Abstract
Even moderate doses of alcohol cause considerable impairment of motor coordination, an effect that substantially involves potentiation of GABAergic activity at delta subunit-containing GABA(A) receptors (delta-GABA(A)Rs). Here, we demonstrate that oxytocin selectively attenuates ethanol-induced motor impairment and ethanol-induced increases in GABAergic activity at delta-GABA(A)Rs and that this ...
Abstract
Even moderate doses of alcohol cause considerable impairment of motor coordination, an effect that substantially involves potentiation of GABAergic activity at delta subunit-containing GABA(A) receptors (delta-GABA(A)Rs). Here, we demonstrate that oxytocin selectively attenuates ethanol-induced motor impairment and ethanol-induced increases in GABAergic activity at delta-GABA(A)Rs and that this effect does not involve the oxytocin receptor. Specifically, oxytocin (1 mu g 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 alpha 4 beta 1 delta and alpha 4 beta 3 delta recombinant GABA(A)Rs. Conversely, ethanol had no effect when applied to alpha 4 beta 1 or alpha 4 beta 3 cells, demonstrating the critical presence of the delta subunit in this effect. Oxytocin had no effect on the motor impairment or in vitro effects induced by the delta-selective GABA(A)R agonist 4,5,6,7-tetrahydroisoxazolo(5,4-c) pyridin-3-ol, which binds at a different site on delta-GABA(A)Rs than ethanol. Vasopressin, which is a nonapeptide with substantial structural similarity to oxytocin, did not alter ethanol effects at delta-GABA(A)Rs. This pattern of results confirms the specificity of the interaction between oxytocin and ethanol at delta-GABA(A)Rs. Finally, our in vitro constructs did not express any oxytocin receptors, meaning that the observed interactions occur directly at delta-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.
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