GABAa receptor subtype mechanisms in nonhuman primate models of alcohol abuse

描述（由申请人提供）：酒精滥用和酒精中毒是普遍存在的公共卫生问题，与使人衰弱的医疗、社会和心理后果有关。酒精滥用是由药物的多重效应控制的，包括其主观和强化效应以及引发复发的能力。临床前方法已经开发出来，以评估这些控制因素及其神经生物学基础的贡献，并为评估潜在的治疗策略提供基于经验的模型。本更新申请的目的是研究a2/3GABAA和a5GABAA受体在非人灵长类动物酒精滥用相关影响中的作用机制。我们将通过确定受体选择性激动剂和拮抗剂如何调节，系统地研究a2/3GABAA受体机制（Specific Aim 1）对酒精行为影响的贡献：1)酒精对恒河猴的鉴别刺激作用，恒河猴被训练去区分灌胃酒精和载体酒精；2)恒河猴的口服自我给药；3)恒河猴在口服自我给药被消灭后，通过酒精启动恢复寻求酒精的行为。了解酒精成瘾效应的神经药理学机制是开发治疗酒精滥用和依赖的候选药物疗法的重要的第一步。此外，我们将继续在这些相同的行为模型中评估具有不同化学结构和可能更合适的行为特征的新型a5GABAA受体逆激动剂（Specific Aim 2）。这些研究的结果应该支持a5GABAA受体作为酒精使用障碍药理学管理的相关靶点的概念。a2/3GABAA和a5GABAA受体配体选择性改变酒精控制行为的影响程度（Specific Aim 3）将在恒河猴中进行评估，这些恒河猴自我服用蔗糖溶液而不是酒精，并同时进行观察研究，研究这些配体单独或与酒精联合对非条件运动行为的影响。选定的a2/3GABAA和a5GABAA配体能够减弱酒精的鉴别刺激作用，减少酒精自我给药，并在不产生普遍行为破坏或衰弱副作用的剂量下减弱启动诱导的酒精寻求恢复，这可能是潜在治疗效用的预测。整合这三个特定目标的结果将提供有关GABAA特定机制的必要信息，这些机制可能是酒精成瘾效应的基础，并将有助于确定酒精滥用和复发的药物管理的受体靶点。

DESCRIPTION (provided by applicant): Alcohol abuse and alcoholism are widespread public health problems that are associated with debilitating medical, social, and psychological consequences. The abuse of alcohol is controlled by multiple effects of the drug, including its subjective and reinforcing effects and its capacity to trigger relapse. Preclinical methods have been developed to assess the contribution of these controlling factors and their neurobiological underpinnings, and to provide empirically-based models for evaluating potential treatment strategies. The purpose of this renewal application is to investigate the role of a2/3GABAA and a5GABAA receptor mechanisms in nonhuman primate models of the abuse-related effects of alcohol. We will systematically investigate the contribution of a2/3GABAA receptor mechanisms (Specific Aim 1) to the behavioral effects of alcohol by determining how receptor selective agonists and antagonists modulate: 1) the discriminative stimulus effects of alcohol in rhesus monkeys trained to discriminate intragastrically-administered alcohol from vehicle, 2) oral self-administration of alcohol in rhesus monkeys, and 3) reinstatement of alcohol seeking in rhesus monkeys whose oral self-administration has been extinguished and subsequently reinstated by alcohol priming. Understanding the neuropharmacological mechanisms underlying the addictive effects of alcohol is an important initial step in the development of candidate pharmacotherapies for the treatment of alcohol abuse and dependence. Additionally, we will continue to evaluate novel a5GABAA receptor inverse agonists with different chemical structures and potentially more suitable behavioral profiles in these same behavioral models (Specific Aim 2). Results from these studies should support the notion of the a5GABAA receptor as a relevant target for the pharmacological management of alcohol use disorders. The degree to which the effects of a2/3GABAA and a5GABAA receptor ligands selectively modify alcohol-controlled behavior (Specific Aim 3) will be evaluated in rhesus monkeys that self-administer a sucrose solution instead of alcohol and in concurrent observational studies of the effects these ligands, alone or combined with alcohol, on unconditioned motor behavior. The ability of selected a2/3GABAA and a5GABAA ligands to blunt the discriminative stimulus effects of alcohol, reduce alcohol self-administration and attenuate priming-induced reinstatement of alcohol seeking at doses that do not produce a generalized disruption of behavior or debilitating side effects may be predictive of potential therapeutic utility. Integration of results from these three specific aims will provide needed information about specific GABAA mechanisms that may underlie the addictive effects of alcohol and will aid identification of receptor targets for the pharmacological management of alcohol abuse and relapse. PUBLIC HEALTH RELEVANCE: Alcohol use disorders are widespread public health problems that are associated with debilitating medical, social, and psychological consequences and for which no universally effective treatment medication is available. Our studies will yield key information about the role of a2/3GABAA and a5GABAA receptor mechanisms in the abuse-related effects of alcohol. Ultimately, our results will provide needed information about specific mechanisms that may underlie the addictive effects of alcohol and will aid identification of receptor targets for the pharmacological management of alcohol abuse and relapse.