Hostility is associated with a heightened prolactin response to meta-chlorophenylpiperazine in abstinent cocaine addicts

Psychiatry Research 80 Ž1998. 1]12

Hostility is associated with a heightened prolactin response to meta-chlorophenylpiperazine in abstinent cocaine addicts Leonard Handelsmana,U , Rene S. Kahn b , Christopher Sturiano c,d , Paul J. Rinaldi e , Steven Gabriel c,d , James P. Schmeidler c,d , David P. Bernstein c,d , Larry Siever c,d , Thomas B. Cooper f a

Duke Uni¨ ersity Medical Center, Box 3516, Durham, NC 27710, USA b Uni¨ ersity of Utrecht, Utrecht, The Netherlands c VA Medical Center, Bronx, NY, USA d Mount Sinai School of Medicine, New York, NY, USA e St. Luke’s-Roose¨ elt Medical Center, New York, NY, USA f Nathan Kline Institute, Orangeburg, NY, USA

Received 3 December 1997; received in revised form 26 March 1998; accepted 10 April 1998

Abstract The prolactin ŽPRL. response to the administration of serotonin Ž5HT. agonists is an index of central nervous system 5HT activity. This index is blunted in association with hostile aggression in personality and depressive disorder patients without substance abuse. We tested whether the PRL response to the oral administration of the partial 5HT agonist meta-chlorophenylpiperazine ŽMCPP., 0.35 mgrkg, was associated with a measure of trait hostility, the Buss Durkee Hostility Inventory ŽBDHI., in cocaine addicts who were completing a 3-week detoxification and rehabilitation program. We also tested whether the cocaine addicts differed from healthy volunteers on their PRL, cortisol ŽCORT. or temperature responses to MCPP. The PRL response to MCPP was positively associated with the total score on the BDHI. There were, however, no differences in the neuroendocrine or temperature responses to MCPP between the cocaine-dependent group and the healthy volunteers once age effects were controlled for. Q 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Serotonin; Aggression; Substance abuse

U

Corresponding author. Tel.: q1 919 6607459; fax: q1 919 6817421; e-mail: [email protected]

0165-1781r98r$19.00 Q 1998 Elsevier Science Ireland Ltd. All rights reserved. PII S0165-1781Ž98.00048-1

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1. Introduction Hostile ideation and behavior, often linked to impulsiveness, aggression and anti-social personality, constitute a serious problem in cocaine or crack addicts ŽBradford et al., 1992.. Although the factors giving rise to hostility are complex ŽTaylor and Chermack, 1993; Olivier et al., 1995., serotonergic Ž5HTergic. abnormalities in the central nervous system ŽCNS. have been reported repeatedly in clinical, forensic and general populations ŽSiever et al., 1991.. One established method to assess CNS 5HTergic function is the 5HT agonist challenge paradigm ŽMurphy et al., 1990.. In this model, the increases in prolactin ŽPRL ., adrenocorticotrophic hormone, and cortisol ŽCORT. levels and in temperature to the administration of a 5HT agonist index the dynamic responsiveness of CNS 5HT activity ŽSiever et al., 1991.. Mediated in part by 5HT2ar2c receptors, these increases may be induced reliably by both direct and indirect 5HT agonists. Meta-chlorophenylpiperazine ŽMCPP. predominantly has the profile of a 5HT2ar2c partial agonist, although recent studies suggest other pharmacological activities ŽBaumgarten and Grozdanovic, 1995.. Administered either orally or intravenously, MCPP rapidly stimulates endocrine and temperature responses in a dose-dependent manner ŽKahn and Wetzler, 1991., and interestingly, produces the sensation of being ‘high’ in some cocaine addicts and alcoholics ŽBenkelfat et al., 1991; Buydens-Branchey et al., 1997; Krystal et al., 1994.. In contrast, fenfluramine primarily induces the release of 5HT from endogenous pre-synaptic stores and thus may index both presynaptic and post-synaptic 5HT activity. It has not been shown to induce high feelings in substance abusers. For these reasons, we selected MCPP as the 5HT challenge agent in our initial studies. The connection between 5HT function and hostility is particularly complex in addictive disorders ŽRoy et al., 1991; Naranjo and Bremner, 1994.. Serotonergic deficits have been detected in early onset ‘Type II’ problem drinking, while studies in rodents demonstrate an association of low CNS 5HT activity with alcohol preference and self-administration behavior ŽRoy et al., 1991.. A

