The proposed research will characterize behavioral and neurochemical interactions between glutamate and dopamine in the context of cocaine self-administration behavior in nonhuman primates. There is convincing evidence derived from rodent studies that the cystine/glutamate transporter and metabotropic glutamate receptors (mGluRs) can modulate the behavioral effects of cocaine associated with its abuse liability. The proposed pharmacological studies in squirrel monkeys will determine the consequences of altered cystine/glutamate transporter, mGluR2/3 and mGluRS function on 1) the behavioral-stimulant effects of cocaine, 2) cocaine self-administration behavior, 3) cocaine-induced reinstatement of self-administration behavior and 4) cocaine-induced changes in monoamines. In vivo microdialysis protocols developed in awake, behaving monkeys during the previous funding period will be used to identify nerochemical mechanisms underlying drug interactions on behavior. Significant drug interactions observed with cocaine will be extended to a selective dopamine transporter inhibitor, RTI-150, which exhibits behavioral, neurochemical and pharmacokinetic properties similar to those of cocaine. It is hypothesized that augmentation of cystine/glutamate exchange will increase extrasynaptic glutamate and enhance inhibitory tone mediated through mGluR2/3 activation, thereby attenuating cocaine-induced increases in dopamine and the behavioral effects of cocaine. Similarly, pharmacological antagonism of mGluRS function is predicted to attenuate the neurochemical and behavioral effects of cocaine. The results obtained will evaluate the effectiveness of glutamatergic systems as potential targets for medications development to treat cocaine abuse. Moreover, the elucidation of basic neurochemical interactions berween glutamate and dopamine in vivo in primates should have significant impact on the development of therapeutics outside the field of drug addiction.
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