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Cocaine produces neuronal alterations, including structural changes in dendritic number and morphology. Emerging data indicate sigma\u20101 receptors (\u03c3\u20101Rs) as a promising candidate for the prevention of cocaine craving. Opipramol is a \u03c3\u20101R agonist approved in some European countries for depression and anxiety. Here we report that opipramol, mediated by Rac1, attenuates cocaine\u2010seeking behavior in a rat model of self\u2010administration. The opipramol effect was shown in two phases. It decreased cocaine\u2010seeking behavior throughout the withdrawal phase and, interestingly, showed a significant reduction of cocaine\u2010primed reinstatement in 75% of the opipramol\u2010treated group (termed \u2018responders\u2019). All opipramol\u2010treated rats showed a decrease in \u03c3\u20101R mRNA expression levels in the nucleus accumbens (NAc) versus controls. Responders also exhibited significantly decreased NAc Rac1 mRNA expression levels, compared with non\u2010responder rats. Hence, Rac1 differentiated responders from non\u2010responders. Rac1 correlated positively with \u03c3\u20101R mRNA levels in opipramol responders. In another experiment, Rac1 inhibitor injected directly into the NAc core decreased active lever presses on the first day of extinction, indicating the critical role of Rac1 in the opipramol effect on drug seeking. We postulate that chronic activation of \u03c3\u20101R, through a dynamic interaction with Rac1, may suggest a new approach to treat substance use disorder (SUD). Rac1 inhibition is a prerequisite for decreasing drug seeking and rehabilitation, and this can be achieved by opipramol, a medication that can be given during detoxification.<\/jats:p>","DOI":"10.1111\/adb.13014","type":"journal-article","created":{"date-parts":[[2021,1,29]],"date-time":"2021-01-29T02:20:24Z","timestamp":1611886824000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Chronic opipramol treatment extinguishes cocaine craving through Rac1 in responders: A rat model study"],"prefix":"10.1111","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7269-4131","authenticated-orcid":false,"given":"Tzofnat","family":"Bareli","sequence":"first","affiliation":[{"name":"Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center and the Faculty of Life Sciences Bar Ilan University  Ramat Gan Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hadas Levi","family":"Ahdoot","sequence":"additional","affiliation":[{"name":"Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center and the Faculty of Life Sciences Bar Ilan University  Ramat Gan Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hila","family":"Ben\u2010Moshe","sequence":"additional","affiliation":[{"name":"Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center and the Faculty of Life Sciences Bar Ilan University  Ramat Gan Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Royi","family":"Barnea","sequence":"additional","affiliation":[{"name":"Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center and the Faculty of Life Sciences Bar Ilan University  Ramat Gan Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4477-2200","authenticated-orcid":false,"given":"Gal","family":"Warhaftig","sequence":"additional","affiliation":[{"name":"Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center and the Faculty of Life Sciences Bar Ilan University  Ramat Gan Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel","family":"Maayan","sequence":"additional","affiliation":[{"name":"The Laboratory of Biological Psychiatry, Felsenstein Medical Research Center and Sackler Faculty of Medicine Tel Aviv University, Beilinson Campus  Petah Tikva Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paola","family":"Roska","sequence":"additional","affiliation":[{"name":"Department for the Treatment of Substance Abuse and Mental Health Services, Israeli Ministry of Health  Jerusalem Israel"},{"name":"The Hebrew University of Jerusalem  Jerusalem Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9765-8938","authenticated-orcid":false,"given":"Abraham","family":"Weizman","sequence":"additional","affiliation":[{"name":"The Laboratory of Biological Psychiatry, Felsenstein Medical Research Center and Sackler Faculty of Medicine Tel Aviv University, Beilinson Campus  Petah Tikva Israel"},{"name":"Research Unit Geha Mental Health Center  Petah Tikva Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4379-8505","authenticated-orcid":false,"given":"Gal","family":"Yadid","sequence":"additional","affiliation":[{"name":"Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center and the Faculty of Life Sciences Bar Ilan University  Ramat Gan Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,1,28]]},"reference":[{"doi-asserted-by":"publisher","key":"e_1_2_7_2_1","DOI":"10.1111\/add.14234"},{"doi-asserted-by":"publisher","key":"e_1_2_7_3_1","DOI":"10.1001\/archpsyc.56.6.507"},{"doi-asserted-by":"publisher","key":"e_1_2_7_4_1","DOI":"10.1001\/archpsyc.1986.01800020013003"},{"unstructured":"Global overview of drug demand and supply.https:\/\/www.unodc.org\/wdr2018. 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