of women. ACKNOWLEDGMENTS: Supported by a grant from the Conrad Hilton Foundation and NIDA Grants T32DA07250 & P50DA09253.

591 SMOKING POPuLATION

BEHAVIORS

IN

AN

ALCOHOLIC

S. Sonne, P. Latham, R. Anton, and K. Brady, Medical 1Jniversity of South Carolina, Charleston, SC This study was designed to investigate the relationship between smoking behaviors and alcohol use in an alcohol dependent population. A subset of individuals from a larger, 12-week, placebo-controlled trial of naltrexone for the treatment of alcoholism were evaluated for their motivation to stop smoking. Smoking and alcohol use were assessed on a weekly basis and motivation to stop smoking was assessed at baselme and week 12. Subjects were 77 alcohol-dependent men and women; 58 (75.3%) were lifetime smokers, and 41 (53.9%) were current smokers. Smoking status was not obtained on one subject. In this subset, there were no differences in smoking or abstinence rates between those who received naltrexone (n = 42) versus those who received placebo (n = 35). There were no differences in motivation to quit smoking between those who remained abstinent from alcohol and those who did not. Twenty-four subjects (31.5:/o) remained abstinent during the 12-week treatment trial. There were significantly fewer cigarettes smoked per day at baseline for the abstainers (7.6 + 14.2) compared to those who drank (16.5 _+16.6; P < 0.03). Similarly, 34 (82.9%) of those who smoked at baseline drank during the 12 week trial versus 17 (50%>1of the non-smokers (P < 0.005). Of the lifetime smok’ers, those who successfully quit smoking prior to baseline were more likely to remain abstinent from alcoh’ol during the trial (P < 0.005). These data suggest that baseline smoking status may have some predictive value for determining those most likely to succeed in alcohol treatment. 592 INCREASED MEDICATION COMPLIANCE REQUIREMENTSFORMETHADONE PATIENTS WITH HIV/AIDS J.L. Sorensen, M. Schissel, Y. Song, C. Jacob, and S. Smolar, University of California, San Francisco, CA We report changes from 1994 to 1999 in the medication strategies used with methadone maintenance patients who have HIV/AIDS. Subjects include a randomly selected 57 of 169 HIV + methadone maintenance patients at San Francisco General Hospital’s methadone maintenance clinic. Procedures involved chart reviews of patient records to determine the number and type of medications they were prescribed, and the number of pills taken daily. Results are compared with a similar survey conducted in 1994. Results indicate a 100% increase in the number of medications prescribed per patient and the number of pills each patient was responsible for ingesting.

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Abstracts

1994 Patients prescribed medications Mean medications prescribed Range Mean pills/capsules required daily Range

1999

95% 96% 3.58 7.28 o-9 O-18 6.35 13.89 O-24 O-51 ___-___

Importance of work: Drug abuse treatment programs increasingly provide care to patients with HIV/AIDS. Patients are receiving more complicated HIV-related prescriptions, which imparts considerable responsibility to patients. The large pill burdens can add to the problems that patients have in adhering to these regimens. Non-compliance to the medications is significant, resulting in drug resistance, exacerbated illness and medical costs. There is a need to improve medication strategies and to assist patients in managing their medications. Supported by NIDA ROl DA1 1344, and P50DA09253.

593 HERRNSTEINS HYPERBOLA, AND THE ACUTE AND CHRONIC PHETAMINE IN RATS

REINFORCER TYPE, EFFECTS OF D-AM-

P.L. Soto and J. Stahl, Emory University and Morris Brown College, Atlanta, GA Previous research has suggested that the parameters of Herrnstein’s hyperbola may be useful in differentiating between the motoric and motivational effects of drugs (Heyman, 1983; Heyman and Seiden 1985). Traditionally, k has been interpreted as measuring motoric properties of the instrumental response and re has been interpreted as measuring reinforcer efficacy or motivational level. The present study investigated the relation between the parameters of Herrnstein’s hyperbola, reinforcer type, and the acute and chronic effects of D-amphetamine on variable-interval (VI) responding in rats. During Phase 1, estimates of k and re were obtained for each of two reinforcer types: 45 mg grain pellets and 45 mg 50% sucrose-50% cellulose pellets. During Phase 2, each session consisted of four VI 17 s components, two of which delivered grain as the reinforcer and the other two delivered sucrose pellets as the reinforcer. Following baseline exposure, subjects received two injections of D-amphetamine at each of four doses (0.2,0.8, 1.6, and 3.2 mg/kg) followed by 30 consecutive daily injections at a fixed dose (dose tailored for each subject). Saline control injections occurred intermittently during the acute injection period. Contrary to theoretical requirements, the mean value of k was significantly higher for sucrose pellets than for grain pellets, t(6) = - 4.34,

P < 0.01. The mean value of re did not vary significantly for the two reinforcer types, t(6) = 1.85, P > 0.05. Dose

response curves obtained from the acute injections showed some elevation of response rates at low doses for some rats followed by dose-dependent suppression of rates for higher doses. The mean level of tolerance for the group was significantly higher for sucrose pelletmaintained responding than for grain pellet-maintained responding, t(6) = - 6.45, P < 0.01. The results suggest two points. First, the parameters of Herrnstein’s hyperbola may not be a useful measures of motoric and motivational aspects of behavior and are therefore limited in interpreting the effects of drugs. Second, the development of behavioral tolerance to the disruptive effects of D-amphetamine may be modulated by the reinforcer type maintaining behavior. This research was supported by a grant from the National Institute on Drug Abuse (NIDA) Minority Institutions Research Development Program 5R24DA07256. 594 COMPARATIVEANALYSISOFSWEATPATCHESFOR COCAINE AND METABOLITES BY GAS CHROMATOGRAPHY-MASS SPECTROMETRY AND RADIOIMMUNOASSAY A.C. Spanbauer, E.K. Smith, J.L. Taccogno, and D.E. Moody, University of Utah, Salt Lake City, UT Sweat patches have been advocated for monitoring illicit drug use during therapy for drug dependence. A gas chromatography/mass spectrometric (GC/MS) method was validated for determination of cocaine, ecgonine methyl ester (EME) and benzoylecgonine (BE). Also a radioimmunoassay (RIA) method was validated for analysis of cocaine immunoequivalents in extracts of sweat patches. Both methods were used to analyze 879 patches worn by subjects in treatment for cocaine dependence. Cutoffs were evaluated at 4, 5 and 10 ng cocaine/ patch. From the GC/MS results, 661, 632 and 584 patches were positive at cocaine cutoffs of 4, 5 and 10 rig/patch, respectively. In positive patches the maximum concentrations of cocaine, EME and BE were 31 900, 2280 and 3460 rig/patch, respectively. When the RIA was used solely to determine if cocaine was present at or above the cutoff (i.e. qualitative), good agreement was found between the two methods. Using receiver-operating characteristic curve analysis, an optimal cutoff of 5 rig/patch was found for both methods where the RIA had a sensitivity (determination of positives) of 92.1% and a specificity (determination of negatives) of 88.7%. The RIA was not consistently acceptable for quantitative analysis. For the runs where quantitation of controls were acceptable, however, a good correlation (r = 0.989, n = 139) was found between GC/MS and RIA results. RIA was useful for screening of sweat patch extracts and determining if dilution would be required during GC/MS quantitation. Supported by NIDA Contract NOlDA-7-8074.

Abstracts

595

NEFAZODONE IN THE TREATMENT WITH COCAINE ABUSE

OF FEMALES

S. Specker, R. Crosby, J. Borden, and D. Hatsukami, University of Minnesota, Minneapolis, MN, and Neuropsychiatric Research Institute, University of North Dakota, Fargo. ND

Cocaine abuse and depression frequently co-exist and may lead to poor outcomes in substance abuse treatment. Serotinergic medications may have a role in both reduction of cocaine use and depression. It was hypothesized that nefazodone, a 5HT-2 antagonist and SSRI, would reduce both craving for cocaine and cocaine use, with a greater effect in depressed women. This study was an S-week, double-blind, placebo-controlled outpatient trial in a 2 x 2 design of 100 women. Primary outcome measures were analyzed in a mixed effects random regression model. No significant effects were found in the drug conditions on percent of positive urines or self-reported drug use, but greater global improvement (P = 0.018) was seen with nefazodone. Reduction in three of the four craving scales was seen in the nefazodone/depressed condition (P = 0.001,0.037,0.01). Nefazodone may treat a subclinical depression and thus impact craving.

596 POLYDRUG USE AND BEHAVIORAL METHADONEANDNICOTINEINTERACTIONS

ECONOMICS:

R. Spiga, A. Gardner, and M. Precourt, University of Texas-Houston Health Science Center, Houston, TX

patients Most methadone-maintained smoke cigarettes. The reinforcing effects of methadone and nicotine have been established in non-humans and humans. However, little is known of patterns of selfadministration when both are concurrently available. Microeconomic theory suggests that availability of alternative reinforcers and the price of reinforcers determines the interactions. Utilizing a unique human drug self-administration procedure this study examined the effect of increasing the price of methadone when nicotine was and was not available. In both conditions methadone and nicotine consumption decreased. However, the amounts of methadone consumed across all price conditions were greatest when nicotine was concurrently available. Increasing the price of nicotine reduced nicotine consumption and only slightly decreased methadone consumption. This was supported by NIDA grant # 12725.

s211

597 EFFECTSOFINTRAVENOUSBACLOFENPRETREATMENT ON FOOD- AND COCAINE-MAINTAINED RESPONDINGINRHESUSMONKEYS D. Stafford and J.R. Glowa, Louisiana State University Health Sciences Center, Shreveport, LA Previous studies in rats found that pretreatment with baclofen decreased cocaine maintained responding under several schedules of reinforcement, while similar doses of baclofen did not reduce behavior maintained by food. Thus, baclofen may have potential for use as a pharmacotherapeutic component in a program for the treatment of cocaine abuse. The present study sought to determine whether similar effects could be obtained in rhesus monkeys. The hypothesis was that baclofen would reduce cocaine-maintained responding at doses that did not affect food-maintained responding. Four male rhesus monkeys equipped with indwelling intravenous catheters and subcutaneous ports were the subjects. Monkeys were restricted to 90% of free-feeding bod,y weight throughout. Responding was maintained by a multiple chained fixed-interval 10 min fixed-ratio 30 (food, 1 g pellets), chained fixed-interval 10 min fixed ratio 30 (cocaine, 5.6 mg/kg per injection) schedule. In each session, 40 food pellets and 40 cocaine infusions were available. Baclofen was delivered via slow pre-session infusion, and a range of doses (0.3-10 mg/kg) were tested for five consecutive sessions each. Baclofen increased rates of cocaine-maintained responding in two monkeys, but did not change the number of infusions earned in any subject at any dose. Food-maintained responding was decreased in two monkeys. Significant side effects were observed in some monkeys at the 10 mg/kg dose: locomotion was uncoordinated, posture was disturbed, and food was refused. These data indicate that baclofen pretreatment as delivered in the present experiment does not selectively reduce responding maintained by cocaine. Future research will be required to determine why these results differ from those previously collected in rats. 598 FEASIBILITY OF STANDARDIZED PATIENT MENT CRITERIA FOR SUBSTANCE USERS

PLACE-

G.L. Staines, S. Magura, N. Kosanke, J. Foote, and A. Delnca, National Development and Research Institutes, New York, NY The American Society of Addiction Medicine (ASAM) Patient Placement Criteria (PPC) were developed to match the needs of patients to an appropriate Level of Care (LOC). LOC recommendations based on the ASAM PPC were determined by regular clinical evaluation (CE) and a standardized, computer-driven algorithm (ALG) [D. Gastfriend et al.]. LOC recommendations were obtained by both methods for

Abstracts

s212

256 consecutive alcoholism admissions and actual placements were determined. ALG and CE agreed for 35% of the applicants; ALG gave a higher LOC than CE for 56% of applicants; and ALG in a lower LOC than CE for 9% of applicants. These discrepancies were due to: clinicians’ questioning validity of certain PPC criteria; clinicians’ reservations about the algorithm’s method of measuring certain PPC criteria; and difficulties in providing or interpreting some of the algorithm’s source data. ALG recommendations and subsequent actual LOC placements matched for 29% of the applicants; CE recommendations and actual LOC placements matched for 71% of the applicants. The mismatches between CE recommendation and actual placement were due mainly to patient/ family preference or inability to comply, rather than to the requirements of insurance or managed care. Regular clinical evaluation and the algorithm produced discrepant LOC recommendations two-thirds of the time. Further, actual LOC placements were more congruent with the clinical evaluation procedure than with the standardized algorithm. Better understanding of the reasons for observed discrepancies in evaluation methods is needed in order to improve the acceptability and utility of automated PPC procedures in substance abuse treatment programs. Supported by: ROl AA10863 from NIAAA. 599

HIV-1

MODULATE

INFECTION THE

AND EXPRESSION

OPIOID

ADMINISTRATION OF

CHEMOKINE

RECEPTORS

A.D. Steele, T.K. Eisenstein, M.W. Adler, E.E. Henderson, and T.J. Rogers, Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA Approximately 30% of Human Immunodeficiency Virus1 (HIV-1)-infected individuals are intravenous drug users, and the majority of these individuals abuse opiates. As a result of the capacity of opioids to modulate a variety of immune functions and the more recent findings that opioids affect HIV-l co-receptor desensitization, our laboratory has speculated that opioids may participate in the host-parasite interaction during HIV infection. Using flow cytometry analysis, we have observed that infection with M- and T-tropic strains (HIV-JRFL and HIV-IIIB) for 48 h modulate CXCR4 and CCR5 expression in human peripheral blood mononuclear cells (PBMCs). Further studies by RNase Protection Analysis (RPA) suggest that modulation of chemokine receptor expression is at the level of transcription. We have also found that DAMGO, a mu opioid agonist, modulates chemokine receptor expression after 48 h based on flow cytometry analysis. We believe this research will provide insight into how the virus infection alone, and together with opioid administration, alters target cell susceptibil-

ity and the spread of HIV in the immune system. These studies will enhance our knowledge of HIV disease progression in intravenous drug users and the role of viral tropism in these patients. This work was supported by NIDA grants DA06650, DA11130, DA12113, T32AI07101, and T32DA07237. 600 MANS

REGIONAL ASSESSED

CNS BY

TOLERANCE

TO

NICOTINE

IN HU-

BOLD FMRI

E.A. Stein, T.J. Ross, R.C. Risinger, B.J. Salmeron, E. Schneider and A.S. Bloom, Medical College of Wisconsin, Milwaukee, WI, and Pfizer Central Research, Groton, CT Nicotine is one of the most addictive substances in humans. However, little is known about its in vivo pharmacodynamics and sites of action in the human brain. To examine the acute CNS effects of multiple nicotine injections in active cigarette smokers (n = 6), nicotine (0.75 mg/70 kg over 30 s) was administered iv 3 min into a 15 min scan while whole-brain fMR1 images were acquired (TR = 6000) on a 1.5 Tesla GE Signa scanner. Acute drug tolerance was determined by a second scan series and nicotine injection 20 or 60 min later. All studies were approved by the MCW IRB. Consistent with nicotine’s behavioral arousing and reinforcing properties, an increase in neuronal activity in multiple brain regions were seen including the insula, cingulate and frontal lobe-structures previously implicated in the behavioral and cognitive properties of other abused drugs, suggesting an overlap in reinforcement mechanisms and dependence properties. Evidence of neuronal tachyphylaxis, manifest as either a decrease in magnitude or a shortening of the elimination phase, was seen at the 20 but not 60 min inter-injection intervals heterogeneously in several frontal areas, while no tolerance was seen in the insula. These data indicate that acute tolerance to nicotine is regional in nature and may help explain the behavioral alterations seen with repeated nicotine use. Supported by DA09465, MO1 RR00058 and Pfizer Central Research. 601 VENOUS

ALCOHOL DRUG

AND USERS

HIV

RISK-TAKING

AMONG

INTRA-

M. Stein, A. Gogineni, P. Friedmann, A. Charuvastra, M. Sobota, R. Swift. and R. Longabaugh, Brown University School of Medicine, Providence, RI Purpose: To determine if HIV risk days are also alcohol use days for active injection drug users (IDUs). Methods: Cross-sectional interview of 187 AUDIT-positive ( 2 8) active IDUs recruited between 4/98- 12199 from a needle exchange program in Providence, RI. A HIVrisk day is defined as: (a) sharing needles; or (b) having

S213

Abstracts

sex without a condom measured using a 30-day Time Line Followback procedure. Results: The sample is 64% male, 87% white, mean age 37 years, 86% also use cocaine. The mean AUDIT score is 19; 82%.met DSMIV criteria for alcohol abuse/dependence. The mean number of HIV risk days per month is 11.07 (SD 10.4). 17% of persons had no risk days in the last month. 43% of HIV risk days were also drinking days. In multivariable logistic models using GEE to cluster by subject, alcohol use was associated with HIV-risk days (OR 1.55; 95% CI 1.222.0; P < O.OOl), controlling for gender, age, race, cocaine use, number of daily injections, methadone treatment and partner drug use. Conclusions: Using risk days as the unit of analysis, alcohol use is associated with HIV risk taking among IDUs. Whether alcohol use precedes or is subsequent to risky HIV behaviors remains to be determined. 602 PATHWAYSTOSUBSTANCEABUSEAMONGJAILED WOMEN IN CALIFORNIA J. Steinberg, C. Grella, and G. Monahan, UCLA Drug Abuse Research Center, Los Angeles, CA Previous research has shown high rates of dependence on alcohol and other drugs (AOD) among jailed women. Less well known are the pathways between early traumatic experiences such as sexual and physical assault and the onset of AOD among adult jailed women. This is the first study using California Drug Use Forecasting Data (CAL-DUF) to assess these factors in a sample of women arrestees. Women who reported a history of assaultive experiences were compared to non-abused women. Hypothesis: women arrestees with a reported history of sexual and physical assault will differ in drug-using behaviors from women who do not report a history of abuse. Methods: Structured interviews were conducted with 391 women arrestees in jails located in 13 counties throughout California. Urinalysis was also performed to validate self-reported drug use. Results: Bivariate analyses and multiple linear regression show that women with a stated history of sexual abuse (21%) and physical abuse (35%) were more likely to report that they used heroin in the previous year, had a history of sexually transmitted diseases, and had higher rates of somatic and mental health problems. Conclusions: Women arrestees would benefit from receiving community referrals to mental health counseling, drug treatment programs and health care services upon their release. 603 CTAP-PRECIPITATED PHINE-DEPENDENT RATS

WITHDRAWAL

IN

MOR-

C.L. Steinmiller, S.E. Bowen, and A.M. Young, Wayne State University, Detroit, MI

The ability of traditional opioid antagonists to precipitate withdrawal in organisms treated chronically with morphine (MS) has been well established. The present set of experiments was designed to evaluate the ability of .L.c.v. CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-PenThr-.NH,), a potent and mu-selective opioid antagonist, to precipitate withdrawal in rodents maintained chronically on MS. Additionally, the ability of CTAP to alter the withdrawal syndrome produced by NTX was examined. Cumulative dose tests were used to examine potency changes and maximal rate-decreasing effects of CTAP and/or NTX before, during, and after continuous infusion of saline, 10 or 32 mg/kg per day MS under a multiple component, schedule of food delivery (5-n-in run/l 5-min timeout, FR 30). NTX was able to produce a withdrawal syndrome as measured by an increase in NTX sensitivity in opioid treated animals. NTX sensitivity was a direct function of opioid maintenance dose, in that rats maintained on higher chronic doses of MS required lower doses of NTX for disruption of operant behavior. CTAP (0.01-32 ug per rat, i.c.v.) sensitivity did not change regardless of the dose of chronic MS. However, pretreatment with CTAP (10 ug per rat) increased sensitivity to S.C. NTX in rats maintained at 10 and 32 mg/kg per day MS. Additional work is currently under way to look at the ability of other opioid antagonists to precipitate a withdrawal syndrome. Supported by NIDA grants DA 03796 and K02 DAOO132. 604

DIFFERENCES TIONBETWEENFEMALE

IN COCAINE-INDUCED ANDMALERATS

SENSITIZA-

0. Sternin, J. Chin, H. Fletcher, S. Jenab, L.I. Perrotti, and V. Quiiiones-Jenab, Hunter College of CUNY, New York, NY New evidence suggests that there are sexually dimorphic behavioral responses to cocaine. To further understand these sex differences, Fischer rats were randomly assigned to cocaine (15 mg/kg per day, i.p.) or saline treatment for 14 days; a subgroup of animals received a challenge dose of cocaine or saline after 6 days of withdrawal (day 21). Stereotypic and locomotor behaviors were monitored on days 1 (acute), 7 (sub-chronic), and 14 (chronic) of cocaine administration and on day 21 (when the challenge dose was given). Cocaine-induced increases in locomotor and stereotypic activities were measured in both female and male rats. Female rats consistently showed significantly higher cocaine-induced stereotypic behavior, total locomotor activity, ambulations, and rearing than male rats. Interestingly, in male rats, chronic cocaine administration caused behavioral sensitization of ambulation and total locomotor activities. There was no sensitization seen in the

S214

Abstructs

stereotypic behavior. Both total locomotor and ambulatory activities were increased in females after the challenge dose in comparison to acute cocaine administration. Moreover, female rats displayed higher overall activity than male rats after this challenge dose. This study confirms previous reports that there are sex differences in the behavioral response to cocaine. Moreover, our observations extend previous studies by demonstrating that sex differences occur in certain aspects of cocaine-induced increases in behavior such as rearing, and ambulatory activity. This work was supported by The Altman Foundation, PSC-CUNY, NTMH-COR grant NH 16705 19 and RCMI RR-0307, MIDARP DA12136, NARSAD Young Investigator Award, (V.Q.J). 605

FROM

CEPTORS

TO PAIN:

