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

Shoupeng Wei; Lei Zheng; Jinlong Chang; Jian Jiang; Zhiyu Zhou; Huanquan Liao; Kun Song; Xiaoma Liu; Xinjin Chi; Huiliang Li; Xin Kuang; Ningning Li

doi:10.1111/acer.15094

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

Alcohol Clin Exp Res (Hoboken). 2023 Jul;47(7):1261-1270. doi: 10.1111/acer.15094. Epub 2023 May 11.

Authors

Shoupeng Wei¹, Lei Zheng^{2

3}, Jinlong Chang¹, Jian Jiang¹, Zhiyu Zhou¹, Huanquan Liao⁴, Kun Song⁵, Xiaoma Liu⁶, Xinjin Chi³, Huiliang Li^{7

8}, Xin Kuang⁹, Ningning Li^{1

8

10}

Affiliations

¹ Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China.
² Shantou University Medical College, Shantou, China.
³ Department of Anesthesiology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China.
⁴ The Clinical Neuroscience Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
⁵ Brain Research Center and Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
⁶ Department of Neurology, The Third People's Hospital of Shenzhen, Shenzhen, China.
⁷ Wolfson Institute for Biomedical Research, Division of Medicine, Faculty of Medical Sciences, University College London, London, UK.
⁸ China-UK Institute for Frontier Science, Shenzhen, China.
⁹ Department of Anesthesia, Affiliated Longhua People's Hospital, Southern Medical University, Longhua People's Hospital, Shenzhen, China.
¹⁰ The Fifth People's Hospital of Datong City, Datong, China.

PMID: 37128649
DOI: 10.1111/acer.15094

Abstract

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^fl/fl (n = 9) and Vgat-Cre;Gpr158^fl/fl 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^fl/fl , t(16) = 0.49, p = 0.631 or Vgat-Cre;Gpr158^fl/fl 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.

Keywords: G protein-coupled receptor 158; ethanol; loss of righting reflex; sensitivity.

Abstract

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