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）：酗酒是我们社会中的一个重大问题。慢性间歇性乙醇（CIE）治疗大鼠（60剂剂量的间歇性中毒和戒断），包括人类酒精中毒的所有主要特征，包括焦虑，降低癫痫发作阈值，并提高了戒断后的酒精偏好。至少其中一些症状可以通过测量的3-氨基丁酸（A）受体（GABAAR）的功能的降低来解释，并改变了对其变构调节剂的敏感性。 Gabaars介导突触（阶段）和外鼻外（补品）抑制作用似乎有所不同。因此，耐受性会发展为海马外突触Gabaars的急性乙醇（ETOH）增强，而突触Gabaars对EtOH产生了高灵敏度。提出了这种矛盾的ETOH敏感性变化，以依靠酒精中毒的发展和持久性。初步研究表明，Gabaars的亚基组成和定位的改变可能是海马内观察到的Gabaar功能的改变。但是，尚不清楚其他关键的大脑区域是否涉及戒酒和依赖性的症状经历类似的神经照射。尚不清楚ETOH诱导的神经退行性是否可以解释这些神经适应。强调CIE引起的变化的持续性是对基本重要性的新观察：单一醉酒的EtOH导致GABAAR变化与CIE治疗后所见的变化相似，但是在这种单剂量后的1-2周中可以看到恢复。该提案的具体目的旨在解决有关Gabaar参与戒酒机制和依赖性机制的关键假设：1）确定CIE治疗的剂量，持续时间和频率依赖性，以产生ETOH依赖的长期症状； 2）研究杏仁核（已知的大脑区域对奖励和依赖机制至关重要）的GABAAR亚基组成和功能的变化，并将其与从单个或多个EtoH治疗中戒断的行为指标有关； 3）确定神经退行性是否通过使用组织化学和立体学技术在EtOH中毒后的GABA能抑制作用中起作用。从提出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具有深远的影响。这些知识也将有助于针对GABA能系统治疗酒精中毒的治疗剂的发展。