POND AND

MAMMALIAN

AMPHIBIAN

SPECULATIONS II-, K-, AND

ON

&OPIOID

OPIOID

THE

UNIRE-

DIVERGENCE

RECEPTOR

OF

TYPES

C.W. Stevens, L.C. Newman, and D.R. Wallace, OSUCollege of Osteopathic Medicine, Tulsa, OK We have been obsessed over the last year with the idea that opioid receptors in frogs have some ancestral relationship with those found in humans and other mammals. Previous behavioral data showed that highly-selective opioid antagonists were not selective at all against p-, IC-, and s-opioids. Recent competetive binding data show that these same antagonists (highlyselective in mammalian species) inhibit the binding of naloxone with the same apparent affinity. Although other interpretations are possible, we speculate that a single type of opioid receptor (unireceptor) binds and results in antinociception following administration of any type of opioid agonist in frogs. But the relative potency of opioid analgesia following administration of selective p-. IC-,and s-opioids is the same in rats and frogs. We envision that the unireceptor has selective sites on the extracellular loops for each of the opioid agonists (see pit) and each same site on MOR, KOR, and DOR maintain the molecular efficacy of the frog ancestral unireceptor. Ongoing PCR studies using degenerate primers based on published vertebrate opioid receptor sequences test the unireceptor hypothesis. Supported by NIDA 12448. 606

ACUTE

ON CORTICAL

EFFECTS AND

OF IV

SYSTEMIC

HEROIN

AND

OXYGENATION

METHADONE IN HUMANS

R. Stohler, K. Dtirsteler Mac-Farland, R. Stormer, and D. Ladewig, Psychiatric University Hospital, Zurich, and University of Basel, Switzerland

The acute effects of intravenous (IV) heroin (60-300 mg) and methadone (80-300 mg) were investigated according to a placebo-controlled, single-blind, crossover design. Subjects were 23 opioid-dependent patients of the Swiss government’s heroin prescribing project (13 males, 2 females) and the IV methadone maintenance program of the Psychiatric University Hospital of Base1 (7 males, 1 female). All subjects underwent three test sessions in which they received 0, 50, and 100% of their heroin or methadone dose in random order. Objective pre- and post-drug effects were compared using near infrared spectroscopy, pulsoxymetry, electrocardiography, and impedance pneumography. Subjective drug effects were assessed by the Opioid Agonist Scale (OAS) and 10 mm visual analog scales. Comparisons of heroin and methadone (twoway ANOVA) yielded a more pronounced cortical and systemic deoxygenation after IV heroin, which was mostly accompanied by reduced heart rates and changes in breathing movements. Post-drug effects on self-ratings of rush and euphoria produced different results: full-dose ratings were higher in the methadone group. Heroin and methadone injections produced different patterns in nine items of the OAS. In conclusion, prescribed IV opioids lead to unpredictable states of repeated hypoxemia that might be clinically essential. IV heroin and methadone differ in the extent of acute physiological and psychological effects. ACKNOWLEDGMENTS: supported by the Swiss Federal Office of Public Health. 607 APY TIENTS

BEHAVIORALLY IN

THE ON

TREATMENT

CONTINGENT OF

PHARMACOTHEROPIOID-DEPENDENT

PA-

LAAM

K. Stoller, J. Carter, V. King, M. Kidorf, and R. Brooner, Johns Hopkins University School of Medicine, Baltimore, MD Patients on methadone or LAAM maintenance often continue to use other drugs such as cocaine. Although combining agonist-based pharmacotherapy with psychosocial treatments or behavioral incentives has been shown to improve outcome, counseling sessions are often missed and behavioral incentives are rarely used. The present study evaluates a model which uses contingent behavioral reinforcement to motivate counseling attendance and abstinence. An escalating schedule of weekly counseling intensity is prescribed in response to missed counseling sessions or drug-positive urines. This preliminary analysis includes 54 opioid-dependent admissions to outpatient substance abuse treatment. Participants were inducted onto LAAM maintenance and randomized into either a Behaviorally Contingent Pharmacotherapy condition (n = 28) which makes the continued availability of LAAM contingent upon

S215

Abstracts

counseling attendance and urinalysis results, or a noncontingent control condition (n = 26) where LAAM was continued regardless of these factors. Preliminary results for the first 6 months. of this 9month evaluation demonstrates comparable but poor retention rates in both conditions (similar to other published studies using LAAM). Counseling attendance rates were significantly higher for the behaviorally contingent condition, particularly for group sessions prescribed to enhance treatment. Opioid and cocaine use declined over time in both conditions; a nonsignificant trend toward greater reduction in cocaine use for the behaviorally contingent condition was evident. In summary, this model of treatment was successfully integrated into routine treatment using LAAM maintenance, and was associated with enhanced rates of counseling attendance. Supported by NIDA grant P50 DA 05273. 608 SENSITIZATION TYPY IS APPETITIVE PLACE PREFERENCE

OF MORPHINE-INDUCED STEREOAS DETERMINED BY CONDITIONED

H.R. Stone, C.M. Knapp, and C. Kornetsky, University School of Medicine, Boston, MA

Boston

Repeated high doses of morphine will elicit stereotypic biting behavior in rats and this biting behavior can be reexpressed at least 6 months later by the administration of a low dose of morphine. Also animals sensitized to high doses of morphine have marked changes in basal metabolic rate of glucose throughout forebrain structures as determined by the [C14]-2-deoxyglucose autoradiography. In order to determine whether the sensitization of this morphine-induced stereotypy was appetitive or aversive we employed the unbiased place preference procedure. Half of the rats were treated with four 10 mg/kg doses of morphine in 36 h, and half with saline on a similar injection schedule. Conditioning sessions commenced three days after the last morphine dose and half of each group received a conditioning dose of 2.0 mg/kg and half with 4.0 mg/kg. During these training sessions all the sensitized rats exhibited the stereotypic biting behavior. On choice days both groups has significant increases in preference at both doses with the sensitized group having a non-statistically significant greater preference. These findings indicate that the sensitization of the morphine-induced stereotypic biting behavior is appetitive suggesting that the effects observed in the metabolic studies may reflect neuronal changes that are related to craving. Supported by NIDA Grants K05-DA00099 and DA02326 to CK.

609 RANDOMIZED COMMUNITY TRIAL OF TWO FIRSTGRADEPREVENTIVEINTERVENTIONSANDTHEIRIMPACT ONTOBACCOSMOKING ONSET

C.L. Storr, N.S. Ialongo, and J.C. Anthony, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD One way to prevent tobacco smoking among children may be to change early developmental antecedents such as shy and aggressive behavior, concentration problems, and poor school achievement. This study estimates the effec:ts on early-onset smoking of two preventive interventions designed to reduce first grade risk behavior, in a sample of predominately African-American inner city youth. The randomized block design assigned teachers and 678 entering pupils to 27 first-grade classrooms, each classroom representing a family-school partnership (FSP) intervention, a separate classroom-centered (CC) intervention, or a control condition. Intervention effects on risk of smoking initiation were estimated via a Cox survival model for group-randomized data, with covariate adjustment. Follow-up to sixth grade showed 1.5% of the students had started smoking, with risk of smoking initiation greater in the control classroom. In a contrast of FSP and control youth, the estimated relative risk (RR) of smoking was 0.53 (95% CI, 0.30-0.94); in the CC-l.o-control contrast, the RR estimate was 0.96 (0.511.81). Subgroup analysis indicated FSP effects mainly limited to girls, especially white girls. FSP-associated risk reduction remained after holding constant variation attributable to imbalances in distribution of covariates such as birthyear; baseline levels of aggression, parental discipline, parental supervision, family history of tobacco use. ‘The FSP intervention seeks to improve early primary school performance and behavior via parent-teacher collaboration and by enhancing parents’ teaching and behavior management skills. This intervention might have a side-benefit in the realm of smoking prevention. ACKNOWLEDGMENTS: T32DA07292, RO 1DA 11796 and ROlMH57005. 610 TREATMENTFORALCOHOLANDNICOTINEDEPENDENCE:AREPATIENTSREADYTOQUITBOTH?

A. Stotts, J. Schmitz, H. Rhoades, A. Schuetz, and J. Grabowski, Substance Abuse Research Center, University Iof Texas-Houston, Houston, TX Numerous studies support a strong link between cigarette smoking and alcohol consumption, yet few substance abuse programs have intervened on both behaviors simultaneously. Recent research has indicated favo:rable responses to concurrent intervention for nicotine and substance dependence in inpatient treatment settings. Success in quitting smoking and drinking con-

S216

Abstracts

currently may depend on relative levels of readiness to change, self-efficacy and coping activity associated with each behavior. This study compared baseline variables related to quitting smoking and drinking in outpatients (N = 55) seeking dual-substance dependence treatment. It was hypothesized that patients’ motivation, processes (coping activites) and self-efficacy to change their smoking and drinking behavior would differ. Results indicated that dually-dependent patients reported differing levels of motivation for changing their alcohol vs. nicotine problem. Those who had higher motivation to change one behavior tended to have lower motivation to change the other. Also, patients reported higher levels of coping activity associated with their drinking problem as compared to their smoking, were more confident in their ability to abstain from drinking than smoking, and were more tempted to smoke than drink. While seeking treatment for both alcohol and nicotine dependence, patients were not equally motivated to change both behaviors. Overall, patients appeared more prepared to change their alcohol use than their nicotine use. AcKNOWLEDGEMENTS: Supported by NIAAA Grant AA11216-02. 611 BLOCKADEEFFECTSOFBUPRENORPHINE/NALOXONECOMBINATION TABLETINOPIOID-DEPENDENTVOLUNTEERS

E.C. Strain, S.L. Walsh, and G.E. Bigelow, Johns Hopkins University School of Medicine, Baltimore, MD Buprenorphine is being developed for opioid dependence treatment. A sublingual tablet combining buprenorphine with naloxone (BupNx) has been developed to decrease abuse potential. Large sublingual BupNx doses might deliver enough naloxone to alter opioid blockade. The purpose of this study was to assess blockade efficacy at different BupNx dose levels, and to characterize blockade efficacy 1 h after a dose of BupNx (expected peak naloxone effect) and 25 h after a dose of BupNx (naloxone effects expected to have dissipated). Participants (n = 6) lived on a research ward for the study’s duration and were maintained for weekly intervals on daily escalating doses of sublingual BupNx (4/l, 812, 16/ 4, 3218 mg, and then 1 week at 32/O mg). Laboratory test sessions consisted of hydromorphone challenges (12 mg i.m.) at each BupNx dose level. During sessions, physiological status was recorded continuously, and tasks assessing psychomotor, subjective and objective status were repeatedly performed. Results showed attenuation of hydromorphone response as maintenance dose of BupNx increased, although subjects did experience some opioid agonist-like response to hydromorphone challenges at all maintenance dose levels tested. There were minimal differences in blockade efficacy of BupNx at 1 versus 25 h after the maintenance dose. These results

show maintenance on sublingual BupNx doses as high as 32/8 mg per day provides partial but not complete blockade to the acute effects of 12 mg i.m. hydromorphone, and that the addition of naloxone does not alter blockade efficacy. Supported by ROl DA08045, K02 DA00332, and K05 DA00050. 612 THE VALIDITY OF SELF-REPORT AMONGDRUG USERS

OF HIV

STATUS

SM. Strauss, G.P. Falkin, and S. Deren, National Development and Research Institutes, Inc., New York, NY The validity of HIV status based on self-report has not yet been established despite the fact that many studies assess this status on the basis of self-report data. This paper examines the validity of self-reported HIV status in drug-using populations by conducting a secondary analysis of data collected the NIDA-funded Cooperative Agreement for AIDS Community-Based Outreach/Intervention Research Program. The analyses assesscriterionbased validity of self-reported HIV status for large samples of high-risk drug users in eight Cooperative Agreement cities (N - 10 000) that performed biological testing (the criterion measure) on virtually all the subjects. In these cities about 15% tested HIV seropositive. Overall, there is a high level of inaccuracy in self-report of HIV status among individuals who tested HIV positive: while 22% also self-reported that they were HIV positive; 34% self-reported an unknown HIV status; and 44% erroneously reported that they were HIV negative. This self-report may be invalid for a variety of reasons, including a lag in time between the collection of the self-report and biological test data. This paper examines the validity of self-report both for those who tested HIV positive and those who tested HIV negative for the sample as a whole, as well as for subgroups, including injection drug users, non-injection crack users, males, females, those who engage in sex exchange, and those who do not engage in sex exchange. The agreement between biological test results and self-report of HIV status is assessed using a variety of statistics, including percent agreement, Cohen’s kappa, sensitivity and specificity, and predictive power of the self-report. The results of these analyses are important in informing AIDS research concerning the strengths and limitations of the use of HIV status based on self-report in drug-using populations. 613

MATERNAL OPIATE ADDICTION, CHILD JUSTMENTANDSOCIODEMOCRAPHICRISK:UNTANGLING THEIR LINKS WITH PARENTING BEHAVIORS

MALAD-

N. Suchman and S. Luthar, Yale University School of Medicine, New Haven, CT, and Teachers College, Columbia University, New York, NY

s211

Abstracts

Although the problematic parenting practices of substance abusing mothers have been well-documented, little is known about the role of sociodemographic risk (SDR) (i.e. low SES, single and minority status, family size) and children’s maladjustment in their parenting behaviors. Our first aim in this study was to identify parenting problems associated with maternal substance abuse (MSA) versus CM and SDR. Based on extant parenting literature and an ecological model of parenting, we expected to find direct links between MSA and parental involvement, CM and limit setting, and SDR and restricted autonomy. A second aim of this study was to explore how SDR’s differentially confer disadvantage for methadone-maintained (MM) versus comparison mothers. A sample of 120 mothers (69 MM and 51 SES-matched comparison) were recruited from MM, primary care, and university settings. Mothers’ mean age was 35; the majority were single (52%) low SES (60%) minority (52%) and had, two children on average. Parenting behaviors were measured with Involvement (INV), Limit Setting (LIM), and Autonomy (AUT) scores derived from the Parent-Child Relationship Inventory (Gerard, 1994). Hierarchical regression results indicated direct links between MSA and lower INV (R- = O.lO**), CM and poorer LIM (R- = 0.44***), and SDR and restricted AUT (R_ = 0.16***). Conditional interaction effects explained additional unique variance in two parenting domains (INV R- = O.lO**, AUT R- = 0.15***); plots of significant interactions indicated that for methadone mothers, single parenthood conferred risk for INV, and having a partner and a small family conferred risk for AUT. Implications: (1) Parental discipline and control problems commonly associated with MSA may be more strongly associated with poverty and children’s maladaptive behavior; (2) parent training for MSA’s should target parental involvement; (3) some sociodemographic factors may unexpectedly confer “double jeopardy’ for parenting problems among MM mothers. (*P < 0.05, **P < 0.01, ***p< 0.001) Supported by NIDA Grants ROlDA11498 and P50DA09241. 614 PREDICTORSOFRETENTIONINBEHAVIORALNALTREXONETHERAPY

M.A. Sullivan, J.L. Rothenberg, S.H. Church, and E.V. Nunes, Columbia University College of Physicians and Surgeons/NY State Psychiatric Institute, New York, NY The goal of this Stage I project was to develop a behavioral therapy to improve the efficacy of naltrexone maintenance. Behavioral Naltrexone Therapy (BNT) is a 6-month therapy approach combining elements of several empirically tested treatments for opiate dependence, including Network Therapy, the Community

Reinforcement Approach, voucher-based contingency management, cognitive-behavioral Relapse Prevention Therapy, and Motivational Enhancement techniques. An uncontrolled pilot trial was conducted with 47 opiate-dependent participants to provide a preliminary evaluation of efficacy and to examine predictors of outcome. Measures of outcome included treatment retention (days to dropout), naltrexone compliance (percentage of doses taken), and abstinence from opiates (percentage of opiate-free urine samples). A hierarchical regression analysis was performed to determine the contribution of selected baseline variables to treatment retention. Severity of current opiate use and regular methadone use prior to detoxification were found to contribute significantly to premature attrition. As severity of opiate use and use of methadone increase, number of days to drop-out decreases (severity of drug use B = - 0.32, P < 0.05; methadone B = - 0.40,P < 0.01). When baseline measures of depression and ambivalence were examined in a hierarchical analysis, depressive symptoms approached significance (P = 0.09); as depressive symptoms increase, retention worsens (B = - 0.24, P = 0.09). Based on these findings, BNT was modified to address more directly severe depressive symptoms and methadone use at baseline. We are currently conducting a small randomized controlled clinical trial to test a refined BNT vs. a standard compliance enhancement approach. We will examine predictors of retention in this controlled trial and offer preliminary findings on the efficacy of BNT for the treatment of opiate dependence. 615 ARTERIOVENOUS COCAINE CONCENTRATION FERE:NCES IN PHARMACOKINETIC-PHARMACODYNAMIC MODELINGOFINTRAVENOUS COCAINE

L. Sun and C.E. Lau, Brunswick, NJ

Rutgers

University,

DIF-

New

Two groups of rats (N= 3) were implanted with dual catheters (jugular vein and femoral artery or femoral vein). Cocaine administration was performed via the jugular vein catheter, whereas blood samples were obtaine:d from either femoral artery (Group 1) or femoral vein (Group 2) catheter. The pharmacokinetics (PK) of cocaine following a bolus dose (2 mg/kg) as well as a 2-h infusion (0.0245 mg/min) was characterized. Significant arteriovenous concentration differences were observed for cocaine. Serum steady state cocaine concentrations (Css) from arterial and venous blood were reached at 6 and 22 min, respectively. In addition, the arterial cocaine Css level (0.189 ug/ml) was found to be significantly higher than venous Css level (0.123 ug/ml). Values for the volume of distribution and mean residence time determined from Group 2 were significantly greater than those from Group 1. Parallel pharmacodynamics (PD) was also conducted to investigate

S218

Abstracts

arteriovenous cocaine concentration-effect relations under a DRL 45-s schedule in 3-h sessions. Changes in the two behavioral measures (shorter-response rate and the reinforcement rate) directly corresponded to functions of cocaine concentration within the respective hypothetical effect compartments using the effect-link stimulatory and inhibitory sigmoidal Emax models, respectively. The half-life of equilibration (t 1/2,eo) between arterial blood and effect compartment is longer than that between venous blood and its effect compartment, indicating the existence of an arteriovenous equilibrium delay. Despite the significant arteriovenous concentration differences, effect-time profiles for each behavioral measure predicted from arterial and venous CTPs approximated each other with the use of effectlink PD models. ACKNOWLEDGEMENTS: Supported by NIDA Grant ROl DA05305. 616

CLINICAL

INCENTIVE DENT

EFFICACY PROGRAMS

OF FOR

ALTERNATIVE PREGNANT

VOUCHER DRUG-DEPEN-

WOMEN

D. Svikis, K. Silverman, N. Haug, H. Jones, R. Mejia and M. Stitzer, Virginia Commonwealth University, Richmond, VA As managed care continues to impact substance abuse treatment services. clinical and economic efficacy as well as practical applicability of behavioral voucher incentive programs are of utmost concern. The present study compares the use of constant and escalating voucher incentives to achieve opiate and cocaine abstinence, in methadone-maintained pregnant drug dependent women. Subjects were predominantly African American single women in their late 20s with less than a high school education. To date, 14 women have been randomly assigned to either the escalating (EV, N = 8) or constant (CV, N = 6) voucher incentive regimens and have participated for at least 10 weeks prior to delivery. Urine drug toxicologies were performed three times per week for a total of 30 opportunities for voucher dispensation. Women in the CV group received $25 for each opiate and cocaine negative drug toxicology. Women in the EV group received $7.50 for the first negative toxicology, and this amount was increased by $1 for each subsequent drug negative result. However, if drug use occurred, the value of the incentive was reset to the initial $7.50. Preliminary analyses suggest the EV schedule is more effective than the CV schedule. Specifically, drug abstinence (three consecutive drug negative urines) was achieved on 7.5 of the 10 weeks for EV patients compared to 5.8 weeks for CV patients. The longest continuous period of abstinence was also longer for EV (7.0 weeks) compared to CV (4.6 weeks) subjects. Interestingly, EV subjects also had better treatment attendance during the initial 5 weeks

of the contingency CV subjects (mean sample size for this contingency group pare maternal and groups. This research was 617 THE

period (mean 27 h per week) than 21 h per week) (P < 0.042). Final study is estimated at 12 subjects per and additional analyses will cominfant birth outcomes for the two supported

PRETREATMENT EXPRESSION

TIZATION:

WITH OF

by Grant IBOGA

AGENTS

DRUG-INDUCED

IMPLICATIONS

FOR

# DA 12403. BLOCKS

DOPAMINE THEIR

SENSI-

ANTI-ADDICTIVE

EFFICACY

K.K. Szumlinski, I.M. Maisonneuve, and SD. Glick, Albany Medical College, Albany, NY The repeated, intermittent administration of psychomotor stimulants and opiates can cause a progressive increase in the dopamine (DA) response to these drugs. Termed sensitization, this phenomenon has been implicated in the development of compulsive drug-seeking and craving in drug addiction (e.g. Robinson and Berridge, 1993). Consistent with this implication, pretreatment with the putative anti-addictive agent, ibogaine (IBO), produces a greater decrease in the accumbal dopamine (DA) response to morphine (MOR) in MOR-experienced, versus - ndive, rats (Pearl et al., 1996). The present study extended these findings by demonstrating that the synthetic iboga alkaloid congener, l%methoxycoronaridine (18-MC; 40 mg/ kg, 19 h earlier), abolishes the sensitized DA response in the NAC to MOR (20 mg/kg) in chronic MORtreated (5 x 20 mg/kg) rats. In addition, both IBO and l&MC (both at 40 mg/kg, 19 h earlier) abolished the sensitized DA response in the NAC to cocaine (COC; 20 mg/kg) in rats treated chronically with COC (5 x 15 mg/kg). As the results of these microdialysis studies are consistent with the ability of iboga agents to decrease MOR and COC self-administration, it is suggested that the anti-addictive efficacy of iboga agents is related to their ability to reset or reverse the neuroadaptations in the mesolimbic system produced by the chronic administration of drugs of abuse. 618 MDMA

SUBJECTIVE AND

MCPP

AND COMPARED

REINFORCING TO

EFFECTS D-AMPHETAMINE

OF IN

HUMANS

M.E. Tancer and C.E. Johanson, Wayne State University School of Medicine, Detroit, MI Conventional wisdom suggests that positive subjective effects and reinforcing properties of drugs are mediated, in large part, by dopamine (DA) systems. In order to directly test this notion, we have compared three drugs which differ in their DA effects: D-amphetamine, a

S219

Abstracts

prototypical DA releaser; mCPP a relatively specific serotonin (5-HT) releaser and 3,4-Methylenedioxymethamphetamine (MDMA) a substituted amphetamine which also releases 5-HT. After giving informed consent, 12 volunteers who are all experienced MDMA users: participated in an eight-session experiment. During the first seven 6-h sessions, subjects received either MDMA (1 or 2 mg/kg); mCPP (0.5 mg/70 kg or 0.75 mg/kg); amphetamine (10 or 20 mg); or placebo under double-blind conditions in a balanced order. The eighth session was a lottery session in which subjects received either money or drug depending on their responses to the multiple choice procedure (MCP). Al. baseline and hourly, the following parameters were obtained: temperature, heart rate and blood pressure, POMS, ARCI, visual analogue scales, and the Hallucinogen Rating Scale. Blood and saliva samples were obtained to measure prolactin and cortisol, respectively. An end of session questionnaire was also completed at 6 h as well as the MCP. Preliminary analyses indicate: (1) MDMA can be safely administered in a controlled laboratory setting; (2) MDMA causes profound physiological arousal; and (3) the three drugs each produce a distinct pattern of subjective effects. This project is supported by NIDA grant K08 DA00370-01 and Joe Young Jr. Research Funds from the State of Michigan. 619

PERSISTENT

TION

BEHAVIOR

DROCANNABINOL

HIGH-RATE MAINTAINED (THC)

IN

I.V.

