Oxytocin prevents ethanol actions at δ subunit-containing GABAA receptors and attenuates ethanol-induced motor impairment in rats
Oxytocin prevents ethanol actions at δ subunit-containing GABAA receptors and attenuates ethanol-induced motor impairment in rats
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DOI：
10.1073/pnas.1416900112
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发表时间：
2015-03-10
影响因子：
11.1
通讯作者：
McGregor, Iain S.
中科院分区：
文献类型：
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作者：
Bowen, Michael T.;Peters, Sebastian T.;McGregor, Iain S.
即使是中等剂量的酒精也会对运动协调造成相当大的损害，这种影响实质上涉及增强含有 δ 亚基的 GABA(A) 受体 (δ-GABA(A)Rs) 的 GABA 活性。在这里，我们证明催产素选择性减弱乙醇诱导的运动障碍和乙醇诱导的 delta-GABA(A)Rs GABA 活性增加，并且这种作用不涉及催产素受体。具体而言，在雄性大鼠的旷场运动试验、吊线试验和翻正反射试验中，在乙醇（1.5 g/kg i.p.）之前给予催产素（1 μg i.c.v.）可减弱乙醇引起的镇静和共济失调。在非洲爪蟾卵母细胞中使用两电极电压钳电生理学，发现催产素可以完全阻断乙醇增强的α4β1δ和α4β3δ重组GABA(A)Rs的活性。相反，当乙醇应用于 α 4 β 1 或 α 4 β 3 细胞时没有任何作用，这证明了 δ 亚基在这种作用中的关键存在。催产素对 δ-选择性 GABA(A)R 激动剂 4,5,6,7-四氢异恶唑并 (5,4-c) 吡啶-3-ol 诱导的运动障碍或体外效应没有影响，该激动剂与乙醇结合在 δ-GABA(A)R 上的位点不同。加压素是一种与催产素结构相似的九肽，不会改变乙醇对 delta-GABA(A)R 的作用。这种结果模式证实了催产素和乙醇在 delta-GABA(A)R 上相互作用的特异性。最后，我们的体外构建体不表达任何催产素受体，这意味着观察到的相互作用直接发生在 delta-GABA(A)Rs 上。在行为和细胞水平上观察到的催产素和乙醇之间深刻而直接的相互作用可能与开发治疗酒精中毒和酒精依赖的新疗法有关。
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.