blunted temperature response to the 5HT2ar2c partial agonist MK-212 and a blunted PRL response to MCPP have both been reported in cocaine addicts ŽLee and Meltzer, 1994; Buydens-Branchey et al., 1997. indicating a possible alteration of 5HT function. Although many of the behavioral effects of cocaine are related to dopamine function, 5HTergic abnormalities have also been linked to chronic exposure to cocaine in rodents ŽLevy et al., 1993; Baumann and Rothman, 1995; Callahan and Cunningham, 1995; Parsons et al., 1995; Schechter and Mehan, 1995.. Serotonergic manipulations may alter the psychological effects of cocaine. For example, MCPP, when administered to cocaine users, causes a ‘high’ ŽBuydens-Branchey et al., 1997.. Treatment with fluoxetine has been reported to alter the high caused by cocaine ŽWalsh et al., 1994. whereas reduction of CNS 5HT by depletion of dietary tryptophan attenuates the cocaine high ŽAronson et al., 1995. as well as cue-triggered craving for cocaine ŽSatel et al., 1995.. Hostile or impulsive personality disordered individuals and auto-aggressive individuals are reported to have a blunted PRL response to 5HT agonist challenge ŽCoccaro et al., 1989; Siever et al., 1991; Mann et al., 1992.. We have found a similar inverse association in abstinent alcoholics whose serotonergic activity was assayed in the same way we describe in this article ŽHandelsman et al., 1996.. In drug addicts, however, studies of the 5HT correlates of personality traits have produced contradictory findings. Moss et al. Ž1990. have reported an association of aggression with blunted PRL response to MCPP administration in anti-social, substance-abusing individuals, and Buydens-Branchey et al. Ž1997. have reported a blunted CORT response to MCPP in aggressive vs. non-aggressive detoxified cocaine addicts. In contrast, Fishbein et al. Ž1989. have reported a positive association between a history of early childhood aggression and the PRL response to fenfluramine, an indirect 5HT agonist, in adult, treatment-seeking addicts. The primary purpose of this study was to examine the association of indices of hostility with the PRL response to the administration of MCPP in cocaine addicts. A secondary purpose was de-

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scriptive: to compare the cocaine addicts with a group of healthy volunteers on their PRL, CORT and temperature responses to MCPP and thus to confirm the finding of a blunted temperature response in cocaine addicts reported by Lee and Meltzer Ž1994. or the finding of a blunted PRL response in cocaine addicts as reported by Buydens-Branchey et al. Ž1997.. 2. Methods 2.1. Subjects Subjects were male veterans who sought a 2]3-week course of detoxification and inpatient rehabilitative treatment for cocaine or crack dependence Ž n s 19.. They were free of psychoactive medication for at least 2 weeks prior to the first challenge with MCPP or placebo. The lifetime years of regular cocaine use on three occasions per week or more were 6.8" 5.0 Žmean " S.D... The number of days that cocaine had been used in the 30 days prior to admission was 18 " 12. The lifetime years of regular ethanol use were 8.6" 8.0. The number of days that alcoholic beverages had been used in the 30 days prior to admission was 9 " 11. There was no history of regular heroin use. Seven of 19 patients were clinically diagnosed with antisocial personality disorder. Healthy control subjects were males recruited from the community by advertisement who typically were unemployed tradesmen or office workers Ž n s 11.. All participants gave written informed consent which had been reviewed and approved by the Human Subjects Committee of the medical center. 2.1.1. Inclusion criteria Patients were included if they were male veterans between 21 and 50 years old and if they fulfilled DSM-III-R criteria ŽAmerican Psychiatric Association, 1987. for cocaine dependence, had active symptoms for at least the 3 months prior to admission for treatment and used cocaine within 1 week prior to admission. All cocainedependent subjects were found to have at least one urine toxicology sample positive for benzoylecgonine by EMIT during the week prior to

