G protein-coupled receptor 158 modulates sensitivity to the sedative-hypnotic effect of ethanol in male mice

Background: Sensitivity to ethanol provides an index of the predisposition to recover from unconsciousness induced by a dose of ethanol. The role of the G protein-coupled receptor 158 (GPR158) in modulating sensitivity to the sedative-hypnotic effect of ethanol has not been investigated. Methods: Loss of righting reflex (LORR) is a behavioral indicator of hypnosis in rodents. In this study, Gpr158 mice and wild-type (WT) littermates (n = 8/genotype) were tested using LORR induced by a dose of 3.5 g/kg ethanol, an open-field 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 Gpr158 mice (n = 6/genotype). We also tested CamK2A-Cre;Gpr158 (n = 9) and Vgat-Cre;Gpr158 mice (n = 10) using the LORR test and OFT to compare with controls (n = 9 and 8, respectively). Results: Gpr158 deficiency prolonged the LORR duration by 110.6%, t(14) = −5.241, p = 0.0001, without altering spontaneous activity, t(14) = −0.718, p = 0.485, or ethanol metabolism, F(1, 8) = 0.259, p = 0.625. Gpr158 knockout did not change the ethanol effect on locomotion, F(1, 10) = 0.262, p = 0.62. The LORR duration increased by 69% in the conditional knockouts of Gpr158 within calcium/calmodulin-dependent protein kinase II alpha-positive (CamK2A) neurons, t(16) = −2.914, p = 0.01, and by 92% in the vesicular GABA transporter-positive (Vgat) neurons, t(9.802) = −2.519, p = 0.023. Locomotion was not altered in Camk2A-Cre;Gpr158, t(16) = 0.49, p = 0.631 or Vgat-Cre;Gpr158 mice, t(16) = 0.035, p = 0.972. Conclusions: This study reveals the key role of neuronal GPR158 in shaping sensitivity to the sedative-hypnotic effect of ethanol. These findings contribute to our understanding of the neurobiology of ethanol intoxication.