Mechanisms of GABAA Receptor Plasticity in Alcoholism

酒精中毒中 GABAA 受体可塑性的机制

• 批准号: 7373972
• 负责人: IGOR SPIGELMAN
• 金额: $ 33.44万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-27 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7373972
• 关键词: 3-aminobutyric acid; Abstinence; Accounting; Acute; Address; Affective; Alcohol abuse; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholic Intoxication; Alcoholism; Alcohols; Aminobutyric Acid; Aminobutyric Acids; Amygdaloid structure; Anesthetics; Anxiety; Area; Behavior; Behavioral; Biochemical; Biological Assay; Brain; Brain region; Cell Line; Cell Nucleus; Cell surface; Cells; Chemosensitization; Chronic; Clinical; Count; Data; Dependence; Development; Diazepam; Dose; Electrons; Emotional; Ethanol; Exhibits; Frequencies; Fright; Hippocampus (Brain); Human Characteristics; Hypnotics and Sedatives; Interneurons; Intoxication; Kinetics; Knowledge; Lead; Ligands; Measures; Mediating; Methodology; Methods; Microscopic; Modeling; Nerve Degeneration; Neurons; Nucleus Accumbens; Outcome; Pharmaceutical Preparations; Play; Population; Primary Cell Cultures; Property; Proteins; Range; Rattus; Recombinants; Recovery; Reflex action; Rewards; Role; Seizures; Series; Silver Staining; Sleeplessness; Slice; Societies; Symptoms; Synapses; System; Techniques; Testing; Time; Week; Western Blotting; Withdrawal; Withdrawal Symptom; Work; alcohol abuse therapy; alcohol exposure; behavior measurement; cell type; day; dentate gyrus; design; experience; fluoro jade; in vivo; neuroadaptation; neurotransmission; novel; preference; receptor; research study; response; sedative; success; therapeutic target

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.

描述（由申请人提供）：酗酒是我们社会的一个重大问题。对大鼠进行慢性间歇性乙醇 (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到的 3-氨基丁酸 (A) 受体 (GABAAR) 功能的降低以及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（强直性）抑制似乎发生了不同的改变。因此，海马突触外 GABAAR 对急性乙醇 (EtOH) 增强的耐受性发展，而突触 GABAAR 对 EtOH 产生高度敏感性。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，GABAAR 亚基组成和定位的改变可能是观察到的海马内 GABAAR 功能变化的原因。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经历类似的神经适应。目前还不清楚乙醇诱​​导的神经变性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：单次致醉剂量的 EtOH 会导致 GABAAR 变化，与 CIE 治疗后所见的变化类似，但在单次剂量后 1-2 周即可恢复。该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核（已知对奖赏和依赖性机制至关重要的大脑区域）内 GABAAR 亚基组成和功能的变化，并将其与单次或多次乙醇戒断的行为测量联系起来治疗； 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 GABA 能抑制改变中发挥作用。从拟议的实验中获得的知识将增加我们对酒精引起的 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。这些知识也将有助于开发针对治疗酒精中毒的 GABA 能系统的疗法。