Poster Presentation The International Congress of Neuroendocrinology 2014

Oxytocin acts as a potent ethanol antagonist in vivo and in vitro possibly via non-oxytocin receptor mediated blockade of ethanol enhanced activity at GABAA δ subunit containing receptor interfaces (#388)

Michael T Bowen 1 , Sebastian Peters 2 , Nathan Absalom 3 , Mary Chebib 3 , Inga D Neumann 2 , Iain S McGregor 1
  1. School of Psychology, University of Sydney, Sydney
  2. Department of Behavioral and Molecular Neurobiology, University of Regensburg, Regensburg
  3. Faculty of Pharmacy, University of Sydney, Sydney

Even moderate doses of alcohol have a considerable impact on motoric function, an effect which is mediated via potentiation of GABAergic activity at GABAA δ subunit-containing receptors. Here we demonstrate that oxytocin selectively blocks ethanol induced motoric impairment and ethanol induced increases in GABAergic activity at GABAA δ subunit-containing receptor interfaces, an effect which does not involve the oxytocin receptor. Specifically, 1 μg of oxytocin given ICV prior to IP injection with 1.5 g/kg ethanol strongly inhibited the pronounced sedation and ataxia induced by ethanol in the open field locomotor test, wire hanging test, and righting reflex test. Using two-electrode voltage-clamp electrophysiology we found that oxytocin completely blocked ethanol induced increases in activity at α4β1δ and α4β3δ interfaces. Conversely, ethanol did not impact currents when applied to α4β1 or α4β3 cells, demonstrating that the presence of δ is critical for ethanol’s effects. Oxytocin had no effect on the motoric impairment or in vitro effectsinduced by the δ selective GABAA agonist THIP, thus oxytocin’s actions are specific to the ethanol binding site at δ containing interfaces. Furthermore, vasopressin, which is structurally similar to oxytocin, did not alter the current induced by ethanol at δ subunit-containing receptors, confirming that the aforementioned effects are specific to oxytocin and not found with other similar peptides. Finally, our in vitro constructs were not expressing any oxytocin receptors. As such, the observed effects of oxytocin were the result of a non-oxytocin receptor mediated action of oxytocin at GABAA δ containing interfaces. This study reports a profound action of oxytocin on the behavioural and cellularresponse to ethanol and provides the first evidence of oxytocin having a direct, non-oxytocin receptor mediated effect on the function of the major inhibitory neurotransmitter system in the central nervous system in response to the most widely abused recreational substance world-wide.