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admission or at admission. Control subjects were males over age 21 who were free of Axis I disorders including current psychoactive substance use disorders with the exceptions of caffeine or nicotine dependencies. 2.1.2. Exclusion criteria Patients were excluded if they had any major medical illness, were taking any systemically active medication for a medical condition or had laboratory signs indicative of liver disease as defined by alanine aminotransferase or aspartate aminotransferase levels greater than five times the laboratory reference maximum level Žmaxima: 45 and 41 IUrl, respectively. or an alkaline phosphatase level twice the laboratory reference maximum level Žmaximum: 115 IUrl.. Patients were excluded if they fulfilled criteria for a major psychiatric disorder including lifetime diagnoses of schizophrenia, bipolar disorder, and current diagnosis of major depression or withdrawal-induced depression. They were also excluded if they fulfilled criteria for another psychoactive substance use disorder in the 3 months prior to the study with the exceptions of caffeine and nicotine dependencies. 2.2. Instruments 2.2.1. Inter¨ iews The Addiction Severity Index ŽASI. ŽMcLellan et al., 1980. is a 1]2-h structured interview assessing the severity and pattern of drug and alcohol use, as well as impairment in several functional areas Ži.e. occupational, medical, legal, interpersonal, and psychiatric.. It was used to delineate criteria for psychoactive substance use disorder diagnoses and various inclusion and exclusion criteria in the cocaine-dependent subjects only. The Structured Clinical Interview for DSM-IIIR ŽSCID-P. ŽSpitzer et al., 1992. is a 1]2-h interview with well-established reliability that covers the entire range of DSM-III-R Axis I disorders, including diagnostic criteria for drug and alcohol abuse and dependence. When the SCID is used to determine psychoactive substance use disorders in clinical populations of addicts and alcoholics, the inter-rater reliability at our institution for these disorders is very high Ž k ) 0.9.. This

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interview was administered to patients during the second week on the drug treatment unit and to the potential normal control subjects by appointment. Methods for training interviewers for the ASI and the SCID have been described elsewhere ŽBernstein et al., 1994.. 2.2.2. Questionnaires The Buss]Durkee Hostility Inventory ŽBDHI. ŽBuss and Durkee, 1957. is a 75-item questionnaire which inquires about various aggressive and angry thoughts, feelings and behaviors in a true]false format. Subjects were instructed to respond in terms of their usual adult behavior when they have not been intoxicated. The BDHI yields an overall score, as well as scores on subscales, although the stability and validity of the subscales has been questioned ŽHolland et al., 1983; Ramaniah et al., 1987.. Despite these potential limitations to the use of the subscales of the BDHI, the personality disorder literature includes reports of selective associations of low PRL response to FEN challenge with the irritability and assaultiveness subscales of the BDHI ŽCoccaro et al., 1989.. Planned statistical analyses were restricted to the BDHI total score, the irritability subscale and the assaultiveness subscale. The questionnaire was administered to the cocaine-dependent subjects only. 2.2.3. Assessments during the MCPP challenge protocols Visual analogue drug discriminant scales consisted of seven non-numerated 100-mm scales which were administered hourly after the administration of MCPP or placebo. The scales, which we designed, measure the resemblance of the subject’s subjective state with alcohol-, benzodiazepine-, narcotics-, or cocaine-induced states and with ‘high’ feelings, unpleasant feelings and cravings to use drugs or alcohol. Each scale is anchored from zero Ž‘not at all’. to 10 Ž‘very strong’.. This instrument was administered to the cocainedependent subjects only. The pulse and blood pressure were measured at baseline prior to administration of MCPP or placebo and every 30 min thereafter Žuntil q210

