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，但调节酒精对大脑影响的神经生物学机制仍然不完全清楚。当前和未来研究的挑战是了解神经生物学变化，这些变化影响导致慢性饮酒的动机系统中的耐受性和依赖性。中央杏仁核(CEA)是大脑的主要组成部分，参与滥用药物和酒精的激励效应(Alheid和Hemer，1988)。抑制性神经递质GABA是CEA回路的关键元件，也是急性和慢性酒精消费行为效应的关键组成部分(Hyytia&Koob，1995；Roberts等人，1996)。到目前为止，CEA的研究主要集中在突触前GABA系统的变化(Roberto等人，2003,2004)。重要的是，还没有研究检测一种特定形式的GABAA受体信号，其特征是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受体信号被称为紧张性抑制，已被证明对乙醇高度敏感(Wallner等人，2003年)，并与酒精对大脑几个区域的影响有关(魏等人，2004年；梁等人，2007年；贾跃亭等人，2008年)。然而，还没有关于CEA中这种类型的GABAA受体信号的研究。因此，本研究的目标是确定CEA中紧张性GABAA受体信号的特征，并研究急性和慢性乙醇暴露对这一信号的影响。应用电生理学和分子技术阐明CEA中紧张性GABAA受体表达和功能的变化，将为促进娱乐饮酒向依赖转变的细胞变化提供重要信息。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。

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.