SELF-ADMINISTRA-

BY

DELTA-PTETRAHY-

SQUIRREL

MONKEYS

G. Tanda, P. Munzar, and S.R. Goldberg, NIDA, Baltimore, MD; Georgetown University School of Medicine, Washington, DC, and University of Cagliari, Italy Important discoveries in the cannabinoid field over the past several years have contributed to a better understanding of the pharmacology of cannabinoids and to an increasing interest in the potential therapeutic efficacy of cannabinoids in memory, cognition, analgesic, stimulation of appetite and reversion of emesis effects. On the other hand Cannabis remains the most abused illicit drug in the world in its different preparations. In spite of its well-established abuse properties documented in humans, our knowledge of the abuse liability of cannabis and the reinforcing properties of its psychoactive constituent THC in animals is still lacking. In the present experiments, active self-administration behavior at high rates of responding was consistently maintained in squirrel monkeys by intravenous injections of the main active ingredient of cannabis, THC, over a wide range of doses (O.OOl-0.008 mg/kg/injection) using a fixed-ratio 10,

time-out 60 s, schedule of reinforcement. This behavior was estinguished by presession treatment with SR141716A (0.3 mg/kg, i.m.), a potent and selective antagonist of CBl cannabinoid receptors. SR141716A (0.3 rng/kg, i.m.) did not alter cocaine self-administration in a control group of monkeys self-administering i.v. cocaine (0.03 mg/kg per injection) under the same conditions. Thus the reinforcing effect of THC on self-a’dministration behavior can be attributed to its direct action on cannabinoid CBl receptors. The availability of this methodology provides an exciting oppo:rtunity for studying not only the reinforcing effects of cannabinoids but, also, the neuropharmacological mechanisms involved in such cannabinoid self-a’dministration behavior. 620 TAL

HIV

SEROPREVALENCE

ACCIDENTAL

DRUG

AMONG OVERDOSE

VICTIMS IN

NEW

YORK

OF

FACITY:

1991-:199s

K. Tardiff, P.M. Marzuk, A.C. Leon, and L. Portera, Weill Medical College of Cornell University, New York, NY This is a descriptive epidemiological survey of all persons over 15 years age (N = 6693) who died of accidental fatal drug overdoses in New York City during 199 lo- 1998. Using medical examiner data, chi-square and logistic regression analyses were conducted. Overall, 28% of persons who overdosed were HIV positive (HIV + ). There were no statistically significant differences by year and the rate of HIV positivity. Women (36%) were more likely than men (26%) to be HIV + African Americans (38%) and Latinos (28%) were more likely than whites (16%) or Asian/others (7%) to be HIV + . Victim’s 35-44 years of age (37%) and 45-54 years of age (31%) had the highest HIV+ rates. The highest rate of HIV positivity (34%) was among persons dying of a combination of cocaine and opiates, followed by opiates alone (26O/o) and cocaine alone (24%). Persons dying from drugs other than opiates and/or cocaine had the lowest HIV positive rate (10%). These finding have policy implications for the prevention of HIV. HIV + rates have not changed from 1991 to 1998. Cocaine as well as opiate use is associated with increased risk of HIV infection. Women had high HIV + rates, probably because of risky sex as well as risky drug practices. AfricanAmerican and Latin0 overdose victims had high HIV-t rates probably due to lack of access to AIDS education and prevention programs. Drug education and ‘reatment and harm reduction should be intensified and targeted especially at minorities, women’s sex behaviors, the young and at use of cocaine as well as opiates.

s220

621

Abstracts

EFFECTS OF COCAINE ON TUMORIGENICITY CYTOKINEPRODUCTIONINAMURINEMODELOFLUNG CANCER

AND

D.P. Tashkin, L. Zhu, S. Sharma, M. Stolina, B. Gardner, M. Roth, G. Baldwin, and S. Dubinett, UCLA School of Medicine, Los Angeles, CA Since cocaine can cause immune alterations in a wide variety of lymphocytes, we hypothesized that cocaine might enhance tumorigenicity in a murine model of lung cancer through disruption of cell-mediated antitumor immunity. Methods: Cells from a Line 1 alveolar cell carcinoma (Ll C2) were implanted S.C.into pathogen-free BALB/C mice 8 12 weeks of age (n = 24), followed by daily administration of 5 mg /kg cocaine in 1 ml saline (n = 12) or saline alone (n = 12) via i.p. injection. Tumor growth was monitored by serial measurements of tumor volume. On the 15th day following implantation, non-necrotic tumors were excised. Assays for TGF-b, IL-10 and PGE2 were performed by ELISA in supernatants from 24 h culture tumor homogenates. In addition, splenic T cells were isolated in cocaine and vehicle-treated BALB/ C mice with or without LIC2 tumors (6 mice per group). After depletion of RBC, B-cells and macrophages, splenocytes were stained with fluorochrome-conjugated antibodies specific for CD4 and for intracellular IL-2 and IFN-g and analyzed by flow cytometry. Results: Beginning y 10 days after tumor implantation, tumor growth accelerated in the cocaine-treated mice compared to the vehicle-treated controls (2200 + 500 [SD] mm 2 vs. 600 + 300 mm 2 at 26 days; P < 0.01). Tumor homogenates from cocaine-treated mice, compared to those from control mice, revealed significantly higher levels of IL- 10 (129 f 20 vs. 73 -t 17 pg/ml/500 mg tumor), TGF-b (4.35 k 0.3 vs. 2.90 i 0.30 rig/ml/500 mg tumor) and PGE2 (33.1 I4.3 vs. 20 &- 0.6 rig/ml/g tumor) (P < 0.05). In non-tumor-bearing mice, cocaine reduced the frequency of CD4 T cells secreting IL-2 (from 11 to 3%) and INF-g (from 13 to 5%) to a level similar to that of the tumor-bearing mice (1 and 3%, respectively). Conclusions: These results suggest that cocaine increases production of immunosuppressive cytokines at the tumor site and, at the same time, down-regulates Thl cytokine networks, thus impairing development of anti-tumor immunity and predisposing to tumor cell growth. Supported by NIDA/NIH grant no. ROl DA 98254. 622 THYROID ACIDANDVITAMIN

FUNCTION, SERUM PROTEINS, FOLIC B-n VALUESOFSUBSTANCEABUSERS

K.Tate, R.I. Herning, W.E. Better, and J.L. Cadet, National Institute on Drug Abuse, National Institutes of Health. Baltimore, MD Little systematic data has been reported concerning blood levels of various diagnostic biological markers in

drug abusers. Thus, we accessed diagnostic biological markers in cocaine abusers (n = 34), cocaine and alcohol abusers (n = 32), poly-substance abusers (n = 38) methadone patients (n = 27): heroin abusers (n = 8) and marijuana abusers(n = 7) as well as in control subjects (n = 41) to determine if any abnormalities existed in substance abusers. Plasma values for thyroid function, serum proteins, folic acid and vitamin B-12 were obtained via a routine blood draw and analyzed by standard medical laboratory. For thyroid function, T4 was significantly higher and T3 uptake was significantly lower for the heroin and methadone groups compared to the control and other substance abusing groups. TSH was lowest for the poly-substance group. Albumin levels were significantly lower in heroin, poly-substance and methadone groups in comparison to other groups. In addition, opiate using individuals had higher levels of crl- and y-globulins than the non-opiate abusing groups. The heroin, methadone and marijuana group had significantly higher levels of folic acid and vitamin B-12. These data will be discussed in terms of their possible clinical importance in the long term medical treatment of these populations. 623 THE RELATIONOFPROBATIONARYINVOLVEMENT AND RACE TO ADOLESCENT REPORTING OF CANNABIS USE,ABUSEAND DEPENDENCE

Z. Tawfik, C. Webb, A.H. Woodard, J. Burleson, and A. Woodard, Alcohol Research Center, University of Connecticut Health Center, Farmington, CT Although considerable evidence suggests that clients in substance abuse treatment are reliable reporters of their use and subsequent symptoms, there is little evidence to counter the assumption that justice involvement does have an impact on client reporting. In this poster, the investigator will test the main effect of having a probationary officer on cannabis use and symptom reporting by adolescents referred for outpatient treatment of a cannabis disorder. Following said analysis, probation main effects will be tested in interaction with race on the assumption that report by certain minorities will be more heavily biased by justice involvement. Analysis will be based on 1069 adolescent cases screened for eligibility to participate in the Cannabis Youth Treatment (CYT) Study as well as the 600 cases ultimately admitted for the study. 624 INTRACTABLE PAIN IS A SEVERE STRESS STATE ASSOCIATEDWITHHYPERCORTISOLEMIAANDREDUCED ADRENALRESERVE

F. Tennant, Veract, Inc., West Covina, CA Intractable pain (IP) is defined in this study as “pain which is excruciating, constant, incurable, and such

s221

Abstracts

severity that it dominates virtually every conscious moment, produces mental and physical debilitation, and may produce a desire to commit suicide for the sole purpose of stopping the pain”. Fourteen adults who met this definition were evaluated to determine if their IP state produced cortisol abnormalities which were indicative of chronic, severe stress. Between 8 and 10 h a serum cortisol determination was done followed by 0.25 mg of cosyntropin given intramuscularly. Followup serum cortisol reserve was considered to be at least doubling of the baseline concentration. Three normal adults served as controls, and all three demonstrated a serum cortisol concentration between 5 and 10 ug/dl with more than a doubling from baseline after cosyntropin administration. Baseline cortisol concentrations ranged from 0.96 to 54.4 with a mean of 17.6 ug/dl. Four of the 14 (28.6%) had high baseline cortisol concentrations over 25.0 ug/dl, and a total of 9 (64.4%) had concentrations above 10 ugjdl. One (7.1%) subject demonstrated almost a negligible cortisol concentration (0.96 ug/dl) and 2 (14.3%) did not show adequate cortisol reserve following cosyntropin. Abnormal cortisol concentrations returned to normal range (5-25 ug/dl) following treatment with a long-acting opioid. This study indicates that intractable pain is an extended stress state which may induce hypercortisolemia, reduced adrenal reserve, and clinical complications associated with these abnormalities. 625 STRUCTURAL FEATURES CRITICAL To 0pIoID s RECEPTOR SELECTIVITY AND AGONIST EFFICACY ARE REVEALED IN SAR STUDIES OF 4-[(N-SUBSTITUTED-C PIPERlDINYL)-ARYLAMINOI-N,N-DIETHYLBENZAMIDES J.B. Thomas, R.B. Rothman, X.M. Herault, R.N. Atkinson, J.P. Burgess, S.W. Mascarella, CM. Dersch, H. Xu, K. McCullough, and F.I. Carroll, Research Triangle Institute, Research Triangle Park, NC, and NIDA Addiction Research Center, Baltimore, MD We recently reported that ( + )-4-[(N-allyl-cis-3-methyl4-piperidinyl) phenyl- amino]-N,N-diethylbenzamide has good affinity and selectivity for the d opioid receptor. In this report we disclose our findings from an extensive SAR investigation of compounds in this series. In this study it was determined that the binding affinity, receptor selectivity, and efficacy of compounds in this series are dramatically influenced by changes to the nitrogen (Rl) and aryl substituents (R4). Other important structural features found to influence overall ligand affinity and selectivity were mono versus dimethyl substitution and the relative stereo-chemistry for substituents in the 3 and 4 positions of the piperidine ring. Details of this study and comparison to the prototypical non-peptide &opioid receptor ligands, BW373U86 and SNC-80, will be provided as well as a

discussion of implications receptor ligands.

for design of new &opioid

626 ASSOCIATIONS AMONG ADHD, CONDUCT DISORDER, EXECUTIVE COGNITIVE FUNCTIONING, AND SUBSTANCEUSE SEVERITY IN ADOLESCENTS L.L. Thompson, S.K. Mikulich, S.K. Hall, and T.J. Crowley, University of Colorado Health Sciences Center, Denver, CO Adolescents with substance use disorders (SUD) often present with comorbid psychiatric disorders that may be associated with executive function (EF) deficits (problems with planning, organizing, impulse control, attention, etc.). These adolescents may be at risk for more severe and persistent SUD. EF deficits have been found in youths with attention deficit hyperactivity disorder (ADHD) and in youths with ADHD and conduct disorder (CD), but not in youths with CD alone. This study explored the relationships of CD, ADHD, EF, and SD in a sample of 140 male and female adolescents who either were in treatment for substance and behavior problems or who were demographically similar comparison subjects. Data were obtained from the adolescents, their parents, and teachers through structured interviews and questionnaires as well a.sfrom activity level monitoring and neuropsychological testing, and ratings from experimenters. Measures of SUD and CD severity involved symptom counts, while ADHD severity was a score derived from factor analysis of multiple measures. Bivariate correlations revealed strong associations between SUD and both ADHD and CD, while ADHD appeared more strongly correlated with EF measures than did either SUD or CD. Multiple regression analyses were performed; after adjusting for the effects of CD, SUD, and Full Scale IQ, ADHD was still significantly associated with several EF measures (R2 ranged from 0.09 to 0.31). Furthermore, in the presence of ADHD and IQ, CD and SUD were seldom significantly related to EF. These results suggest that EF deficits in these youths with multiple problems are specifically related to ADHD symptoms. The relationships of ADHD and EF deficits to the treatment and prognosis of SUD will be discussed. 627 GENDERDIFFERENCESINTHESEVERITYANDPATTERNS OF VICTIMIZATION AMONG ADOLESCENTS TREATED FOR SUBSTANCE ABUSE: INTAKE STATUS AND OUTC'DMES J.C. Titus, W.L. White, M. Dennis, and C.K. Scott, Chestnut Health Systems, Bloomington and Chicago, IL

Abstracts

s222

The relationship of victimization to substance use and related factors was examined for 214 adolescents (82 girls, 132 boys) entering substance abuse treatment (28 outpatient, 186 inpatient). A General Victimization Index (GVI) was defined from 15 items on lifetime traumatic events (physical, sexual, and emotional abuse), characteristics of traumatic events (age of onset, duration of abuse, number of perpetrators, relationship of perpetrator(s) to adolescent, fear for life, degree of boundary invasion, response to disclosure of abuse), and current worries about traumatic events. The items appear to fall along a common underlying dimension of trauma severity (coefficient CL= 0.88 for the GVI), and evidence was generated to validate previously proposed cut-points for low, medium, and high-severity trauma. Significantly more girls than boys reported higherseverity items related to sexual abuse. When used as grouping variables, gender and severity of victimization significantly interacted with measures of intake status, including patterns of substance use, substance disorders, violence, and psychiatric co-morbidity. They were also significant predictors of 3-month post-discharge treatment outcomes. 628 PREDICTORS OUT IN PREGNANT

OF PREMATURE TREATMENT DRUG-DEPENDENTWOMEN

DROP-

G.Q. Tran, M.L. Stitzer, H.E. Jones, J.J. Israel, and D.S. Svikis, Johns Hopkins University School of Medicine, Baltimore, MD The present study prospectively examined substance use, psychiatric severity, and motivation-related variables as predictors of pregnant drug-dependent women’s premature termination of abstinence-based residential treatment. Sample consisted of 37 (66%) residential treatment completers and 19 (34%) dropouts who terminated treatment against medical advice. Patients typically completed assessment within the first 2 days of treatment. Results indicated that substance use and psychiatric severity at treatment admission and during the month before admission predicted residential treatment drop-out. Specifically, patients who left treatment against medical advice (AMAs) spent more time using heroin/cocaine and being high on the day before admission than those who completed the 7-day treatment. Compared to completers AMAs also reported more frequent use of heroin and less frequent use of cocaine and alcohol during the month before treatment. AMAs were less likely to be psychiatrically distressed during the month before admission. However, AMAs reported more depressive symptoms during residential treatment than completers did. Group differences were not found on the women’s readiness to change and self-efficacy related to their heroin/cocaine use. Results suggest that clear behavioral predictors are available

that could be used to trigger more intensive early intervention for women at risk of treatment drop-out. 629 PEER MENTORING HIV-AFFECTED FAMILIES

FOR EARLY

ADOLESCENTS

IN

J. Truell, Y. McCombs, S. Magura, A. Rosenblum, and C. Norwood, National Development and Research Institutes and Health Force, New York, NY The evaluation of a peer mentoring program for young adolescents at risk for HIV and substance abuse is described and pilot data are presented. This program, which is operated by an inner-city community-based AIDS outreach organization, relies on trained older adolescents to function as peer mentors for younger mentees. Under adult supervision, peer mentors: (1) co-acilitate support groups for mentees; (2) arrange and conduct weekend excursions and activities; and (3) provide guidance, advice and support to mentees throughout the week via individual and informal contacts. Study subjects (lo-15-year-old youths with HIVill parents) are being randomly assigned to the peer mentoring program (N= 80) or to the agency’s regular services (counseling plus referrals) (N = 80). The primary behavioral outcome variables are preventionreduction of drug/alcohol use, HIV risk behaviors, delinquent behaviors and increase in prosocial activities. Pilot outcome data indicated that 86% (37143) of mentored youths from disadvantaged, inner city families were clinically judged to have functionally improved during up to 1 year of program participation. Participation of the peer mentors was fairly stable, with 75% (12/16) having been in the program between 2 and 3 years at the time of the pilot. It is imperative to develop practical models of community support for these youths. There is very little experience or research with intragenerational mentoring models. Supported by grant No R01 HD37350-1 from the National Institute on Child Health and Human Development NICHHD. 630 THE CUMULATIVE LEVEL OF COCAINE AS A NOVEL METHOD FOR THE ANALYSIS OF DRUG SELF-ADMINISTRATION STUDIES V.L. Tsibulsky and A.B. Norman, University Cincinnati College of Medicine, Cincinnati, OH

of

We have recently proposed a quantitative pharmacological model of cocaine self-administration that states that the time between self-administrations (T) = ln( 1 + DU/DST).t1/2/0.693 where DU is the cocaine unit dose, DST is the minimum maintained level of cocaine and t1/2 is the cocaine elimination half-life (Brain Research 839:85-93, 1999). Therefore, the cocaine level in

S223

Abstracts

the body appears fundamental in the regulation of responding for drugs. We have generated a program that calculates the cumulative levels of cocaine at the time of each lever press during a self-administration session. These calculated levels are then presented graphically. These analyses demonstrate that the cocaine levels rise rapidly following reinstatement, corresponding to the drug-loading phase of a session. Approximately lo-15 min after reinstatement, the inter-injection intervals abruptly become longer, but remain regular. During maintenance the calculated cocaine levels at the initiation of each injection are observed to remain constant, at all unit doses, if the t 11’2 of cocaine is assumed to be approximately 7- 12 min. Extinction responding in relation to the declining cocaine levels can also be observed. These analyses are consistent with self-administration behavior occurring only when cocaine levels are at or below a satiety threshold. Supported by DA 12043. 631 DETAILED BEHAVIORAL RISK ASSESSMENTS DISCRIMINATE BETWEEN GAY/BISEXUAL HIV-INFECTED AND HIV-NON-INFECTED METHAMPHETAMINEABUSERS IN Los ANGELES

G. Twitchell, S. Shoptaw, A. Huber, C. Reback, V. Gulati, and T. Freese, UCLA Drug Abuse Research Center, Friends Research Institute, Van Ness Recovery House, Los Angeles, CA Over the past 20 years investigators have focused on refining the accuracy of methods for assessing high-risk behaviors for HIV transmission. One concern is that HIV risk measures are either broad, covering a wide range of risk behaviors over long periods of time, or narrow, assessing a few specific behaviors over a short period of time. Our objective was to compare two measures of HIV-related risk behaviors, one a standardized general measure (Risk Assessment BatteryRAB) and the other a recently developed behaviorally-detailed measure (Behavioral Questionnaire Assessment-BQA), in three samples of methamphetamine dependent individuals in drug treatment in Los Angeles (76 gay/bisexual men, 57 heterosexual men, and 33 heterosexual women). The RAB total risk score showed a stepwise differentiation in risk levels, with gay/bisexual men scoring at significantly higher risk (F(2, 165) = 17.91, P < 0.001; M= 9.64, SD = 3.93) than either heterosexual men (M = 5.96, SD = 4.35) or women (M = 5.73, SD = 3.73). However, the RAB total risk score failed to discriminate between HIV infected and HIVnon-infected gay/bisexual men. In contrast, the behaviorally specific BQA demonstrated the ability to discriminate between HIV infected and HIV non-infected gay/bisexual men as measured by a significant

difference in number of instances of unprotected anal receptive intercourse with partner ejaculation (t = 2.79, df = 68.84, P < 0.01; HIV infected, M= 5.45, SD = 8.67; HIVnon-infected, A4 = 1.38, SD = 3.89). Our findings provide empirical support to guide clinicians and researchers in the selection of measures of HIV risk. Data suggest that general measures, e.g. RAB, have utility for describing broad risk across heterogeneous groups of substance users. More detailed measures are necessary for distinguishing differences among high-risk populations such as substance abusing gay/bisexual men. This work was supported by NIDA grant # 1 ROl DA11031 & # 1 ROl DA10923. 632 A FUNCTIONAL MAGNETIC RESONANCE IMAGING STUDY OF THE EFFECT OF AMPHETAMINE ON BRAIN ACTIVITY

