P1 SUMMARY: Dramatic rates and consequences of alcohol use disorder (AUD) continue to be a major public health concern. Treatment approaches remain limited and translational research is imperative for the development of more effective interventions for AUD. AUD is associated with a hyper-glutamatergic state and CTNA5 will focus on the mGluR5 negative allosteric modulator (NAM), mavoglurant, as a novel therapeutic for AUD. Project 1 will investigate how AUD impacts alcohol-seeking behaviors and decision-making processes by focusing on translational behavioral approaches and systems-level techniques in rodent models. Project 1 will serve the overall CTNA mission by testing the overarching hypothesis that mavoglurant inhibition of mGluR5 will normalize alcohol-induced disturbances in cortico-striatal glutamate signaling and behavioral dysfunction Our preliminary and published data establish glutamatergic projections from the prefrontal cortex (PFC) to the striatum (nucleus accumbens, NAc) as an essential circuit involved in alcohol-seeking behaviors. Our data also have established key cortico-striatal circuits that mediate distinct aspects of reinforcement learning processes that govern habitual (model-free) and goal-directed (model-based) decision making, which are known to be altered in addictions. Aim 1 will assess the role of mavoglurant in alcohol-seeking behaviors. Fiber photometry in PFCàNAc circuits will be used to assess neural activity dynamics, and, critically, the ability of mavoglurant to block motivation for alcohol and cue-induced reinstatement in male and female alcohol- exposed mice. Aim 2 will investigate the ability of mavoglurant to alter alcohol-induced aberrant decision-making. Decision-making processes will be assessed using our novel rodent version of the multi- stage decision-making (MSDM) task that has been shown to be sensitive to altered response strategies in AUD. Decision-making strategies in male and female alcohol-exposed mice will be determined and the ability of mavoglurant treatment to restore both MSDM strategies and neural activity will also be characterized. While there are known sex differences in the neurobiology of AUD, few systematic studies have investigated the interface between sex, alcohol-seeking behaviors, and decision-making processes in alcohol-exposed mice, and these studies will provide new insights into these interactions. To extend our studies to the cellular level, mGluR5 signaling will be assessed ex vivo and correlated with behavior. The proposed research is highly integrated with the planned human CTNA5 studies in Projects 2 and 3, that will use analogous laboratory models of AUD, drinking behaviors, and decision-making tests to examine the ability of mavoglurant to alter behavior and neural circuits. This preclinical project complements the clinical studies by generating a level of mechanistic insight that is not possible for studies in huma...