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广泛的公共卫生问题，与衰弱的医疗，社会和心理后果有关。酒精的滥用受药物的多种作用的控制，包括其主观和强化作用及其引发复发的能力。临床前方法已被开发，以评估这些控制因素及其神经生物学基础的贡献，并提供基于解剖学的模型，用于评估潜在的治疗策略。本更新申请的目的是研究α 2/3GABAA和α 5GABAA受体机制在酒精滥用相关效应的非人灵长类动物模型中的作用。我们将系统地研究α 2/3GABAA受体机制的贡献（具体目标1）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：1）酒精在恒河猴中的辨别性刺激作用，所述恒河猴被训练以区分胃内给予的酒精与媒介物，2）在恒河猴中口服自我给予酒精，和3）恢复恒河猴的酒精寻求，其口服自我给药已经熄灭，随后通过酒精引发恢复。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的重要第一步。此外，我们将继续评估具有不同化学结构的新型α 5 GABAa受体反向激动剂和在这些相同行为模型中可能更合适的行为特征（具体目标2）。这些研究的结果应该支持α 5 GABAA受体作为酒精使用障碍的药理学管理的相关靶标的概念。α 2/3GABAa和α 5GABAa受体配体选择性地改变酒精控制行为的作用程度（具体目标3）将在自我施用蔗糖溶液而不是酒精的恒河猴中以及在这些配体单独或与酒精组合对无条件运动行为的作用的同时观察性研究中进行评价。选择的α 2/3GABAa和α 5GABAa配体在不产生行为的普遍破坏或使人衰弱的副作用的剂量下减弱酒精的辨别性刺激作用、减少酒精自我施用和减弱引发诱导的酒精寻求的恢复的能力可以预测潜在的治疗效用。整合这三个具体目标的结果将提供所需的信息，具体的GABAA机制，可能会成为酒精成瘾作用的基础，并将有助于识别酒精滥用和复发的药理学管理的受体靶点。 公共卫生相关性：酒精使用障碍是广泛存在的公共卫生问题，与衰弱的医疗，社会和心理后果有关，并且没有普遍有效的治疗药物。我们的研究将产生关于α 2/3GABAA和α 5GABAA受体机制在酒精滥用相关效应中的作用的关键信息。最终，我们的研究结果将提供所需的信息，具体的机制，可能是酒精成瘾的影响，并将有助于识别受体靶点的药物管理酒精滥用和复发。

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.