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Ethanol and cocaine both reduce AMPK activity in addiction\u2010related brain regions. Though AMPK activation has been found to reduce cocaine seeking, its role in harmful drinking and alcohol use disorder (AUD) progression remains unclear. We asked whether metformin, a first\u2010line type 2 diabetes medication that targets AMPK, can reduce binge\u2010like ethanol intake in inbred High Drinking in the Dark Line\u20101 (iHDID\u20101) mice, a genetic risk model for drinking to intoxication. We then determined whether metformin altered ethanol clearance in iHDID\u20101 mice. Next, we tested whether metformin and\/or ethanol altered AMPK signaling in the nucleus accumbens (NAc), a brain region critically important for harmful drinking.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We measured the effects of metformin [0 or 250\u2009mg\/kg; intraperitoneal injection (i.p.)] on binge\u2010like ethanol intake in separate acute (Experiment 1) and chronic (Experiment 3A) drinking studies (<jats:italic>n<\/jats:italic>\u2009=\u20096\u20138 iHDID\u20101 mice\/sex\/treatment\/experiment). The effect of metformin (0 or 250\u2009mg\/kg) on ethanol (2.0\u2009g\/kg, i.p.) clearance was tested in iHDID\u20101 mice (Experiment 2; <jats:italic>n<\/jats:italic>\u2009=\u20097\u20139\/sex\/treatment). Lastly, we measured NAc AMPK and phosphorylated AMPK (pAMPK) levels in response to chronic ethanol (or water) drinking (<jats:italic>n<\/jats:italic>\u2009=\u20096 iHDID\u20101 mice\/sex\/treatment\/fluid type; Experiment 3B) and an intoxicating dose of ethanol (2.0\u2009g\/kg; i.p.; Experiment 4).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Metformin reduced binge\u2010like ethanol drinking intake in acute and chronic studies in both male and female iHDID\u20101 mice (<jats:italic>p<\/jats:italic>'s\u2009&lt;\u20090.05). We found no significant changes in ethanol clearance in response to metformin. Moreover, no differences in AMPK or pAMPK levels in the NAc were observed with either ethanol or metformin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These findings provide early support for the repurposing of metformin, an affordable and safe diabetes medication, to reduce harmful ethanol intake and lay a foundation for testing its efficacy to treat individuals with AUD.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.15460","type":"journal-article","created":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T15:00:22Z","timestamp":1732633222000},"page":"2269-2280","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Effects of metformin on binge\u2010like ethanol drinking and adenosine monophosphate kinase signaling in inbred high drinking in the dark line 1 mice"],"prefix":"10.1111","volume":"48","author":[{"given":"Kolter","family":"Grigsby","sequence":"first","affiliation":[{"name":"Research and Development Service Portland Veterans Affairs Medical Center  Portland Oregon USA"},{"name":"Department of Behavioral Neuroscience, Portland Alcohol Research Center Oregon Health and Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Palacios","sequence":"additional","affiliation":[{"name":"Research and Development Service Portland Veterans Affairs Medical Center  Portland Oregon USA"},{"name":"Department of Behavioral Neuroscience, Portland Alcohol Research Center Oregon Health and Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy E.","family":"Chan","sequence":"additional","affiliation":[{"name":"Research and Development Service Portland Veterans Affairs Medical Center  Portland Oregon USA"},{"name":"Department of Behavioral Neuroscience, Portland Alcohol Research Center Oregon Health and Science University  Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sade M.","family":"Spencer","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Minnesota  Minneapolis Minnesota USA"},{"name":"Medical Discovery Team on Addiction University of Minnesota  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8387-1156","authenticated-orcid":false,"given":"Angela R.","family":"Ozburn","sequence":"additional","affiliation":[{"name":"Research and Development Service Portland Veterans Affairs Medical Center  Portland Oregon USA"},{"name":"Department of Behavioral Neuroscience, Portland Alcohol Research Center Oregon Health and Science University  Portland Oregon 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