GABAa receptor subtype mechanisms in nonhuman primate models of alcohol abuse

描述（由申请人提供）：酒精中毒是一个公共卫生问题，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。本研究的目的是探讨α 1 GABAA和α 5 GABAA受体机制在非人灵长类动物酒精滥用相关效应模型中的作用。最近的研究结果支持α 1 GABAA和α 5 GABAA受体机制在酒精对猴子的辨别刺激作用和对啮齿动物的强化作用中的作用。我们将在这些新发现的基础上系统地研究α 1GABAA的作用。（特定目标1）和α 5 GABAA（具体目标2）通过确定受体选择性激动剂和拮抗剂如何调节酒精行为效应的受体机制：1）酒精在被训练区分胃内给予的酒精与媒介物的恒河猴中的辨别刺激效应，2）在恒河猴中口服自我给药酒精，和3）在口服自我给药已经熄灭并随后通过酒精引发恢复的恒河猴中恢复酒精寻求。将在自我给予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联合对非条件运动行为的影响的同步观察性研究中，评价α 1 GABAA和α 5 GABAA受体配体选择性改变酒精控制行为（具体目标3）的影响程度。选择的α 1GABAA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、减少酒精自我给药和减弱引发诱导的酒精寻求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。

DESCRIPTION (provided by applicant): Alcoholism is a public health problem that is 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 proposal is to investigate the role of alpha1GABAA and alpha5GABAA receptor mechanisms in nonhuman primate models of the abuse-related effects of alcohol. Recent findings support a role for both alpha1GABAA and alpha5GABAA receptor mechanisms in alcohol's discriminative stimulus effects in monkeys and its reinforcing effects in rodents. We will build on these new findings to systematically investigate the contribution of alpha1GABAA (Specific Aim 1) and alpha5GABAA (Specific Aim 2) receptor mechanisms 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. The degree to which the effects of alpha1GABAA and alpha5GABAA 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 alpha1GABAA and alpha5GABAA 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.