GABA(A) Receptor Complex In Alcohol Dependence

描述（由申请方提供）：本研究的目的是确定GABAA受体复合物（GABAR）的持续改变是否可以为酒精中毒动物模型中乙醇的身体依赖性的发展提供分子解释。慢性间歇性乙醇（CIE）给药大鼠具有许多类似人类酒精滥用行为的特征，包括长期易感性复吸。乙醇（EtOH）诱导的神经系统抑制和随后的反弹性过度兴奋（戒断）的多次发作已被证明会产生类似点燃的作用，即，过度兴奋性戒断症状的严重程度持续增加。以这种方式处理的大鼠变得EtOH依赖性，一种测量方法是对惊厥药物戊四唑（PTZ）（GABAR的阻断剂）的癫痫发作阈值降低。PTZ的过度兴奋（点燃）在停止使用乙醇后至少持续40天。CIE大鼠表现出焦虑升高，对EtOH的镇静作用表现出耐受性，对其他镇静剂表现出交叉耐受性，并且海马记忆受损。神经化学和电生理学的研究一直集中在酒精戒断综合征是否可以与GABAR的改变，并已证明了一个显着的减少，特别是在海马结构，GABAR的功能，以及多种改变的GABAR的分子特性。我们发现GABAR亚基组成的重组与GABAR介导的突触和突触外紧张电流的电药理学变化一致。这些生化和生理变化似乎与行为改变有关。在CIE中观察到的相同的持续性变化在单次给予中毒剂量的EtOH后也短暂观察到。在未来，我们建议研究GABAR可塑性发展的分子和细胞机制，以及它如何变得持久。除了急性和慢性EtOH处理的大鼠，我们将模型扩展到小鼠，以允许对GABAR改变的基因工程动物进行研究，以帮助确定它们在形成依赖性中的作用。我们认为，减少GABAR功能在酒精依赖的个人有深远的影响，对各种情绪和智力方面的大脑活动。找到负责的分子机制可能有助于治疗戒断症状，并有望减少乙醇依赖。这种类型的哺乳动物模型似乎有很大的潜力，揭示重要的见解滥用机制。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了解哪些环境和遗传因素有助于酒精滥用的易感性，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改变和药物。公共卫生相关性：本计画以啮齿类动物为模型，研究酒精依赖的细胞与分子机制，以期开发出预防与治疗酒精中毒的药物。大鼠和小鼠被给予慢性间歇性乙醇（CIE），并研究了涉及神经递质3-氨基丁酸（GABA）受体的脑中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中观察到的行为变化有关，如过度兴奋，焦虑增加，睡眠障碍和癫痫发作易感性。

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.