GABA(A) Receptor Complex In Alcohol Dependence

酒精依赖中的 GABA(A) 受体复合物

• 批准号: 7812107
• 负责人: RICHARD W OLSEN
• 金额: $ 33.31万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7812107
• 关键词: 3-aminobutyric acid; Acute; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Amaze; Animal Model; Animals; Anti-Anxiety Agents; Anxiety; Area; Behavior; Behavior Therapy; Behavioral; Benzodiazepines; Biochemical; Biochemistry; Bite; Blood alcohol level measurement; Brain; Brain region; Breathing; Cell Surface Proteins; Cell Surface Receptors; Cell surface; Cells; Chronic; Complex; Conscious; Convulsants; Dependence; Development; Disease; Dose; Drug Modulation; Electron Microscope; Emotional; Engineering; Ethanol; Ethanol dependence; Exhibits; Family health status; Funding; Future; GABA Receptor; GABA-A Receptor; Gene Expression Regulation; Genetic; Health Professional; Hippocampal Formation; Hippocampus (Brain); Hour; Human; Hyperactive behavior; Individual; Intoxication; Kindling (Neurology); Knock-out; Knockout Mice; Location; Measures; Mediating; Memory; Mental Depression; Modeling; Molecular; Movement; Mus; Nature; Nervous system structure; Neurotransmitter Receptor; Pentylenetetrazole; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Physical Dependence; Physiological; Physiology; Plastics; Predisposition; Prevention; Property; Rattus; Recombinants; Regulation; Research; Research Personnel; Rodent Model; Role; Seizures; Severities; Sleep; Sleep disturbances; Slice; Staging; Steroid Receptors; Substance Withdrawal Syndrome; Synapses; Testing; Therapeutic; Time; Time Study; Tissues; Western Blotting; Withdrawal; Withdrawal Symptom; alcoholism therapy; crosslink; gamma-Aminobutyric Acid; hypnotic; in vivo; insight; interdisciplinary approach; interest; neurochemistry; neurosteroids; neurotransmission; novel; protein complex; protein transport; public health relevance; receptor; response; sedative; trafficking

DESCRIPTION (provided by applicant): The objectives of this study are to determine whether persistent alterations in the GABAA receptor complex (GABAR) can provide a molecular explanation for the development of physical dependence on ethanol in an animal model of alcoholism. Chronic intermittent ethanol (CIE) administration to rats has many features resembling human alcohol abuse behavior, including long-lasting susceptibility to readdiction. The numerous episodes of ethanol (EtOH)-induced depression of the nervous system and the following rebound hyperexcitability (withdrawal) have been shown to exert a kindling-like effect, i.e., a persistent increased severity of the hyperexcitable withdrawal symptoms. Rats treated in this manner become EtOH-dependent, one measure being a decreased seizure threshold to the convulsant drug pentylenetetrazol (PTZ), a blocker of the GABAR. The hyperexcitability to PTZ (kindling) lasts at least 40 days after cessation of EtOH. The CIE rats exhibit elevated anxiety, show tolerance to the sedative action of EtOH and cross-tolerance to other sedatives, and impaired hippocampal memory. Neurochemical and electrophysiological studies have been focused on whether this ethanol withdrawal syndrome can be associated with alterations in GABAR, and have demonstrated a significant reduction, specifically in the hippocampal formation, in GABAR function, as well as multiple alterations in the molecular properties of GABAR. We showed a restructuring of GABAR subunit composition consistent with changes in electropharmacology of GABAR-mediated synaptic and extrasynaptic tonic currents. These biochemical and physiological changes appear relevant to the altered behaviors. The same persistent alterations seen in CIE are also observed transiently after a single administration of an intoxicating dose of EtOH. In future we propose to study the molecular and cellular mechanisms whereby this GABAR plasticity develops and how it becomes persistent. In addition to acute and chronically EtOH-treated rats we will extend the model to mice to allow studies on genetically engineered animals with altered GABAR to help determine their role in developing dependence. We suggest that reduced GABAR function in ethanol-dependent individuals has profound effects on various emotional and intellectual aspects of brain activity. Finding the molecular mechanisms responsible may help in treatment of withdrawal symptoms and hopefully in reduction of ethanol dependence. This type of mammalian animal model seems to have great potential for uncovering important insights into abuse mechanisms. In addition, our studies on animal models of alcoholism will allow families and health professionals' better understanding of what environmental and genetic factors contribute to the susceptibility for alcohol abuse, of the behavioral changes of the alcohol abuser, and of possible behavioral modification and medications to consider in treating the disorder. PUBLIC HEALTH RELEVANCE: This project studies the cellular and molecular mechanisms of alcohol dependence in a rodent model in hopes of developing therapeutics for prevention and treatment of alcoholism. Rats and mice are given chronic intermittent ethanol (CIE) and studied for changes in inhibitory neurotransmission in brain involving receptors for the neurotransmitter 3-aminobutyric acid (GABA). The amounts, locations, and functions of the GABA receptors are related to the behavioral changes seen in alcohol dependence such as hyperexcitability, increased anxiety, sleep disturbances, and seizure susceptibility.

