Novel mechanism of alcohol self-administration and relapse

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Project Summary / Abstract Pathological alcohol-seeking behavior is regulated in part by glutamate AMPA receptor (AMPAR) activity in the amygdala. Transmembrane AMPA receptor regulatory proteins (TARPs) profoundly affect the trafficking and function of AMPARs in synaptic and behavioral plasticity. Although the TARP family of proteins is expressed throughout the brain, the TARP γ-8 subtype is restricted to forebrain regions including the basolateral amygdala (BLA); a brain region that is critical to addiction. However, the role of TARP γ-8 in alcohol use disorders (AUD) or other addictions is unknown. To fill this gap in knowledge, the parent R01 project is conducting an innovative set of behavioral, genetic, bidirectional systemic and site-specific pharmacological, molecular, and physiological studies in mice to evaluate the mechanistic role of TARP γ-8 in alcohol reinforcement, escalated self-administration, and cue-induced reinstatement of alcohol-seeking behavior as a model of relapse. In this Administrative Supplement to Promote Diversity, it is proposed that the candidate will enhance and extend this work by evaluating: 1) the mechanistic role of TARP γ-8 in alcohol reward using conditioned place preference (CPP); and 2) alcohol- induced changes in TARP γ-8 (Cacng8) gene expression in the amygdala and other reward- related brain regions in mice. These innovative experiments are within the scope but not redundant with studies proposed in the parent grant and will provide continued research training and additional publications to promote the candidate’s career trajectory toward being an independent academic scientist focused on evaluating the neural mechanisms of AUD. Successful completion of the studies proposed in this Administrative Supplement for Diversity will move the field forward in understanding the molecular mechanisms by which alcohol hijacks reward processes and has potential to inform development of new pharmacotherapeutic strategies that target AMPAR function in a highly selective brain region-specific manner.