{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T18:06:16Z","timestamp":1793297176471,"version":"4.5.0"},"reference-count":99,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,9]],"date-time":"2022-06-09T00:00:00Z","timestamp":1654732800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007359","name":"Fondazione Banco di Sardegna","doi-asserted-by":"publisher","award":["Prat.2014.0072"],"award-info":[{"award-number":["Prat.2014.0072"]}],"id":[{"id":"10.13039\/100007359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Behav. Neurosci."],"abstract":"<jats:p>Gamma-aminobutyric acid type B receptor (GABA<jats:sub>B<\/jats:sub>R) has been extensively involved in alcohol use disorders; however, the mechanisms by which this receptor modulates alcohol drinking behavior remain murky. In this study, we investigate alcohol consumption and preference in mice lacking functional GABA<jats:sub>B<\/jats:sub>R using the 2-bottle choice paradigm. We found that GABA<jats:sub>B(1)<\/jats:sub>, knockout (KO), and heterozygous (HZ) mice drank higher amounts of an alcoholic solution, preferred alcohol to water, and reached higher blood alcohol concentrations (BACs) compared to wild-type (WT) littermates. The GABA<jats:sub>B<\/jats:sub>R agonist GHB significantly reduced alcohol consumption in the GABA<jats:sub>B(1)<\/jats:sub> HZ and WT but not in the KO mice. Next, because of a functional crosstalk between GABA<jats:sub>B<\/jats:sub>R and \u03b4-containing GABA<jats:sub>A<\/jats:sub> receptor (\u03b4-GABA<jats:sub><jats:italic>A<\/jats:italic><\/jats:sub>R), we profiled \u03b4 subunit mRNA expression levels in brain regions in which the crosstalk was characterized. We found a loss of the alcohol-sensitive GABA<jats:sub>A<\/jats:sub>R \u03b4 subunit in the hippocampus of the GABA<jats:sub>B(1)<\/jats:sub> KO alcohol-na\u00efve mice that was associated with increased \u0263<jats:sup>2<\/jats:sup> subunit abundance. Electrophysiological recordings revealed that these molecular changes were associated with increased phasic inhibition, suggesting a potential gain of synaptic GABA<jats:sub>A<\/jats:sub>R responsiveness to alcohol that has been previously described in an animal model of excessive alcohol drinking. Interestingly, voluntary alcohol consumption did not revert the dramatic loss of hippocampal \u03b4-GABA<jats:sub>A<\/jats:sub>R occurring in the GABA<jats:sub>B(1)<\/jats:sub> KO mice but rather exacerbated this condition. Finally, we profiled hippocampal neuroactive steroids levels following acute alcohols administration in the GABA<jats:sub>B(1)<\/jats:sub> KO and WT mice because of previous involvement of GABA<jats:sub>B<\/jats:sub>R in the regulation of cerebral levels of these compounds. We found that systemic administration of alcohol (1.5 g\/kg) did not produce alcohol-induced neurosteroid response in the GABA<jats:sub>B(1)<\/jats:sub> KO mice but elicited an expected increase in the hippocampal level of progesterone and 3\u03b1,5\u03b1-THP in the WT controls. In conclusion, we show that genetic ablation of the GABA<jats:sub>B(1)<\/jats:sub> subunit results in increased alcohol consumption and preference that were associated with functional changes in hippocampal GABA<jats:sub>A<\/jats:sub>R, suggesting a potential mechanism by which preference for alcohol consumption is maintained in the GABA<jats:sub>B(1)<\/jats:sub> KO mice. In addition, we documented that GABA<jats:sub>B(1)<\/jats:sub> deficiency results in lack of alcohol-induced neurosteroids, and we discussed the potential implications of this finding in the context of alcohol drinking and dependence.<\/jats:p>","DOI":"10.3389\/fnbeh.2022.893835","type":"journal-article","created":{"date-parts":[[2022,6,9]],"date-time":"2022-06-09T07:54:26Z","timestamp":1654761266000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Increased Voluntary Alcohol Consumption in Mice Lacking GABAB(1) Is Associated With Functional Changes in Hippocampal GABAA Receptors"],"prefix":"10.3389","volume":"16","author":[{"given":"Gabriele","family":"Floris","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gino Paolo","family":"Asuni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Talani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Biggio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Giuseppina","family":"Pisu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary Tresa","family":"Zanda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliana","family":"Contu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Maciocco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariangela","family":"Serra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Follesa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1093\/alcalc\/agr017","article-title":"Dose-response effect of baclofen in reducing daily alcohol intake in alcohol dependence: secondary analysis of a randomized, double-blind, placebo-controlled trial.","volume":"46","author":"Addolorato","year":"2011","journal-title":"Alcohol Alcohol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1038\/npp.2011.216","article-title":"Novel therapeutic strategies for alcohol and drug addiction: focus on GABA, ion channels and transcranial magnetic stimulation.","volume":"37","author":"Addolorato","year":"2012","journal-title":"Neuropsychopharmacology"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2014.00140","article-title":"GABAB receptor ligands for the treatment of alcohol use disorder: preclinical and clinical evidence.","volume":"8","author":"Agabio","year":"2014","journal-title":"Front. 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