描述(由申请人提供)：这项研究的目的是确定GABAA受体复合体(GABAR)的持续变化是否可以为酒精中毒动物模型中对乙醇的身体依赖提供分子解释。大鼠长期间歇给予乙醇(CIE)有许多类似于人类酒精滥用行为的特征，包括对复瘾的长期易感性。乙醇(Etoh)诱导的神经系统多次抑郁和随后的反弹高兴奋性(戒断)已被证明具有点燃样效应，即高兴奋性戒断症状的持续加重。以这种方式治疗的大鼠变得对乙醇依赖，其中一项措施是降低惊厥药物戊四唑(PTZ)的癫痫发作阈值，PTZ是GABAR的阻滞剂。对PTZ(点燃)的高兴奋性在Etoh停药后至少持续40天。CIE大鼠表现出高度的焦虑，对乙醇的镇静作用表现出耐受，对其他镇静剂表现出交叉耐受，并损害了海马区的记忆。神经化学和电生理学研究的重点是乙醇戒断综合征是否与GABAR的改变有关，并且已经证明GABAR的功能显著降低，特别是在海马结构中，以及GABAR的多种分子特性的改变。我们发现GABAR亚单位组成的重组与GABAR介导的突触和突触外紧张性电流的电药理学变化一致。这些生化和生理变化似乎与改变的行为有关。在CIE中看到的同样的持续性变化也在单次注射令人陶醉的剂量的乙醇后短暂观察到。在未来，我们建议研究这种GABAR可塑性发展的分子和细胞机制，以及它如何变得持久。除了急性和长期使用乙醇治疗的大鼠外，我们还将把该模型扩展到小鼠身上，以允许对具有改变的GABAR的基因工程动物进行研究，以帮助确定它们在形成依赖中的作用。我们认为酒精依赖者的GABAR功能降低对大脑活动的各个情绪和智力方面都有深远的影响。找到相关的分子机制可能有助于戒断症状的治疗，并有望减少对酒精的依赖。这种类型的哺乳动物动物模型似乎有很大的潜力来揭示虐待机制的重要见解。此外，我们对酒精中毒动物模型的研究将使家庭和健康专业人员更好地了解哪些环境和遗传因素导致酒精滥用的易感性，酒精滥用者的行为变化，以及在治疗这种疾病时可能考虑的行为调整和药物。公共卫生相关性：该项目在啮齿动物模型中研究酒精依赖的细胞和分子机制，以期开发预防和治疗酒精中毒的疗法。大鼠和小鼠被给予慢性间歇乙醇(CIE)，并研究涉及神经递质3-氨基丁酸(GABA)受体的脑内抑制性神经传递的变化。GABA受体的数量、位置和功能与酒精依赖时的行为变化有关，如过度兴奋、焦虑增加、睡眠障碍和癫痫易感性。