{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T22:24:05Z","timestamp":1787005445780,"version":"build-2736575974"},"posted":{"date-parts":[[2026,3,18]]},"group-title":"Neuroscience","reference-count":60,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T00:00:00Z","timestamp":1773792000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01-AA028782"],"award-info":[{"award-number":["R01-AA028782"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P60-AA011605"],"award-info":[{"award-number":["P60-AA011605"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["T32-AA007573"],"award-info":[{"award-number":["T32-AA007573"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Alcohol use disorder (AUD) is associated with dysregulated glutamatergic signaling within mesocorticolimbic circuits that govern reinforcement and excessive ethanol intake. Group II metabotropic glutamate receptors (mGlu2\/3) act primarily as presynaptic autoreceptors that regulate glutamate release. However, how voluntary alcohol intake alters mGlu2\/3 expression within reward circuitry remains unclear.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods and Results<\/jats:title>\n                  <jats:p>We examined mGlu2\/3 protein expression following a history of voluntary ethanol exposure and operant self-administration and, in separate cohorts, assessed the functional impact of group II receptor modulation on binge-like ethanol intake. Male C57BL\/6J mice received two weeks of home-cage access to sweetened ethanol or sucrose followed by 35 days of operant self-administration. Immediately after the final session, tissue punches from the nucleus accumbens (NAc), amygdala, and prefrontal cortex were collected for immunoblot analysis. mGlu2\/3 expression was reduced in the NAc of ethanol exposed mice with no statistically significant changes detected in the amygdala or prefrontal cortex. In separate binge-drinking cohorts, systemic administration of the mGlu2\/3 agonist LY379268 reduced binge-like ethanol intake in a limited-access home-cage drinking model, whereas positive allosteric modulation of mGlu2 receptors with LY487379 was ineffective.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Voluntary ethanol self-administration was associated with reduced mGlu2\/3 protein expression in the NAc. Systemic pharmacological activation of group II receptors suppressed binge-like ethanol consumption. These findings identify mGlu2\/3 dysregulation in a key reward-related brain region as a molecular adaptation associated with voluntary ethanol intake and demonstrate mechanistic regulation of binge drinking. This suggests that group II metabotropic glutamate signaling is a viable therapeutic target for treating AUD.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.03.18.712674","type":"posted-content","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T07:15:16Z","timestamp":1773904516000},"source":"Crossref","is-referenced-by-count":0,"title":["Ethanol Self-Administration Reduces mGlu2\/3 Protein Expression in the Nucleus Accumbens and mGlu2\/3 Activation Suppresses Binge Drinking in Male Mice"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9119-7212","authenticated-orcid":false,"given":"Cassandra G.","family":"Modrak","sequence":"first","affiliation":[{"name":"Bowles Center for Alcohol Studies"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah E.","family":"Holstein","sequence":"additional","affiliation":[{"name":"Bowles Center for Alcohol Studies"},{"name":"Department of Psychology Lycoming College Williamsport, PA 17701 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"April","family":"Kim","sequence":"additional","affiliation":[{"name":"Bowles Center for Alcohol Studies"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth G.","family":"Shannon","sequence":"additional","affiliation":[{"name":"Department of Psychiatry"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Faccidomo","sequence":"additional","affiliation":[{"name":"Bowles Center for Alcohol Studies"},{"name":"Department of Psychiatry"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyce","family":"Besheer","sequence":"additional","affiliation":[{"name":"Bowles Center for Alcohol Studies"},{"name":"Department of Psychiatry"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6860-7955","authenticated-orcid":false,"given":"Clyde W.","family":"Hodge","sequence":"additional","affiliation":[{"name":"Bowles Center for Alcohol Studies"},{"name":"Department of Psychiatry"},{"name":"Department of Pharmacology School of Medicine The University of North Carolina at Chapel Hill Chapel Hill, NC 27599 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026081714250857000_2026.03.18.712674v3.1","doi-asserted-by":"publisher","DOI":"10.1111\/acer.12819"},{"key":"2026081714250857000_2026.03.18.712674v3.2","doi-asserted-by":"publisher","DOI":"10.1111\/acer.12645"},{"key":"2026081714250857000_2026.03.18.712674v3.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2005.10.051"},{"key":"2026081714250857000_2026.03.18.712674v3.4","doi-asserted-by":"publisher","DOI":"10.1097\/01.ALC.0000149977.95306.3A"},{"key":"2026081714250857000_2026.03.18.712674v3.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2009.09.016"},{"key":"2026081714250857000_2026.03.18.712674v3.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2006.06.008"},{"key":"2026081714250857000_2026.03.18.712674v3.7","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1111\/adb.12357","article-title":"Potentiation of amygdala AMPA receptor activity selectively promotes escalated alcohol self-administration in a CaMKII-dependent manner","volume":"22","year":"2017","journal-title":"Addict Biol"},{"key":"2026081714250857000_2026.03.18.712674v3.8","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2011.121"},{"key":"2026081714250857000_2026.03.18.712674v3.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.alcohol.2024.01.006"},{"key":"2026081714250857000_2026.03.18.712674v3.10","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/s00213-008-1444-9","article-title":"Increased operant responding for ethanol in male C57BL\/6J mice: specific regulation by the ERK1\/2, but not JNK","volume":"204","year":"2009","journal-title":"MAP kinase pathway. 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