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Here, we used a mouse model of adolescent binge drinking and focussed on G protein-gated inwardly rectifying potassium (GIRK) channels which are a molecular target of both ethanol and the pluripotent growth and differentiation factor activin A. In whole-cell recordings from dentate gyrus granule cells in brain slices from alcohol-naive mice, we found a striking reversal of the effect of activin A on ethanol-evoked GIRK current as the mice matured: Whereas activin A reduced the ethanol response in cells from adult mice, the already lower ethanol threshold in cells from young mice was brought down even further by activin A. In cells from adult mice with binge drinking-like experience in their youth, the reversal of the activin effect on ethanol-evoked GIRK current with maturation was abrogated, thereby perpetuating the adolescent phenotype of activin-boosted ethanol sensitivity into adulthood. Underscoring the translational significance of an aberrantly enhanced GIRK current response to ethanol, the GABA\n                    <jats:sub>B<\/jats:sub>\n                    receptor agonist baclofen, which is used as an \u201coff-label\u201d prescription against alcohol use disorders, suppressed the permanently enhanced GIRK response to ethanol after heavy adolescent drinking.\n                  <\/jats:p>","DOI":"10.1038\/s41380-025-03210-x","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T12:29:02Z","timestamp":1756902542000},"page":"1027-1040","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Heavy adolescent drinking makes the adult brain more vulnerable to ethanol by permanently altering the age-dependent interplay between alcohol, GIRK channels and activin"],"prefix":"10.1038","volume":"31","author":[{"given":"Sophia","family":"St\u00fcrzenberger","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"B\u00fclow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liubov S.","family":"Kalinichenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5762-6354","authenticated-orcid":false,"given":"Rebecca","family":"Licha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker","family":"Eulenburg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Dahlmanns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5325-9900","authenticated-orcid":false,"given":"Christian P.","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5699-8063","authenticated-orcid":false,"given":"Fang","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3910-5072","authenticated-orcid":false,"given":"Christian","family":"Alzheimer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,3]]},"reference":[{"key":"3210_CR1","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.dcn.2015.12.010","volume":"17","author":"EP Shulman","year":"2016","unstructured":"Shulman EP, Smith AR, Silva K, Icenogle G, Duell N, Chein J, Steinberg L. 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