Cocaine abuse continues to be a serious problem in the United States. An understanding of the neurobiological mechanisms controlling cocaine abuse can contribute significantly to the design of rational interventions. Self-administration research in animals has played a central role in establishing the neurobiological mechanisms mediating drug abuse. Pharmacological studies consistently suggest the importance of CNS dopamine (DA) mechanisms in cocaine abuse. However, interpretation of those studies is ambiguous and the quantitative relationship between pharmacological mechanism and reinforcing effect has not been established. The research in the present proposal is designed to examine that relationship by testing the hypothesis that relative intrinsic efficacy of a DA agonist determines its relative efficacy as a positive reinforcer. To do this, we will conduct intravenous self-administration studies in monkeys using drugs that are agonists for DA receptors and transporters. We will also conduct parallel in vitro studies in rhesus monkey brain tissue designed to rigorously test our mechanistic hypothesis.
Specific Aim 1 is to continue our examination of D1 DA receptor mechanisms. We propose to establish progressive-ratio (PR) self- administration of a full D1 agonist or cocaine and examine the effect of the pretreatment with a D1 antagonist and with partial agonists. We predict that each of these compounds will shift the dose-response function for both the D1 agonist and cocaine to the right, evidence for antagonism. We also propose to study the interaction between D1 and D2 mechanisms in DA agonist self-administration.
Specific Aim 2 is to extend our examination of D2 DA receptor mechanisms. We propose first to use a fixed-ratio schedule of reinforcement to examine the reinforcing effects of a group of D2 agonists. Next, we will use a PR procedure, in addition to in vitro studies, to compare the relative reinforcing efficacies and intrinsic efficacies of a series of D2 agonists. We then propose to pursue antagonism studies that will be conceptually identical to those proposed for D1 agonists.
Specific Aim 3 is to use novel compounds to study the relationship between relative reinforcing efficacy of DA transporter blockers and their efficacy in blocking DA uptake. We propose first to examine the reinforcing effects of a series of benztropine analogs that block DA uptake but do not have cocaine-like behavioral effects in other paradigms. We also propose to extend that comparison to novel compounds of different chemical classes that block DA uptake in vitro. The research described in the present application will have important implications for understanding basic pharmacological mechanisms of drug reinforcement. In addition, these studies will have significant implications for the development of treatment medications. Partial D1 or D2 agonists, as well as partial efficacy DA transporter ligands may block or reduce the reinforcing effect of cocaine in monkeys. Those compounds would be predicted to be useful for treatment of cocaine abuse.
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