GABA(A) Receptor Complex In Alcohol Dependence

酒精依赖中的 GABA(A) 受体复合物

• 批准号: 7467875
• 负责人: RICHARD W OLSEN
• 金额: $ 34.65万
• 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/7467875
• 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; Chromosome Pairing; 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; Hypnotics and Sedatives; 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; Proteins; Public Health; Rate; Rattus; Recombinants; Regulation; Research; Research Personnel; Rodent Model; Role; Score; Seizures; Severities; Sleep; Sleep disturbances; Slice; Staging; Steroid Receptors; Steroids; Substance Withdrawal Syndrome; Synapses; Testing; Therapeutic; Time; Time Study; Tissues; Week; Western Blotting; Withdrawal; Withdrawal Symptom; alcohol abuse therapy; crosslink; day; gamma-Aminobutyric Acid; in vivo; insight; interdisciplinary approach; interest; intracellular protein transport; neurochemistry; neurotransmission; novel; protein transport; 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）：这项研究的目标是确定GABAA受体复合物（GABAR）的持续变化是否可以为在酒精中毒动物模型中的物理依赖性发展提供分子解释。大鼠的慢性间歇性乙醇（CIE）给药具有许多类似人类滥用行为的特征，包括对读书的长期敏感性。乙醇（ETOH）诱导的神经系统抑郁症的众多发作和以下反弹过度兴奋性（戒断）已显示出具有类似点燃的效应，即，过度可见的戒断症状的严重程度持续增加。以这种方式治疗的大鼠依赖于EtOH，一种方法是癫痫发作阈值降低了GABAR的阻滞剂的抽搐药物甲状酸甲酸酯（PTZ）。 PTZ（点燃）的过度兴奋性持续至少在停止EtOH后持续40天。 CIE大鼠表现出较高的焦虑症，表现出对EtOH和对其他镇静剂的镇静作用的耐受性，并遭受了海马记忆的损害。神经化学和电生理研究一直集中在该乙醇戒断综合征是否与Gabar的改变有关，并显示出显着降低，特别是在海马形成中，Gabar功能以及Gabar分子特性的多种变化。我们展示了与Gabar介导的突触和突触外强调电流的电药学变化一致的Gabar亚基组成的重组。这些生化和生理变化似乎与改变的行为有关。在单一施用陶醉的EtOH剂量后，在CIE中看到的相同的持续变化也会瞬时观察到。将来，我们建议研究这种Gabar可塑性发展以及如何持续的分子和细胞机制。除了急性和慢性ETOH处理的大鼠外，我们还将将模型扩展到小鼠，以允许对具有GABAR改变的基因工程动物进行研究，以帮助确定其在发展依赖性方面的作用。我们建议，依赖乙醇的个体中的Gabar功能降低对大脑活动的各种情感和智力方面具有深远的影响。找到负责的分子机制可能有助于治疗戒断症状，​​并希望减少乙醇依赖性。这种类型的哺乳动物模型似乎有很大的潜力来揭示对滥用机制的重要见解。此外，我们对酒精中毒动物模型的研究将使家庭和卫生专业人员更好地理解哪些环境和遗传因素有助于对酒精滥用，对酗酒者的行为变化以及可能的行为修改和药物的易感性，以治疗该疾病。公共卫生相关性：该项目研究了啮齿动物模型中酒精依赖的细胞和分子机制，以期开发用于预防和治疗酒精中毒的治疗剂。为大鼠和小鼠提供慢性间歇性乙醇（CIE），并研究了涉及神经递质3-氨基丁酸（GABA）受体的脑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性的行为变化有关，例如过度兴奋，焦虑，睡眠障碍和癫痫发作敏感性。