Project Summary 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, we propose 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. Elucidating the neural mechanisms of these three critical behavioral domains has high translational value for understanding the development, progression, and maintenance of AUD. Successful completion of the studies in this application will provide fundamental mechanistic insights into TARP γ-8 regulation of pathological alcohol-seeking behavior. Moreover, this work moves 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.

Project Narrative Repetitive alcohol use, escalated intake, and relapse are hallmark pathologies of alcohol use disorders (AUD). In this preclinical project, we are focused on evaluating TARP γ-8, a novel target in the brain that controls alcohol- seeking behavior. We are taking a multidisciplinary approach that involves genetic, behavioral, pharmacological, molecular, and physiological techniques to fully characterize TARP γ-8 regulation of alcohol use, escalated intake, and relapse in mouse behavioral models. Successful completion of the proposed studies has potential to lead to new therapeutic strategies for treating behavioral pathologies associated with AUD.