Mechanisms of GABAA Receptor Plasticity in Alcoholism

描述（由申请人提供）：酗酒是我们社会中的一个重大问题。大鼠的慢性间歇性乙醇（CIE）治疗（60剂间歇性中毒和戒断）涵盖了人类酒精中毒的所有主要特征，包括焦虑、癫痫发作阈值降低和戒断后酒精偏好增强。这些症状中的至少一些可以通过测量的3-氨基丁酸（A）受体（GABAAR）功能的降低和对其变构调节剂的敏感性改变来解释。GABAAR介导的突触（阶段性）和突触外（紧张性）抑制似乎发生了不同的变化。因此，耐受性发展到海马突触外GABAAR的急性乙醇（EtOH）增强，而突触GABAAR发展到EtOH的高敏感性。乙醇敏感性的这种矛盾变化被认为是酒精中毒的发展和持续的基础。初步研究表明，改变亚基组成和本地化的GABAARs可能占海马内观察到的GABAAR功能的改变。然而，目前还不清楚其他与酒精戒断和依赖症状有关的关键大脑区域是否经历了类似的神经适应。也不知道EtOH诱导的神经变性是否可以解释这些神经适应。强调CIE诱导的变化的持续性是一个具有根本重要性的新观察结果：单次中毒剂量的EtOH导致GABAAR的变化与CIE治疗后观察到的变化相似，但在该单次剂量后1-2周观察到恢复。该提案的具体目的旨在通过以下方式解决有关GABAAR参与酒精戒断和依赖机制的关键假设：1）确定CIE治疗的剂量、持续时间和频率依赖性，以产生长期的EtOH依赖症状; 2）研究杏仁核和基底外侧核内GABAAR亚单位组成和功能的变化（已知对奖赏和依赖机制具有重要意义的脑区域）并将它们与从单一或多个EtOH处理中戒断的行为测量相关联;和3）通过使用组织化学和体视学技术确定神经变性是否在EtOH中毒后改变的GABA能抑制中起作用。从拟议的实验中获得的知识将增加我们对酒精诱导的GABAAR功能改变的理解，这对大脑活动的各个情感和智力方面都有深远的影响。这方面的知识也将是有用的治疗药物的发展，针对GABA能系统治疗酒精中毒。

DESCRIPTION (provided by applicant): Alcohol abuse represents a significant problem in our society. Chronic intermittent ethanol (CIE) treatment of rats (60 doses of intermittent intoxication and withdrawal), encompasses all of the major characteristics of human alcoholism, including anxiety, lowered seizure thresholds, and enhanced alcohol preference after withdrawal. At least some of these symptoms may be explained by the measured reduction in the function of the 3-aminobutyric acid (A) receptor (GABAAR) and altered sensitivity to its allosteric modulators. GABAARs mediating synaptic (phasic) and extrasynaptic (tonic) inhibition appear to be altered differently. Thus, tolerance develops to acute ethanol (EtOH) potentiation of hippocampal extrasynaptic GABAARs, while synaptic GABAARs develop high sensitivity to EtOH. Such paradoxical changes in EtOH sensitivity are proposed to underlie both the development and persistence of alcoholism. Preliminary studies suggest that altered subunit composition and localization of GABAARs may account for the observed alterations in GABAAR function within the hippocampus. However, it is unknown whether other key brain areas implicated in symptoms of alcohol withdrawal and dependence experience similar neuroadaptations. It is also unknown whether EtOH-induced neurodegeneration may account for these neuroadaptations. Underscoring the persistence of CIE-induced changes is a new observation of fundamental importance: a single intoxicating dose of EtOH results in GABAAR changes similar to those seen after CIE treatment, but recovery is seen by 1-2 weeks after this single dose. The specific aims of this proposal were designed to address key hypotheses regarding GABAAR involvement in mechanisms of alcohol withdrawal and dependence by: 1) determining the dose-, duration-, and frequency-dependence of CIE treatment to produce long-lasting symptoms of EtOH dependence; 2) studying changes in GABAAR subunit composition and function within nucleus accumbens and basolateral nucleus of the amygdala (brain areas known to be of major importance for the mechanisms of reward and dependence) and relating them to the behavioral measures of withdrawal from single or multiple EtOH treatments; and 3) determining whether neurodegeneration plays a role in altered GABAergic inhibition after EtOH intoxication through the use of histochemical and stereological techniques. The knowledge acquired from the proposed experiments will increase our understanding of the alcohol-induced alterations in GABAAR function, which has profound effects on various emotional and intellectual aspects of brain activity. This knowledge will also be useful to the development of therapeutics targeting the GABAergic system for the treatment of alcoholism.