min. using an automated Dinamap system. Temperature was measured orally on the same schedule using an IVAC thermometer. 2.2.4. Assays of blood moieties During each challenge, blood samples were drawn via an indwelling, heparinized venous catheter at baseline and every 30 min until q210 min. Blood was drawn back into a syringe and then centrifuged under refrigerated conditions. Plasma was partitioned and stored in a freezer at y808C. 2.2.5. Hormone assays PRL was quantified using a room-temperature modification of the radioimmunoassay materials provided by ICNrMicromedic ŽCarson, CA.. Samples, standards and control samples were assayed in 100-m l aliquots and run under equilibrium conditions with 100 m l each of primary antibody and radio-iodinated tracer. Phase separation was achieved by the addition of 0.5 ml of a goat anti-rabbit gamma globulinrpolyethylene glycol solution followed by centrifugation, decanting and gamma-counting of the precipitate. All samples were run in duplicate. The PRL radioimmunoassay has a sensitivity of 1.5 ngrml. The intra- and inter-assay coefficients of variation are 4 and 10%, respectively. CORT concentrations were determined in unextracted plasma using a kit purchased from ICNrMicromedic ŽCarson, CA.. The CORT antibody displays 100% cross-reactivity with CORT, 35% cross-reactivity with prednisolone, 14% cross-reactivity with 11-deoxycortisol, 11% cross-reactivity with corticosterone, 2% cross-reactivity with prednisone and cortisone, 0.05% cross-reactivity with dexamethasone and no significant recognition of other adrenal or gonadal steroids. The primary CORT antibody is covalently bound to test tubes while sample, buffer and w 125 IxCORT are added in rapid succession and incubated at 378C. Phase separation was achieved by decanting the supernatant and counting the tube-bound radioactivity. All samples were run in duplicate. Sensitivity of the assay is 0.5 m g% and the ED50 is 8.2 m g%. The intra- and inter-assay coefficients of variation are 6 and 10%, respectively.

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2.2.6. Plasma MCPP le¨ el MCPP was assayed by a published HPLC method in the laboratory of Thomas Cooper ŽSuckow et al., 1990.. Samples were obtained at 60 and 180 min after ingestion of MCPP or placebo. Peak plasma MCPP level was used as a covariate in correlational analyses testing the association of biological or subjective responses with measures of behavioral or personality traits or in comparisons of biological responses between the two experimental groups. 2.3. Procedures 2.3.1. Recruitment, enrollment, compliance and pre-protocol preparation Enrollment for all subjects was conducted after obtaining written informed consent. Cocaine subjects were screened for inclusion and exclusion features by the psychiatric director of the rehabilitation unit upon admission. Those subjects who appeared to meet the study criteria were invited to participate and gave written informed consent for further evaluation and study. During the subsequent 2 weeks, subjects were administered the ASI, SCID-P, and BDHI by research assistants and continued only if the study criteria were formally fulfilled. During the 2 weeks following admission to the controlled-access, inpatient drug treatment unit and immediately prior to the MCPP challenge protocol, the cocaine-dependent subjects participated in a behavioral rehabilitation program which included random breathalyzer testing for alcohol level and random urine toxicology tests. Any positive test disqualified the subject from participating in the study. Subjects received no medication apart from vitamin supplements and chloral hydrate, 500 mg p.o., for insomnia. In no case was a medication discontinued nor was any patient deprived of a clinically indicated medication. Caffeinated beverages and tobacco were available on the ward. Three days prior to the MCPP protocol, a low monoamine diet was instituted. Subjects remained on this diet until completion of both active and placebo sessions of the MCPP challenge. Healthy control subjects were recruited from the community by

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advertisement in a local newspaper as part of another study conducted in the same clinical laboratory. Screening included a complete medical evaluation, a laboratory panel consisting of an SMA20, complete blood count, urinalysis, and VDRL, and a SCID-P interview. Healthy control subjects were asked to follow the same medication free regimen and low monoamine diet while they continued to live at home. All subjects were reimbursed for their participation. 2.3.2. Medication preparation, dose, randomization, blinding Each subject was administered MCPP and placebo in a randomized order. MCPP was purchased from Aldrich Chemicals and manufactured into 5-mg capsules by the pharmacy of the medical school affiliate, which also manufactured identical placebo capsules. The dose of MCPP was 0.35 mgrkg, p.o., rounded to the nearest 5-mg unit. This dose was selected based on the suggestion that a dose intermediate between 0.25 and 0.50 mgrkg was best in situations in which the direction of the findings was uncertain ŽKahn et al., 1990.. The order of the administration of MCPP and placebo was assigned randomly by an independent physician who was on call to the protocol in case of medical problems, but was otherwise separated from the experiment. The research assistant and patient were both blind to medication order assignment. 2.3.3. MCPPr placebo challenge protocol The challenges consisted of a pair of identical protocols separated by at least 72 h. The flow sheet for each session is depicted in Table 1. 2.4. Statistical analyses Comparisons between the cocaine-dependent subjects and normal control subjects were performed using t-tests, chi-square tests or analyses of variance and covariance. Comparisons between psychological responses under MCPP and placebo conditions were performed using Wilcoxon tests. Associations between hormonal or temperature responses to MCPP administration and behav-

