This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. here is a critical need to develop effective medications to treat cocaine addiction. Medication effectiveness in reducing cocaine use was determined in a nonhuman primate model of intravenous drug self-administration. The project continued to focus on the behavioral pharmacology and in vivo neurochemistry of monoamine transporter inhibitors as complementary approaches to characterize the neuropharmacology of cocaine. In addition, we have emphasized behavioral and neurochemical interactions between glutamate and dopamine. The glutamate receptor agonist, LY379268, was effective in blocking the behavioral-stimulant, reinforcing and reinstatement (relapse) effects of cocaine. Complementary neurochemical studies with in vivo microdialysis indicated that LY379268 was also effective in blocking cocaine-induced increases in extracellular dopamine, a potential mechanism underlying drug interactions on behavior. We have initiated studies with monoamine releasers having different affinity for dopamine and serotonin receptors. The results indicate that compounds with high potency for serotonin release have a behavioral profile of low abuse liability. We continue to develop a novel protocol to study drug-induced reinstatement (relapse) of self-administration behavior that eliminates the need for active extinction learning and better models drug abstinence in humans. The integration of in vivo neurochemistry and behavioral pharmacology in nonhuman primates will define neurochemical mechanisms that underlie the addictive properties of cocaine and related stimulants. The results obtained will direct efforts to treat cocaine abuse in humans. Moreover, a comprehensive evaluation of interactions between glutamate and dopamine should have significant implications toward understanding and treating a variety of neurological and psychiatric disorders including schizophrenia, Parkinson's disease and anxiety disorders.
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