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著的抗焦虑作用，临床诊断为焦虑症的个体滥用和依赖乙醇的风险大大增加。长期使用乙醇，除了酒精渴求的感觉外，还与焦虑增加有关。这被认为会导致持续使用乙醇的循环。我们开始了解这些过程的生物学基础，这一应用的目标是继续探索乙醇诱导的焦虑缓解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。我们特别感兴趣的是大电导电压和钙调节电流，即BK电流。先前的行为学研究表明，这些离子通道对低浓度乙醇高度敏感，解剖学研究表明，它们在中央杏仁核（CeA）中大量表达。杏仁核的形成在抗焦虑药物（如乙醇）的作用中起着关键作用，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影响etoh介导的焦虑缓解和戒断诱导的焦虑发生。我们的主要合作伙伴Candice Contet博士（Scripps研究所）在实验室进行的研究表明，使用慢性间歇乙醇模型的慢性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已经建立在行为实验的基础上，现在可以在细胞水平上进行机制研究，以解决乙醇和扩展杏仁核中BK通道之间的相互作用。因此，我们建议使用药理学和遗传学方法来表征这些通道对乙醇对CeA神经元兴奋性的作用的具体贡献。最终，更好地了解酒精诱导的CeA中这些离子通道系统的改变可能有助于开发治疗酒精中毒的新疗法。

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.