Cellular and molecular neuroadaptations that occur during exposure to cocaine likely contribute to the perpetuation of cocaine addiction by mediating the processes of drug dependence, tolerance, sensitization, withdrawal, and craving. The ability of cocaine to enhance dopaminergic neurotransmission in the mesocorticolimbic pathway undoubtedly plays a critical role in the initial reinforcing properties of this drug. However, other neurotransmitter systems are also integral to the addiction process. One such system is the endogenous opioid system. A large body of data indicates that opioidergic and dopaminergic neurotransmitter systems together regulate emotional, locomotor, and goal-directed behaviors. In addition, previous studies from our lab demonstrate that chronic binge-pattern cocaine can profoundly alter the expression and function of opioid receptors in brain regions critically involved in cocaine addiction. Of specific importance to this application, chronic cocaine administration results in the desensitization of delta opioid receptor signaling through adenylyl cyclase in the nucleus accumbens and caudate putamen. This functional desensitization is mediated by cocaine's actions on dopamine D1 receptors. Results from the studies proposed herein will determine the molecular mechanism(s) mediating cocaine-induced delta opioid receptor heterologous desensitization and the behavioral impact of attenuated delta receptor fuction.
Specific Aims are as follows: 1) to characterize the cellular interactions of dopamine D1 and delta opioid receptors in the nucleus accumbens and caudate putamen, 2) to determine the molecular mechanisms by which cocaine caused the desensitization of delta opioid receptor function, and 3) to determine the functional significance of cocaine-induced delta receptor desensitization in the whole animal using models of locomotor activity, anxiety, and depression. The innovation lies in combining several powerful techniques to address these aims at ultrastructural, anatomical, molecular, and behavioral levels. ? ?
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