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We examined the role of TLR3 in behavioral responses to alcohol and GABAergic drugs by studying <jats:italic>Tlr3<\/jats:italic> <jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice. Because of opposing signaling between TLR3 and MyD88 pathways, we also evaluated <jats:italic>Myd88<\/jats:italic> <jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice. Ethanol consumption and preference decreased in male but not in female <jats:italic>Tlr3<\/jats:italic> <jats:sup>\u2212\/\u2212<\/jats:sup> mice during two\u2010bottle choice every\u2010other\u2010day (2<jats:sc>BC<\/jats:sc>\u2010EOD) drinking. There were no genotype differences in either sex during continuous or limited\u2010access drinking. Null mutations in <jats:italic>Tlr3<\/jats:italic> or <jats:italic>Myd88<\/jats:italic> did not alter conditioned taste aversion to alcohol and had small or no effects on conditioned place preference. The <jats:italic>Tlr3<\/jats:italic> null mutation did not alter acute alcohol withdrawal. Male, but not female, <jats:italic>Tlr3<\/jats:italic> <jats:sup>\u2212\/\u2212<\/jats:sup> mice took longer than wild\u2010type littermates to recover from ataxia by ethanol or diazepam and longer to recover from sedative\u2010hypnotic effects of ethanol or gaboxadol, indicating regulation of GABAergic signaling by TLR3. Acute functional tolerance (AFT) to alcohol\u2010induced ataxia was decreased in <jats:italic>Tlr3<\/jats:italic> <jats:sup>\u2212\/\u2212<\/jats:sup> mice but was increased in <jats:italic>Myd88<\/jats:italic> <jats:sup>\u2212\/\u2212<\/jats:sup> mice. Thus, MyD88 and TLR3 pathways coordinately regulate alcohol consumption and tolerance to intoxicating doses of alcohol and GABAergic drugs. Despite similar alcohol metabolism and similar amounts of total alcohol consumed during 2BC and 2<jats:sc>BC<\/jats:sc>\u2010EOD procedures in C57BL\/6J mice, only 2<jats:sc>BC<\/jats:sc>\u2010EOD drinking induced tolerance to alcohol\u2010induced ataxia. Ataxia recovery was inversely correlated with level of drinking in wild\u2010type and <jats:italic>Tlr3<\/jats:italic> <jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> littermates. Thus, deleting <jats:italic>Tlr3<\/jats:italic> reduces alcohol consumption by reducing AFT to alcohol and not by altering tolerance induced by 2<jats:sc>BC<\/jats:sc>\u2010EOD drinking.<\/jats:p>","DOI":"10.1111\/adb.12932","type":"journal-article","created":{"date-parts":[[2020,6,30]],"date-time":"2020-06-30T22:57:34Z","timestamp":1593557854000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Deletion of <i>Tlr3<\/i> reduces acute tolerance to alcohol and alcohol consumption in the intermittent access procedure in male mice"],"prefix":"10.1111","volume":"26","author":[{"given":"Yuri A.","family":"Blednov","sequence":"first","affiliation":[{"name":"Waggoner Center for Alcohol and Addiction Research The University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Da Costa","sequence":"additional","affiliation":[{"name":"Waggoner Center for Alcohol and Addiction Research The University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jody","family":"Mayfield","sequence":"additional","affiliation":[{"name":"Waggoner Center for Alcohol and Addiction Research The University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8870-5950","authenticated-orcid":false,"given":"R. 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