GABAa receptor subtype mechanisms in nonhuman primate models of alcohol abuse

描述(由申请人提供)：酗酒和酗酒是普遍存在的公共卫生问题，与衰弱的医疗、社会和心理后果有关。酒精的滥用受到药物的多种影响的控制，包括其主观和强化的影响以及引发复发的能力。临床前方法已经被开发来评估这些控制因素的贡献及其神经生物学基础，并为评估潜在的治疗策略提供基于经验的模型。这一更新应用的目的是研究a2/3GABAA和a5GABAA受体机制在酒精滥用相关影响的非人灵长类动物模型中的作用。我们将通过确定受体选择性激动剂和拮抗剂如何调节酒精的行为效应来系统地研究a2/3GABAA受体机制(特指1)对酒精行为效应的贡献：1)酒精对恒河猴的辨别刺激效应，经训练以辨别灌胃给药的酒精和交通工具的酒精；2)恒河猴口服酒精的自我给药；以及3)在口服自我给药已经停止并随后通过酒精启动恢复酒精寻求的恒河猴中恢复酒精寻求。了解酒精成瘾作用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初始步骤。此外，我们将继续评估具有不同化学结构的新型a5GABAA受体反向激动剂，并在这些相同的行为模型中潜在地更适合的行为特征(特定目标2)。这些研究的结果应该支持a5GABAA受体作为酒精使用障碍的药理学管理的相关靶点的概念。A2/3GABAA和a5GABAA受体配体选择性地改变酒精控制行为的效果(特定目标3)将在自我给药蔗糖溶液而不是酒精的恒河猴身上进行评估，并同时观察这些配体单独或与酒精联合对无条件运动行为的影响。选择的a2/3GABAA和a5GABAA配体能够钝化酒精的歧视性刺激效应，减少酒精的自我给药，并减弱启动诱导的酒精寻求的恢复，而剂量不会产生广泛的行为障碍或衰弱的副作用，这可能是潜在的治疗有效性的预测。整合这三个特定目标的结果将提供有关酒精成瘾效应可能基础的特定GABAA机制的必要信息，并将有助于识别酒精滥用和复发的药理学管理的受体靶标。 公共卫生相关性：酒精使用障碍是一种普遍的公共卫生问题，与衰弱的医疗、社会和心理后果有关，目前还没有普遍有效的治疗药物。我们的研究将提供有关a2/3GABAA和a5GABAA受体机制在酒精滥用相关效应中作用的关键信息。最终，我们的结果将提供关于酒精成瘾效应可能基础的特定机制的必要信息，并将有助于识别酒精滥用和复发的药物管理的受体靶标。

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.