Research with animals has shown that dopamine (DA) receptors mediate many of coaine's behavioral effects. Within the DA system there are two receptor families, D1 and D2, based mainly upon different anatomical localization and functional mechanisms. Preclinical studies have shown that D2-like antagonists can decrease cocaine self- administration, but typically only at doses that decrease other reinforced behaviors. Within the D2 family, molecular cloning techniques have identified three receptor subtypes, termed D2, D3 and D4. Because the relative expression of D3 and D4 receptor mRNA in rat ventral striatum is significantly less than that for D2 receptor mRNA, we hypothesize that preferential blockade of D3 and/or D4 receptors may lead to selective antagonism of cocaine's reinforcing effects, whereas antagonists acting primarily at D2 receptors are also likely to result in extrapyramidal side effects. The overall goal of these studies is to examine, in rhesus monkeys, how newly synthesized compounds selective for D2, D3 and D4 receptors modify cocaine's effects in several animal models of drug abuse.
The Specific Aims of this proposal are to evaluate, in monkeys, the effects of DA-selective antagonists on: (1) cocaine's discriminative stimulus effects. We hypothesize that D3-selective antagonists will be the most effective at attenuating cocaine's stimulus effects; (2) cocaine's reinforcing effects when responding is maintained under a multiple fixed-interval (FI) schedule of food and cocaine presentation. Under the FI schedule, cocaine intake and response rates are relatively independent. We hypothesize that D3-selective antagonists will be more potent at decreasing cocaine intake relative to response rates and will be more selective on cocaine vs. food-maintained responding; and (3) cocaine-induced reinstatement. We hypothesize that D3-selective antagonists will be most effective at attenuating cocaine's ability to reinstate """"""""drug seeking"""""""". When complete, results from the present application will provide clinically relevant information regarding the ability of D2, D3 and D4 antagonists to selectively decrease the reinforcing and discriminative stimulus effects of cocaine. Such knowledge will be vital for understanding the neuropharmacology of cocaine and to the development of effective pharmacotherapies for cocaine abuse.
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