S.J. Uftring, S.R. Wachtel, D.N. Levin, and H. de Wit, University of Chicago, Chicago, IL Although there is an ever-increasing amount of research using functional magnetic resonance imaging (fMR.1) to study brain activation associated with sensory, motor, and cognitive processes, few reports have examined the effects of psychoactive drugs on brain activation related to these processes. In this study, fMRI[ was used to evaluate the effects of D-amphetamine on brain activation elicited by an auditory task and a simple motor task. Four healthy male volunteers (2 right-hand dominant, 2 left-hand dominant), participated in double-blind crossover design. Each subject served as his own control, receiving either placebo or D-amphetamine (20 mg), orally in capsules, on two separate occasions at least 1 week apart. Two hours after ingesting the drug, the subjects underwent a series of fMR1 scans (T2*echo-planar imaging) while performing an auditory vigilance task and while performing a sequential finger-tapping task. D-Amphetamine augmented the volume of brain activation in both left and right primary auditory cortex during the auditory vigilance task and produced a similar trend in contr
ACTION:

G.R. Uhl, S. Hall, I. Sora, F. Xu, and D.L. Murphy, NIDA, NIMH, IRP, NIH, Baltimore, MD

S224

Abstracts

Cocaine blocks uptake by neuronal plasma membrane transporters for dopamine (DAT), serotonin (SERT) and norepinephrine (NET). DAT blockade has been most linked to cocaine reward. We have examined cocaine reward in mice with knockouts of DAT, of SERT or of NET, largely by conditioned place preference. None reduces cocaine reward. Indeed, cocaine reward is enhanced in mice with SERT and NET knockouts. High doses of the SERT-selective blocker fluoxetine and the NET-specific blocker nisoxetine each gain rewarding properties in DAT knockouts. We discuss the current state of information concerning the molecular mechanisms of cocaine reward in light of these data, and initial data from combined transporter and transporter/receptor knockout mice. Each of these observations points toward cocaine as a dirty drug. 634 MDL

NEW 100907,A

CHEMICAL

AND

HIGHLY

BIOLOGICAL

SELECTIVE

STUDIES

SEROTONIN

ON

s-HTzA

ANTAGONIST

T. Ullrich, W. Fantegrossi, L.R. McMahon, K.A. Cunningham, J.H. Woods, and K.C. Rice, NIH, Bethesda, MD, University of Texas Medical Branch, Galveston, TX, and University of Michigan, Ann Arbor, MI MDL 100907 (1) has been reported to be effective in the treatment of a variety of disease states, e.g. psychotic illnesses, related to its selective 5-HT2A antagonizing properties. Furthermore, MDL 100907 is subject to investigation of self-administration behavior related to several drugs of abuse. Following a method developed independently by our group and Hoechst Marion Roussel, we synthesized the racemic N-nor-derivative (rat-2) and resolved this material in order to provide the option of obtaining both enantiomers through fractional crystallization and to introduce any desired substituents R’. We also developed parallel methodology to provide phenolic material (3), a precursor for an llClabelled PET-ligand. Pharmacological studies are currently in progress. and results will be presented. 635

STAGES

AND

COCAINE

OF

CHANGE

USERS

(URICA)

ENTERING

AMONG

METHADONE

HEROIN TREAT-

MENTRESEARCH

A. Umbricht, D.H. Epstein, W.E. Hawkins, and K.L. Preston, NIDA Intramural Research Program, Baltimore, MD URICA (Prochaska and DiClemente), a 32-item questionnaire, measures stages of changes for altering harmful behaviors. The five identified stages changes are precontemplation, preparation, contemplation, action and maintenance. URICA was initially developed to describe and measure readiness to quit in smokers and

predict success in smoking cessation; it was later adapted to other areas of behavioral medicine. This study evaluates whether the properties of URICA are replicable among heroin and cocaine users applying for drug abuse treatment. Participants (N = 18.5; mean age: 39 & 7; AA: 70%; M: 56%) were methadone maintenance patients who were randomized in a clinical trial to receive contingency management [CM] and/or coping skills training. They answered the URICA at intake, and at week 6, 12, and 18 of the methadone research program. At intake, URICA profiles were clustered into four of the five clusters previously described in treatment-seeking alcoholics: Precontemplators (PC: n = 14) Contemplators (C: n = 68) Participators (Pa: y1= 50) and Ambivalents (Am: n = 53). URICA clusters did not differ by demorgraphic or treatment characteristics. Mean T scores for each subscale for the whole group or by cluster were similar to those found by others. URICA clusters at intake did not predict cocaine (nor heroin) use later in treatment. URICA clusters correlated only with two of many intake psychological variabies. Conclusion: Although URICA clusters seem replicable among heroin-dependent cocaine users, they were not useful for predicting treatment outcome. 636

DOPAMINERGIC

WITH

ALCOHOL

CHALLENGE

IN

ADOLESCENTS

ABUSE

H.P. Upadhyaya, K.T. Brady, G. Sethuraman, F.R. Sallee, and M. Wharton, Medical University of South Carolina, Charleston, SC and University of Cincinnati, Cincinnati, OH There is a lack of neurobiological research relating to adolescent substance abuse. Our objective was to study the dopaminergic system in adolescents with alcohol abuse (ALC) vs. controls (CONT). We hypothesized that adolescents with alcohol abuse will have an exaggerated neuroendocrine response to a dopaminergic challenge as compared to controls. We recruited 12 controls and 11 subjects for the study. Methylphenidate (10 mg) was administered on Day 1. All subjects complete a visual analog mood scale (VAMS) at 1, 0, 1, 2, 3 h post methylphenidate. On Day 2, pergolide (50 mcg) is administered and VAMS obtained at -- 1, 0, 1,2,4, 6, and 8 h. Blood pressure and pulse were monitored and blood samples drawn [for plasma prolactin (PRL) and growth hormone (GH) assays] as per the above-mentioned time points. Growth hormone (GH) levels were drawn 15 min prior and every 1.5 min for 2 h post medication. Our analysis to date shows that plasma GH levels were significantly lower after methylphenidate in the ALC group vs. CONT. The ALC group tended to be less ‘Alert’ and less ‘Happy’ vs. CONT (not significant). Pergolide caused the ex-

s225

Abstracts

petted changes in the plasma PRL and GH levels, which were not significantly different between the ALC and CONT groups. Above results may indicate possible differences between alcohol abusing and non-abusing adolescents. Results from more detailed analysis will be presented. 637

GENDER

CIGARETTE THAN

DIFFERENCES SMOKING:

GIRLS

IN ARE

SUSCEPTIBILITY MORE

TO

RESPONSIVE

BOYS

C.V. Valdez, F.G. Castro, and J. Brook, Arizona State University, Tempe, AZ, and Mt. Sinai Medical Center, New York, NY This research examined gender differences in the social influence of significant others (parents, older siblings, best friend) on youth smoking behavior. The study will examine a developmental psychosocial model whereby gender, age, and ethnic identity of the youth will predict to what extent parents and peers influence his/her level of smoking as moderated by the strength of the respective attachments. Preliminary analyses support the idea that the model of influence will differ for males and females. A multiethnic sample of approximately 3171 youth (3rd-8th graders in the greater Phoenix area) participated in a culturally-oriented tobacco prevention program which sought to improve youth knowledge, beliefs, and attitudes about tobacco. These youths completed pre-program and post-program surveys about their smoking behaviors, attitudes, and beliefs, and which also investigated such constructs as ethnic identity and self-efficacy. Preliminary descriptive analyses (x2 analyses) of 6-8th grade youths (N= 1717) suggest that within this age group, girls, relative to boys, exhibited a stronger social influence effect, especially as these girls were influenced by best friend, older brother, and older sister. Specifically, higher concordance rates of cigarette smoking between the youth and significant others (i.e. mother, father, older sister, older brother, and best friend) were observed for girls relative to those observed for boys. While all relationships were significant for both boys and girls, these results suggest that youth susceptibility to social influence is particularly significant for girls. This further suggests that effective tobacco prevention programs delivered to young girls may need to offer an additional focus on this apparent. greater susceptibility to smoking behavior among young girls. Additional analyses will be conducted to evaluate the stability of these initial effects across age and ethnic identity. These analyses will include multivariate analyses, e.g. regression analyses that test specific social influence models on the differential effects of social influence for smoking among young girls as compared with young boys.

638

THE

EFFECTS ERGIC

COCAINE-LIKE OF VENLAFAXINE

AND

SEROTONERGIC

DISCRIMINATIVE ARE

MEDIATED

STIMULUS BY DOPAMIN-

MECHANISMS

E.M. Valencia and K.M. Kantak, Boston, MA

Boston University,

Venlafaxine is a dual action antidepressant drug with a high affinity for the 5-HT transporter, a slightly lesser affinity for the NE transporter, and a lo-fold lesser affinity for the DA transporter. Previous drug discrimination research has shown that venlafaxine substitutes nearly completely for cocaine and significantly displaces the cocaine dose-response function to the left. The effects of venlafaxine on the discriminative stimulus effects of cocaine resemble effects that we have observed with selective DA and 5-HT uptake inhibitors, but not NE reuptake inhibitors. The present experiment was conducted to examine the relative importance of DA a.nd 5-HT mechanisms in modulating the cocainelike discriminative-stimulus effects of venlafaxine by using the non-selective Dl/D2 DA antagonist alphaflupenthixol and the non-selective 5-HT( lC/2) antagonist cyproheptadine as pre-treatments to venlafaxine in a drug discrimination paradigm. Male Wister rats (n = 6) were trained to discriminate 10 mgjkg cocaine from saline in a food reinforced operant task. Cocaine (0.317.8 mg/kg), venlafaxine (3.0-30.0 mg/kg), alpha-flupenthixol (0.05 mg/kg), and cyproheptadine (2.5 mg/kg) were examined in substitution tests. Venlafaxine fully substituted for cocaine in five of six rats, reaching a maximum average of 7 1% cocaine-appropriate responding after 30 mg/kg. Venlafaxine was 4-fold less potent than cocaine in producing cocaine-like discriminative stimulus effects. The cocaine-like effects of venlafaxine were .&ttenuated by the Dl/D2 DA receptor antagonist and the 5-HT( lC/2) receptor antagonist after doses that were equi-effective in producing decreases in response rates. Alpha-flupenthixol pre-treatment significantly decreased the cocaine-like effects of venlafaxine by more than 4-fold, while cyproheptadine produced a significant lo-fold decrease in the relative potency of venlafaxine. These results suggest that both DA and 5-HT mechanisms may mediate the cocaine-like discriminative stimulus effects of venlafaxine. The relative role of 5-HT and DA mechanisms found in this study suggests that venlafaxine may have some utility as an anti-craving medication without having high abuse potential. 639 PATIENTS

CLINICAL WITH

FEATURES OF OPIOID-DEPENDENT A COCAINE-POSITIVE BASELINE

INURINE

SPECIMEN

S. Va.lero, R. Bosch, J. PCrez de 10s Cobos, A. Tejero, F. Batlle, and M. Casas, Hospital de Sant Pau, Universitat Autbnoma de Barcelona, Barcelona, Spain

S226

Abstracts

Background: A cocaine-positive baseline urine specimen (CPB) predicts treatment attrition in cocaine-dependent patients. Objective: To assessclinical features of opioiddependent patients with CPB who requested detoxification treatment in a closed addiction unit. Methods: We assessed 45 patients admitted for a heroin detoxification treatment, and 36 patients in methadone maintenance (MM) admitted for cocaine, alcohol and/or benzodiacepine detoxification treatment. CPB was detected in 34 patients (42%). Cinical features were assessed with the Addiction Severity Index (ASI), Cloninger’s Temperament and Character Inventory (TCI), and the Millon Clinical Multiaxial Inventory-II. The effects of CPB, MM and CPB by MM interaction were analyzed with a two-factor ANOVA. Results: Opioid-dependent inpatients with CPB showed higher scores on the AS1 composite drug score (F[l, 82]= 5.62, P = 0.02) and lower on the TCI character trait of Self-Directedness (F[l, 77]= 4.15, P = 0.045); more specifically, the aspect of Resourcefulness vs. Inertia (F[l, 77]= 5.35, P = 0.023). These results suggest that opioid-dependent patients with CPB, although more severely dependent on drugs, could be specially responsive to psychosocial treatment aimed at acquiring new problem-solving skills. Supported by: &gan Tecnic de Drogodependencies, Generalitat de Catalunya. 640

THE

SURE

AMONG

TIES

THAT ACTIVE

BIND:

DISCLOSURE

INJECTION

DRUG

OF

HIV

EXPO-

USERS

M. Valle, M.W. Smith, C. Shannon and J.A. Levy, University of Illinois at Chicago, School of Public Health, Chicago, IL Despite a high prevalence of AIDS among active injecting drug users (IDUs) and their sexual partners, little is known about the processes though which IDUs who test HIV sero-positive inform members of their social networks about shared exposure to the virus. Using snowball sampling techniques, 951 active IDUs were recruited via street outreach for HIV counseling, testing, and partner notification. Of these, 172 tested seropositive for HIV. This analysis examines the personal and social network characteristics that predict which at-risk partners HIV sero-positive IDUs choose to identify and inform of their sero-status through self-disclosure or outreach-assisted partner notification. Results indicate the contributions of four theoretical constructs: homophily, social proximity, stability, and general diffusion of information within the network. Understanding the factors that influence IDUs’ decisions to disclose a positive HIV test outcome to partners also at risk is critical in identifying unknown cases and promoting preventive behavior.

641

DOSE-DEPENDENT

CUE-ELICITED

COCAINE

EFFECTS

OF

PRAMIPEXOLE

ON

CRAVING

A. VandenEynden, J. Bayuk, J. Ranker, R. Padich, S. Schewe, C. Tsiboulski, S. Wanek, T. Borowski, A. Franc0 and S.P. Berger, University of Cincinnati, Cincinnati, OH Medications that suppress responses to naturalistic cues conditioned to drugs of abuse such as cocaine could be useful in promoting abstinence or preventing relapse. Previous studies have shown that dopamine agonists increase and dopamine antagonists decrease the response to cocaine cues administered in a short-term human laboratory setting. Chronic administration of medications suppressing dopaminergic function to cocaine abusers may not be feasible due to accompanying side effects. Recent pre-clinical studies have shown effects of D3 agonists to be equivalent to D2 antagonists in a variety of pre-clinical behavioral paradigms including drug self administration. These pharmacological studies are consistent with recent genetic and postmortem studies linking the D3 receptor to addiction. Pramipexole is a newly introduced anti-parkinsonian agent that is both more selective for the D3 receptor and much better tolerated clinically than other dopaminergic agents, We have evaluated pramipexole’s effects in a human laboratory setting in order to determine the hypothesized role of the D3 receptor in cue reactivity and identify an agent suitable for a longerterm clinical trial. In separate sequentially studied groups of subjects, a double blind, counterbalanced, two-session, placebo-controlled design was used to evaluate the effects of a single low dose (0.1 mg) or high dose of pramipexole (0.25 mg). The low dose of pramipexole selectively attenuated cue-induced euphoria but not craving, whereas the higher dose selectively attenuated craving but not euphoria. Pramipexole did not attenuate the significant increase in cortisol, homovanillic acid or Galvanic Skin Response induced by cues. Given the exceptional side effect profile of pramipexole, it may be feasible to selectively attenuate different components of the complex response to naturalistic cocaine cues encountered during a clinical trial and evaluate the hypothesized relationship to cocaine use. 642 ELICITED

CARDIOVASCULAR BY

INTERMITTENT

AND

CARDIAC ADMINISTRATION

RESPONSES OF

METHAMPHETAMINE

K.J. Varner, B.A. Ogden, and J.B. Delcarpio, Louisiana State University Health Sciences Center, New Orleans, LA

s221

Abstracts

METH use is often characterized by a cyclic pattern of frequent injections (‘run’) followed by a period of abstinence. This study tested the hypothesis that a pattern of repeated, intermittent exposure to METH can alter cardiovascular and/or cardiac function. Male SpragueDawley rats (n = 12) were treated with METH (3 mg/ kg, i.v., b.i.d. for 4 days) followed by a 12-day drug-free period. The protocol was then repeated 2 more times. The mean arterial pressure (MAP) and heart rate (HR) responses elicited by acetylcholine (Ach), serotonin (5HT), nitroprusside (NP), phenylephrine (PE) and isoproterenol (ISO) were also determined prior to each METH run and 12 days after the last run. Radio telemetry was used to record the MAP and HR responses elicited by METH and other drugs in the conscious rats. The pressor and HR responses elicited by METH were relatively constant during the first run. However, the pressor responses elicited by the first three doses of METH in the 2nd and 3rd runs were significantly larger than those elicited during the lsr run. The HR responses were the same across the three runs. Treatment with METH progressively decreased the bradycardic component of the Bezold-Jarish reflex elicited by 5HT. The hypotensive response to 5HT was progressively reduced and converted to a pressor response. 12 days after the 3rd run, the decreases in MAP elicited by NP, IS0 and Ach were significantly reduced, however the tachycardic responses were unaltered. The MAP and HR responses elicited by PE were not changed. Histologic examination of the hearts revealed contraction band necrosis, fibrosis, edema and lymphocytic infiltration. We conclude that intermittent administration of METH produces significant cardiac damage and alters cardiovascular function and responsiveness. Supported DA 08255.

643 DELTA-~ IN A WORKING TER MAZE

THC DISRUPTS PERFORMANCEOFMICE MEMORYVERSIONOFTHEMORRISWA-

S. Varvel, A. Lichtman, and B. Martin, lege of Virginia, Richmond, VA

Medical Col-

A great deal of experimental evidence has supported the hypothesis that cannabinoid systems are integral components of mechanisms mediating various aspects of cognition, particularly working memory. However, these effects have not yet been characterized in the Morris water maze, an increasingly popular paradigm used to investigate spatial memory. In order to better understand the role of cannabinoids in spatial memory systems, we have been investigating the effects of D-9 THC (s.c.) in C57BL/6 mice in two different water maze tasks. Both 10.0 and 30.0 mg/kg D-9 THC (but not 3.0 mg/kg) disrupted performance in a task heavily

dependent on working memory (F(3, 35) = 5.77, P < 0.01) while performance in a well-trained reference memory task was not disrupted until 100.0 mg/kg (F(4,29) = 6.96, P < 0.01). Average swim speeds were not affected by any dose tested. These effects of THC in the working memory task were blocked by the CBl antagonist SR141716A (F(3, 27) = 5.60,P < O.Ol), supporting the hypothesis that THC’s disruptive effects on working memory are mediated via CBl receptors. The:je preliminary results suggest that the water maze may be a useful paradigm for investigating the cognitive deficits produced by cannabinoids in mice.

644 HYDROXYL FREE RADICAL PRODUCTION AND VASCULAR TOXICITY OF COCAINE DURING MID-EMBRYONIC CHICKENDEVELOPMENT L. Venturini and S.B. Sparber, University sota, Minneapolis, MN

of Minne-

Increased free radical production, due to ischemia and reperfusion, has been postulated as a cause of cocaine’s developmental toxicity. With this study we confirm and extend previous observations derived from experiments done at a late stage of chicken embryogenesis. After injecting a nontoxic dose of NaSalicylate (SAL, 100 mg/:icg egg) into eggs with embryos on E12, the eggs were injected with five doses of cocaine (COC, 13.5 mg/kg egg every 1.5 h) because the SAL reacts with the hydroxyl free radicals (OH) to form stable, quantifiable reaction products which can be measured with HPLC. We found an increased.OH production in the younger embryo’s brain regions analyzed (P < 0.05) and heart (P <: 0.05) after injection of COC. Moreover, the developmental toxicity of COC, manifest as reduced hatchability, was enhanced rather than reduced by SAL injection (67% fewer chicks hatched in the SAL + COC group, compared to the embryos treated only with COC), even at this much earlier stage of development. Excessive bleeding caused by the combination seems the most likely cause, based upon observations of hemorrhages in the embryos (64% of SAL + COC treated embryos had hemorrhage on the head, and 55% on the body). The results may be important in light of possible exposure of human fetuses to both COC and SAL because of a misdiagnosis of preeclampsia in COC abusing pregnant women and the suggestion that aspirin may be indicated for treatment of chronic COC abusers at risk for cerebrovascular accidents.

645 CORTISOL LEVELS AND MOTOR ACTIVITY IN RESPONSE TO STRESS ARE LINKED TO NICOTINE DEPENDENCEINHUMAN SUBJECTS J. Vignau, M. Auriacombe, B. Aouizerate, P. Franques, M. Rashedi, J. Tignol, M. LeMoal, and P.V. Piazza, Universitk Victor Segalen Bordeaux, Bordeaux, France

Abstracts

S228

The goal of this study was to examine cortisol levels (CL) and motor activity (MA) in response to stress in high and low Sensation Seekers (SS) or drug dependent versus abstinent subjects. Twenty-eight male and female volunteers aged 18-40 years were included after exclusion of any medical or psychiatric disease other than nicotine dependence. All subjects completed a comprehensive evaluation. MA was monitored continuously by an automated device and CL was measured through saliva collections every 20 min. Subjects were monitored over a period of 2 h, starting 20 min prior to the beginning of a stress challenge consisting of an attention test. No significant correlation was found between SS scores of subjects and CL. However, when grouping subjects as nicotine abstinent (n = 16) user (n = 8) and dependent (n = 4) based on Fagerstrom Scale scores, significant group differences were found for CL [F(l4.18) = 2.60, P < O.OOl] and MA [F(2.23) = 3.75, P < 0.005]. The nicotine dependent group showed higher CL and MA than the other groups. This preliminary study supports the hypothesis of a relationship between corticoid secretion, motor activity and addiction in humans. 646

PET

MINISTRATION

CHARACTERIZATION AND ABSTINENCE

OF

ETHANOL SELF-ADIN CYNOMOLGUS

MONKEYS

J.A. Vivian, M.A. Nader, J.E. Young, H.A. Green, N. Buckheimer, H.D. Gage, R.H. Mach, and K.A. Grant, Wake Forest University School of Medicine, Winston-Salem, NC While a relationship between ethanol as a reinforcer and dopamine is widely accepted, this relationship is not well-documented in primates. We are evaluating the effects of self-administered ethanol, and its subsequent abstinence, on dopamine D2 function within the basal ganglia through the use of positron emission tomography (PET). Four female and two male cynomolgus monkeys were allowed to self-administer ethanol (4%) for a minimum of 3 months, followed by 6-month abstinence. Using the D2 ligand 18Ffluoroclebopride, whole brain PET images were obtained immediately after the last ethanol exposure. During ethanol exposure, monkeys consumed an ethanol dose of 2.4 + 0.3 g/kg per day, which produced blood ethanol concentrations greater than 100 mg/dl. A negative correlation between basal ganglia D2 binding potential and daily ethanol consumption (v = - 0.68) was demonstrated. That is, D2 binding potentials were lowest in monkeys that consumed the most ethanol daily. After 6-month abstinence, binding potentials were no longer correlated with previous ethanol intake. Taken together, these results suggest that high dose ethanol consumption reversibly changes the

basal ganglia dopaminergic system as measured by PET. Supported by USPHS Grants AA 10254 and AA 11997.

