Although the subjective effects of cocaine are understood to play an important role in cocaine abuse, studies in humans have revealed an incomplete overlap between discriminative stimulus (SD) and reinforcing (SR) effects of drugs. Moreover, the lack of a clear understanding of the precise roles of dopamine (DA), serotonin (5-HT) and norepinepherine (NE) in these effects has hindered efforts to develop medications for cocaine dependence. The overarching goals of the research in this proposal are to gain a better understanding of the relationship between the SD and SR effects of cocaine and to better elucidate the pharmacological and neurochemical mechanisms that underlie these effects. To accomplish these aims, rhesus monkeys will be trained to discriminate a response-contingent injection of 0.1 mg/kg cocaine from saline, with an opportunity to self-administer 0.1 mg/kg cocaine under a second-order schedule immediately following the discrimination component. Using this procedure, the effects of a range of doses of cocaine, other indirect and direct DA receptor agonists will be characterized, including direct agonists that differ in efficacy at stimulating D1- and D2-like DA receptors (Specific Aim 1). To characterize the extent of overlap of the neurochemical mechanisms involved in production of these abuse-related effects of cocaine, parallel microdialysis studies will measure extracellular DA in the ventral striatum during discrimination and self- administration components of selected doses (Specific Aim 2). Mechanisms by which 5-HT and NE can modulate the behavioral effects of cocaine will be examined in subsequent behavioral and microdialysis studies (Specific Aim 3) that characterize the effects of 5-HT and NE indirect and direct agonists on the SD, SR and neurochemical effects of cocaine. By assessing behavioral and neurochemical effects within a behavioral session in the same monkeys, these innovative studies will: (1) better describe the importance of SD effects to self-administration, (2) more clearly elucidate dopaminergic mechanisms involved in production of the abuse-related effects of cocaine, and (3) provide a unique characterization of pharmacological and neurochemical mechanisms that will aid the development of effective pharmacotherapies for cocaine dependence. Relevance: The proposed studies will provide unique information about the neurobiological mechanisms through which the addictive effects of cocaine are produced. Importantly, the results will provide novel information to aid efforts to develop effective medications for cocaine addiction, and will enhance our understanding and interpretation of data collected in animal models of drug addiction.
