Inhibitors of Calcium-Activated Anion Channels Modulate Hypnotic Ethanol Responses in Adult Sprague Dawley Rats
Inhibitors of Calcium-Activated Anion Channels Modulate Hypnotic Ethanol Responses in Adult Sprague Dawley Rats
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DOI：
10.1111/acer.12957
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发表时间：
2016-02-01
影响因子：
3.2
通讯作者：
Werner, David F.
中科院分区：
文献类型：
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作者：
Carter, Jenna M.;Landin, Justine D.;Werner, David F.
背景乙醇因其抑郁作用而广为人知；然而，其潜在的神经生物学机制尚不清楚。钙激活的阴离子通道(CAAC)参与调节中枢神经系统的抑制机制，从而影响细胞外氯离子水平。因此，我们假设CAAC通过改变CAAC的表达来影响酒精的行为敏感性。方法通过几种非选择性CAAC阻滞剂的侧脑室注射，我们评估了CAAC在乙醇诱导的翻正反射(LOR)和运动活动丧失中的作用。结果乙醇诱导LORR(4.0g/kg，腹腔注射)；4种CAAc阻滞剂均能显著减弱上述效应。阻断CAAC不影响乙醇的低剂量(1.5g/kg，i.p.)运动障碍的影响。CAAC蛋白表达的生化分析显示，单次注射乙醇(3.5g/kg，腹腔注射)后30分钟，皮质Bestrophin1(Best1)和Tweety1水平就降低了。24小时后，P2组分仍呈下降趋势。皮质Best1水平在1.5g/kg剂量后也有所降低。然而，在单次酒精暴露后，纹状体中CAAC的表达没有改变。结论CAACs是乙醇在体内的主要作用靶点，对这些通道的调控有助于乙醇的行为选择。
BackgroundEthanol is widely known for its depressant effects; however, the underlying neurobiological mechanisms are not clear. Calcium-activated anion channels (CAACs) contribute to extracellular chloride levels and thus may be involved in regulating inhibitory mechanisms within the central nervous system. Therefore, we hypothesized that CAACs influence ethanol behavioral sensitivity by altering CAAC expression.MethodsWe assessed the role of CAACs in ethanol-induced loss of righting reflex (LORR) and locomotor activity using intracerebroventricular infusions of several nonselective CAAC blockers. CAAC expression was determined after ethanol exposure.ResultsEthanol-induced LORR (4.0g/kg, intraperitoneally [i.p.]) was significantly attenuated by all 4 CAAC blockers. Blocking CAACs did not impact ethanol's low-dose (1.5g/kg, i.p.) locomotor-impairing effects. Biochemical analysis of CAAC protein expression revealed that cortical Bestrophin1 (Best1) and Tweety1 levels were reduced as early as 30minutes following a single ethanol injection (3.5g/kg, intraperitoneally [i.p.]) and remained decreased 24hours later in P2 fractions. Cortical Best1 levels were also reduced following 1.5g/kg. However, CAAC expression was unaltered in the striatum following a single ethanol exposure. Ethanol did not affect Tweety2 levels in either brain region.ConclusionsThese results suggest that CAACs are a major target of ethanol invivo, and the regulation of these channels contributes to select behavioral actions of ethanol.