- Email: [email protected]
Dopamine re-uptake blockers and drug seeking behavior
THURSDAY,, MAY 19
BIOL PSYCHIATRY 625 1994;35:615-747
correlated with reduction of delta and theta activity. These findings contrasted with lifetime exposure to alcohol which was significantly correlated with increasing levels of delta and theta activity. Greater lifetime exposure to cocaine was associated with greater anterior delta asymmetry; Greater lifetime exposure to alcohol as associated with greater posterior delta, theta, alpha and beta asymmetry. Duration of marijuana use was associated with reduction of QEEG power at all four frequency bands. These results suggest chronic cocaine use is associated with reduced low frequency EEG power, mainly left anteriorly. Chronic use of alcohol can be related to reduction of left parietal EEG power. They also indicate CNS effects of chronic polysubstance abuse can be seen in extended periods of abstinence.
Supported in part by DA06728, S07-RR05417, The Einstein Society, and Cadwell Laboratories.
37. HOSTILE/IMPULSIVE TRAITS IN ADDICTS: 5-HT BEHAVIORAL PHARMACOLOGY
nicotine abuse, there has been no clear consensus as to how to develop an effective medication for it. Cocaine supports self-administration behavior, providing an animal model of cocaine abuse. These reinforcing effects of cocaine have been strongly linked with the ability of that chug to block the reuptake of dopamine. However, other long-acting dopamine-selective reuptake blockers have been described recently that appear to lack abuse potential in both animals and humans. The current studies explore the effects of several of these agents on drug-seeking behavior in monkeys. lever-press responding of 6-10 kg male rhesus monkeys was maintained under multiple FR 30-response schedules of food delivery and intravenous cocaine injections. Relatively low doses (3-10 lxg/kg/injection) of cocaine maintained high rates of responding in the drug delivery components of the multiple schedule, and responding maintained by food pres. entation was not affected unless high cocaine maintenance doses were used. When comparable rates of responding were maintained by food and cocaine, GBR12909 and GBR! 2935 decreased cocaine-seeking behavior (up to 100%) at doses that had little or no effect on food-seeking behavior. These effects are compared to other agents having affinity for the DA re-uptake site, including d-amphetamine, LR-I I I I, DM-69, and CFT. The results show that drug-seeking behavior can be selectively attenuated by high-affinity dopamine reuptake inhibitors, suggesting that such agents may be useful in treating cocaine abuse.
L. Handelsman l, D. Bernstein l, K. Holloway I, I. Sheikh l, R. Trestman I, L. Siever I, & T. Cooper 2 tBronx VA Medical Center, Bronx, NY; 2NY State Psychiatric Institute NY, NY Brain 5-HT abnormalities have been linked to hostility, aggression and impulsivity as well as a heritable form of early onset alcoholism (VypeI!). We used a 5-HT agonist challenge strategy to confirm and extend these observations to two groups of substance abusers: treatment.seeking alcoholics and cocaine addicts. To date, meta-chlorophenylpiperazine (mCPP) .35 mg/kg po and placebo have been administered to 12 alcoholics & 10 cocaine addicts. Central 5-HT activity was measured by peak prolactin (PRL) and peak temperature responses and by subjective identification of substance-related feelings after mCPP administration. Trait hostility was measured by the Buss Durkee Hostility Inventory, trait impulsivity by the Barratt lmpulsivity Scales. Two distinct patterns of biobehavioral correlations were observed, in alcoholics, 5-HT activity (PRL or temp indices) was smaller in individuals with greater trait hostility and interpersonal impulsivity. Subjective responses to mCPP were greater in alcoholics with greater hostility and impulsivity, and greater in those with blunted PRL or temp responses, in contrast, for cocaine addicts, PRL and temp responses were greater in individuals with greater trait hostility and impulsivity, while subjective responses to mCPP were greater in individuals with greater levels of impulsivity. PRL and subjective responses were correlated. In addition, for cocaine addicts, subjective responses to mCPP were stronger in individuals with lower levels of dopamine activity (plasma HVA). The alcoholic pattern resembles 5-HT/hostility correlations in personality disordered patients, while the cocaine-related pattern resembles that in another study of treatment seeking addicts and in prepubertal aggressive boys with ADHD.
