Tonic GABAA receptor signaling in the Central Amygdala and alcohol dependence

描述（由申请人提供）：在美国和世界范围内，酒精滥用是一种主要的临床疾病。尽管酒精依赖的普遍性和众所周知的慢性酒精暴露的不良影响，介导酒精在大脑中的作用的神经生物学机制仍未完全了解。当前和未来研究的挑战是了解影响导致慢性饮酒的动机系统的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，涉及滥用药物和酒精的动机效应（Alheid和Heimer， 1988）。抑制性神经递质GABA是CeA回路的关键元素，也是急性和慢性酒精摄入对行为影响的关键组成部分（Hyytia & Koob, 1995; Roberts et al., 1996）。迄今为止，对CeA的研究主要集中在突触前GABA系统的改变上（Roberto et al., 2003,2004）。重要的是，没有研究检验GABAA受体信号传导的特定形式，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受体信号被称为强直性抑制，已被证明对乙醇具有高度敏感性（Wallner等人，2003年），并且涉及酒精对几个大脑区域的影响（Wei等人，2004年；Liang等人，2007年；Jia等人，2008年）。然而，目前还没有关于这类GABAA受体在CeA中的信号传导的研究。因此，本研究的目的是表征CeA中的强直性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强直性GABAA受体在CeA中的表达和功能的变化，将为从娱乐性饮酒到酒精依赖的转变提供重要的细胞变化信息。这一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.