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In rodents, the activity\u2010regulated cytoskeleton\u2010associated protein (Arc) can regulate glutamatergic synaptic transmission, and cocaine regulates Arc expression and subcellular localization in multiple brain regions, including the nucleus accumbens (NAc)\u2014a brain region linked to CUD\u2010related behavior. We show here that repeated, non\u2010contingent cocaine administration in global\n                    <jats:italic>Arc<\/jats:italic>\n                    KO male mice produced a dramatic hypersensitization of cocaine locomotor responses and drug experience\u2010dependent sensitization of conditioned place preference (CPP). In contrast to the global\n                    <jats:italic>Arc<\/jats:italic>\n                    KO mice, viral\u2010mediated reduction of Arc in the adult male, but not female, NAc (shArc\n                    <jats:sup>NAc<\/jats:sup>\n                    ) reduced both CPP and cocaine\u2010induced locomotor activity, but without altering basal miniature or evoked glutamatergic synaptic transmission. Interestingly, cell type\u2010specific knockdown of Arc in D1 dopamine receptor\u2010expressing NAc neurons reduced cocaine\u2010induced locomotor sensitization, but not cocaine CPP; whereas, Arc knockdown in D2 dopamine receptor\u2010expressing NAc neurons reduced cocaine CPP, but not cocaine\u2010induced 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\u2010 and sex\u2010specific manner to support cocaine\u2010context associations and locomotor responses.\n                  <\/jats:p>","DOI":"10.1111\/gbb.12910","type":"journal-article","created":{"date-parts":[[2024,8,21]],"date-time":"2024-08-21T22:16:25Z","timestamp":1724278585000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The activity\u2010regulated cytoskeleton\u2010associated protein (Arc) functions in a cell type\u2010 and sex\u2010specific manner in the adult nucleus accumbens to regulate non\u2010contingent cocaine behaviors"],"prefix":"10.1111","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1874-7738","authenticated-orcid":false,"given":"Daniel 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