38. DOPAMINE RE-UPTAKE BLOCKERS AND DRUG SEEKING BEHAVIOR J.R. Glowa l, F.H.E. Wojnicki l, D. Matecka I, K.C. Rice 1, & R.B. Rothman 2 tLaboratory of Medicinal Chemistry, NIDDK/NIH, Bethesda, MD 20892; 2Clinical Psychopharmacology Section, NIDA, Baltimore, MD 21224 Cocaine abuse is a major health problem and, in contrast to heroin and
39. MIXED BIPOLAR STATES AT FIRST HOSPITALIZATION T. Suppes l, D.A. Yurgelun-Todd 2, M. Tohen 2, G. Faedda 3, M. Kolbrenner 2, M. Weiss2, S. Strawkowski 4, P. Mayer 2, & A. Stoll 2 1University of Texas Southwestern Medical Center, Dallas, TX 75235; ZPsychosis Program, McLean Hospital, Belmont, MA 02178; 3Albert Einstein College of Medicine, Bronx NY 10461; 4University of Cincinnati, Cincinnati OH 45267 The Mclean Hospital First Psychosis Project (Tohen et a1.,1992), prospectively studies all first admissions for mania and/or psychosis, with diagnoses established by the SCID for DSM IlI-R (Spitzer & Williams, 1988). The number of bipolar disorder patients estimated to experience mixed or dysphoric manic episodes is up to 50% or more, and mixed states have been associated with a history of head injury or other neurologic insult/abnormality and substance abuse (Himmelhoch et a1.,1976,1986). We were interested if first admission bipolar patients presented with a similar distribution of mixed vs classic mania to analysis done later in the course of illness. Also, if the rates of preceding neurological insult, abnormality, or substance abuse were higher in patients with mixed states at first hospitalization, in a consecutive sample of 86 patients with bipolar disorder, manic,15% (n-13) met SCID criteria for a mixed state. A number of trends emerged supporting that mixed bipolars are more likely to show evidence of CNS abnormalities. Examining for a history of neurological soft signs, which included an abnormal neurologic exam, CT or MRI, seizure history, or past history of significant medical or neurologic illness (e.g. meningitis), 92% (n-I 2) of mixed bipolar patients had ANY abnormality vs.64% (n-47)of manic bipolar patients. Ten mixed patients received EEG studies and 50% were abnormal vs. 43 manic patients had EEG's and 26% were abnormal. Of 9 mixed patients receiving CT or MRI, 78% were abnormal and in 42 manic patients, 36% were abnormal as rated by a neurologist and a blinded investigator (DTY). Of 9 mixed patients, 56% had a history of head injury and of 41 manic patients, 32% had a history of head injury. A history of seizures was found in 20% of mixed patients (n-10) and 7% of manic patients (n-46). Comorbidity for substance abuse, as defined by SCID diagnosis was 46% of mixed patients (n-! 3) and 23% of manic patients (n-65). Additionally, neuropsychiatric testing was completed on >40% of all patients, and results will be reported. Statistical analyses will be presented and potential significance discussed.
BIOL PSYCHIATRY 625 1994;35:615-747
correlated with reduction of delta and theta activity. These findings contrasted with lifetime exposure to alcohol which was significantly correlated with increasing levels of delta and theta activity. Greater lifetime exposure to cocaine was associated with greater anterior delta asymmetry; Greater lifetime exposure to alcohol as associated with greater posterior delta, theta, alpha and beta asymmetry. Duration of marijuana use was associated with reduction of QEEG power at all four frequency bands. These results suggest chronic cocaine use is associated with reduced low frequency EEG power, mainly left anteriorly. Chronic use of alcohol can be related to reduction of left parietal EEG power. They also indicate CNS effects of chronic polysubstance abuse can be seen in extended periods of abstinence.
Supported in part by DA06728, S07-RR05417, The Einstein Society, and Cadwell Laboratories.
37. HOSTILE/IMPULSIVE TRAITS IN ADDICTS: 5-HT BEHAVIORAL PHARMACOLOGY
nicotine abuse, there has been no clear consensus as to how to develop an effective medication for it. Cocaine supports self-administration behavior, providing an animal model of cocaine abuse. These reinforcing effects of cocaine have been strongly linked with the ability of that chug to block the reuptake of dopamine. However, other long-acting dopamine-selective reuptake blockers have been described recently that appear to lack abuse potential in both animals and humans. The current studies explore the effects of several of these agents on drug-seeking behavior in monkeys. lever-press responding of 6-10 kg male rhesus monkeys was maintained under multiple FR 30-response schedules of food delivery and intravenous cocaine injections. Relatively low doses (3-10 lxg/kg/injection) of cocaine maintained high rates of responding in the drug delivery components of the multiple schedule, and responding maintained by food pres. entation was not affected unless high cocaine maintenance doses were used. When comparable rates of responding were maintained by food and cocaine, GBR12909 and GBR! 2935 decreased cocaine-seeking behavior (up to 100%) at doses that had little or no effect on food-seeking behavior. These effects are compared to other agents having affinity for the DA re-uptake site, including d-amphetamine, LR-I I I I, DM-69, and CFT. The results show that drug-seeking behavior can be selectively attenuated by high-affinity dopamine reuptake inhibitors, suggesting that such agents may be useful in treating cocaine abuse.
