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The underlying mechanisms are unclear and no approaches exist to prevent or reverse these unwanted effects of antipsychotic treatment. Here we demonstrate that behavioral supersensitivity stems from long-lasting pre, post and perisynaptic plasticity, including insertion of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -permeable AMPA receptors and loss of D2 receptor-dependent inhibitory postsynaptic currents (IPSCs) in D2 receptor-expressing medium spiny neurons (D2-MSNs) in the nucleus accumbens core (NAcore). The resulting hyperexcitability, prominent in a subpopulation of D2-MSNs (21%), caused locomotor sensitization to cocaine and was associated with behavioral endophenotypes of antipsychotic treatment resistance and substance use disorder, including disrupted extinction learning and augmented cue-induced cocaine-seeking behavior. Chemogenetic restoration of IPSCs in D2-MSNs in the NAcore was sufficient to prevent antipsychotic-induced supersensitivity, pointing to an entirely novel therapeutic direction for overcoming this condition.\n                  <\/jats:p>","DOI":"10.1038\/s41380-021-01235-6","type":"journal-article","created":{"date-parts":[[2021,8,4]],"date-time":"2021-08-04T09:02:39Z","timestamp":1628067759000},"page":"6159-6169","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Accumbens D2-MSN hyperactivity drives antipsychotic-induced behavioral supersensitivity"],"prefix":"10.1038","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9267-9492","authenticated-orcid":false,"given":"Anna","family":"Kruyer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Parrilla-Carrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney","family":"Powell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lasse","family":"Brandt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Gutwinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariana","family":"Angelis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reda M.","family":"Chalhoub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas C.","family":"Jhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9487-0119","authenticated-orcid":false,"given":"Peter W.","family":"Kalivas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3630-0147","authenticated-orcid":false,"given":"Davide","family":"Amato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,4]]},"reference":[{"key":"1235_CR1","doi-asserted-by":"publisher","first-page":"319","DOI":"10.2165\/11533120-000000000-00000","volume":"24","author":"TL Mark","year":"2010","unstructured":"Mark TL. 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