Role of nucleus accumbens core in ethanol reward and binge-like drinking: Focus on sex as a biological variable

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Project Summary Binge alcohol drinking is a risk factor for Alcohol Use Disorder (AUD), and while alcohol use and AUD diagnoses are more prevalent in men than women, this gap has drastically narrowed. Promising therapeutic candidates for the treatment of AUD have been identified using rodent models; however, few studies have addressed sex as a biological variable (SABV). Increasing our understanding of SABV in the neural circuitry that underlies binge-like drinking could lead to more tailored interventions. The nucleus accumbens core (NAcc) has diverse afferent connections that underlie its crucial involvement in all stages of AUD. In treatment resistant male patients with AUD, NAcc deep-brain stimulation reduced alcohol craving and promoted either lower alcohol intake or total abstinence, underscoring the relevance of this brain region in translational AUD research. In rodents, ethanol (EtOH) drinking increases c-Fos (a biomarker for neuronal activity) in the NAc, and manipulations of the NAc (via lesion, DBS, or chemogenetics) changes EtOH drinking. Lesioning the NAcc in male DBA/2J mice prevents acquisition of EtOH conditioned place preference (CPP), a measure of sensitivity to the rewarding effects of EtOH. Since there are some known sex-differences in the rodent NAcc, both basally and in response to EtOH, it is imperative to address SABV in studies testing the importance of the NAcc in EtOH reward and AUD. There are apparent sex differences in EtOH Drinking-in-the-Dark (DID) intake following chemogenetic manipulation of the NAcc, where inhibition reduces intake in C57BL/6J (B6) males but increases intake in females. Conversely, stimulation of the NAcc reduces DID EtOH intake in females, with no effect seen in males. These findings suggest that NAcc manipulation may alter sensitivity to the rewarding effects of EtOH in a sex-dependent manner, and if so, this could underlie chemogenetically-induced changes in drinking. Overall, this proposal addresses the importance of the NAcc and SABV in B6 mice during 2 facets of binge/intoxication – 1) how changing NAcc activity impacts the positive subjective effects of an intoxicating dose of EtOH and 2) determining the NAcc circuitry engaged during binge-like drinking. Aim 1 tests whether chemogenetic manipulation of the NAcc alters the conditioned rewarding effects of EtOH using an EtOH conditioned place preference (CPP) task. Aim 2 uses whole-brain imaging to identify regions engaged during DID (through analysis of c-Fos expression), in combination with use of a viral retrograde tracer administered into the NAcc. This will allow for quantification of co-labeled c-Fos and GFP-expressing NAcc inputs to determine which NAcc circuits are engaged during this behavior. Inclusion of both sexes allows us to determine whether there are differences in c-fos induction, and whether projections to the NAcc are differentially engaged during DID. The proposed studies will critically improve our understanding of 1) how NAcc activity may sex-specifically impact the rewarding effects of EtOH, and 2) whole brain and NAcc specific circuits engaged by binge-like EtOH drinking in males and females.