title: Oxytocin prevents ethanol actions at δ subunit-containing GABAA receptors and attenuates ethanol-induced motor impairment in rats.
abstract: Even moderate doses of alcohol cause considerable impairment of motor coordination, an effect that substantially involves potentiation of GABAergic activity at δ subunit-containing GABA(A) receptors (δ-GABA(A)Rs). Here, we demonstrate that oxytocin selectively attenuates ethanol-induced motor impairment and ethanol-induced increases in GABAergic activity at δ-GABA(A)Rs and that this effect does not involve the oxytocin receptor. Specifically, oxytocin (1 µg i.c.v.) given before ethanol (1.5 g/kg i.p.) attenuated the sedation and ataxia induced by ethanol in the open-field locomotor test, wire-hanging test, and righting-reflex test in male rats. Using two-electrode voltage-clamp electrophysiology in Xenopus oocytes, oxytocin was found to completely block ethanol-enhanced activity at α4β1δ and α4β3δ recombinant GABA(A)Rs. Conversely, ethanol had no effect when applied to α4β1 or α4β3 cells, demonstrating the critical presence of the δ subunit in this effect. Oxytocin had no effect on the motor impairment or in vitro effects induced by the δ-selective GABA(A)R agonist 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol, which binds at a different site on δ-GABA(A)Rs than ethanol. Vasopressin, which is a nonapeptide with substantial structural similarity to oxytocin, did not alter ethanol effects at δ-GABA(A)Rs. This pattern of results confirms the specificity of the interaction between oxytocin and ethanol at δ-GABA(A)Rs. Finally, our in vitro constructs did not express any oxytocin receptors, meaning that the observed interactions occur directly at δ-GABA(A)Rs. The profound and direct interaction observed between oxytocin and ethanol at the behavioral and cellular level may have relevance for the development of novel therapeutics for alcohol intoxication and dependence.
authors.affiliation: School of Psychology, University of Sydney, Sydney, NSW 2006, Australia; Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia; and.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bowen
authors.affiliation: Department of Behavioral and Molecular Neurobiology, University of Regensburg, Regensburg 93053, Germany.
authors.forename: Sebastian T
authors.initials: ST
authors.lastname: Peters
authors.affiliation: Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia; and.
authors.forename: Nathan
authors.initials: N
authors.lastname: Absalom
authors.affiliation: Faculty of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia; and.
authors.forename: Mary
authors.initials: M
authors.lastname: Chebib
authors.affiliation: Department of Behavioral and Molecular Neurobiology, University of Regensburg, Regensburg 93053, Germany.
authors.forename: Inga D
authors.initials: ID
authors.lastname: Neumann
authors.affiliation: School of Psychology, University of Sydney, Sydney, NSW 2006, Australia; iain.mcgregor@sydney.edu.au.
authors.forename: Iain S
authors.initials: IS
authors.lastname: McGregor
mesh_terms: D000818:Animals; D000431:Ethanol / Q000494:pharmacology*; D007278:Injections, Spinal; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D010121:Oxytocin / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects*
chemical_list: D011963:Receptors, GABA-A; D000431:Ethanol; D010121:Oxytocin
keywords: GABA; alcohol; electrophysiology; motor impairment; oxytocin