647 AND

CHILDREN PROTECTIVE

OF

METHAMPHETAMINE

USERS:

RISK

FACTORS

C.L. von Mayrhauser, M.L. Brecht, and M.D. Anglin, UCLA Drug Abuse Research Center/Integrated Substance Abuse Programs, Neuropsychiatric Institute, Los Angeles, CA There is now strong scientific evidence that children of parents who abuse drugs are at risk developmentally, emotionally, socially and physically. Little research to date, however, has investigated how children of amphetamine/methamphetamine (A/M) users are affected by this drug use history and its associated socioeconomic, legal, and health problems. Our research addresses that gap. We will present primary data on risk and protective factors identified for children of A/M-using parents in Los Angeles. These data come from our ongoing longitudinal study of A/M use and abuse, in which we interview a random sample (n = 400) stratified by gender, ethnicity and treatment modality in order to document the natural history of A/M abuse and assess treatment affects. Here we present data from the first 250 interviews with African-American, Latino/a and White European-American men and women. We will first describe sociodemographic backgrounds of the parents in our sample, focusing on income, education, occupation, criminal histories, severity of drug problems, and HIV/AIDS risk behaviors. Second, we will present childbearing and childrearing responsibilities of the parents in our sample. Third, we will present data on developmental delays in children. Fourth, we will describe the childrearing and parenting classes completed by the sample population while in treatment. Fifth, we will describe specific childbearing concerns voiced by parents in our sample, as well as actions the respondents reportedly undertook to reduce harm to their children (such stopping all drug use while pregnant). Our discussion will expand on specific cases of reported child mortality, morbidity, displacement, separation from sibling and parent group, and environmental risk factors; and identify aspects of the parents’ backgrounds that may indicate earlier risk or protective factors. We will conclude by identifying which service-utilization barriers appear to exist for A/M-abusing parents in Los Angeles County and suggesting ways we can better support parents (and foster parents) in their care of these vulnerable children.

Abstracts 648

TOLERANCE

TO

THE

INCENTIVE

PROPERTIES

OF

COCAINE

S.R. Vorel, X. Liu, R. Hayes, and E.L. Gardner, Albert Einstein College of Medicine, Bronx, NY Some treatment efforts for cocaine addiction are based on the exposure of addicted subjects to cues eliciting craving. The present work studies the effect of regular, repetitive administration of small doses of cocaine in the ‘reinstatement’ animal model of relapse to cocaine addiction. We allowed rats (N = 6) to press a lever for cocaine (1 .O mg/kg/i.v.) in operant chambers during daily 3 h sessions. After 7 days of cocaine self-administration we substituted saline for cocaine. After a 12-day drug-free interval the lever press responding had extinguished. We reinstated lever pressing by non-contingent i.v. administration of a cocaine prime (1.0 mg/kg). We repeated this cocaine prime daily for IO-16 days until there was no reinstatement of lever pressing. The next 7 days we administered no cocaine primes. After this drug-free interval we administered another cocaine prime. We found no reinstatement. On the final day lever presses resulted again in cocaine delivery; cocaine self-administration resumed as before extinction. Thus, we find complete tolerance to the incentive, but not the reinforcing properties of cocaine after this treatment regimen. This finding suggests a dissociation of the incentive and reinforcing properties of cocaine. Moreover, it supports our previous cocaine reinstatement work showing a dissocation of incentive and reinforcing electrical brain stimulations. Finally, it supports the potential benefit of cue exposure as a treatment modality at the clinical level. This work was supported by the New York State Office of Mental Health, the New York State Office of Alcoholism and Substance Abuse Services, and the Julia Sullivan Medical Research Fund.

649 A

COMPARISON

SMOKED

MARIJUANA

IN

OF THE AND

SUBJECTIVE

EFFECTS

OF

6-9-TETRAHYDROCANNABINOL

HUMANS

S.R. Wachtel and H. Chicago, Chicago, IL

de Wit,

The University

of

Patients have argued that they achieve better therapeutic effects from smoked marijuana than from oral doses of s-9-tetrahydrocannabinol (THC), the primary cannabinoid in marijuana. The purported superiority of marijuana may be due to pharmacokinetic factors related to smoking versus oral dosing, or to the presence of other active cannabinoids in the marijuana plant. To examine this issue, the effects of smoked marijuana were compared to the effects of an equivalent dose of smoked THC (without other cannabinoids). Seven male

S229

and six female marijuana users participated in a double-blind, crossover experiment. On 5 sessions, the subjects smoked either l/2 or 1 marijuana cigarette (2.1% THC), l/2 or 1 placebo marijuana cigarette spiked with THC (2.1%) or 1 placebo marijuana cigarette. Dependent measures included standardized self-report measures of subjective effects, physiological measures, and psychomotor performance. Although marijuana and THC alone produced many similar effects, the increase in heart rate and the magnitude of self-reported drug effects were greater after marijuana than after THC alone. These results provide limited support for the idea that cannabinoids other than THC may contribute to the effects of marijuana, including perhaps its therapeutic efficacy. Supported by USPHS grants ROl DA03517 and GCRC MO1 RR00055.

650

AGE-

AND

SION

FROM

FIRST

DENCE

ON

SEX-SPECIFIC

COCAINE,

USE

TO

HAZARDS FIRST

MARIJUANA,

F.A. Wagner, and J.C. Anthony, versity, Baltimore, MD

FOR

SYMPTOM AND

PROGRESOF

DEPEN-

ALCOHOL

Johns Hopkins

Uni-

Focus: This study extends prior research on comparative epidemiology of drug dependence with respect to marijuana, cocaine, and alcohol, focusing upon ageand :sex-specific risks. Methods: The work involved new survival analyses of self-report interview data from the National Comorbidity Survey (NCS), with attention to unequal subject selection probabilities and survey design effects. Among 8098 NCS subjects age 15-54 years, there were 220 users who had become cocaine dependence, 354 marijuana dependence cases, and 1212 alcohol dependence cases. Results: These new estimates confirm prior impressions, but offer novel national survey evidence about previously unreported male-female differences in time to dependence among users. For example, from the 1st year of drinking, there is exces,smale risk for onset of alcohol dependence problems (P = 0.0001). For marijuana users, excess male risk for marijuana problems does not surface until later: during the first 3 years, women users are just as likely as men to develop the prodrome of marijuana dependence. As for cocaine, no male-female difference emerges: men and women are equally likely to develop symptoms during the 1st year of use and thereafter. Discussion: This work was possible because of the NCS epidemiologic sample of mainly untreated drug users and an assessment of age at first use of individual drug dependence symptoms. The data now are almost 10 years old, but to our knowledge there is no recent epidemiological work on these issues. ACKNOWLEDGMENT: NIDA ROlDA09897 and Ron Kessler’s NCS research group.

S230

Abstracts

651 EFFICACYOFSUBSTANCEABUSETREATMENTSFOR HISPANICANDANGLOYOUTH H.B. Waldron, A.S. Aragon, T.R. Peterson, T.R. Apodata, and S. Kern-Jones, University of New Mexico Center for Family and Adolescent Research, Albuquerque, NM To evaluate cognitive-behavioral and family therapy interventions for treating adolescent substance use disorders, adolescents were randomly assigned to one of four treatment conditions: individual cognitive-behavioral therapy (CBT), Functional Family Therapy (FFT), an integrative treatment combining both FFT and CBT, or an education/skills group therapy comparison condition. Treatment outcomes for Anglo (n = 59) and Hispanic (n = 45) adolescents, aged 13-17 years, were examined at pre- and post- treatment. The outcome data showed that adolescents who received FFT or FFT + CBT significantly reduced their substance use from pre- to post-treatment compared to CBT and group interventions. The findings suggest that family interventions produced better treatment outcomes overall and that substance use and treatment outcomes may be culturally influenced. The higher correspondence found among family and substance use variables for Hispanic family members and improved outcome in family interventions for Hispanic youth might be understood in terms of important culture-specific values. The findings also have implications for the potential of matching adolescent substance abusers to treatment on the basis of ethnicity. 652 INTER- AND INTRA-SUBJECT VARIABILITY FORCINGEFFECTSOFNITROUSOXIDEASASSESSEDBYA MULTIPLE-TRIAL, FREE-CHOICE PROCEDURE

IN REIN-

D.J. Walker and J.P. Zacny, The University of Chicago, Chicago, IL This study examined the degree of inter- and intra-subject variability in reinforcing effects of nitrous oxide (N,O) using a procedure that can provide quantitative data on relative reinforcing efficacy. Twelve volunteers attended five sessions; in each they sampled 30% N,O in 0, (‘Agent A’), 100% 0, (placebo, ‘Agent B’), and ‘drug-free air’ (also 100% 0,). Later they chose which agent to inhale (A or B or drug-free air) every 5 min for 45 min. Reinforcing efficacy of N,O varied across subjects, from 0 to 87% NzO choice. Within-subject variability across sessions (mean SD = 1.1 N,O choices) was low compared to between-subject variability (mean SD = 3.1 N,O choices). Inclusion of a non-drug alternative allowed us to avoid problems of interpretation that can occur when subjects are ‘forced’ to choose between drug and placebo. Preference ratios (N,O choices/[N,O choices + 0, choices]) were usually close to 1.0 in the present study,

even when N,O choice was low. Had subjects been ‘forced’ to choose between drug and placebo, preference ratios may have been considerably lower, which would suggest that N,O was not functioning as a reinforcer. These data indicate that N,O’s reinforcing effects are relatively stable within-subject and that our procedure is sensitive to quantitative differences in reinforcing efficacy. ACKNOWLEDGMENT: NIDA Grant DA-08391 653 POPULATION ANALYSIS OF SEX AND OVARIECTOMYEFFECTSONCOCAINE-STIMULATEDLOCOMOTION INRATS Q.D. Walker, S. Li, J. Cabassa, K.A. Kaplan, J. Haroon, and C.M. Kuhn, Duke University Medical Center, Durham, NC We have conducted population analysis of sex and endocrine effects on locomotion after 10 mg/kg ip cocaine. Robust sex differences were always observed: locomotion in females administered vehicle or cocaine was significantly greater than in males by 51 and 227%, respectively. Locomotion in males was normally distributed following vehicle or cocaine (N = 84 and 96) but high responding females significantly skewed the distributions of locomotion following both treatments (N= 119 and 155). About 31% of female rats had greater cocaine-stimulated activity than the highest male. We postulated that ovarian hormones might mediate these sex differences. Population analysis of a large set of ovariectomized and sham-ovariectomized animals (IV = 162) confirmed that ovariectomy decreased cocaine-stimulated locomotion (P < 0.003) most likely by attenuating the sub-population of high responding females. However, a subset of these animals (N = 84) in which estrous cycle stage was monitored by vaginal lavage did not exhibit the decrease in cocaine-stimulated activity following ovariectomy. The present studies show that the sex difference in cocaine-stimulated locomotion may result from a high responding sub-population of females. These results illustrate the complex interactions of the genetics of individual differences, environment, and endocrine state. Supported by DA 09079. 654 ELEMENTSOFDAYTREATMENTFORCOCAINE-DEPENDENTHOMELESS: WHICH ARE MOSTIMPORTANT DEVELOPING ABSTINENCE?

IN

D. Wallace, J.B. Milby, S. Usdan, J.E. Schumacher, C. MC Namara, and S. Frison, University of Kansas School of Medicine, Kansas City, KS, University of Alabama at Birmingham, AL Analyses examine effects on abstinence of components of day treatment in a 2-group randomized controlled study (N= 141) that involved day treatment alone (DT)

S231

Abstracts

and day treatment with abstinence contingencies for work and housing (DT + ). The 20 day treatment components were examined using questionnaires from staff (N = 14) and client (N = 10) on importance *of individual components based on a 5 point Likert scale (1 = not at all important to 5 = extremely important) and on a ranking scale from most important (1) to least important component (20). Regression models examined the association between exposure to specific components and abstinence measured as total weeks abstinent over a 2-month treatment period. Based on Likert scores, staff rated individual counseling (4.71), individual goal development (4.43), goal review (4.31) and relapse prevention (4.31) as most important, while clients rated AIDS awareness (4.91), process group (4.83), therapeutic community (4.67), and relapse prevention (4.58) as most important. The rankings generally identified the same components, but process group was ranked as second most important component by staff, and 12 steps was the third ranked component by clients. Regression analyses indicated that differences in exposure in the 20 individual components explained 74% of the variance in weeks abstinent, with indications of substantial correlation among components. In individual regression models, process group explained 67% of the variance in abstinence, relapse prevention 60% and goal review 60%. Results changed minimally with adjustment for treatment. The findings that day treatment plays an important role in establishing abstinence with the importance of individual components varying widely have important implications for designing day treatment programs. Supported by NIDA grant ROl DA08475. 655 EVALUATIONOFENADOLINEANDBUTORPHANOL EFFECTS ON COCAINE SELF-ADMINISTRATION CAINEPHARMACODYNAMICSINHUMANS

AND CO-

S.L. Walsh, B. Geter-Douglas, E.C. Strain, and G.E. Bigelow, Johns Hopkins University School of Medicine, Baltimore, MD This study examined the potential efficacy of enadoline (ENAD), a full K agonist, and butorphanol (BUT), a mixed P/K agonist, against cocaine in humans. Volunteers (n = 8) with polysubstance abuse histories participated in 21 test sessions during this S-week inpatient study. Seven dosing conditions (i.m.) were examined in randomized order: ENAD (20,40 and 80 pg/70 kg), BUT (1.5, 3, and 6 mg/70 kg) and placebo. Each condition was examined during three consecutive sessions conducted within a 5-day block (M-W-Fri). Cocaine (0, 20 and 40 mg i.v, at 1 h intervals) was given at 30 min after the i.m. dose during the 1st session of each

week; numerous dynamic measures were collected. During the 2nd weekly session, subjects received a sample dose of cocaine (40 mg, i.v.) 30 min after the test agent and were presented 30-min later with 6 trials (15-min apart) in which they could choose the same dose of i.v. cocaine or money ($1,4,7, 10, 13 or 16). The 3rd weekly session was similar to the 2nd except no sample dose was given, and money choices were in descending order. ENAD (80 pg) significantly reduced responses to i.v. cocaine on measures of positive mood effects, but no other test conditions yielded significant dynamic interactions with cocaine. ENAD and BUT failed to alter cocaine self-administration with either choice procedure, although there was a trend for cocaine self-administration to increase after ENAD (80 pg). These data do not provide strong support for the efficacy of K agonists in the treatment of cocaine dependence. ROl DA10753, ROl DA05196, T32 DA07209, K05 DA00050 and K02 DA00332. 656 THE ROLE OF SPIRITUAL BELIEF FROM ILLICIT DRUGS BY HIV-POSITIVE MAINTAINED PATIENTS

IN ABSTINENCE METHADONE-

L.A. Warburton, SK. Avants, and A. Margolin, University, New Haven, CT

Yale

The current study examined the association between support and comfort derived from religion or spirituality and abstinence from illicit drugs in a sample of 43 HIV-positive injection drug users entering a methadone maintenance program. Patients with high ratings of spiritual or religious support were abstinent from illicit drugs 2.5 times longer during the first 6 months of methadone maintenance than were patients with lower ratings. Controlling for the influence of pretreatment variables (addiction and psychiatric severity, CD4 count, social support, and optimism), and during treatment variables (methadone dose and attendance at counseling sessions), hierarchical regression analysis showed that strength of religious and spiritual support was a significant independent predictor of abstinence, accounting for an additional 11% of the variance in abstinence. These findings suggest that spirituality may be an important dimension of patient experience to assess in addiction treatment research. 657

ZOLPIDEMEFFECTSONSLEEPAND SHIFT WORKERS

BEHAVIOROF

AS. Ward, C.L. Hart, M. Haney, R.W. Foltin, and M.W. Fischman, Columbia University and New York State Psychiatric Institute, New York, NY Sleep medication is often used by individuals who work irregular shifts. This study examined the effects of the

Abstracts

S232

hypnotic, zolpidem, on sleep, task performance, and mood of individuals living in a residential laboratory. Seven volunteers with a history of working irregular hours participated in a 24day study. They received either placebo or zolpidem (5, 10 mg) one hour before bedtime for 3 consecutive days under two shift conditions. On the day shift, participants performed computer tasks from 08:30 to 17:30 h and went to bed at 24 h. On the night shift, participants performed computer tasks from 00:30 to 09:30 h and went to bed at 16:00 h. Sleep was measured using the Nightcapa portable sleep monitor. Shifts alternated four times during the study; shift conditions were separated by an ‘off day during which participants were not on a schedule and data were not collected. Zolpidem dose-dependently reduced the latency to sleep onset and improved subjective ratings of sleep satisfaction without affecting sleep topography. Under placebo conditions, performance on several tasks was impaired on the night shift relative to the day shift. These deficits were not observed under active zolpidem conditions. Ratings of ‘I feel friendly’ and ‘1 feel mellow’ were lower on the night shift relative to the day shift. These data suggest that zolpidem, by improving shift work-related disturbances in sleep and work performance, may be useful for shift workers. ACKNOWLEDGMENTS: Supported by NIDA grant DA03746. 658

MECHANISMS

METABOLISM

IN

OF VITRO

COCAINE AND

IN

HYDROLYSIS VIVO:

AND

A CLARIFICATION

A. Warner and A.B. Norman, University of Cincinnati, Cincinnati, OH Cocaine forms two major hydrolytic metabolites, benzoylecgonine (BE) and ecgonine methyl ester (EME). EME is formed by the action of esterases present in serum and tissues. BE is commonly assumed to be produced non-enzymatically in vivo, however the observed half-life (f-) of cocaine in intact animals requires an enzymatic mechanism. Spontaneous hydrolysis to BE occurs at a rate of 4.8%/h (t- = 14.4 h) at pH 7.4, 37°C. The tp of cocaine in rats is m 12 min with 75% of the dose transformed to BE. Also in humans cocaine t- is 31-80 min with w 50% of the total dose transformed to BE. In both situations spontaneous hydrolysis cannot account for the majority of the BE formed. Brzezinski et al. (1994, Biochem Pharmacol. 48:174755) characterized esterases in human liver microsomes which catalyze the formation of BE. The t- of cocaine is one major determinant of the rate of self-administration (Tsibulsky and Norman 1999, Brain Res. 839:8593) and increasing the cocaine t- is predicted to decrease the consumption of cocaine. Therefore, these esterases may provide a potential target for inhibition resulting in a decrease in cocaine consumption, an

effect that may be useful in studying treatments cocaine addiction. 659

A

COMPARISON

RELATES

OF

OF SUBSTANCE

ADOLESCENTS

IN

THE

USE

PUERTO

PREVALENCE

DISORDERS RICO

AND

AND

for

COR-

AMONG

OLDER

THE

UNITED

STATES

L.Warner, G. Canino, and H. Colon, Rutgers University, Piscataway, NJ, University of Puerto Rico, and Universidad Central de Caribe, San Juan, PR Although there are ample data on adolescent substance use, little systematic research has studied the prevalence of adolescent substance disorders in general populations, let alone cultural differences in disorder prevalence. In this paper we report the prevalence and correlates of alcohol and drug use and disorder among older adolescents on Puerto Rico and in the U.S. We hypothesize that rates of disorder conditional upon use will differ between the sites, and because of cultural differences, the prevalence of specific substance disorder symptoms will also differ significantly between the two sites. Data on adolescents come from an island-wide survey of the Puerto Rican general residential population (15- 18 year old subsample, unweighted N = 922) and from the National Comorbidity Survey of the U.S. household population (15- 18 year old subsample, unweighted N = 641). Both surveys used a similar staninterview based on the Composite dardized International Diagnostic Interview (CIDI). Bivariate analyses and logistic regression are used, with standard errors of estimates adjusted for the complex sample designs. Alcohol use and disorder among drinkers are higher among NCS adolescents, as is drug use. However, drug dependence among users is higher among Puerto Rican adolescents. Consistent with our hypothesis, there are significant differences in the symptoms associated with substance use that are endorsed by youth in the two surveys, with higher rates of endorsement of problems with relatives and police, physical illness and emotional problems among Puerto Rican youth. By identifying the variant, as well as invariant patterns of substance use, this study may be helpful in determining the interventions that are appropriately transmitted across cultures, and the degree and type of modifications that may be necessary to prevent the negative sequelae that stem from substance use. 660

Do

LIER

COURT INTERVENTION

DIVE:RSION FOR

PROGRAMS ADOLESCENT

LEAD

TO EARCANNABIS

ABUSERS?

