Mechanisms of GABAA Receptor Plasticity in Alcoholism

描述（由申请人提供）：酗酒是我们社会的一个严重问题。对大鼠进行慢性间歇乙醇（CIE）治疗（60剂量间歇中毒和戒断），包括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。至少其中一些症状可以用测量到的3-氨基丁酸(A)受体（GABAAR）功能降低和对其变构调节剂的敏感性改变来解释。介导突触（相位）和突触外（强直）抑制的GABAARs似乎有不同的改变。因此，海马突触外GABAARs对急性乙醇（EtOH）增强产生耐受性，而突触GABAARs对EtOH产生高度敏感性。这种EtOH敏感性的矛盾变化被认为是酒精中毒的发展和持续存在的基础。初步研究表明，GABAAR亚基组成和定位的改变可能解释了观察到的海马内GABAAR功能的改变。然而，尚不清楚与酒精戒断和依赖症状有关的其他关键大脑区域是否也经历了类似的神经适应。etoh诱导的神经退行性变是否可以解释这些神经适应尚不清楚。强调CIE诱导变化的持久性是一项具有根本重要性的新观察：单次中毒剂量的EtOH导致GABAAR变化与CIE治疗后相似，但单次剂量后1-2周即可恢复。本提案的具体目标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，以产生持久的EtOH依赖症状；2)研究伏隔核和杏仁核基底外侧GABAAR亚基组成和功能的变化（已知对奖励和依赖机制具有重要意义的脑区），并将其与单次或多次EtOH治疗退出的行为措施联系起来；3)通过使用组织化学和体视学技术确定神经退行性变是否在乙醚中毒后gaba能抑制的改变中起作用。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，这对大脑活动的各种情感和智力方面都有深远的影响。这一知识也将有助于开发针对gaba能系统的治疗方法来治疗酒精中毒。

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.