Cocaine abuse in the United States is a dangerous and pervasive health, social and economic issue that consumes an enormous amount of federal and state resources. A key site of cocaine's actions in the brain, both in humans and in experimental animals, is the nucleus accumbens (NAc)-a regulator of motivated behaviors. Repeated exposure to cocaine results in persistent adaptations in the NAc that are thought to underlie behavioral abnormaltites in well-established animal models of addiction, such as behavioral sensitization. Adaptations in glutamatergic synaptic transmission in the NAc appear to be particularly important. Recent studies have established that repeated cocaine exposure that induces robust behavioral sensitization also induces a depression in synaptic efficacy at glutamatergic synapses formed by prefrontal cortical afferents to the NAc. Our proposed studies will combine behavioral analysis with whole-cell electrophysiology in NAc brain slices to delineate the relationship between cocaine-induced synaptic plasticity and behavioral sensitization. We hypothesize that depression at NAc glutamatergic synapses is a critical neural substrate for sensitization. As such, fundamental factors controlling the behavioral adaptations, such as dose, temporal pattern and context of drug administration will similarly regulate NAc synaptic plasticity and the time course of the cellular modification will mirror the behavioral changes. In fulfilling the aims of the current proposal, the study of synaptic function in brain slices from animals exposed to drugs of abuse should provide crucial information necessary to make the link between drug-induced adaptations at the level of molecules and gene expression to those systems level adaptations that ultimately must underlie addiction ? ?
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