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The role of the G protein\u2010coupled receptor 158 (GPR158) in modulating sensitivity to the sedative\u2010hypnotic effect of ethanol has not been investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Loss of righting reflex (LORR) is a behavioral indicator of hypnosis in rodents. In this study, <jats:italic>Gpr158<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice and wild\u2010type (WT) littermates (<jats:italic>n<\/jats:italic>\u2009=\u20098\/genotype) were tested using LORR induced by a dose of 3.5\u2009g\/kg ethanol, an open\u2010field test (OFT), and a measure of blood ethanol concentration. The OFT was used to examine the role of GPR158 in the ethanol effect on motor activity in <jats:italic>Gpr158<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice (<jats:italic>n<\/jats:italic>\u2009=\u20096\/genotype). We also tested <jats:italic>CamK2A\u2010Cre;Gpr158<\/jats:italic><jats:sup><jats:italic>fl\/fl<\/jats:italic><\/jats:sup> (<jats:italic>n<\/jats:italic>\u2009=\u20099) and <jats:italic>Vgat\u2010Cre;Gpr158<\/jats:italic><jats:sup><jats:italic>fl\/fl<\/jats:italic><\/jats:sup> mice (<jats:italic>n<\/jats:italic>\u2009=\u200910) using the LORR test and OFT to compare with controls (<jats:italic>n<\/jats:italic>\u2009=\u20099 and 8, respectively).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>Gpr158<\/jats:italic> deficiency prolonged the LORR duration by 110.6%, <jats:italic>t<\/jats:italic>(14)\u2009=\u2009\u22125.241, <jats:italic>p<\/jats:italic>\u2009=\u20090.0001, without altering spontaneous activity, <jats:italic>t<\/jats:italic>(14)\u2009=\u2009\u22120.718, <jats:italic>p<\/jats:italic>\u2009=\u20090.485, or ethanol metabolism, <jats:italic>F<\/jats:italic>(1, 8)\u2009=\u20090.259, <jats:italic>p<\/jats:italic>\u2009=\u20090.625. <jats:italic>Gpr158<\/jats:italic> knockout did not change the ethanol effect on locomotion, <jats:italic>F<\/jats:italic>(1, 10)\u2009=\u20090.262, <jats:italic>p<\/jats:italic>\u2009=\u20090.62. The LORR duration increased by 69% in the conditional knockouts of <jats:italic>Gpr158<\/jats:italic> within calcium\/calmodulin\u2010dependent protein kinase II alpha\u2010positive (CamK2A<jats:sup>+<\/jats:sup>) neurons, <jats:italic>t<\/jats:italic>(16)\u2009=\u2009\u22122.914, <jats:italic>p<\/jats:italic>\u2009=\u20090.01, and by 92% in the vesicular GABA transporter\u2010positive (Vgat<jats:sup>+<\/jats:sup>) neurons, <jats:italic>t<\/jats:italic>(9.802)\u2009=\u2009\u22122.519, <jats:italic>p<\/jats:italic>\u2009=\u20090.023. Locomotion was not altered in <jats:italic>Camk2A\u2010Cre;Gpr158<\/jats:italic><jats:sup><jats:italic>fl\/fl<\/jats:italic><\/jats:sup>, <jats:italic>t<\/jats:italic>(16)\u2009=\u20090.49, <jats:italic>p<\/jats:italic>\u2009=\u20090.631 or <jats:italic>Vgat\u2010Cre;Gpr158<\/jats:italic><jats:sup><jats:italic>fl\/f<\/jats:italic>l<\/jats:sup> mice, <jats:italic>t<\/jats:italic>(16)\u2009=\u20090.035, <jats:italic>p<\/jats:italic>\u2009=\u20090.972.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study reveals the key role of neuronal GPR158 in shaping sensitivity to the sedative\u2010hypnotic effect of ethanol. These findings contribute to our understanding of the neurobiology of ethanol intoxication.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.15094","type":"journal-article","created":{"date-parts":[[2023,5,2]],"date-time":"2023-05-02T06:05:30Z","timestamp":1683007530000},"page":"1261-1270","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["G protein\u2010coupled receptor 158 modulates sensitivity to the sedative\u2010hypnotic effect of ethanol in male mice"],"prefix":"10.1111","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0453-5008","authenticated-orcid":false,"given":"Shoupeng","family":"Wei","sequence":"first","affiliation":[{"name":"Tomas Lindahl Nobel Laureate Laboratory The Seventh Affiliated Hospital, Sun Yat\u2010Sen University  Shenzhen China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Zheng","sequence":"additional","affiliation":[{"name":"Shantou University 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