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Table 1 Flow chart for MCPPrplacebo challenge session Time 12:01 h 08.00]08.30 h

09.40 h Žy20 min. 09.55 h Žy 5 min. 10.00 h Ž0 min. Double blind administration of MCPP 0.35 mgrkg or else placebo by mouth 10.30 h Žq30 min. 11.00 h Žq60 min. 11.30 h Žq90 min. 12.00 h Žq120 min. 12.30 h Žq150 min. 13.00 h Žq180 min. 13.30 h Žq210 min. Catheter is removed. Subject returns to ward. Normal control goes home

Nothing by mouth except water Subject arrives in protocol room and rests in semi-recumbent position. IV catheter is placed Baseline 1: Vital signs ŽVS. Blood: baseline 1 PRL, CORT Baseline 2: VS blood: baseline 2 PRL, CORT

VS Blood: PRL, CORT VS Blood: PRL, CORT, MCPP level Discrimination analogue scales VS Blood: PRL, CORT VS Blood: PRL, CORT, MCPP level Discrimination analogue scales VS Blood: PRL, CORT VS Blood: PRL, CORT Discrimination analogue scales VS Blood: PRL, CORT

Abbre¨ iations: MCPP, meta-chlorophenylpiperazine; PRL, prolactin; CORT, cortisol.

ioral trait measures were examined with Pearson product-moment coefficients or partial correlations. The main hypothesis that hostility in cocainedependent individuals is associated with 5HT activity was tested with a partial correlation of peak increase in PRL level Ž D peak PRL. induced by MCPP administration with the BDHI total score controlling for the peak plasma level of MCPP. We controlled for peak plasma MCPP level because preliminary analyses revealed an association between MCPP level and D peak PRL Ž D peak PRL, r Ž ns 30 . s 0.48, P- 0.01; D peak temperature, r Ž ns 30 . s 0.41, P- 0.05; D peak CORT, r Ž ns 30 . s 0.26, P) 0.05.. D peak PRL was defined as the difference between the maximum PRL level after administration of MCPP and the average of the two baseline measures obtained 20 and 5 min prior to administration of MCPP. Similarly, we tested the association of the BDHI irritability and assaultiveness subscales with the PRL response using partial correlations. For each par-

tial correlation, statistical significance was set at 0.05, two-tailed. Based on the finding of Lee and Meltzer Ž1994., we compared cocaine-dependent subjects and control subjects with regard to D peak temperature induced by MCPP by conducting an analysis of variance, covarying for age, with a significance level set at 0.05, two-tailed. Similar analyses of variance Žcovarying only for respective baseline values. for D peak PRL and D peak CORT levels were conducted with a significance level set at 0.05, two-tailed. The analysis for the PRL response was used to confirm the finding by Buydens-Branchey et al. Ž1997. of a blunted PRL response to MCPP in cocaine addicts compared with normal subjects. In order to confirm the findings based on ‘D peak’ measures, we compared the groups for the temperature, PRL and CORT responses, respectively, using analyses of variance covarying for peak plasma MCPP level, the respective baseline measurement and, in the case of temperature, age. ŽAge of the subject was

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associated inversely with D peak temperature w r Ž ns 30 . s y0.48, P- 0.01x, but not with D peak PRL or D peak CORT.. Using mixed factorial and repeated measures analyses of variance with Huynh]Feldt corrections, we also tested whether the groups differed in the shape of the respective response curves over time. Statistical significance for these analyses of variance and covariance was set at 0.05, two-tailed. The statistical comparisons of the cocaine addicts vs. healthy volunteers tests should be understood as having heuristic value only, since the MCPP challenges in the cocaine addicts and healthy volunteers were not conducted contemporaneously. Analyses were limited to subjects with a full complement of MCPP samples. Nineteen cocaine-dependent individuals and 11 healthy volunteers were included in the final data analysis. Some analyses contain fewer subjects due to missing data points. 3. Results The demographic features and baseline PRL, CORT and temperature of the cocaine-dependent and healthy subjects are depicted in Table 2. The group of cocaine addicts was older and

Table 2 Demographic features and baseline PRL, CORT and temperature of the cocaine addicts and healthy subjects Cocaine Addicts a

Age Žyears.