L. Handelsman l, D. Bernstein l, K. Holloway I, I. Sheikh l, R. Trestman I, L. Siever I, & T. Cooper 2 tBronx VA Medical Center, Bronx, NY; 2NY State Psychiatric Institute NY, NY Brain 5-HT abnormalities have been linked to hostility, aggression and impulsivity as well as a heritable form of early onset alcoholism (VypeI!). We used a 5-HT agonist challenge strategy to confirm and extend these observations to two groups of substance abusers: treatment.seeking alcoholics and cocaine addicts. To date, meta-chlorophenylpiperazine (mCPP) .35 mg/kg po and placebo have been administered to 12 alcoholics & 10 cocaine addicts. Central 5-HT activity was measured by peak prolactin (PRL) and peak temperature responses and by subjective identification of substance-related feelings after mCPP administration. Trait hostility was measured by the Buss Durkee Hostility Inventory, trait impulsivity by the Barratt lmpulsivity Scales. Two distinct patterns of biobehavioral correlations were observed, in alcoholics, 5-HT activity (PRL or temp indices) was smaller in individuals with greater trait hostility and interpersonal impulsivity. Subjective responses to mCPP were greater in alcoholics with greater hostility and impulsivity, and greater in those with blunted PRL or temp responses, in contrast, for cocaine addicts, PRL and temp responses were greater in individuals with greater trait hostility and impulsivity, while subjective responses to mCPP were greater in individuals with greater levels of impulsivity. PRL and subjective responses were correlated. In addition, for cocaine addicts, subjective responses to mCPP were stronger in individuals with lower levels of dopamine activity (plasma HVA). The alcoholic pattern resembles 5-HT/hostility correlations in personality disordered patients, while the cocaine-related pattern resembles that in another study of treatment seeking addicts and in prepubertal aggressive boys with ADHD.
38. DOPAMINE RE-UPTAKE BLOCKERS AND DRUG SEEKING BEHAVIOR J.R. Glowa l, F.H.E. Wojnicki l, D. Matecka I, K.C. Rice 1, & R.B. Rothman 2 tLaboratory of Medicinal Chemistry, NIDDK/NIH, Bethesda, MD 20892; 2Clinical Psychopharmacology Section, NIDA, Baltimore, MD 21224 Cocaine abuse is a major health problem and, in contrast to heroin and
39. MIXED BIPOLAR STATES AT FIRST HOSPITALIZATION T. Suppes l, D.A. Yurgelun-Todd 2, M. Tohen 2, G. Faedda 3, M. Kolbrenner 2, M. Weiss2, S. Strawkowski 4, P. Mayer 2, & A. Stoll 2 1University of Texas Southwestern Medical Center, Dallas, TX 75235; ZPsychosis Program, McLean Hospital, Belmont, MA 02178; 3Albert Einstein College of Medicine, Bronx NY 10461; 4University of Cincinnati, Cincinnati OH 45267 The Mclean Hospital First Psychosis Project (Tohen et a1.,1992), prospectively studies all first admissions for mania and/or psychosis, with diagnoses established by the SCID for DSM IlI-R (Spitzer & Williams, 1988). The number of bipolar disorder patients estimated to experience mixed or dysphoric manic episodes is up to 50% or more, and mixed states have been associated with a history of head injury or other neurologic insult/abnormality and substance abuse (Himmelhoch et a1.,1976,1986). We were interested if first admission bipolar patients presented with a similar distribution of mixed vs classic mania to analysis done later in the course of illness. Also, if the rates of preceding neurological insult, abnormality, or substance abuse were higher in patients with mixed states at first hospitalization, in a consecutive sample of 86 patients with bipolar disorder, manic,15% (n-13) met SCID criteria for a mixed state. A number of trends emerged supporting that mixed bipolars are more likely to show evidence of CNS abnormalities. Examining for a history of neurological soft signs, which included an abnormal neurologic exam, CT or MRI, seizure history, or past history of significant medical or neurologic illness (e.g. meningitis), 92% (n-I 2) of mixed bipolar patients had ANY abnormality vs.64% (n-47)of manic bipolar patients. Ten mixed patients received EEG studies and 50% were abnormal vs. 43 manic patients had EEG's and 26% were abnormal. Of 9 mixed patients receiving CT or MRI, 78% were abnormal and in 42 manic patients, 36% were abnormal as rated by a neurologist and a blinded investigator (DTY). Of 9 mixed patients, 56% had a history of head injury and of 41 manic patients, 32% had a history of head injury. A history of seizures was found in 20% of mixed patients (n-10) and 7% of manic patients (n-46). Comorbidity for substance abuse, as defined by SCID diagnosis was 46% of mixed patients (n-! 3) and 23% of manic patients (n-65). Additionally, neuropsychiatric testing was completed on >40% of all patients, and results will be reported. Statistical analyses will be presented and potential significance discussed.