The goal of this project is to achieve a better understanding of the pharmacological and behavioral determinants of the reinforcing and discriminative stimulus effects of cocaine in several primate models of cocaine abuse. Previous research has shown that dopamine (DA) neurotransmission mediates may of the reinforcing and discriminative stimulus effects of cocaine. However, less information is available regarding the interactions of cocaine with the serotonergic (5-HT) system. The chemistry project of this Center has developed a series of tropane analogs with extraordinary potencies at DA and 5-HT transporters. The studies proposed in this project are designed to evaluate, in rhesus monkeys, the role of DA and h-HT in the behavioral sequelae leading to cocaine's high abuse liability.
The Specific Aims of this project are: (1) To investigate the reinforcing efficacy of DA and 5-HT transport blockers relative to cocaine. Self-administration will be studied under a progressive-ratio (PR) schedule, because this measure of reinforcement is affected less by drugs with long durations of action. An additional goal is to compare our PR results with an evaluation of the reinforcing efficacy of each tropane, relative to cocaine, using a discrete-trials choice procedure. We hypothesize that compounds that have higher break points will be chosen over drugs that maintain lower break points. (2) To investigate the ability of tropanes with differential selective for either DA or 5-HT transporters to selectively decrease cocaine self- administration. Monkeys will self-administer cocaine under a multiple food, drug, food schedule and compounds selective for the DA or 5-HT transport will be administered as pre-treatments. Evaluation of the behavioral effects of these tropane analogs will provide valuable information about the relative contribution of DA and 5-HT to the effects of cocaine that mediate its high abuse potential. (3) To investigate the ability of tropanes that inhibit DA or 5-HT transporters to reinstate extinguished cocaine self-administration. Results from these experiments will provide information about the contribution of DA and 5-HT transport mechanisms in cocaine relapse. (4) To investigate the role of DA and 5-HT transporters in the discriminative stimulus effects of cocaine. Monkeys will be trained to discriminate cocaine in a drug discrimination paradigm, and the ability of selective DA or 5-HT transport blockers to substitute for cocaine will be assessed. When completed, this research will provide additional knowledge regarding the role of DA and 5-HT transporters under several models of cocaine abuse. The expertise to effectively combine unique pharmacological tools and sensitive behavioral measures in monkeys represents an important strength of this project.
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