Charles P.M. Webb and Joseph A. Burleson, Alcohol Research Center, University of Connecticut Health Center, Farmington, CT

S233

Abstracts

This study used cross-sectional data to explore the possibility that extensive urine/breathalyzer testing, probation/parole and incarceration explain why adolescents coming to substance abuse treatment from criminal justice report a lower substance use frequency (SUF) and fewer substance problems (SUP) relative to other referral types. The effects of ‘pre-intervention’ were controlled for in a hierarchical model testing for differences in SUF and SUP as functions of criminal justice referral (CJR). Results based on 569 adolescents participating in a field effectiveness study of outpatient treatment for cannabis abuse found CJR youth reporting lower SUF, SUP than other referrals F (1537) = 6.84, P = 0.001, and reporting a greater likelihood of a urine/ breathalyzer tests, P = 0.000, probationary/parole supervision, P = 0.000, and incarceration, P = 0.012, prior to treatment. Results found that incarceration corresponded with lower SUF, SUP, F (1517) = 3.76, P = 0.024, particularly among high-social-risk youth, F (15 17) = 6.88, P = 0.001. Results did not explain lesser SUF, SUP by CJRs as a function of pre-intervention. This document prepared with support from CSAT grants (UR4-Tll1320; UR4-TIl1324; UR4-TIll317; UR4-Tlll321; UR4-TIll323).

661 ALTERATIONOFCYTOKINEPRODUCTION,LEUKOcYTEFUNCTION,ANDINDUCTIONOFCACHEXIAINRATS PHYSICALLY DEPENDENTONHEROIN R.J. Weber, R. Gomez-Flores, J.E. Smith, and T.J. Martin, University of Illinois College of Medicine at Peoria, Peoria, IL, and Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC Altered immune function has been reported in heroin addicts and is thought to be associated with increased infectious disease in this population. In rats made physically dependent by intravenous injections of heroin, we observed significant (P < 0.01) 1.5-2.3-fold suppression of splenic T lymphocyte proliferative responses to concanavalin A or in response to cross-linking of the T-cell receptor (TCR) plus IL-2. In addition, significant (P < 0.01) increased production of nitric oxide and TNF-alpha, 2.2- and 6-fold respectively, by resting and activated resident splenic macrophages was observed in the heroin-treated group. Plasma TNF-alpha levels in heroin-treated rats were 4 times higher than those of saline-treated controls. indicating an inflammatory response in this group. Plasma endotoxin (4.65 EU/ml) was detected in heroin-treated animals, suggesting the presence of infection. Natural killer cell activity was not affected by heroin treatment, and plasma levels of interferon-alpha, and the interleukins (IL) IL-l-beta, IL-2, IL-6, and IL-IO were normal. We also observed a significant (P < 0.01) 12-fold decrease in plasma leptin, accompanied with weight loss in heroin-treated animals.

Heroin dependence and T-cell immunodeficiency may be related to the increased production of nitric oxide and TNF-alpha from macrophages, the increase in plasma TNF-alpha, and indicate the presence of an active, subclinical infection. These immune sequelae may promote cachexia and weight loss. Immunodeficiency associated with heroin abuse may explain the increase in infectious diseases and weight loss in addicts, and serve as a cofactor in the high incidence of AIDS in this population. This work was supported by NIDA/NIH Grants DA/ A108988; DA12095, DA 06634, DA 00114 and DA00247 and F-32DA05865.

662 SELF-INJECTIONOFFLUNITRAZEPAMALONEAND INTHECONTEXTOFMETHADONEMAINTENANCEINBABOONS E.M. Weerts, N.A. Ator and R.R. Griffiths,.Johns Hopkins University School of Medicine, Baltimore, MD Patient interviews suggest that methadone may increase the reinforcing effects of benzodiazepines. The present study evaluated the intravenous reinforcing effects of fluni trazepam alone and in the context of methadone maintenance using a cocaine substitution procedure. Drug was available under a fixed-ratio (FR 160) schedule of injection with a 3-h timeout after each injection. High levels of self-injection (6-8 per day) were established with 0.32 mg/kg cocaine, then each dose of flunilrazepam (0.001-0.32 mg/kg) or its vehicle was substituted for cocaine for at least 15 days. Flunitrazepam maintained self-injection greater than vehicle at three or more doses in all three baboons. The dose-effect function was an inverted U shape which peaked at 0.01-0.032 mg/kg flunitrazepam. At these doses, peak levels of flunitrazepam self-injection ranged from moderate (5.2 and 5.6 injections per day) to high (6.6 injections per day) across baboons. When baboons were then maintained on oral methadone (1.8-3.2 mg/ kg per day), low doses of 0.0032-0.01 mg/kg flunitrazepam maintained moderate to high levels of self injections which were greater than those previously obtained for flunitrazepam alone in two of three baboons. These data suggest that methadone may increase the reinforcing effects of low doses of flunitrazepam. Howlever, when the flunitrazepam dose-effect curve was redetermined after baboons were no longer maintained on methadone, similar moderate to high rates of self-injection were obtained for low doses of flunitrazepam. Additional studies are necessary to determine if the leftward shift in the flunitrazepam dose effect function is rellated to repeated experience with flunitrazepam self-injection. Still, these data indicate that flunitrazepam functions as an intravenous reinforcer. Supported by NIDA contract DA57050 and NIDA grant DA01 147.

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663

REASONS FOR AND EFFECTS OF SUBSTANCE INPATIENTSWITHBIPOLARDISORDERANDSUBSTANCE DEPENDENCE

Abstracts USE

R.D. Weiss, M.E. Kolodziej, L.M. Najavits, L.M. Fucito, S.F. Greenfield, and M.L. Griffin, Harvard Medical School, Boston, and Alcohol and Drug Abuse Program, McLean Hospital, Belmont, MA This study of patients with bipolar disorder and substance dependence investigated self-reported reasons for substance use. We explored improvement reported by patients in relieving symptoms, and whether this perceived improvement was associated with substance use over time. We recruited 45 patients for a study of group psychotherapy for individuals with comorbid bipolar and substance use disorders. Patients were recruited in sequential blocks for either Group Therapy (GT) or for monthly assessments only (non-GT). Structured interviews and self-report measures were conducted over a 6-month period for all patients. We examined the relationships between: (a) reasons for use and symptom improvement; and (b) symptom improvement and days of substance use over time. The majority of patients reported depression, racing thoughts, or irritability as reasons for using drugs or alcohol. Although most patients who used drugs or alcohol for depression, sleep, or racing thoughts reported symptom improvement, the majority of patients did not report improvement from other bipolar symptoms. The GT cohort had fewer days of drug use over time, but cohort differences were not significant for alcohol use. Among patients who perceived symptom improvement from substance use, the non-GT cohort had more days of drug use over time, but differences in alcohol use were not significant. 664

THERAPEUTIC ALLIANCE AND PSYCHOSOCIAL OUTCOMES IN A SUBSTANCE ABUSE TREATMENT PROGRAM FORINCARCERATEDWOMEN

J. Wellisch, E.A. Hall, and M. Prendergast, Drug Abuse Research Center, University of California, Los Angeles, CA Considerable resources have been expended to identify program structures and client characteristics that consistently facilitate substance abuse treatment success; however, another aspect of treatment, the relationship between client and drug treatment counselor, has received scant attention. In psychotherapy, therapeutic alliance (TA) has been found to be an important contributor to the success of treatment. We investigated: (1) what are the relationships among treatment motiva-

tion, psychological functioning, and TA in a population receiving treatment for substance abuse; (2) to what extent does TA predict change in psychosocial functioning in this population and is TA better at predicting outcomes for clients with greater levels of psychological impairment? Subjects ( 119 incarcerated women) were assessed at intake and pre-release. Measures included: California Psychotherapy Alliance Scale patient version and Texas Christian University psychological functioning and treatment motivation scales. We found significant improvement in psychological status between intake and release (paired-sample t-tests), and correlations among the psychological functioning measures and some of the motivation measures (bivariate analysis). Desire for Help and Treatment Readiness were positively correlated with TA. At pre-release, TA was positively correlated with depression. Analysis of high impairment groups showed, for the high depression group, TA at pre-release strongly correlated with an improvement in depression; for the low self-esteem group, TA at intake correlated with improvement in self-esteem. The findings regarding the role of TA with this population are suggestive, but overall not sufficiently coherent to be useful for predicting in-treatment outcomes in psychosocial functioning for incarcerated women. We are currently investigating long-term (lyear) outcomes. 665 MOTIVATIONAL ENHANCEMENT TO DECREASE DRUG USE AMONG COCAINE USERS: A STAGE 11 EFFICACYTRIAL E.A. Wells, P.L. Peterson, D.A. Calsyn, S.M. Perry, and T.R. Jackson, University of Washington, Evergreen Treatment Services, Puget Sound Health Care System of the Veterans Administration, Seattle, WA At CPDD 1997 we presented data from a randomized pilot test of a street outreach and Motivational Enhancement (ME) intervention with crack users. Participants receiving feedback about their drug use reduced their cocaine use at 1 month follow-up relative to an Assessment Only (AO) control group and maintained the reduction at 2 months. The current study is a larger-scale (n = 300) randomized efficacy trial attempting to replicate results from the pilot. The design is a three-group design with two waiting list controls. At initial contact, The ME group receives a structured assessment and feedback, the A0 group, an assessment but no feedback, and the Assessment at Follow-up Only (AFO) group (a control for assessment effects), only brief outcome measures. Follow-ups are at 1 and 6 months, and the control groups receive ME feedback after the 6-month interview. Outcome variables include stage of change, self-efficacy, decisional balance, service

S235

Ahstwcts

utilization, and drug use. Preliminary analysis of data from 56 participants, 41 of whom had data at 1 month, had been completed. By CPDD conference time, we expect to have initial and 1 month data on 80-90 participants. Current participants are 76% male, 61% African American, 24% European American, 12% of mixed racial/ethnic background, and 2% Hispanic with a mean age of 40. Preliminary analyses indicate a different pattern of results than we found in our pilot study. All groups show reductions in 30-day cocaine use at 1 month, and, although not significant, the A0 and ME groups appear to show greater reductions (ME: from 15.93 to 9.33 days, AO: from 15 to 7.5 days) than the AFO group (from 15.93 to 13.25 days). These results suggest a helpful effect of assessment and underscore the importance of controlling for assessment effects when testing brief interventions. 666

B~OAVAILABILITY

NALOXONE

TABLETS

OF WHEN

BUPRENORPHINE

ADMINISTERED

AND ORALLY

AND

SUBLINGUALLY

S. Welm, R.T. Jones, E. Fernandez, R. Upton, C. Chin, and J. Mendelson, Langley Porter Psychiatric Institute, University of California, San Francisco, CA Buprenorphine and naloxone tablets for sublingual (SL) administration will soon be available for opiate dependence treatment. While the bioavailability (F) of small analgesic doses of oral (PO) buprenorphine is well known, less is known about the relatively large buprenorphine and naloxone doses needed for opiate dependence treatment. This study assessed the relative and absolute F and pharmacodynamic effects of a buprenorphine (8 mg) and naloxone (2 mg) tablet (4:l ratio) when administered PO and SL. Nine experienced opiate users were tested in a three session, placebo-controlled, balanced design study with tablets administered PO and SL. F was determined after intravenous (IV) buprenorphine (2 mg) and naloxone (0.5 mg) by AUC ratio between IV, PO, and SL treatments. The relative F for PO buprenorphine is only 44% of SL with absolute Fs of 14.7% for SL vs. 6.4% for PO. SL administration yields 2.5 times more buprenorphine than after PO dosing. Naloxone absorption (absolute F 3% vs. 0%) was minimal with either SL or PO dosing. Pharmacodynamic effects paralleled pharmacokinetic results, with the SL dosing producing larger decreases in respiration rate and pupil size and higher rating of ‘drug liking’, ‘good drug effect’, and opiate intoxication than PO dosing. We conclude that, despite potential advantages of PO dosing, SL administration of buprenorphine and naloxone will be needed to obtain adequate drug absorption and pharmacological effects. Supported by NIDA contract NOIDA-4-8306 and NIH RR-00079 (GCRC, UCSF).

667

THE

TYPE

MRNA

PENDENCE

EXPRESSION AND

IN

OF MUSCARINIC

SPINAL

CORD

DURING

RECEPTOR

SUB-

MORPHINE

DE-

WITHDRAWAL

Z. Wenhua, L. Huifeng, X. Xiaohu, and Y. Guodong, Ningbo Addiction Research and Treatment Center, Ningbo, China The present study was initiated to investigate the expression of muscarinic receptor subtype mRNA in spinal cord during morphine dependence and withdrawal in rats. The level of muscarinic receptor subtype including m 1, m2, m3 and m4 mRNA was assayed by reverse transcription polymerase chain reaction (RTPCR) with the beta-actin mRNA as an internal control. The basic expression of muscarinic receptor subtype mRNA is m4 > m3 > m2 > ml mRNA in normal rats. The ml, m2 and m3 mRNA levels were increased in morphine dependence, and decreased at 1 h after administration of naloxone (4 mg/kg) in morphine dependent rats. Meanwhile, the m4 mRNA was not changed during morphine dependence and withdrawal. The pretreatment with L-N-nitric arginine methylester (10 mg/ kg), the expressions of ml, m3 and m4 mRNA were decreased. The ml mRNA levels were decreased, and m2 and m3 were increased by treatment with either MK801 (0.5 mg/kg) or methyl-scopolamine (0.5mg/kg). The ml, m2and m3 mRNA levels were increased by treatment with the pirenzepine (10 mg/kg). When intrathecal injection of SP-CAMPS, activator of protein kinase A, ml,m2 and m3 mRNA levels increased, and the ml,m2, m3 and m4 mRNA were decreased by treatment with RP-CAMPS (it), an inhibitor of protein kinase A, meanwhile, the mland m2 mRNA levels increased by treatment with calyculin A, an activator of protein phosphatase. The results suggested that the adaptation of muscarinic receptor subtype may be involved in the expression of morphine dependence, and expression of these genes may be regulated differently by muscarinic receptor itself, NMDA receptor, nitric oxide pathways. 668

PHARMACOLOGY

OF

CHIRAL

S-AMINO-3-

(TETRAHYDROFURYL)METHYL-BENZOMORPHANS

M.P. Wentland, Q. Zhou, D.J. Cohen, and J.M. Bidlack, Rensselaer Polytechnic Institute, Troy, and University of Rochester, Rochester, NY We recently reported the synthesis and opioid receptor binding properties of a novel series of cyclazocine analogues where the 8-OH was replaced by amino and substituted-amino groups (Bioorgan. Med. Chem. Lett. 2000, 10, 183-187). Our goal was to identify new structures that have a similar profile (kappa agonist/mu antagonist) to cyclazocine but were longer acting in

Abstructs

S236

vivo. Our results showed that certain g-amino derivatives had very high affinity for kappa and mu opioid receptors. This was particularly evident for the ( - )(2R,6R, 11R)-8-phenylamino analogue which had subnanomolar affinity for kappa receptors. To determine if the potential benefits of this OH to NHR replacement is transferable to the (tetrahydrofuryl)methylcontaining core structure pioneered by Merz and coworkers, we have synthesized and evaluated the opioid binding properties of a small series of chiral compounds where the 3-OH group of the Merz core is replaced by amino and phenylamino groups. We made these targets by a Pd-catalyzed amination of the corresponding 8-triflate ester. The ( - )-(2R,6R,l lR,2”S)-8amino and 8-phenyl-amino analogues had 82- and 16-fold lower affinity for mu receptors, respectively, and 107- and 27- fold less affinity for kappa receptors, respectively, than the parent Merz compound. In contrast to our earlier benzomorphan studies, NH2 is not an effective bioisosteric replacement for the 3-OH of the Merz core. Supported by DA09676, DAO1674, DA03742, DA1 2180, and KOS-DA00360.

669

IDENTIFICATION AND DIAGNOSIS POLYDRUG USING WOMEN: COMPARING SUBSTANCE USE

OF PREGNANT MEASURES OF

P.L. Wilbourne, W.R. Miller, and L.B. Curet, University of New Mexico, Albuquerque, New Mexico While identifying women at risk for substance use during and following pregnancy is an important part of prenatal care, limits of experience in drug use assessment and time in medical settings create a need for efficient, accurate and generalizable measures. Three measures of drug use frequency gathered at entry into prenatal care: self-reported questionnaire for past 30 days, past 30 days from the AS1 and urine toxicology are compared. Significant paired sample Pearson correlations (P < 0.0005) among all of the measures for the number of drugs used ranged from r = 0.210 to 0.384. Significant differences were also detected among all pairs of measures using paired samples r-tests (P < 0.0005) for the number of drugs used. Comparing frequency measures, a paired samples Pearson correlation of Y = 0.467, (P < 0.0005) was found with no significant difference between the values. Only the percentage of positive toxicologies significantly predicted diagnosis of the mother with substance use, abuse or dependence at the time of birth (u = 0.338, P < 0.001). It was hypothesized that information gathered at the time of birth would best predict women who were diagnosed at birth. This hypothesis was confirmed as the ratio of positive drug tests in the third trimester were more highly correlated

with diagnosis (r = 0.490, P < 0.001) than those in the first trimester (Y = 0.243, P < 0.029). Using a multiple regression, only third trimester toxicologies maintained a unique relationship with maternal diagnosis (/J = 0.550, P < 0.011). These findings are problematic since most pregnant women reduce their use by the third trimester, but do not maintain these reductions postpartum. Emphasis on third trimester drug screens for maternal diagnosis or risk assessment likely overlooks many pregnancies that are affected by perinatal substance use and at risk for post partum drug use.

670

THE SELF-ADMINISTRATION OF COCAINE ANALOG RTI 113:RELATIONSHIP TO DOPAMINE TRANSPORTER OCCUPANCY DETERMINED BY PET NEUROIMAGING INMONKEYS

K.M. Wilcox, M.M. Goodman, J.R. Votaw, L. Martarello, K.P. Lindsey, T.M. Howard, F.I. Carroll, and L.L. Howell, Yerkes Regional Primate Research Center and Emory Lniversity Atlanta, GA, and Research Triangle Institute, Research Triangle Park, NC Dopaminergic mechanisms are thought to play a central role in the reinforcing effects of cocaine. The present study examined the reinforcing effects of the phenyltropane cocaine analog RTI-113 under a second-order schedule of i.v. self-administration in rhesus monkeys. Subjects were trained to respond for injections of cocaine (0.1 mg/kg per injection). When responding was stable cocaine (0.003-1.0) and RTI-113 (0.03-0.3) were substituted for the baseline dose of cocaine. RTI-113 and cocaine produced inverted-U doseeresponse functions, but RTI- 113 maintained fewer responses/session. To characterize the neurochemical mechanism of the reinforcing effect, dopamine transporter occupancy was examined in rhesus monkey striatum during neuroimaging with positron emission tomography (PET). Dopamine transporter occupancy was determined by displacement of the high affinity dopatnine transporter ligand 8-(2[ 18F]fluoroethyl)-2b-carbomethoxy-3b-(4-chlorophenyl) nortropane (FECNT). RTI-113 and cocaine were administered iv. l-2 h after i.v. administration of [18F]FECNT. Displacement of FECNT by RTI- 113 was dose-dependent, and greater than displacement by cocaine at the maximum reinforcing doses of each drug. These data suggest that percent dopamine transporter occupancy is important in determining the reinforcing effects of RTI- 113. Additionally, the pharmacokinetics of RTI-1 I3 may contribute to the relationship between its reinforcing effects and dopamine transporter occupancy. Supported by USPHS grants DA-10344 (L.L.H.) and RR-00165.

S231

Abstracts

671

QUANTITATIVE

HUMAN

HAIR

BY

MATOGRAPHY-MASS

DETERMINATION HIGH

OF

PERFORMANCE

CODEINE

LIQUID

IN CHRO-

SPECTROMETRY

D.G. Wilkins, M. Augsburger, M.H. Slawson, and D.E. Rollins, Center for Human Toxicology, University of Utah, Salt Lake City, UT Codeine exposure experiments in drug-free human subjects require very sensitive methods for drug quantification. Because the concentration of drugs found in hair are often very small ( < 1.0 ng/mg), a highly sensitive LC-MS method was developed. After addition of deuterated internal standard and overnight digestion of hair samples, a basic liquid-liquid extraction with n-butyl chloride-acetonitrile (4: 1, v/v) was used. Extracts were analyzed by LC-MS (API-ES) (HP 1100 Series) using a mixture of H,O + 0.1% HCOOH - methanol as mobile phase, a YMC Cl 8 120 A reversed-phase column, and operating in SIM mode. The curve was linear from 20 pg/mg (LOQ) to 10 ng/mg (Y > 0.99). Intra-assay precision was less than 15% at 50, 300 pg/mg, and 5 ng/mg. The method was successfully used in multiple-dose disposition studies to quantify codeine in human hair.

672 AND

DIFFERENTIAL EMPLOYMENT

OF IMPLEMENTATION FAMILIES

CHANGES COMPOSITE LEVEL

IN

AS1

SCORES OF THE

ALCOHOL,

DRUG,

AS A FUNCTION

CASAWORKS

FOR

PROGRAM

J.M. Willem, A.T. McLellan, M. Gutman, B. Ketterlinus, L. MacPherson, and B. Harris, Treatment Research Institute at the University of Pennsylvania, Philadelphia, PA In response to welfare reform, The National Center on Addiction and Substance Abuse (CASA) has designed a demonstration program to address the specific needs of substance-abusing women on welfare. The CASAWORKS model focuses on providing intensive case management while addressing the problem areas of addiction, poverty, and abuse by providing a comprehensive set of services. In a preliminary analysis, the participating sites (N = 11) were ranked to determine level of service implementation and level of case management implementation. Service implementation was operationally defined as the average number of services as recorded by the Treatment Services Review (TSR). Case management implementation was operationally defined as the average number of case manager contacts with the client as recorded by the Case Management Activity Review (CMR). The highest four ranking sites were categorized for each instrument as high-implementing and the lowest four ranking sites were categorized as low-implementing. A total of 140 baseline ASIs and 140 6-month follow-up ASIs were analyzed. Preliminary

analyses showed that the AS1 Alcohol, Drug, and Employment composite scores did not differ significantly at baseline for the service implantation levels. These composite scores did not differ at baseline with the exception of the Employment composite score for the case management implementation levels (P < 0.01). It was expected that the high implementing sites would show the largest changes in these composite scores from baseline to the 6-month follow-up, and the low implementing sites would show the smallest changes. Preliminary results indicate that service implementation level does not have an effect on Alcohol, Drug, and Employment 6-month outcomes, but that case management level does appear to have an effect on 6-month outcome (F(3, 108) = 2.45). Future analysis is necessary to verify that more contact with case managers may lead to better outcomes.

