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One reason for the prevalence of AUD is that heavy alcohol drinking can produce alcohol dependence. In addition, alcohol dependence dysregulates the body's stress systems to increase alcohol drinking. Therefore, targeting dependence\u2010 and\/or stress\u2010related alcohol drinking clinically could reduce heavy drinking in patients with AUD. One key mechanism thought to contribute to behaviors associated with AUD is long\u2010lasting epigenetic alterations of gene expression. We recently showed that the epigenetic regulatory enzyme G9a (also known as euchromatic histone\u2010lysine N\u2010methyltransferase 2 or EHMT2) is downregulated in the nucleus accumbens (NAc) in mice by alcohol dependence produced by the chronic intermittent alcohol (CIE) model. Also, we showed that either viral\u2010mediated NAc G9a knockdown or a systemically administered G9a inhibitor reduced stress\u2010potentiated alcohol drinking by the kappa\u2010opioid agonist U50,488.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, we tested whether NAc G9a knockdown reduces escalated alcohol drinking in a mouse model of combined dependence plus forced swim stress (CIE\u2009+\u2009FSS) in male mice. We also tested for changes in sucrose drinking, sucrose preference, and water consumption as controls. In addition, we tested whether systemic administration of a G9a inhibitor, UNC0642, could reduce alcohol drinking in the CIE\u2009+\u2009FSS model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that either NAc G9a knockdown or repeated systemic UNC0642 administration reduced escalated ethanol drinking following CIE\u2009+\u2009FSS, but without altering control levels of ethanol drinking or sucrose drinking or water drinking in male mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These preclinical data suggest that reducing NAc G9a levels, or suppressing its enzymatic activity, can effectively reduce potentiated alcohol drinking produced by stress and\/or alcohol dependence. These data suggest that G9a inhibition holds promise as a potential therapeutic for individuals who suffer from AUD.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.70142","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T04:34:52Z","timestamp":1757478892000},"page":"2267-2277","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting G9a decreases escalated alcohol drinking in male\u00a0mice in a model of combined stress and chronic alcohol\u00a0exposure"],"prefix":"10.1111","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5885-7371","authenticated-orcid":false,"given":"Marcelo F.","family":"Lopez","sequence":"first","affiliation":[{"name":"Department of Neuroscience Medical University of South Carolina  Charleston South Carolina USA"},{"name":"Department of Psychiatry and Behavioral Sciences, Charleston Alcohol Research Center Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paulina","family":"Misztak","sequence":"additional","affiliation":[{"name":"Department of Comparative Biomedical Sciences Louisiana State University  Baton Rouge Louisiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8042-6957","authenticated-orcid":false,"given":"Howard C.","family":"Becker","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Medical University of South Carolina  Charleston South Carolina USA"},{"name":"Department of Psychiatry and Behavioral Sciences, Charleston Alcohol Research Center Medical University of South Carolina  Charleston South Carolina USA"},{"name":"Ralph H. 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