Stimulation of Adenosine Receptors in the Nucleus Accumbens Reduces Dopamine Receptor-Induced Cocaine Seeking by Antagonizing Dopamine-Mediated Modulation of Glutamate Transmission

Hobson, Benjamin

Undergraduate Honors Thesis

Stimulation of Adenosine Receptors in the Nucleus Accumbens Reduces Dopamine Receptor-Induced Cocaine Seeking by Antagonizing Dopamine-Mediated Modulation of Glutamate Transmission Pubblico Deposited

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Citeable URL: https://scholar.colorado.edu/concern/undergraduate_honors_theses/1544bp651

Abstract

Cocaine addiction is a brain disorder that affects millions of people and generates enormous social and economic costs to society. The continuous potential for relapse during periods of withdrawal makes treatment of cocaine addiction especially difficult. These studies investigate the molecular mechanisms mediating relapse behavior in a rodent model of cocaine addiction. Recent studies have demonstrated that AMPA glutamate receptor-dependent synaptic plasticity in the nucleus accumbens (NAc) core plays a critical role in cocaine seeking. It is unclear, however, how dopamine receptor signaling interacts with NAc AMPA receptors to mediate this behavior. Here, we investigate the interaction between dopamine and AMPA receptors in the nucleus accumbens and explore how adenosine receptor stimulation may counteract dopamine receptor-induced cocaine seeking and modulation of AMPA receptor trafficking. Specifically, we tested whether stimulating adenosine A1 or A2A receptors in the NAc could reduce dopamine D1 or D2, respectively, receptor-induced reinstatement. We also determined whether stimulating A1 or A2A receptors in the NAc would reduce D1 or D2 receptorinduced changes in synaptic GluR1 phosphorylation using a synaptoneurosome preparation and subsequent immunoblot analyses. As a correlate to these studies, we used viral-mediated gene transfer to determine the effects of expressing a GluR1S845A phosphomutant (Ser 845 Ala) in the NAc on cocaine, D1, and D2-induced reinstatement. Our results demonstrate that stimulation of A1 receptors decreases D1-induced cocaine seeking and GluR1S845 phosphorylation. Stimulation of A2A receptors both increases GluR1S845 phosphorylation and decreases D2-induced cocaine seeking and GluR1 internalization. Interestingly, overexpressing the GluR1S845A phosphomutant in the NAc significantly reduced D2, but not D1 or cocaine-induced. reinstatement. These findings suggest that adenosine receptors act to offset dopamine receptormediated modulation of AMPA receptor trafficking that drives cocaine seeking.

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