673

CHARACTERISTICS

BEHAVIOR

IN

OF

PSYCHIATRIC

DRUG-RELATED

SUICIDAL

INPATIENTS

J.D. Wines, Jr., S.V. Eisen, P. Kon, and J.H. Mendelson, Alcohol and Drug Abuse Research Center and McLean Hospital-Harvard Medical School, Belmont, MA Preventing suicide continues to challenge the mental health field. Substance abuse is a risk factor for suicidal behavior; approximately half of all completed suicides involve alcohol or other drugs. Despite extensive scientific literature documenting the strong statistical association between drug use and suicidal behavior, clinical information regarding this phenomenon is lacking. Patients (n = 226) admitted to a locked, dual-diagnosis unit completed The Behavior and Symptom Identification Scale (Basis-32) on admission (Adm) and discharge (D/c). The Basis-32 is a 32-item, self-report instrument used to assesspatient functioning and psychiatric symptoms, including suicidal behavior. Results are as follows: (a) Demographics: Male 70%, Female 30%; Mean age: 40; Not Married 43%; Unemployed 64%; Medicare: 52%; Mean LOS: 11 days; Primary diagnosis: Alcohol 47%, Illicit Drugs 340/o, Mood Disorder 11%; (b) Mean Basis32 Score Adm 2.1 vs D/c 1.3, P < 0.001; (c) Mean Suicide Score Adm 1.13 vs D/c.47, P < 0.001; and (d) Suicidal Behavior rated ‘Quite a bit’ or ‘Extreme:’ Adm 19% vs D/c 6%. Further research, including prospective studies, is needed to more fully characterize the natural history of drug-related suicidal behavior. ACKNOWLEDGEMENTS: Supported in part by grants K23-DA00455, K05-DA00064 and DA04059 from NIDA, NIH.

674 TRIAL:

MEASURING A COMPARISON

OUTCOME

IN

OF SWEAT

A COCAINE PATCHES

CLINICAL AND

URINE

BENZOYLECGONINE

T. Winhusen, B. Singal, P. Horn, E. Somoza, N. Chiang, R. Hawks, and A. Montgomery, Cincinnati VA/

Abstracts

S238

UC/ NIDA MDRU, VA Medical Center, Cincinnati, OH, and NIDA Division of Treatment Research and Development, Bethesda, MD Analytic techniques have been developed for the detection of drugs of abuse in human sweat collected on specialized collection pads (Sweat Patches), placed on the skin. This technology may offer advantages over urine toxicology, the objective outcome measure traditionally used in substance abuse clinical trials. The utility of using sweat patch analyses in clinical trials was assessed in a IO-week open label trial testing the efficacy of Methylphenidate as a treatment for cocaine dependence in participants with ADHD. For 34 participants in this trial, sweat patches were applied on a weekly and a per-visit (3 times per week) basis to participants’ right and left arms, respectively. Patches have greater sensitivity for cocaine than cocaine metabolites and, thus, were analyzed for cocaine. Urine was collected at each visit and analyzed for benzoylecgonine (BE), a cocaine metabolite. Study results indicate that the per-visit patch offered a slight advantage over urine BE in terms of the completeness of data provided while the weekly patch offered a slight disadvantage. Specifically, the per-visit patch provided data for 70% of all study days while urine BE and the weekly patch provided 67.7 and 65.3% respectively. This presentation will compare the study results based on urine BE vs. patches and will discuss the advantages and disadvantages associated with each technology. 675 TIONAL

EFFECTS OF THC DLSCRIMINATIONS

ON RETENTION IN MONKEYS

OF CONDI-

P. J. Winsauer and J.M. Moerschbaecher, Louisianna State University Health Sciences Center, New Orleans, LA The effects of delta-9-tetrahydrocannabinol (THC), both alone and in combination with the CBl-receptor antagonist SR141716A, were determined on retention in patas monkeys using a baseline of repeated-acquisition and delayed-performance. Each session was divided into three phases: acquisition, delay and performance. During acquisition, subjects acquired a two-member conditional discrimination reinforced under a variable-ratio schedule of food presentation. When an acquisition criterion was met (10 consecutive errorless completions of the discrimination), the stimuli turned off and a 60-min delay (retention interval) began. Following this delay, the stimuli were illuminated again for the performance phase during which subjects responded on the same complex discrimination learned in acquisition. When saline was administered i.m. immediately after acquisition, no disruption in retention was observed as measured by the percent savings in the

errors to criterion. However, when doses of THC (0.01-0.32 mg/kg, i.m.) were administered, dose-dependent decreases in retention were evident during the performance phase and these decreases frequently occurred at doses that had little or no effect on overall response rate or percentage of errors. Administered in combination with THC, a 0.32 mg/kg dose of SRl41716A antagonized the effects of THC on retention and shifted the doseeeffect curves for THC-induced disruptions in retention to the right. Together, these data indicate that THC can dose-dependently disrupt memory at doses that do not affect other measures of responding and that these effects on retention are mediated by the CBl-receptor. Supported by DA1 1417. 676

MONITORING ACCESS TO TREATMENT LESCENTDRUGABUSERS

FOR ADO-

K.C. Winters and R. Stinchfield, University of Minnesota, Minneapolis, MN Whereas a range of treatment approaches has enabled adolescents to address their drug abuse, there are indications that current cost containment pressures in the health care service delivery system are shifting treatment referral criteria away from less-severe cases. It is hypothesized that this trend has resulted in a significant drop in the probability of moderately severe cases gaining access to treatment for drug abuse. The Center for Adolescent Substance Abuse Research has monitored for several years patterns of problem severity characteristics of youth seeking drug abuse treatment. The present analysis compares intake problem severity data collected from consecutive intake assessments during 1994 and 1998 at a large upper Midwest adolescent drug treatment program (n’s = 262 and 238, respectively). The analysis compared intake scores from a standardized and validated self-report measure of adolescent drug use severity (Personal Involvement with Chemicals). The ‘treatment access threshold score,’ which was defined as the scale score at which > 80% of clients received a referral for drug treatment, was about one-half a standard deviation (0.47) higher for 1998 compared to 1994. The 1998 threshold score was applied to the distribution of 1994 data to identify a ‘treatment orphan’ group, that is, those that received access in 1994 but had a scale score below the 1998 access threshold score. Substance use disorders were common in this group (15% no diagnosis, 53% abuseonly diagnosis, 32% one substance dependence diagnosis), although low rates of psychiatric comorbidity (16%) and prior criminal history (9%) were observed. By contrast, the 1998 adolescents who exceeded that year’s threshold score all had at least one dependence diagnosis, and high rates of psychiatric comorbidity

54239

Abstracts

(64%) and prior criminal history (57%) were observed. In sum, the trend analysis suggests that shifts in access to drug treatment for youth decrease the probability of treatment for youth with just an abuse diagnosis and those without a comorbid psychiatric disorder. 677

FACTORSASSOCIATEDWITHINTAKEANDEND-OF TREATMENT SITUATIONAL-CONFIDENCE AMONG CAINE-DEPENDENT OIJTPATIENTS

CO-

C.J. Wong, S. Anthony, G.J. Badger, and ST. Higgins, University of Vermont Substance Abuse Treatment Center, Burlington, VT Patients’ confidence in their ability to abstain from drug use in high-risk situations (i.e. situational-confidence) predicts treatment outcome across various types of drug abusers. Furthermore, situational-confidence has been demonstrated to increase during the course of treatment and to be associated with during-treatment abstinence. The present study examined subject characteristics at intake that were associated with situationalconfidence at intake and end-of-treatment among cocaine-dependent outpatients. Data were collected from 126 subjects who received one of the following treatments: CRA plus contingent vouchers, CRA plus non-contingent vouchers, or vouchers only. A modified version of the Situational Confidence Questionnaire (SCQ) was administered at intake, 6, 12, and 24 weeks of treatment. Situational-confidence increased significantly during the course of treatment. Stepwise multiple regression revealed that prior treatment for cocaine abuse and higher BDI scores predicted lower SCQ scores, while being male and greater number of years of regular cocaine use predicted higher SCQ scores at intake. These variables accounted for 17% of the variance in predicting intake SCQ scores. With regard to predictors of end-of-treatment SCQ scores, multiple regression revealed that abstinence achieved during 24 weeks of treatment, intake SCQ scores and an intranasal route of cocaine use predicted higher end-oftreatment SCQ scores. These variables accounted for 38% of the variance in predicting end-of-treatment SCQ scores. These results further elucidate the factors associated with changes in confidence during outpatient treatment for cocaine dependence. 678 FINAL RESULTS FROM A PREVENTION NEEDS ASSESSMENT STUDY ON ALCOHOL AND OTHER DRUG USE AMONG MIDDLE-AGED AND ELDERLY PERSONS IN CALIFORNIA M.M. Wong and M. Douglas Anglin, UCLA Drug Abuse Research Center and WestEd, Los Angeles, CA

To a:jsess the need for alcohol and other drug (AOD) prevention services for older users, especially seniors aged 65 years and older, we conducted three principal tasks: (1) a literature review; (2) a secondary analysis of multiple databases from Californians aged 50 years and older, ranging from general household surveys to a criminal justice survey; and (3) a series of small focus groups and interviews with elderly persons, service providers for the elderly, and elder advocates. The existing research indicates a lack of data linkages and research findings of limited generalizability. Overall findings from this study indicate heterogeneity in the older AOD user population, particularly with regard to AOD prevalence rates, rates of consequent problems, and need for prevention, intervention, treatment, and ancillary services. In summary, a system of care is indicated for the various older populations in the older AOD user community. Importantly, there are various barriers to receiving or delivering these services; chief among them are elderly people’s denial of AOD problems, insufficient funding and resources that address special needs of older users, and detection of AOD problems during late stages of use, when consequences have been likely sustained. Next steps for this research include: (1) collecting new AOD data through intensive interviews or focus groups to identify areas of service needs specific to older user populations; (2) estimating the financial and social costs of elderly AOD use; and (3) identifying prevention, intervention, and treatment components that are effective or ineffective for older AOD users. 679

EFFECTOF CNQX ON COCAINE-INDUCED EXTRACELLULAR DOPAMINE OVERFLOW IN THE MEDIAL PREFRONTALCORTEX

W.R. Wu, N. Li, R.M. Craft, and B.A. Sorg, Washington State University, Pullman, WA This study investigated the effect of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an antagonist of the AMPA/kainate subtype glutamate receptor, on the cocaine-induced increase in extracellular dopamine and metabolite levels in the medial prefrontal cortex (mPFC). Male Sprague-Dawley rats were infused with micrcdialysis buffer, and four baseline samples (20 min/sample) were collected. Animals were then infused with ‘either CNQX (50 PM) or microdialysis buffer as before (control). After 1 h, CNQX was replaced with dialys,is buffer, and a cocaine injection (15 mg/kg, ip) was administered. After 2 h of sample collection, another injection of cocaine (30 mg/kg, ip) was given, and an additional 2 h collection period followed. Cocaine (15 and 30 mg/kg) dose-dependently increased extracellular dopamine levels in the mPFC to a maximum of approximately 240”/0 and 500% of baseline. respectively.

Abstructs

S240

While CNQX itself had no significant effect on basal dopamine levels, it attenuated the cocaine-induced increase at both doses of cocaine. No significant differences were found between treatment groups in DOPAC levels, and HVA levels were slightly reduced during CNQX infusion, with no differences between groups after either dose of cocaine administration. These results demonstrate that AMPA/kainate receptors play an important role in the regulation of cocaine-induced elevations in mPFC dopamine levels. Supported by DA 11787. 680

SUPPRESSION

POLYSACCHARIDE WITH

OF IN

FEVER RATS

RESPONSE TREATED

TO

LIPO-

CHRONICALLY

MORPHINE

L. Xin, J.C. Cabassa, J.D. Vincent, E.B. Geller. and M.W. Adler, Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA We have reported that acute administration of either mu-opioid receptor agonists or proinflammatory cytokines produces fever and increases beta-endorphin (beta-E) release from the brain. It has also been demonstrated recently by our laboratory that increased beta-E release in the brain may contribute to tolerance to the morphine (M) body temperature (Tb) effect in rats treated chronically with M. In the present study, we investigated whether Tb response to lipopolysaccharide (LPS), a stimulator of proinflammatory cytokine release, might be changed in rats treated chronically with M. Male S-D rats were implanted S.C.with 2 M pellets (75 mg each) or 2 placebo pellets for 3 days. Tb was monitored in the morning and afternoon each day. On the 4th day, rats were injected i.p. with 50 ug/kg LPS or saline and Tb was monitored for 5 h. Average Tb baseline in rats implanted with M pellets was 0.23, 0.75, 1.O and 1.3”C higher than that in the placebo group, during the 1st day to 4th day after pellet implantation, respectively. Injection of LPS induced a 1.75 & 0.2. Twenty-two points, plus triple-word-score, plus 50 points for using all my letters. Game is over. I am outta here. “C increase in peak Tb response in the placebo group, but only 0.2 + 0.12”C Tb change in the M group. The glucocorticoid receptor antagonist RU486 does not change the suppression of LPS fever by M, indicating that the M suppression effect is not dependent on corticosterone. These results demonstrate a suppression of LPS fever development in rats treated chronically with M, suggesting that either M impairment to the immune system or increased endogenous opioids resulting in desensitization of mu-receptors might be involved. Supported by grant DA 00376.

681

RELATIVE

EFFICACY

OF THE

LYL-3-METHYLa-PIPERIDINYL) ETHYLBENZAMIDE OPIOID

ISOMERS

OF 4-l(N-AL-

PHENYLAMINOI-N,N-DIAT

THE

CLONED

HUMAN

DELTA

RECEPTOR

H. Xu, J.B. Thomas, F.I. Carroll, K.C. Rice and R.B. Rothman, IRP, NIDA, NIH. Baltimore, MD, Research Triangle Institute, Research Triangle Park, NC, and NIDDK, NIH, Bethesda, MD Previous data obtained from both binding and functional assays demonstrated that ( - )-4-[(N-allyl-3methyl - 4 - piperidinyl)phenylamino] - N, N - diethylbenzamide [( - )-RTI5989-541 displays selective binding and full agonist activity relative to ( + )-RTI5989-54 for the d opioid receptor. The present study was conducted to evaluate the activities of structurally diverse opioid receptor d ligands in the [35S]GTP-g-S binding assay, comparing the relationship between receptor binding, activation, efficacy and intrinsic efficacy. The data, obtained with cloned human d receptors, demonstrated that ( - )-RTI5989-54 behaves like the prototypical d agonist SNC80. Addition of the hydroxyl group to RTI5989-54 (RTI5989-61) or replacement of the ally1 group with the trans-crotyl group on the piperidine nitrogen of RTI-5989-61 (RTI5989-62) increased binding affinity and full agonist activity for the d opioid receptor. But, their intrinsic efficacy was decreased. The order of potency for the EC50 (GTP-g-S) was RTI5989-62 (0.20 nM) > RTI5989-61 (0.43 nM) > SNC80 (1.92 nM) > ( - )-RT15989-54 (17.6 nM). The order of intrinsic efficacy was SNC80 = ( - )-RTI598954 > RTI5989-62 > RT15989-61. Comparison of the [3H]-naltrindole binding Ki to the functional Ki for d antagonists [Ki (NTI)/Ki (GTP-g-S)] suggest that antagonists attenuate agonist-stimulated [35S]GTP-g-S binding at different levels of receptor occupation. 682 TIENT

MOTIVATIONAL, COCAINE-ABUSING

INTERVIEWING ADULTS

WITH

OUTPA-

C.E. Yahne, J.S. Tonigan, and W.R. Miller, The University of New Mexico Center on Alcoholism, Substance Abuse, and Addictions, Albuquerque, NM Motivational Interviewing (MI) is a directive, clientcentered, brief intervention to elicit behavior change by helping people explore and resolve their ambivalence about their drug use. One hundred and fifty-two outpatients were recruited to participate in this study of adults presenting for drug problems other than alcohol. Half of them targeted their use of cocaine/crack as their reason for seeking treatment. The clients presenting with cocaine problems (53% women) averaged 31 years of age, and were mostly unemployed and unmarried. Hispanic clients comprised 42% of the sample. Follow-

s241

Ahstructs

ing a 5 h assessment battery, they were randomly assigned to receive or not receive one session of MI prior to proceeding with standard outpatient treatment. The motivational interview lasted from 60 to 90 min and was videotaped. It included an orientation phase, a personal feedback phase, and a negotiation phase about the client’s behavior change. All clients were offered standard outpatient care, and the average client received 12 sessions which included individual and group counseling. Three months later, 91% of them completed a follow-up battery using the Form 90 semi-structured assessment procedure. Cocaine-abusing clients who were offered an MI session reported a significantly greater percentage of days abstinent than did those who were not assigned to the MI session.

sion of sensitization in any motor index. Multiple valproate injections prevented the initiation of MPD elicited sensitization. Multiple administration of valproate also prevented the expression of MPD sensitization to total distance and vertical activity. In conclusion, valproate given before or during the induction phase of MPD is more effective in preventing MPD sensitization than when given after the locomotor effect of MPD has developed.

683

Cocaine and related drugs bind to and block the dopamine transporter (DAT), thereby elevating extracellular dopamine (DA) levels. The direct effects of substrates and transporter blockers on DAT trafficking have not been fully explored. We report the effects of dopamine, amphetamine, and cocaine on DAT trafficking in stably transfected HEK-293 cells expressing human DAT (hDAT), as monitored by confocal microscopy. Within 10 min of exposure of cells to 100 nM DA, a physiologically relevant concentration, the transporter was internalized to intracellular compartments, suggesting that the transporter does not serve as a fixed channel in the membrane of this cell line. After 30 min, the DAT recycled from intracellular compartments to the surface. The internalized DAT was co-localized with nucleolin in the nucleolus. DA exposure also induced transporter dependent nuclear c-fos expression, suggesting that DAT may be involved in gene regulation. Another DAT substrate, amphetamine (200 nM), caused rapid upregulation and internalization of the transporter within 10 min. Treatment with 100 nM cocaine alone, corresponding to the Ki of cocaine for the DAT, also resulted in redistribution and upregulation of the transporter, but differently than DA effects. In the presence of dopamine (100 nM), cocaine ( 100 nM) blocked dopamine-induced internalization of the DAT and [3H]dopamine transport. DA treatment did not change protein levels (Western blot, C-terminal DAT antibody) throughout the time-course, whereas cocaine treatment increased detection of DAT protein. This is the first demonstration that DA alone mobilizes and promotes internalization of the DAT and that cocaine prevents this mobility. This model of DAT trafficking may be useful to identify drugs that block cocaine binding to DAT while permitting DA transport. These results also suggest a novel mechanism for dopamine transport, for drug blockade, and possibly dopamine or dopamine transporter mediated regulation of gene expression. This work was supported by DA 06303, DA 11538, DA 00304,, and RR 00168.

