This proposal is a continuation of studies of pharmacological modification of the reinforcing effects of cocaine. Rhesus monkeys receive intravenous cocaine contingently on lever-press responses, and the reinforcing effects of cocaine are measured by the rates at which the monkeys press the levers. Four different doses of cocaine are available to the subjects during twice- daily 130 min sessions. These doses have been selected so that rates of lever-pressing increase as the dose of cocaine increases. The ability of a variety of drugs to antagonize cocaine's reinforcing effect or selectively suppress cocaine self administration will be examined when the drugs are given as pretreatments. Three classes of agents are of particular interest in this proposal. First is a series of monoclonal antibodies that have been found to catalytically degrade cocaine without themselves being destroyed in the process. These antibodies may represent a potential """"""""vaccine"""""""" against cocaine use, particularly since they may have a duration of action of two weeks. Second is a continuation of work tempting to understand the nature of dopamine's interaction with the reinforcing effects of cocaine; the effects of elective dopamine agonists on cocaine self-administration will be evaluated. Finally, the effects of serotonin uptake inhibitors and agonists on the reinforcing effect of cocaine will be tested. The selective nature of drug-induced suppression of cocaine-maintained responding will be determined by comparing the potency of the drugs to modify behavior maintained by cocaine with their potency in modifying similar behavior maintained by alfentanil or by food. The goal of the evaluation is to identify a drug that decreases cocaine's potency as a reinforcer or suppresses cocaine maintained responding at doses that have no effect on alfentanil-maintained responding. Such a drug will be suggested s having potential usefulness in treating cocaine abuse. A basic research aspect of the proposal involves a modification of the current procedure so that the doses of cocaine used to maintain responding can be combined with standard doses of various other drugs. Both drugs will be delivered contingently on the animal's response. The effects of combinations of cocaine and drugs with either abuse potential of their own (e.g., heroin, amphetamine, alfentanil) or with the potential to modify cocaine-maintained responding selectively (e.g., dopamine antagonists, buprenorphine) will be evaluated in this procedure and the results compared to data obtained when the drugs were given as pretreatments. This modification may allow a limited evaluation of polydrug abuse as well as furthering an understanding of how methodological issues influence the interaction between cocaine and potential antagonists of its reinforcing effects.

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University of Michigan Ann Arbor
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Bergman, J; Yasar, S; Winger, G (2001) Psychomotor stimulant effects of beta-phenylethylamine in monkeys treated with MAO-B inhibitors. Psychopharmacology (Berl) 159:21-30
Aspen, J M; Winger, G (1997) Ethanol effects on self-administration of alfentanil, cocaine, and nomifensine in rhesus monkeys. Psychopharmacology (Berl) 130:222-7
Zernig, G; Lewis, J W; Woods, J H (1997) Clocinnamox inhibits the intravenous self-administration of opioid agonists in rhesus monkeys: comparison with effects on opioid agonist-mediated antinociception. Psychopharmacology (Berl) 129:233-42
Hursh, S R; Winger, G (1995) Normalized demand for drugs and other reinforcers. J Exp Anal Behav 64:373-84
Winger, G D; Yasar, S; Negus, S S et al. (1994) Intravenous self-administration studies with l-deprenyl (selegiline) in monkeys. Clin Pharmacol Ther 56:774-80
Skjoldager, P; Winger, G; Woods, J H (1993) Effects of GBR 12909 and cocaine on cocaine-maintained behavior in rhesus monkeys. Drug Alcohol Depend 33:31-9
Bradberry, C W; Nobiletti, J B; Elsworth, J D et al. (1993) Cocaine and cocaethylene: microdialysis comparison of brain drug levels and effects on dopamine and serotonin. J Neurochem 60:1429-35
Winger, G; Skjoldager, P; Woods, J H (1992) Effects of buprenorphine and other opioid agonists and antagonists on alfentanil- and cocaine-reinforced responding in rhesus monkeys. J Pharmacol Exp Ther 261:311-7
Jatlow, P; Elsworth, J D; Bradberry, C W et al. (1991) Cocaethylene: a neuropharmacologically active metabolite associated with concurrent cocaine-ethanol ingestion. Life Sci 48:1787-94
Winger, G; Palmer, R K; Woods, J H (1989) Drug-reinforced responding: rapid determination of dose-response functions. Drug Alcohol Depend 24:135-42

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