GABAa receptor subtype mechanisms in nonhuman primate models of alcohol abuse

描述(由申请人提供)：酗酒是一种公共卫生问题，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。这项建议的目的是研究alpha1GABAA和alpha5GABAA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。最近的发现支持了alpha1GABAA和alpha5GABAA受体机制在酒精对猴子的区别性刺激效应和对啮齿动物的强化效应中所起的作用。我们将在这些新发现的基础上，通过确定受体选择性激动剂和拮抗剂是如何调节酒精的行为效应来系统地研究alpha1GABAA(特异性目标1)和alpha5GABAA(特异性目标2)受体机制对酒精行为效应的贡献：1)酒精对恒河猴的歧视性刺激效应，经训练以区分从车辆中灌胃给药的酒精，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。Alpha1GABAA和Alpha5GABAA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。选定的Alpha1GABAA和Alpha5GABAA配体能够钝化酒精的歧视性刺激效应，减少酒精自我给药，并减弱启动诱导的酒精寻求的恢复，剂量不会产生广泛的行为中断或衰弱副作用，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。

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.