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The medial prefrontal cortex (mPFC) serves as a pathophysiological nexus point underlying many cannabis-related pathophysiological outcomes. Nevertheless, the molecular mechanisms underlying these risk factors are poorly understood. THC increases oxidative stress, which is a well-established causal factor for increased neuropsychiatric risk, including schizophrenia. N-acetylcysteine (NAC) is an antioxidant glutathione precursor that normalizes glutamate and GABA activity in neuropathological states. We examined if NAC may prevent the pathophysiological impacts of THC using a rodent model of adolescent brain development and chronic THC exposure. We report that NAC treatment prevents cognitive, synaptic, neuronal and neurochemical deficits induced by adolescent THC. These findings highlight the critical role of THC-induced oxidative stress as a contributing factor to cannabinoid-mediated neuropsychiatric risk and identifies a novel antioxidant treatment candidate for the prevention and\/or reversal of these pathophysiological outcomes.<\/jats:p>","DOI":"10.1038\/s41398-025-03580-4","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T06:34:10Z","timestamp":1759732450000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The antioxidant N-acetylcysteine prevents cortical neuropathological phenotypes caused by adolescent \u0394-9-tetrahydrocannabinol exposure in male rats"],"prefix":"10.1038","volume":"15","author":[{"given":"Hanna J.","family":"Szkudlarek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajkamalpreet","family":"Singh Mann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krystyna","family":"Wieczerzak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5511-2638","authenticated-orcid":false,"given":"Mohammed Halit","family":"Sarikahya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taygun C.","family":"Uzuneser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"De Felice","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1583-5997","authenticated-orcid":false,"given":"Mar","family":"Rodr\u00edguez-Ruiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Pablo","family":"Galindo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathusha","family":"Pusparajah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawn N.","family":"Whitehead","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter J.","family":"Rushlow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5445-273X","authenticated-orcid":false,"given":"Daniel B.","family":"Hardy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5366-8061","authenticated-orcid":false,"given":"Susanne","family":"Schmid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6933-2941","authenticated-orcid":false,"given":"Ken K.-C.","family":"Yeung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven R.","family":"Laviolette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,6]]},"reference":[{"key":"3580_CR1","doi-asserted-by":"publisher","first-page":"1212","DOI":"10.1136\/bmj.325.7374.1212","volume":"325","author":"L Arseneault","year":"2002","unstructured":"Arseneault L, Cannon M, Poulton R, Murray R, Caspi A, Moffitt TE. 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