Tonic GABAA receptor signaling in the Central Amygdala and alcohol dependence

描述（由申请人提供）：酒精滥用是美国和世界范围内的一种主要临床疾病。尽管酒精依赖的流行和众所周知的慢性酒精暴露的不良影响，调节酒精在大脑中的影响的神经生物学机制仍然没有完全理解。当前和未来研究的挑战是了解导致慢性饮酒的动机系统中影响耐受性和依赖性的神经生物学变化。中央杏仁核（CeA）是大脑的一个主要组成部分，与滥用药物，特别是酒精的动机效应有关（Alheid和Heimer，1988年）。 抑制性神经递质GABA是CeA回路的关键要素，并且是急性和慢性乙醇消耗的行为效应的关键组分（Hyytia & Koob，1995; Roberts等人，1996年）。迄今为止，对CeA的研究主要集中在突触前GABA系统的改变（Roberto et al.，2003年，2004年）。重要的是，没有研究检查了GABAA受体信号传导的特定形式，其特征在于由具有不同亚基组成的GABAA受体介导的持续抑制电流。这种形式的GABAa受体信号传导被称为紧张性抑制，已显示对乙醇具有高敏感性（Wallner等人，2003），并与酒精在几个脑区的作用有关（Wei等人，2004; Liang等人，2007; Jia等人，2008年）。然而，尚未对CeA中的这种类型的GABAA受体信号传导进行研究。因此，本提案的目标是表征CeA中的紧张性GABAA受体信号传导，并研究急性和慢性乙醇暴露对该信号传导的影响。应用电生理学和分子技术来阐明紧张性GABAA受体的表达和功能在CeA的改变将提供重要的信息，细胞的变化，有助于从娱乐性酒精消费的依赖过渡。这些信息可能有助于改善酒精依赖的治疗和/或开发潜在的治疗方法。 公共卫生相关性：该建议利用电生理和分子技术来表征CeA中乙醇暴露的新型细胞神经适应。总体假设是CeA中的紧张性GABAA受体信号传导的变化是酒精依赖发展的主要促成因素。这些研究的结果将提供重要的信息，与酒精依赖的发展相关的潜在机制之一，并可能有助于改善酒精依赖的治疗和/或潜在的治疗方法的发展。

DESCRIPTION (provided by applicant): Alcohol abuse represents a major clinical condition in the Unites States and worldwide. Despite the prevalence of alcohol dependence and the well-known adverse effects of chronic alcohol exposure, the neurobiological mechanisms mediating alcohol's effects in the brain are still not fully understood. The challenge of current and future studies is to understand the neurobiological changes that influence tolerance and dependence in motivational systems that lead to chronic drinking. The central amygdala (CeA) is a major component of the brain involved in the motivational effects of drugs of abuse and alcohol in particular (Alheid and Heimer, 1988). The inhibitory neurotransmitter GABA is a key element of the CeA circuitry and is a critical component of the behavioral effects of acute and chronic ethanol consumption (Hyytia & Koob, 1995; Roberts et al., 1996). To date, studies in the CeA have predominantly focused on alterations in the presynaptic GABA system (Roberto et al., 2003, 2004). Importantly, no studies have examined a specific form of GABAA receptor signaling characterized by persistent inhibitory currents mediated by GABAA receptors with a distinct subunit composition. Denoted tonic inhibition, this form of GABAA receptor signaling has been shown to have high sensitivity to ethanol (Wallner et al., 2003) and has been implicated in the effects of alcohol in several brain regions (Wei et al., 2004; Liang et al., 2007; Jia et al., 2008). However, no studies have been performed on this type of GABAA receptor signaling in the CeA. Therefore, the goal of this proposal is to characterize tonic GABAA receptor signaling in the CeA and to investigate the effects of acute and chronic ethanol exposure on this signaling. Applying electrophysiological and molecular techniques to elucidate alterations in tonic GABAA receptor expression and function in the CeA will provide important information as to the cellular changes that contribute to the transition from recreational alcohol consumption to dependence. This information could contribute to improved treatment of alcohol dependence and/or the development of potential therapeutics. PUBLIC HEALTH RELEVANCE: This proposal utilizes electrophysiological and molecular techniques to characterize a novel cellular neuroadaptation to ethanol exposure in the CeA. The overarching hypothesis is that changes in tonic GABAA receptor signaling in the CeA are a major contributing factor in the development of alcohol dependence. The results of these studies will provide important information as to one of the underlying mechanisms related to the development of alcohol dependence and could contribute to improved treatment of alcohol dependence and/or the development of potential therapeutics.