Ethnicity Euro]American African]American Hispanic Baseline hormone and temperaturea PRL Žngrml. CORT Ž m g%. Temp Ž8C. a

Mean " S.D.

Normals

Statistic

37.1" 3.7 31.7" 6.5 t Ž28. s 2.93 P- 0.007 1 13 5

9 2 }

x2 s 18.7 P- 0.001

7.5" 3.0 t Ž27. s 2.51 P- 0.02 11.7 " 3.8 9.7" 3.7 t Ž28. s 1.47 Ps 0.15 36.3" 0.2 36.4" 0.4 t Ž28. s y0.66 Ps 0.51 10.7" 3.4

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included a greater proportion of African] Americans than the group of healthy control subjects. Baseline PRL levels for the cocaine addicts were modestly but significantly higher than for control subjects. Fig. 1 depicts the temperature, PRL and CORT responses to the administration of MCPP. We found no significant differences between the cocaine-dependent group and the healthy volunteers in their D peak responses to challenge with MCPP: temperature response, covarying for peak MCPP level and age, F1,26 s 0.73, Ps 0.40, 95% confidence interval Žy0.40, 0.13.; PRL response, covarying for peak MCPP level, F1,26 s 1.5, Ps 0.23, 97.5% confidence interval Žy1.2, 10.4.; CORT response, covarying for peak MCPP level, F1,26 s 0.02, Ps 0.88, 97.5% confidence interval Žy1.9, 2.7.. If age were not controlled for in the between-groups comparison of D peak temperature, the cocaine addicts would appear to have had a marginally significant blunting of the oral temperature response to MCPP compared with the control subjects: F1,27 s 4.5, P- 0.05. Confirmatory tests using analyses of variance and covariance for repeated measures yielded similar results Žsee legend for Fig. 1.. After covarying for the respective baseline measurement, for the peak plasma MCPP level and, in the case of temperature, for age, we found no differences between groups in the magnitude or temporal pattern of the temperature, PRL or CORT responses to the MCPP challenge. Table 3 depicts the correlations of the PRL, CORT and temperature responses to MCPP with BDHI scores. We found a positive association between the BDHI total score and D peak PRL covarying for peak plasma MCPP in the cocaine addict group. We also found a positive association between the BDHI irritability subscale and D peak PRL, but not between the assaultiveness subscale and D peak PRL. There were no statistically significant correlations found between D peak temperature or D peak CORT and the BDHI total score, respectively. The subjective responses to the administration of MCPP, 0.35 mgrkg, p.o., were modest. Of the seven types of responses, only ‘feeling high’ and ‘unpleasant feeling’ were significantly greater in

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Fig. 1. Differences between groups in the respective response measures Žmean, S.D... Prolactin: F1,24 s 1.36, Ps 0.26 Žco-varying for peak plasma MCPP level and baseline prolactin level.. Cortisol: F1,25 s 0.18, Ps 0.68 Žco-varying for peak plasma MCPP level and baseline cortisol level.. Temperature: F1,25 s 2.93, Ps 0.10 Žco-varying for peak plasma MCPP level, baseline temperature and age.. Differences between groups in the respective response curves over time. Prolactin: group by repeated measures FHu ynh ] Feldt 2.6, 68.6 s 2.25, Ps 0.18. Cortisol: group by repeated measures FHuynh ] Feldt 3.7, 98.8 s 1.33, Ps 0.55. Temperature: group by repeated measures FHu ynh ] Feldt 4.6, 127.8 s 2.32, Ps 0.11.

response to MCPP than to placebo Žsee Table 4.. In no case did the magnitude of the Pearson product-moment coefficient between a peak subjective response and the peak plasma MCPP level reach statistical significance Ž n s 19, P) 0.05, one-tailed..

