The proposed research will establish a nonhuman primate model to characterize drug-induced changes in brain neurochemistry during cocaine self-administration. The primary objective is to evaluate the effectiveness of selective dopamine and serotonin transporter inhibitors to attenuate cocaine self-administration and cocaine-induced changes in neurochemistry. Behavioral studies of intravenous cocaine self- administration will be complemented by in vivo microdialysis and pharmacokinetic studies. The proposed use of in vivo microdialysis techniques in conscious monkeys trained to self-administer cocaine will characterize neurochernical changes associated with the reinforcing or addictive properties of cocaine, and will identify neurochemical mechanisms that mediate drug effects on behavior. Experiments will be conducted in squirrel monkeys surgically prepared with chronically- indwelling venous catheters for drug administration. Stereotaxic procedures will be employed in conjunction with magnetic resonance imaging (MRI) to implant guide cannulae into selected target areas and to verify the accuracy of probe placement. A major focus of the research plan will involve the pharmacological manipulation of monoamine transporter function to access changes in sensitivity to the behavioral and neurochemical effects of cocaine. Accordingly, experiments will determine the effectiveness of acutely and chronically administered transporter inhibitors selective for the dopamine and serotonin transporters to attenuate the reinforcing effects of cocaine and cocaine-induced changes in neurochemistry. in addition, serum blood levels of cocaine and its primary metabolite, benzoylecgonine, will be assayed to characterize the pharmacokinetics of cocaine, and to determine whether altered sensitivity to the behavioral and neurochernical effects of cocaine may involve changes in cocaine metabolism or clearance. Collectively, the proposed studies will enhance our understanding of the neurochemical substrates that underlie cocaine self-administration in nonhuman primates, and will evaluate the potential utility of monoamine transporters as targets for the pharmacotherapy of cocaine abuse.
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