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N-acetylcysteine (NAC) has shown promise in preventing drug relapse by normalizing glutamate function, potentially mediated by glutamate 2\/3 (mGlu2\/3) receptor activation. This study investigated the therapeutic potential of NAC in reducing cocaine-seeking behavior using the self-administration model. After establishing stable cocaine self-administration and a 7-day abstinence period, rats received a single dose of NAC (100\u2009mg\/kg, i.p.) 30\u2009min before the first extinction training session. NAC significantly reduced cocaine-seeking behavior on the first day of extinction but not in subsequent extinction sessions. Following extinction, tests for cue-induced reinstatement and spontaneous recovery were conducted. Results showed that NAC administration on the first day of extinction effectively reduced cocaine-seeking during the reinstatement test, with effects lasting at least 28 days. The mGlu2\/3 antagonist LY341495 (1\u2009mg\/kg) fully blocked this enduring suppression of reinstatement without altering the immediate decrease in drug-seeking observed on the first day of extinction. Additionally, NAC administration on the initial extinction day also reduced context-induced reinstatement of cocaine-seeking behavior. These results indicate that NAC exerts its anti-relapse effects via mGlu2\/3 receptors. A single NAC treatment combined with extinction training can produce lasting suppression of relapse, highlighting its therapeutic promise for addiction treatment.<\/jats:p>","DOI":"10.1038\/s41398-026-03954-2","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T16:37:09Z","timestamp":1773938229000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A single extinction-based treatment with N-Acetylcysteine produces long-term reduction in cocaine relapse"],"prefix":"10.1038","volume":"16","author":[{"given":"Shihao","family":"Huang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhihao","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cuijie","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan","family":"Tao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Wen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yisi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yixiao","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"3954_CR1","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1146\/annurev-psych-122414-033457","volume":"67","author":"BJ Everitt","year":"2016","unstructured":"Everitt BJ, Robbins TW. 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