4. Discussion In this study of abstinent cocaine addicts, we found a positive association between the BDHI total score measuring hostility and D peak PRL in response to the administration of the partial

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Table 3 Biological serotonergic markers and hostility in cocaine addicts Controlling for peak plasma MCPP level DPeak PRL Buss-Durkee Hostility Inventory Total Irritability subscale Assaultiveness subscale

U

0.45 a U 0.46 a y0.03a

DPeak CORT

DPeak Temp

0.14a 0.19a y0.00a

y0.01b 0.00b y0.17b

a

Partial corr, d.f.s 14. Partial corr, d.f.s 15. U P- 0.05, test for planned analysis. b

5HT agonist MCPP. We also found a positive association between the BDHI irritability subscale score and D peak PRL, but not between the assaultiveness subscale score and D peak PRL. These results suggest that subjective irritability rather than manifest aggression may be better correlated with 5HTergic activity in adult cocaine addicts. The positive correlation between D peak PRL and hostility Žtotal BDHI score. in the group of abstinent cocaine addicts is opposite to the inverse correlation we found previously in abstinent alcoholics who were studied contemporaneously ŽHandelsman et al., 1996.. It also runs counter to the inverse association between the BDHI irritability and assaultiveness subscales and D peak

PRL to fenfluramine challenge reported for personality disordered patients ŽCoccaro et al., 1989. and the inverse association reported in anti-social addicts ŽMoss et al., 1990.. The absence of a statistically significant association between the CORT response to MCPP and the BDHI scores is not consistent with the implication of the findings by Buydens-Branchey et al. Ž1997. that aggressive cocaine addicts demonstrate a more blunted CORT response to MCPP than do nonaggressive cocaine addicts. This divergence may be due to differences in the dose of MCPP used in each study or unspecified biases in the recruitment procedures. Our findings are consistent, however, with the direction of the positive association of the PRL response to FEN and the sever-

Table 4 Subjective response to the administration of MCPP, 0.35 mgrkg p.o., or placebo in cocaine addicts Ž n s 19. a Response

MCPP peak responsea

Placebo peak responsea

Wilcoxon test Z, P Žone-tailed.

1. Alcohol-like 2. Valium-like 3. Heroin-like 4. Cocaine-like 5. Feel ‘high’ 6. Unpleasant feeling 7. Cravings

1.5" 2.8 Ž0]9.5. 1.6" 2.8 Ž0]10. 1.5" 2.7 Ž0]10. 0.7" 1.4 Ž0]4.5. 2.3" 3.7 Ž0]10. 2.8" 3.4 Ž0]10.

1.5" 3.1 Ž0]10. 1.2" 2.5 Ž0]10. 0.6" 2.3 Ž0]10. 0.7" 2.3 Ž0]10. 1.1" 2.7 Ž0]10. 1.6" 2.2 Ž0]7.8.

y0.12, 0.45 y0.95, 0.17 y1.4, 0.80 y0.34, 0.37 y1.95, 0.03U y2.24, 0.02U

0.6" 1.1 Ž0]3.5.

0.8" 2.3 Ž0]10.

y0.63, 0.26

a U

Mean " S.D. Žrange.. P- 0.05, one-tailed.

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ity of a history of childhood aggression reported by Fishbein et al. Ž1989. in treatment-seeking addicts. Conduct disorder and childhood aggressiveness are well-described precursors of adolescent and adult substance abuse ŽMannuzza et al., 1993; Lyons et al., 1995.. It is therefore of interest that the positive association of the PRL response to MCPP with adult trait hostility in cocaine addicts is concordant with the positive association of the PRL response to fenfluramine with aggression in two studies of prepubertal boys ŽHalperin et al., 1994; Pine et al., 1997.. The convergence of our results with those of the literature on the 5HTergic correlates of childhood aggressive traits raises the possibility that, while CNS 5HT activity is low in some subgroups of hostile individuals, it is high in others. Further studies are needed to determine whether heightened CNS 5HT activity in hostile individuals is a stable trait or rather a state marker dependent on such factors as age or the emergence of cocaine dependence. A secondary finding in this study is the absence of a difference between male cocaine-dependent subjects and the healthy volunteers in the temperature, PRL or CORT responses to the administration of MCPP. This finding is not consistent with the hypothesis that cocaine addiction per se either results from or induces a hyposerotonergic state and does not replicate the findings of Lee and Meltzer Ž1994., who reported a blunted oral temperature response to the administration of MK-212, or the work of Buydens-Branchey et al. Ž1997., who reported a blunted PRL response to MCPP in cocaine addicts. The difference between the studies may be attributable to the use of different 5HT agonists, although MK-212 and MCPP are thought to have similar 5HT receptor subtype activity ŽLevy et al., 1992. or different doses of MCPP Ž0.35 mgrkg vs. 0.50 mgrkg.. In the Lee and Meltzer study, the cocaine-using group was somewhat older than the control subjects; their findings of a blunted temperature response may be attributable to this factor. In addition, unspecified recruitment biases may account for the divergence of our findings from these two other studies. The magnitude of the subjective behavioral responses to MCPP administration was modest.

