The activity‐regulated cytoskeleton‐associated protein (Arc) functions in a cell type‐ and sex‐specific manner in the adult nucleus accumbens to regulate non‐contingent cocaine behaviors

Abstract

AbstractRepeated cocaine use produces adaptations in brain function that contribute to long‐lasting behaviors associated with cocaine use disorder (CUD). In rodents, the activity‐regulated cytoskeleton‐associated protein (Arc) can regulate glutamatergic synaptic transmission, and cocaine regulates Arc expression and subcellular localization in multiple brain regions, including the nucleus accumbens (NAc)—a brain region linked to CUD‐related behavior. We show here that repeated, non‐contingent cocaine administration in global Arc KO male mice produced a dramatic hypersensitization of cocaine locomotor responses and drug experience‐dependent sensitization of conditioned place preference (CPP). In contrast to the global Arc KO mice, viral‐mediated reduction of Arc in the adult male, but not female, NAc (shArcNAc) reduced both CPP and cocaine‐induced locomotor activity, but without altering basal miniature or evoked glutamatergic synaptic transmission. Interestingly, cell type‐specific knockdown of Arc in D1 dopamine receptor‐expressing NAc neurons reduced cocaine‐induced locomotor sensitization, but not cocaine CPP; whereas, Arc knockdown in D2 dopamine receptor‐expressing NAc neurons reduced cocaine CPP, but not cocaine‐induced locomotion. Taken together, our findings reveal that global, developmental loss of Arc produces hypersensitized cocaine responses; however, these effects cannot be explained by Arc's function in the adult mouse NAc since Arc is required in a cell type‐ and sex‐specific manner to support cocaine‐context associations and locomotor responses.