The proposed studies will examine how cocaine exposure affects AMPA receptor subunit (GluR) expression in the nucleus accumbens shell (NASh) and basolateral amygdala (BLA). The behavioral significance of changes in GluR expression in each region will be examined using state-of-the-art molecular methods (viral-mediated gene transfer) to directly modulate their expression. We will study the NASh because it mediates, at least in part, the rewarding effects of cocaine. We will study the BLA because it sends a direct glutamatergic projection to the NASh, and it is implicated in the development of cocaine sensitization. We have preliminary data showing that repeated intermittent exposure to cocaine regulates GluR expression in the BLA, and other investigators have shown cocaine regulation of GluRs in the nucleus accumbens as a whole.
In Aim 1, we will examine the effects of repeated intermittent cocaine (associated with behavioral sensitization) and continuous infusion of cocaine (associated with tolerance) on GluR expression in the BLA and NASh. Tissue will be examined at numerous time points following termination of drug treatment. To examine the pharmacological specificity of cocaine effects, we will conduct parallel studies with the selective dopamine reuptake inhibitor GBR 12909.
In Aim 2, we will use viral-mediated gene transfer to selectively alter expression of GluR1 and GluR2 in the BLA and NASh to examine the relevance of altered GluR expression on cocaine reward. In place conditioning experiments, we have preliminary data showing that increased expression of GluR2 in either region increases cocaine reward, whereas increased expression of GluR1 in either region decreases cocaine reward (and can make cocaine aversive).
In Aim 3, we will examine whether the effects of altered GluR expression on cocaine reward involve changes in the anxiety-related effects of the drug. We have preliminary data showing, in the BLA, that increased expression of GluR1 makes cocaine more anxiety-provoking, whereas increased expression of GluR2 makes cocaine less anxiety-provoking. Together, these studies provide a framework for future studies in which we will use additional behavioral and molecular techniques to explore mechanistic links between drug-induced neuroadaptations, reward, aversion, and anxiety. Understanding mechanistic links between cocaine-induced adaptations in gene expression and adaptations in behavior may facilitate the development of novel treatments for cocaine addiction and craving.
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