Only the ‘feeling of being high’ and ‘unpleasant feelings’ of the seven possible categories of subjective response differed between the MCPP and placebo conditions. Thus, while the administration of MCPP induced a high feeling it did not increase the level of non-cue-induced craving. The unpleasant feelings induced by MCPP were most likely similar to the anxiogenic effects of MCPP reported previously ŽKahn et al., 1990; Kahn and Wetzler, 1991.. When administered at higher oral doses in cocaine addicts ŽBuydensBranchey et al., 1997. or intravenously in alcoholics ŽKrystal et al., 1994., MCPP induced strong euphoric effects or craving effects. In contrast, lowering 5HT activity by dietary depletion of tryptophan appeared to attenuate the high induced by cocaine itself ŽAronson et al., 1995. and the cravings induced by cocaine-related environmental cues ŽSatel et al., 1995.. Our findings are thus consistent with the idea that 5HTergic systems play some role in the psychological effects of cocaine. A considerable amount of literature has examined dopaminergic neurotransmission after the cessation of chronic cocaine use in animals and humans Žcf. Mello and Mendelson, 1997; Volkow et al., 1997.. Since dopamine and serotonin modulate each other’s activity in the CNS, it is conceivable that baseline prolactin and 5HT activity could be affected by alterations in dopamine function that result from the cessation of cocaine use. Since studies by Lee and Meltzer Ž1994. and Buydens-Branchey et al. Ž1997. also tested addicts with a similar duration of abstinence, it is not apparent how differences in dopamine function would result in differences between their results and ours. In our sample, duration of cocaine use and frequency of recent use in the previous 30 days prior to admission to treatment were not associated with any of the 5HT indices. It is conceivable, however, that in other samples trait hostility might be associated with dopaminergic function during early abstinence. Several factors limit the interpretation of our findings. First, the results were derived from a small sample of males who were accrued because of clinical convenience in the case of the cocaine addicts or response to advertisements in the case

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of the control subjects; these groups differed in age and ethnic composition. Second, the comparison between the cocaine addicts and the healthy volunteers must be qualified, because the MCPP challenges for each group, although adhering to the same techniques, were not conducted contemporaneously. Third, the control subjects were not subjected to the same level of scrutiny longitudinally to detect substance use or abuse as were cocaine addicts, and the two groups differed in age and ethnic composition. Fourth, the measures of hostility were not comprehensive and did not include objective measures of overt and aggressive behavior ŽNetter et al., 1995.. Fifth, we cannot exclude the possibility that the chloral hydrate that was permitted as a sleep medication for the patients had some effect on the 5HT indices. Finally, the results are limited to male cocaine addicts. In summary, in cocaine addicts, trait hostility was associated positively with the PRL response to the oral administration of MCPP, 0.35 mgrkg, an index of CNS 5HT activity. Although findings of a positive association of childhood aggression with the PRL response to a 5HT agonist challenge have been reported previously, this is the first report of a positive association of 5HT activity with adult trait hostility in a clinically meaningful sample. Our finding is opposite in direction to the more frequently reported inverse association between hostility and 5HT function in personality disordered individuals and alcoholics, including one study of alcoholics conducted contemporaneously at our center that used the same techniques as those in the present study of cocaine addicts ŽHandelsman et al., 1996.. This work suggests that the associations between hostile ideas or behavior and abnormalities in CNS 5HT function may be more heterogeneous than previously believed. In contrast to two reports of blunted 5HT activity in cocaine addicts compared with normal volunteers, we were not able to detect such a difference. References American Psychiatric Association, 1987. Diagnostic and Statistical Manual, 3rd ed., revised. APA Press, Washington, D.C.

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