NEUROBIOLOGY OF COCAINE WITHDRAWAL AND SOCIAL STRESS

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DESCRIPTION: (Applicant's Abstract) The long-term objectives of the project are to characterize the neuroadaptive events underlying stress-induced alteration and sensitization following cocaine self-administration in forebrain circuits of the rat. An integrated behavioral, neurochemical and molecular approach will be used to elucidate the regulatory changes underlying the effects of stress exposure on cocaine sensitization. The specific aims of the project are: (1) to characterize the time course and the cellular basis of behavioral sensitization induced by cocaine self-administration in corticostriatal circuits, (2) to examine the impact of a salient social stressor on dopaminergic and glutamatergic response to cocaine challenge in the nucleus accumbens (NAc) during cocaine withdrawal, (3) to determine the neural circuits by which acute or chronic social stress can enhance the response to cocaine challenge, and (4) to assess the influence of glutamatergic input on stress induced alteration of cocaine response by examining changes in the expression of glutamate receptor mRNA and by assessing the effect of NMDA receptor blockade during chronic social stress exposure on the response to a subsequent cocaine challenge. Rats will be implanted with intravenous catheters, then exposed to chronic social stress or cocaine self-administration followed by 0, 3 or 21 days of withdrawal. Cellular response to acute intravenous cocaine challenge with or without prior acute stress will be examined in mesocorticolimbic and other neurons using in situ hybridization histochemistry (ISHH) with oligodeoxynucleotide probes complementary to the sequence encoding c-fos to detect cellular activation, which will be correlated with motor activity data obtained from the same animals. In vivo microdialysis will be used to examine extracellular levels of dopamine, glutamate and cocaine, and their metabolites following cocaine challenge. The influence of chronic stress or cocaine exposure on glutamate receptors will be examined using ISHH to assess NMDA and AMPA receptors in order to differentiate and localize selective regional effects. Together, these studies will examine the functional link in neural circuits between stress and sensitization during cocaine withdrawal, which could result in cocaine craving and relapse to cocaine self-administration. The results will elucidate the mechanism(s) underlying reinforcing and stressful stimuli as well as the cellular and molecular alterations which develop during cocaine withdrawal. This know]edge will permit the design of better approaches to treat cocaine dependence.