VALPROATE PREVENTS THE INITIATION ANDTHE EXPRESSION OF LOCOMOTOR SENSITIZATION TO METHYLPHENIDATE(RITALIN)

P. Yang, A. Beasley, K. Eckermann, A. Swann, and N. Dafny, University of Texas-Houston Medical School, Houston, TX Repetitive exposure to methylphenidate (MPD) elicits sensitization to its locomotor effects. Drugs that affect the GABA system may modify the chronic effects of drug exposure. Therefore, the effect of sodium valproate, which enhances GABA function, was investigated on the development, or initiation, and the expression of sensitization to MPD in rats. An automated, computerized animal activity monitoring system recorded locomotor activities for 14 consecutive days. Each rat was used as its own control. The doses are 2.5 mg/kg MPD (s.c.) and 50 mg/kg VAL (i.p.). Forty-four male Sprague-Dawley rats were randomized into five treatment groups: [l] a day of baseline and saline injection, MPD for 6 consecutive days (Day 3-8) followed by five washout days and a re-challenge at Day 14 with MPD: [2] similar protocol to the previous group except for a single dose of valproate 1 h prior to the first MPD injection (Day 3); [3] similar protocol to the first group except for a repeated daily dose of valproate 1 h prior to MPD (Days 4-8); [4] similar protocol to the first group except for a single valproate injection prior to washout (Day 9); and [5] similar protocol to the first group except 5 daily doses of valproate after the daily MPD injections were completed (Days 9-- 13). Horizontal activity, total distance, vertical activity, and number of stereotypic movements were recorded and analyzed using ANOVA and posthoc Fischer’s (LSD) test. Multiple injection of MPD elicited sensitization to its locomotor and stereotypic effects. The single valproate injection prevented the initiation of MPD elicited sensitization in two of four motor indices studied but did not prevent the expres-

684

COCAINE BLOCKS DOPAMINE-INDUCED NALIZATION OFTHE DOPAMINETRANSPORTER

INTER-

S.M. Yatin, G. Miller, M. Goulet, X. Alvarez, and B.K. Madras, Harvard Medical School, New England Regional Primate Center, Southborough, MA

Abstracts

s242

685 IN-PATIENT SAFETY EVALUATION (ALPHA-2 ADRENERGIC AGONIST) WITHDRAWAL

OF LOFEXIDINE FOR OPIATE

E. Yu, B.H. Herman, K. Miotto, A. Montgomery, P.J. Fudala, C.N. Chiang, C. Fisher, K. Kampman, V. Dhopesh, K. Mechanic, J. Cornish, B. Walsh, K. Davies, F. Vocci, P. Bridge, W. Ling, and C.P. O’Brien. Phila. VAMC, Phila., PA, DTRD/NIDA/ NIH, Bethesda, MD, Long Beach/LA VAMC, Britannia Pharm, Los Angeles, CA Preliminary data have indicated that lofexidine may be effective for the clinical management of opiate detoxification while producing less hypotension than clonidine. This inpatient study was conducted to assess the relative safety of lofexidine and to obtain information related to its potential efficacy. Opiate-dependent individuals were stabilized on morphine subcutaneously (25 mg four times daily) for l-8 days. Then morphine was discontinued and lofexidine was administered daily for 5 or 10 days followed by no medication for 2 days. Nine subjects took lofexidine in the 1.6 mg per day dosage group (0.8 mg 2 x per day), 23 in the 2.4 mg per day group (14 at 1.2 mg 2 x per day and 9 at 0.8 mg 3 x per day), 12 in the 3.2 mg per day group (0.8 mg 4 x per day) and 3 in the 4.0 mg per day group (1.0 mg 4 x per day). No serious adverse events were observed. One subject (1.2 mg 2 x per day) displayed transient syncope and one subject (0.8 mg 4 x per day) had transient hypertension (165,’ 133 mmHg) the morning after completing lofexidine detoxification. There were transient, orthostatic systolic BP changes (sys BP < 85 mmHg): I .6 mg (n = 2), 2.4 mg (II = 19) 3.2 mg (n = 7) 4.0 mg (n = 3). There were also apparent dose-dependent decreases in opiate withdrawal symptoms. Overall, lofexidine appeared to have minimal hypotensive effects up to up to 4.0 mg per day, although transient orthostatic changes occurred. Support: Britannia Pharmaceutical Ltd and interagency agreements (YOl-DA30012-02, YOl-DA5003800) between NIDA and the Philadelphia and Long Beach VA Medical Centers, respectively. 686 SYNTHESIS AND PHARMACOLOGICAL TION OF 3-(3,4-DICHLOROPHENYL)-l-INDANAMINES LIGANDSFOR BIOGENICAMINETRANSPORTERS

EVALUAAS

H. Yu, X.R. Tian, X.H. Gu, R.B. Rothman, C. Dersch, J.S. Partilla, and K.C. Rice, LMC, NIDDK, NIH, Bethesda, and IRP, NIDA, NIH, Baltimore, MD In our efforts in developing

a single molecular

entity

which would block the effects of methamphetamine at dopamine, serotonin, and norepinephrine transporters, we synthesized a series of 3-(3,4-dichlorophenyl)-l-indanamine analogs. In order to make the compounds amenable to ‘depot’ injection. techniques, a medium to long chain carboxylic acid ester needs to be incorporated into the molecules. Thus, hydroxyl groups were included in these analogs. The binding data indicated that (-)-trans-3-(3,4-dichlorophenyl)-6-hydroxyl-Nmethyl-1-indanamine has high affinities at all three biogenic amine transporters. Biological results to date will be presented. 687

PERPETRATORS.VICT~MS AND OBSERVERS OF VIOLENCE: GENDER DIFFERENCES IN OUT-OF-TREATMENT CHRONIC DRUG USERSVERSUS NON-DRUG USERS

H.V. McCoy, University of Miami Florida International

Z.Yu,

S.E. Messiah, and P. Shapshak, School of Medicine, Miami, and University, North Miami, FL

Introduction: The literature has reported that female drug users experience violence more often than nondrug using women. This paper examines this relationship in more depth by exploring women’ roles as victim, perpetrator and observer of specific violent acts. The purposes of this analysis were to (1) compare the prevalence of violence in males versus females among a sample of out-of-treatment chronic drug users (CDUs) and non-chronic drug users (NCDUs) in Miami-Dade County, Florida and (2) determine the level of risk by gender of becoming a victim, perpetrator, or observer of violence if one uses drugs. Methods: A stratified sample of 1479 NCDlJs and NDUs were interviewed as part of a NIDA-funded health services research study. Subjects provided information pertaining to their exposure to violence as a victim, perpetrator, or observer. Specific violent acts included assault, shooting/stabbing, robbery, killing, and sexual assault. T-tests and logistic regressions were conducted. Results: CDU females committed significantly more violent acts than their NCDU counterparts, but they were also significantly more likely to be the victims of violent acts as well. Whereas NCDU females and males were not significantly different on violent acts. CDU females became victims of violence significantly more often than their male CDU counterparts. Interestingly, female CDUs were also more likely than male CDUs to perpetrate violent crimes, although the difference was not statistically significant. Conclusion: Violence plays a significant role in the lives of female street CDUs. Because female CDUs were more likely than their NCDUs counterparts to be not only victims, but perpetrators of violence as well should shift our views to include these new roles. Specific intervention strategies that take into con-

S243

Abstructs

sideration these multifaceted roles are recommended facilitate violence reduction in women CDUs. 688

MATERNAL

OF THE

OPIOID

RESTRAINT

SEPARATION SYSTEM STRESS

IN AND

AFFECTS ADULT

RATS

TESTS

MRNA

LEVELS

SUBJECTED OF

to

TO

MORPHINE

ANTINOCICEPTION

V. Yuferov, K.W. Easterling, SD. Schlussman, J.R. Mantsch, M. Kalinichev, A. Ho, S.G. Holtzman, and M.J. Kreek, The Rockefeller University, New York, NY. and Emory University School of Medicine, Atlanta. GA Early life experience has been shown to affect the response of animals to stressors in adulthood. Rat pups separated from their mothers for 3 h daily over the first 2 weeks of life (MS) show, as adults, exaggerated behavioral and endocrine response to stressors compared to non-handled (NH) or handled (H) controls. In this study, we measured levels of mRNA of some genes of the opioid system by RNase protection solution hybridization assays in specific brain regions of MS, H and NH rats just after restraint stress (80 min) and tests of morphine-induced antinociception (cumulative dose 8.0 mg/kg; tail flick test). We examined levels of dynorphin (DYN), and ~1opioid receptor (MOR) mRNAs in caudate putamen (CPU) and nucleus accumbens (NAc), and K opioid receptor (KOR) mRNA in substantia nigra (SN) and ventral tegmental area (VTA). Dyn mRNA in NAc was significantly lower in H than in either NH or MS (P < 0.02), but significantly higher in CPU in H compared to MS (P < 0.05). KOR mRNA levels were higher in SN in MS than in the NH (P < 0.05). Finally, levels of MOR mRNA were significantly higher in CPU in H rats than in MS animals (P < 0.05). These results show that early life experiences that alter adult responsivity to stressors can also alter expression of genes in specific brain regions of the opioid system. Supported by: NIH-NIDA grants PSO-DA 05130, K05-00049 to MJK and DA 11384 and K05 DA00008 to SGH. 689 ON

MODULATING EFFECTS OF COLD MORPHINE EFFECTS IN VOLUNTEERS

J.P. Zacny, The University

WATER

STIMULI

of Chicago, Chicago, IL

A painful stimulus has been shown to act as a ‘natural antagonist’ to the respiratory depressant effects of morphine in both volunteers and patients. In the present study we sought to determine if painful stimuli of varying magnitudes would attenuate the subjective and psychomotor effects of morphine in volunteers. Healthy volunteers are currently being enrolled in a randomized, double-blind, placebo-controlled, crossover trial, and

results from this trial will be reported at the meeting. Using a cumulative dosing procedure, volunteers are injected on an hourly basis with intravenous saline (three sessions) or increasing doses of intravenous morphine: 0, 2.5, 5.0, and 10.0 mg/70 kg (three sessions). Thirty minutes after each injection subjects immerse their nondominant forearm in an ice chest for 3 min which contains 37”/ water (not painful), 10% water (PAIN-l) and 2% water (PAIN-2). Forty seconds into the water immersion, subjects complete, with their dominant hand, a 14-item visual analog mood scale corresponding to how they are currently feeling. One hundred ten seconds into the immersion, subjects complete a I-min Digit Symbol Substitution Test. At other fixed times in the immersion, subjects are queried on how painful the water is and how much it bothers them on a scale of O-10. This experimental methodology allows us to manipulate intensity of the painful stimulus as well as dose of morphine in a 2 (saline vs. morphine) x 3 (37%lo%,-2%) design to determine the degree to which pain of different intensities alters subjective and psychomotor effects of a prototypic mu opioid. Studies which examine potential interactions of opioid effects and painful stimuli may have more relevance to clinical populations (e.g., postoperative patients in pain) than studies which examine opioid effects in psin-free volunteers. Supported in part by NIDA grant DA-08573. 690

STIMULANT

DREN

WITH

HYPERACTIVITY

OR

MEDICATIONS WITHOUT

DSM-IV

AMONG ATTENTION

RURAL

CHILDEFICIT

DISORDER

G. Zahner, Li-Tzy Wu, and G. Bobashev, Research Triangle Institute, Research Triangle Park, NC This study examined the extent to which stimulant medications were prescribed for children with or without parent-reported DSM-IV disruptive behavior disorders/syndromes. The general population sample that was studied consisted of 1252 children ages 4- 11 living in a four-county rural area in Maine whose primary caregivers completed structured interview schedules. Diagnoses were based on parent’s reports on the child’s behaviors elicited by Diagnostic Interview Schedule for Children (NIMH-DISC-IV). Data on medication use were based on parent’s reports. Patterns of medication use during the previous 12 months were examined separately for parent-reported DSM-IV Attention Deficit Hyperactivity Disorder (ADHD), Oppositional Defiant Disorder (ODD), and Conduct Disorder (CD), as well as by three additional subclinical subgroups and co-occurring syndromes. In the total sample, 4.4% of children used any psychotropic medication, 2.1°/ were treaied with Ritalin, and 2.7% were treated with other stimulants other than Ritalin or other psychotropic

Abstracts

s244

drugs (e.g. antidepressants). Psychotropic medication use varied by age and the highest rate (9.9%) was observed among children aged 10 at the time of the assessment. Use of Ritalin and other psychotropic medications tends to be higher among children with parentreported CD (12.3%) than ADHD (5.6%) or ODD (5.3%). For ADHD and ODD, rates of Ritalin or other medication use did not differ among clinical, subclinical, and no-disruptive syndrome categories. Children with clinical CD had significantly higher rates of Ritalin use (9.2%) than children with subclinical CD (2.1%) and non-CD cases (1.9%) [c2 = 8.11, df = 2, P = 0.0171. For rural children whose parents reported a clinical syndrome, psychotropic medication use among boys was 16.2% for CD, 8.3% for ODD, and 7.7% for ADHD. No girls with clinical CD or ADHD used any psychotropic medication and only 1.3% of girls with clinical ODD received psychotropic medication, none of which was Ritalin. Comorbidity of disruptive behavior disorders/syndromes appears to have no association with the use of Ritalin and other psychotropic medications in rural 4- 11 year old children. The high rate of psychotropic medication use for CD is not consistent with recent clinical practice guidelines. Continuing attention needs to be given to gender differences in treatment of disruptive behavior syndromes. Supported by NIH cooperative agreement UOlMH51465. 691 LATION

RITANSERIN CAUSED

BLOCKS BY

OPIATE

EXTRA-EMBRYONIC WITHDRAWAL

VASODIIN

CHICKEN

EMBRYOS

X. Zhang and S.B. Sparber, University of Minnesota, Minneapolis, MN Infusion of naloxone (Nx) into eggs with opiate-dependent or control chicken embryos was carried out on day 15 of embryogenesis (E15) in order to determine the effect upon the apparent diameter of extra-embryonic blood vessels as a measure of a cardiovascular manifestation of withdrawal. A total of 28 eggs were used. The opiate-dependency was induced by a bolus injection of NLAAM (5mg/kg egg) into eggs on E3 and saline (NaCl) as the control. Vessels in the membrane beneath the air cell were video recorded through a surgical endoscope on E 15 and analyzed with NIH image before and at 5, 7.5, 10 min after starting an infusion (Inf) with Nx (0.5mg/kg egg/min) and 5 min after the infusion (PI). Eggs were injected with the 5-HT2 antagonist ritanserin (Rit, 0.3mg/kg egg) or its tartrate vehicle (Ta) 16-24 h ealier. The results (table 1) show that Nx caused significant vasodilation in opiate-dependent embryos and it was blocked by Rit pre-treatment. We conclude that the vasodilation is a compensatory cardiovascular response to the increased metabolic de-

mands of embryonic opiate withdrawal and 5-HT2 receptors play an important role. If upstream manifestations are antagonized by Rit, compensatory vasodilation ceases to be necessary. 692 LEASE

EFFECT IN THE

PUTAMEN, FISCHER

AN

OF ORPHANIN FQ ON NUCLEUS ACCUMBENS

DOPAMINE REAND CAUDATE

IN

STUDY

VIVO

MICRODIALYSIS

IN

THE

RAT

Y. Zhang, S.D. Schlussman, E. Butelman, A. Ho, and M.J. Kreek, The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY Orphanin FQ is the endogenous ligand of the orphan opioid-like receptor, which is widely distributed throughout the CNS. Orphanin FQ shares sequence homology with the endogenous opioids, particularly dynorphin. In this study the effect of Orphanin FQ on the release of the neurotransmitter dopamine and its metabolites in the shell of the nucleus accumbens and the caudate putamen were studied in the awake freelymoving male Fischer rat by in vivo microdialysis. Orphanin FQ was applied to the shell of the nucleus accumbens or caudate putamen by reverse dialysis while extracellular dopamine was collected through the same microdialysis probe. Orphanin (1 mM) significantly decreased basal dopamine levels in the nucleus accumbens and caudate putamen by 43.2 and 26.7%, respectively (n = 6, P < 0.05). Orphanin FQ also significantly decreased the levels of the dopamine metabolite DOPAC by 8.8% in the nucleus accumbens (n = 6, P < 0.05) but did not change the basal levels of DOPAC in the caudate putamen. Preliminary analysis of an ongoing study showed that Orphanin FQ significantly attenuates the cocaine-induced release of dopamine in the nucleus accumbens (n = 4 per group, P < 0.05). These data suggest that the neuropeptide Orphanin FQ may be involved in regulation of the neurotransimitter dopamine, and may blunt cocaine-induced dopamine release in the nucleus accumbens and caudate putamen, areas known to be important in addiction. Supported by NIH-NIDA grants P50 DA05130 and K05 DA00049 to MJK. 693 COCAINE

ROLE

OF ESTROGEN TREATMENT

IN THE

IN FEMALE

RESPONSE

TO

ACUTE

RATS

W. Zhou, K.A. Cunningham, and M.L. Thomas, University of Texas Medical Branch, Galveston, TX The behavioral effects of psychostimulants such as cocaine and amphetamine are more pronounced in female than male rats. Data from our laboratory have demonstrated that estrogen (E) is an important component of

S245

Absiracts

the gender difference in response to cocaine. To address the mechanisms underlying this E effect, we have determined the dose-response relationship for cocaine to evoke hyperactivity in the presence and absence of E. Mature female rats (n = 8 rats per group, 8 groups total) were ovariectomized (OVX) or OVX and implanted with E-filled silastic capsules (OVX + E). Three weeks later, locomotor behavior was recorded for 120 min following i.p. administration of saline, 5, 10, or 20 mg/kg cocaine. Analysis of the resulting data revealed E enhancement of the hyperactivity in response to cocaine, as well as a significant interaction between E and cocaine treatments (two-way ANOVA, P = 0.03). Based on these results, we hypothesize that E may modulate the behavioral response to cocaine via its regulation of gene expression of components of the serotonin (5-HT) and dopamine (DA) systems within the mesolimbic circuit that is important in the response to cocaine. Thus, ribonuclease protection assays will be used to determine differences in transcript levels for specific 5-HT and DA receptors and transporters between OVX and OVX + E rats. The results from these studies should provide new insights into gender-dependent aspects of both abuse liability and potential therapeutic strategies for drug dependence in women. Supported by DA 06511 and DA 00260. 694 TOLERANCE OF HPA RESPONSE DEVELOPS AFTER CHRONIC ‘BINGE' COCAINE WITH INCREASES IN PITUITARY CRFI RECEPTOR AND POMC Y. Zhou, R. Spangler, SD. Schlussman, KS. LaForge, A. Ho. and M.J. Kreek, Rockefeller University, New York, NY We have previously examined the time course of the effects of cocaine on CRF mRNA levels in the hypothalamus and plasma corticosterone levels during 14 days of ‘binge’ pattern cocaine administration (BPCA), and have found that there are increases in CRF mRNA with elevated corticosterone after 1 day of acute BPCA, followed by decreases in CRF mRNA with attenuated corticosterone responses after 14 days of chronic BPCA. In the present study, BPCA (3 x 15 mg/kg per day) to male Fischer rats led to elevated HPA hormone levels after 1, 3 or 7 days, followed by significantly attenuated HPA hormone responses after 14 days, as measured by plasma ACTH and corticosterone levels. We also examined the time course of CRFl receptor and POMC mRNA levels at the pituitary and hypothalamic levels. In the anterior pituitary, CRFl receptor and POMC mRNA levels were increased after 14 days with no changes from 1 through 7 days. In contrast, in the neurointermediate lobe/posterior lobe, POMC mRNA levels were reduced from 3 through 14 days. In the hypothalamus, no alterations of either CRFl recep-

tor or POMC were found. These changes in the functional integrity of the HPA axis may affect responsivity, which in turn may contribute to the development and persistence of an addiction. NIH NIDA Grant P50 DA-05130 and K0.5 DA-00049. 695

TWO-YEAR OUTCOMES ERY AFTER 2%DAY INTENSIVE

AND CHANGES IN RECOVRESIDENTIAL TREATMENT

D. Ziedonis, 1. Pinsky, J. Krecji, and C. Eick, Robert Wood Johnson Medical School, Piscataway, NJ, and Pavillon International, Mill Spring, NC Hypothesis: Patients treated in 2%day treatment programs will maintain long-term abstinence, and engagemenl. in 12-Step activities will be associated with improved outcomes. Procedures: 420 consecutive patients admitted for 2%day addiction treatment were evaluated using the Addiction Severity Index (ASI) at baseline and every 6 months for 2 years. The treatment program is a closed-group model with about 25 patients per treatment session and each session starts and ends with the same group of patients. Results: About 27% were alcohol dependent only, 51% drug and alcohol dependent, and 22% were poly-drug dependent. Baseline ASI severity scores was 1.3 medical, 2.8 employmenl., 1.0 legal, 5.9 family, and 5.3 psychological. Statistical analysis included t-test. x’, and multi-variate anal:ysis. At follow-up, 63% reported complete abstinence at six-months (70% follow-up) and abstinence rates were 69% at 12 months, 76% at 18 months, and about 80% at 24 months. Patients staying active in 12-Step recovery had better outcomes. By the second year patients in recovery became active in other social networks (religious in particular). Iqxwtanc~r of fimlings: This study is one of only a few reports on the long,-term outcomes for 2%day intensive residential programs. Private addiction treatment recovery programs can participate in evaluating outcomes and improving our understanding of the recovery process. 696

GENDER DIFFERENCES IN LEPTIN ING 14 DAYSOFCOCAINEWITHDRAWAL

INCREASE

DUR-

Z. Zimolo, R.M. Berman, H. Klumpp, G.R. Heninger, and R.T. Malison, Yale University, New Haven, CT, Relapse on cocaine use is influenced by stress. Cocaine use and withdrawal have been associated with the change in appetite and food intake. Leptin, initially described as an adipocyte derived 16 kDa signaling protein that regulates food intake, has been shown to be produced in brain. Leptin receptors are expressed in multiple brain areas including hypothalamus, cortex, cerebellum and dorsal raphe nucleus. Leptin is involved

S246

Abstract5

in several neuroendocrine functions: food intake, energy expenditure, metabolism, neovascularization, immune response, brain reward circuitry and has been shown to affect the activity of the HPA axis. It inhibits the corticosterone and ACTH response to restraint stress in rats and inhibits hypoglycemia induced CRH release in isolated, perfused rat hypothalami. Diurnal changes in plasma cortisol and leptin demonstrate an inverse relationship in healthy humans. We have previously shown that surgical stress decreases leptin and increases cortisol in humans during the first 2 h of surgery that is followed by leptin increase over baseline 24 h later. In this study we followed weight and serum leptin levels in male (n = 5) and female (n = 5) subjects who were acutely withdrawing from cocaine. Subjects were hospitalized within 2 days of the last cocaine use and leptin levels were measured on days 1,2,4,6,9 and 13 at 8 h. Leptin was assayed by ELISA. Results: Over 13 days, mean leptin levels increased 32.4 _+ 4.64% (S.E.M. P < 0.01) over baseline in all subjects. When assessed by gender, leptin levels increased 58.5 &- 12.2% in females and 12.9 f 8.4% over baseline in males, exhibiting gender difference (P < 0.05). Females exhibited robust increase already on the second day of hospitalization (mean = 30.0%). Although, the subjects exhibited transient increase in weight, no statistically significant changes in weight or body mass index occurred over 13 days. As acute leptin changes have been described to occur in stress and leptin is related to the HPA axis activity and possibly brain reward circuitry, this could suggest that men and women, as assessed by leptin changes, could have different stress response during cocaine withdrawal.

697 SYNTHESIS OF NOVEL PHOTOAFFINITY FORTHEDOPAMINETRANSPORTERBASEDONN-SUBSTITUTED4',4<-DIFLUOROBENZTROPINE

LABELS

M. Zou, T. Kopajtic, J.L. Katz, and A.H. Newman, National Institute on Drug Abuse-Intramural Research Program, NIH, Baltimore, MD Benztropine and its analogs are tropane ring-containing dopamine uptake inhibitors that display binding and behavioral profiles that are distinct from cocaine. We previously prepared a benztropine-based photoaffinity label (GA 11-34) that covalently attached to the l-2 transmembrane region of the dopamine transporter (Vaughan, et al. 1999). This was in contrast to the 4-7 transmembrane region photolabeled by a cocaine-based photoaffinity label, RTI 82. In order to further characterize these different binding domains, optimization of binding potency was required for the benztropine-based ligand. Since the addition of the I and N3 functions decreased binding affinity of the parent ligand (Nbutylphenyl) by 20-fold, we reasoned that shortening the alkyl chain between the N and the pendant phenyl ring might achieve higher affinity at the dopamine transporter. In this pursuit, we have synthesized the propylphenyl analog, MFZ I-l 17 as well as two irreversible ligands that do not require photoactivation (MFZ 11-7, MFZ I-121). The synthesis of these target compounds was achieved using a modification of the strategy developed for GA II 34 and irreversible binding experiments are underway. When the optimal N-substitution is identified, this substituent will be incorporated into a cocainebased ligand to allow a direct comparison of the two photolabels for further characterization of their binding domains at the dopamine transporter.