Mechanisms of GABAA Receptor Plasticity in Alcoholism

描述(申请人提供)：酗酒是我们社会的一个严重问题。慢性间歇性乙醇(CIE)治疗大鼠(60剂间歇性醉酒和戒断)涵盖了人类酒精中毒的所有主要特征，包括焦虑、癫痫阈值降低和戒断后酒精偏好增强。这些症状中至少有一部分可以通过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。调节突触(时相)和突触外(强直)抑制的GABA受体似乎发生了不同的变化。因此，耐受性发展到急性乙醇(EtoH)增强海马区突触外GABAARs，而突触GABAARs对乙醇高度敏感。酒精敏感性的这种自相矛盾的变化被认为是酒精中毒发展和持续的基础。初步研究表明，GABAAR亚基组成和定位的改变可能解释了所观察到的海马区GABAAR功能的变化。然而，目前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经历了类似的神经适应。目前还不清楚乙醇诱导的神经退行性变是否可以解释这些神经适应。一项具有根本重要性的新观察结果强调了CIE引起的变化的持久性：单次醉酒剂量的乙醇可导致与CIE治疗后类似的GABAAR变化，但在单次剂量后1-2周即可恢复。该建议的具体目的是为了解决有关GABAAR参与酒精戒断和依赖机制的关键假说，方法是：1)确定CIE治疗可产生持久的乙醇依赖症状的剂量、时间和频率依赖关系；2)研究伏隔核和杏仁基底外侧核(已知在奖赏和依赖机制中具有重要作用的大脑区域)内GABAAR亚单位组成和功能的变化，并将它们与戒断单一或多个乙醇治疗的行为措施联系起来；3)利用组织化学和体视学技术，确定神经退行性变是否在乙醇中毒后改变的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功能变化的理解，GABAAR功能对大脑活动的各个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能系统的治疗酒精中毒的疗法。

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.