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Ethanol modulates neuronal excitability in part through activation of G-protein-gated inwardly rectifying potassium (GIRK\/Kir3) channels, which dampen neuronal activity in reward- and stress-related circuits implicated in AUD pathophysiology. In this study, we investigated the therapeutic potential of targeting activation of GIRK channels in mouse models of ethanol intoxication. GiGA1 (G protein-independent GIRK activator type 1) is a selective activator of GIRK1\/GIRK2 channels and has good brain bioavailability. Systemic GiGA1 administration prevented acquisition of ethanol-induced conditioned place preference (CPP) in both male and female mice. GiGA1 also significantly reduced voluntary ethanol intake and decreased blood alcohol concentrations, when administered to mice after they developed high preference and consumption of ethanol. Similarly, Baclofen, a GABA\n                  <jats:sub>B<\/jats:sub>\n                  receptor agonist that leads to activation of GIRK channels also decreased ethanol consumption. However, systemic Baclofen did not prevent acquisition of ethanol-dependent CPP, suggesting a broader efficacy of direct GIRK1\/GIRK2 activation by GiGA1. Whole-brain c-Fos mapping as a proxy for neuronal activity revealed that GiGA1 blunted ethanol-induced neuronal activation in several AUD-relevant brain regions, including the central amygdala, paraventricular thalamus, paraventricular hypothalamus, and Edinger\u2013Westphal nucleus. These findings demonstrate that pharmacological activation of GIRK channels modulates key neural circuits involved in ethanol reward and intake, supporting GiGA1 as a promising lead compound for targeted AUD therapy.\n                <\/jats:p>","DOI":"10.64898\/2026.01.30.702835","type":"posted-content","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T02:16:01Z","timestamp":1770084961000},"source":"Crossref","is-referenced-by-count":0,"title":["SELECTIVE ACTIVATION OF GIRK POTASSIUM CHANNELS REDUCES BEHAVIORAL AND BRAIN RESPONSES TO ETHANOL IN MICE"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6291-835X","authenticated-orcid":false,"given":"Jaume","family":"Taura","sequence":"first","affiliation":[{"name":"Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arianna","family":"Marrazzo","sequence":"additional","affiliation":[{"name":"Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Se In","family":"Son","sequence":"additional","affiliation":[{"name":"NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Rockville, Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ganesha","family":"Rai","sequence":"additional","affiliation":[{"name":"NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Rockville, Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Max","family":"Kreifeldt","sequence":"additional","affiliation":[{"name":"The Scripps Research Institute, Department of Translational Medicine, La Jolla, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Candice","family":"Contet","sequence":"additional","affiliation":[{"name":"The Scripps Research Institute, Department of Translational Medicine, La Jolla, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3868-7528","authenticated-orcid":false,"given":"Paul A.","family":"Slesinger","sequence":"additional","affiliation":[{"name":"Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026020512090743000_2026.01.30.702835v1.1","unstructured":"NIAAA (2025). 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