Chronic Alcohol, Intrinsic Excitability, and Potassium Channels: Neuroadaptations and Drinking Behavior.
Chronic Alcohol, Intrinsic Excitability, and Potassium Channels: Neuroadaptations and Drinking Behavior.
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DOI：
10.1007/164_2017_90
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发表时间：
2018
影响因子：
--
通讯作者：
Mulholland PJ
中科院分区：
文献类型：
--
作者：
Cannady R;Rinker JA;Nimitvilai S;Woodward JJ;Mulholland PJ
酒精使用障碍的神经机制仍然难以捉摸，这种缺乏了解减缓了有效治疗策略的发展，以降低复发率和延长禁欲。虽然慢性酒精暴露产生的突触适应已被广泛的特点，在各种大脑区域，关键投射神经元的内在兴奋性的变化研究不足。越来越多的证据表明，长期饮酒和酒精依赖产生可塑性的内在兴奋性的变化，诱发动作电位放电和后超极化幅度。在本章中，我们描述了长期酒精暴露后投射神经元细胞放电的功能变化，这些变化发生在不同物种和多个大脑区域。适应钙激活（KCa2），电压依赖性（KV7）和G蛋白偶联内向整流（Kir3或GIRK）钾通道，调节诱发放电和后超极化平行功能的变化，内在兴奋性慢性酒精。此外，酒精相关行为与编码KCa2、KV7和GIRK通道的基因之间存在很强的遗传联系，靶向这些通道的抑制剂可以减少酒精消耗和酒精相关行为。总之，这些研究表明，长期饮酒在KCa2，KV7和GIRK通道中产生适应性变化，导致后超极化和异常细胞放电的调节受损。用KCa2和KV7通道的正调节剂纠正后超极化的缺陷，并改变GIRK通道结合口袋以阻断酒精的进入，代表了一种潜在的高度有效的药理学方法，可以恢复内在兴奋性的变化，并减少受影响个体的酒精消耗。
Neural mechanisms underlying alcohol use disorder remain elusive and this lack of understanding has slowed the development of efficacious treatment strategies for reducing relapse rates and prolonging abstinence. While synaptic adaptations produced by chronic alcohol exposure have been extensively characterized in a variety of brain regions, changes in intrinsic excitability of critical projection neurons are understudied. Accumulating evidence suggests that prolonged alcohol drinking and alcohol dependence produce plasticity of intrinsic excitability as measured by changes in evoked action potential firing and after-hyperpolarization amplitude. In this chapter, we describe functional changes in cell firing of projection neurons after long-term alcohol exposure that occur across species and in multiple brain regions. Adaptations in calcium-activated (KCa2), voltage-dependent (KV7) and G protein-coupled inwardly rectifying (Kir3 or GIRK) potassium channels that regulate the evoked firing and after-hyperpolarization parallel functional changes in intrinsic excitability induced by chronic alcohol. Moreover, there are strong genetic links between alcohol-related behaviors and genes encoding KCa2, KV7, and GIRK channels, and pharmacologically targeting these channels reduces alcohol consumption and alcohol-related behaviors. Together, these studies demonstrate that chronic alcohol drinking produces adaptations in KCa2, KV7, and GIRK channels leading to impaired regulation of the after-hyperpolarization and aberrant cell firing. Correcting the deficit in the after-hyperpolarization with positive modulators of KCa2 and KV7 channels and altering the GIRK channel binding pocket to block the access of alcohol represent a potentially highly effective pharmacological approach that can restore changes in intrinsic excitability and reduce alcohol consumption in affected individuals.