Mutation of the inhibitory ethanol site in GABA A ρ1 receptors promotes tolerance to ethanol-induced motor incoordination.

Autor: Blednov YA; The University of Texas at Austin, Waggoner Center for Alcohol and Addiction Research, Austin, TX 78712, United States., Borghese CM; The University of Texas at Austin, Waggoner Center for Alcohol and Addiction Research, Austin, TX 78712, United States., Ruiz CI; The University of Texas at Austin, Waggoner Center for Alcohol and Addiction Research, Austin, TX 78712, United States., Cullins MA; The University of Texas at Austin, Waggoner Center for Alcohol and Addiction Research, Austin, TX 78712, United States., Da Costa A; The University of Texas at Austin, Waggoner Center for Alcohol and Addiction Research, Austin, TX 78712, United States., Osterndorff-Kahanek EA; The University of Texas at Austin, Waggoner Center for Alcohol and Addiction Research, Austin, TX 78712, United States., Homanics GE; University of Pittsburgh, Departments of Anesthesiology, Neurobiology, and Pharmacology & Chemical Biology, Pittsburgh, PA 15261, United States., Harris RA; The University of Texas at Austin, Waggoner Center for Alcohol and Addiction Research, Austin, TX 78712, United States. Electronic address: harris@austin.utexas.edu.
Jazyk: angličtina
Zdroj: Neuropharmacology [Neuropharmacology] 2017 Sep 01; Vol. 123, pp. 201-209. Date of Electronic Publication: 2017 Jun 13.
DOI: 10.1016/j.neuropharm.2017.06.013
Abstrakt: Genes encoding the ρ1/2 subunits of GABA A receptors have been associated with alcohol (ethanol) dependence in humans, and ρ1 was also shown to regulate some of the behavioral effects of ethanol in animal models. Ethanol inhibits GABA-mediated responses in wild-type (WT) ρ1, but not ρ1(T6'Y) mutant receptors expressed in Xenopus laevis oocytes, indicating the presence of an inhibitory site for ethanol in the second transmembrane helix. In this study, we found that ρ1(T6'Y) receptors expressed in oocytes display overall normal responses to GABA, the endogenous GABA modulator (zinc), and partial agonists (β-alanine and taurine). We generated ρ1 (T6'Y) knockin (KI) mice using CRISPR/Cas9 to test the behavioral importance of the inhibitory actions of ethanol on this receptor. Both ρ1 KI and knockout (KO) mice showed faster recovery from acute ethanol-induced motor incoordination compared to WT mice. Both KI and KO mutant strains also showed increased tolerance to motor impairment produced by ethanol. The KI mice did not differ from WT mice in other behavioral actions, including ethanol intake and preference, conditioned taste aversion to ethanol, and duration of ethanol-induced loss of righting reflex. WT and KI mice did not differ in levels of ρ1 or ρ2 mRNA in cerebellum or in ethanol clearance. Our findings indicate that the inhibitory site for ethanol in GABA A ρ1 receptors regulates acute functional tolerance to moderate ethanol intoxication. We note that low sensitivity to alcohol intoxication has been linked to risk for development of alcohol dependence in humans.
(Copyright © 2017 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: