Ethanol actions on ion channels in the extended amygdala

描述（由申请人提供）：乙醇增强特性的一个重要组成部分可能是其显着的抗焦虑作用，并且临床诊断患有焦虑症的个体滥用和依赖乙醇的风险大大增加。随着长期使用，除了对乙醇的渴望之外，戒断乙醇还会导致焦虑增加。据信这会导致乙醇持续使用的循环。我们开始了解这些过程的生物学基础，该应用的目标是继续探索乙醇诱导的抗焦虑作用和戒断诱导的焦虑发生的机制。 INIA West 已经确定了由编码神经元钾通道的家族组成的靶基因。 我们对大电导电压和钙调节电流（BK 电流）特别感兴趣。先前的行为研究表明这些离子通道对低浓度的乙醇高度敏感，解剖学研究表明它们在中央杏仁核（CeA）中大量表达。杏仁核形成在乙醇等抗焦虑药物的作用中起着关键作用，并且可能是研究乙醇调节焦虑机制的最合适的大脑区域。因此，我们认为杏仁核中这些通道的改变可能会影响乙醇介导的抗焦虑作用和戒断诱导的焦虑发生。我们的主要合作者 Candice Contet 博士（斯克里普斯研究所）的实验室进行的研究表明，使用慢性间歇性乙醇模型的长期乙醇暴露可调节杏仁核中 BK 通道亚基的基因表达。这些重要的基础研究基于行为实验，现在适合在细胞水平上进行机制研究，以解决扩展杏仁核中乙醇和 BK 通道之间的相互作用。因此，我们建议使用药理学和遗传操作来表征这些通道对乙醇对 CeA 神经元兴奋性作用的具体贡献。 最终，更好地了解酒精引起的 CeA 离子通道系统的改变可以促进治疗酒精中毒的新疗法的开发。 公共卫生相关性：酒精依赖是一种慢性疾病，其特征是无法控制的过量饮酒。目前可用的药物干预措施的有益效果有限。该项目将研究酒精依赖背后的候选机制，即调节与酒精影响有关的关键大脑区域的神经元活动的钾通道。该项目的成果将有助于开发更有效的药理学疗法来改善和/或

DESCRIPTION (provided by applicant): A significant component of the reinforcing properties of ethanol may be its pronounced anxiolytic effect, and individuals with clinically diagnosed anxiety disorders are at greatly increased risk for ethanol abuse and dependence. With prolonged use, withdrawal from ethanol is associated with increased anxiety, in addition to the sensation of ethanol craving. This is believed to lead to a cycle of continued ethanol use. We are beginning to understand the biological basis of these processes, and this application is targeted toward continued exploration of the mechanisms of ethanol-induced anxiolysis and withdrawal-induced anxiogenesis. INIA West has identified target genes comprised of families coding for neuronal potassium channels. We are particularly interested in a large conductance voltage- and calcium- regulated current, the BK current. Previous behavioral studies indicate that these ion channels are highly sensitive to low concentrations of ethanol, and anatomical studies demonstrate that they are heavily expressed in the central amygdala nucleus (CeA). The amygdala formation has a critical role in the action of anxiolytic drugs such as ethanol, and may be the most appropriate brain area for investigating the mechanisms of ethanol's regulation of anxiety. Thus, we believe that alterations in these channels in the amygdala may affect EtOH-mediated anxiolysis and withdrawal-induced anxiogenesis. Studies done in the laboratory of our primary proposed collaborator, Dr. Candice Contet (Scripps Research Institute) indicate that chronic ethanol exposure using the chronic intermittent ethanol model regulate gene expression of subunits of the BK channel in the amygdala. These important groundwork studies have been based on behavioral experiments, and it is now appropriate to carry out mechanistic studies at the cellular level that address interactions between ethanol and BK channels in the extended amygdala. Therefore, we propose to use pharmacologic and genetic manipulations to characterize the specific contribution of these channels to the action of ethanol on neuronal excitability in the CeA. Ultimately, a better understanding of alcohol-induced alterations in these ion channels systems in the CeA could facilitate development of novel therapies for treatment of alcoholism. PUBLIC HEALTH RELEVANCE: Alcohol dependence is a chronic disease characterized by uncontrollable excessive consumption of alcohol. Currently available pharmacological interventions have limited beneficial effects. This project will be investigating a candidate mechanism underlying alcohol dependence, a potassium channel that regulates neuronal activity in critical brain regions implicated in effects of alcohol. The outcome of this project will contribute to develop more effective pharmacological therapeutics to ameliorate and/or