Ethanol actions on ion channels in the extended amygdala

乙醇对扩展杏仁核离子通道的作用

• 批准号: 8231747
• 负责人: Scott D. Moore
• 金额: $ 12.84万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-05 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231747
• 关键词: Acute; Address; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Amygdaloid structure; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Area; Behavioral; Biological; Brain; Brain region; Calcium; Cell Nucleus; Chronic; Chronic Disease; Code; Development; Diagnosis; Esthesia; Ethanol; Ethanol dependence; Exhibits; Exposure to; Family; Gene Expression; Gene Targeting; Heavy Drinking; In Vitro; Individual; Intervention; Ion Channel; Knockout Mice; Laboratories; Lead; Measures; Mediating; Modeling; Neurons; Outcome; Pharmaceutical Preparations; Physiological; Physiology; Potassium Channel; Process; Property; Regulation; Research Institute; Risk; Role; Site; Synapses; System; Techniques; Therapeutic; Withdrawal; adeno-associated viral vector; alcohol craving; alcohol effect; alcohol exposure; alcohol sensitivity; alcoholism therapy; base; behavioral tolerance; clinically relevant; genetic manipulation; in vivo; interest; large-conductance calcium-activated potassium channels; neuronal excitability; neurotransmitter release; novel; presynaptic; research study; small hairpin RNA; voltage

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

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人滥用酒精和依赖的风险大大增加。随着时间的延长，停止使用乙醇会增加焦虑，此外还有对乙醇的渴望。这被认为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，这一应用旨在继续探索乙醇诱导的焦虑缓解和戒断诱导的焦虑产生的机制。伊尼亚·韦斯特已经确定了由神经元性钾通道编码家族组成的目标基因。我们特别感兴趣的是一种大电导电压和钙调节电流，即BK电流。以往的行为学研究表明，这些离子通道对低浓度乙醇高度敏感，解剖学研究表明，它们在杏仁中央核(CEA)大量表达。杏仁核在乙醇等抗焦虑药物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会影响乙醇介导的焦虑缓解和戒断诱导的焦虑产生。我们的主要合作者Candice Contet博士(斯克里普斯研究所)的实验室所做的研究表明，使用慢性间歇乙醇模型的慢性酒精暴露调节杏仁核中BK通道亚单位的基因表达。这些重要的基础研究一直基于行为学实验，现在适合在细胞水平上进行机制研究，解决扩展的杏仁核中乙醇和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在乙醇对CEA神经元兴奋性的作用中的具体贡献。最终，更好地了解酒精诱导CEA中这些离子通道系统的变化将有助于开发治疗酒精中毒的新疗法。 与公共卫生相关：酒精依赖是一种慢性疾病，其特征是无法控制地过度饮酒。目前可用的药理干预措施有益效果有限。这个项目将研究酒精依赖的候选机制，酒精依赖是一种钾通道，调节与酒精影响有关的关键脑区的神经元活动。该项目的成果将有助于开发更有效的药物疗法来改善和/或