A GABA Pathway to Faster Acting Antidepressants

描述(由申请人提供)：有临床前和临床证据表明GABA能缺陷是严重抑郁障碍(MDD)的一个重要因素。然而，存在这些缺陷的神经元回路以及调节抑郁样行为的单个GABAA受体亚型尚不清楚。通过分析对慢性社会失败应激的反应，一个具有结构、面孔和预测效度的啮齿动物模型，我们建议研究在已定义的神经元回路中包含a2和a3的GABAA受体如何在行为从“正常”状态到“下”(即抑郁)状态的转换中起作用，反之亦然。使用一种新的遗传-药理学方法，我们将进一步评估在社会失败期间使用高度a2特异性[或a3特异性]激动剂是否可以防止[或促进]从“正常”状态到“下”状态的转变。我们还将评估这种激动剂是否能在停止慢性社会失败后使用时，强烈地促进(或防止)从抑郁状态向正常状态的转变。这项拟议的研究有望证明2-特异性激动剂产生急性抗抑郁药样作用，并将为开发一类新型抗抑郁药提供概念验证。 公共卫生相关性：目前可用的抗抑郁药物针对单胺或5-羟色胺能系统，需要数周时间才能产生疗效，并不是对所有抑郁症患者有效；因此，迫切需要开发起效迅速和/或靶点与现有药物不同的抗抑郁药物。我们建议研究单个GABAA受体亚型在调节“正常”和“下调”/抑郁状态之间的转换中的作用，并预期包含a2和a3的GABAA受体具有相反的功能；具体地说，包含a2的GABAA受体将发挥抗抑郁药样作用，而包含A3的GABAA受体将具有促抑郁药样作用，而包含a2的GABAA受体的药理激动剂将具有急性抗抑郁剂样作用。通过将我们的研究引导到以前未被识别的潜在药物靶点，我们希望为开发具有更快起效的新型药理药物提供原则证明。

DESCRIPTION (provided by applicant): There is converging preclinical and clinical evidence that GABAergic deficits are an important factor in major depressive disorders (MDD). However, the neuronal circuits in which these deficits exist and the individual GABAA receptor subtypes that modulate depressive-like behavior are unknown. By analyzing the response to chronic social defeat stress, a rodent model of depression with construct, face, and predictive validity, we propose to study how a2- and a3-containing GABAA receptors in defined neuronal circuits play a role in the behavioral transition from a "normal" state to a "down" (i.e. depressed) state and vice versa. Using a novel genetic-pharmacological approach we will further assess whether a highly a2- specific [or a3-specific] agonist administered during social defeat can prevent [or promote] the transition from the "normal" state to the "down" state. We will also assess whether such an agonist can acutely promote [or prevent] the transition from the depressed state back to the normal state when administered after cessation of chronic social defeat. The proposed studies are expected to demonstrate that a2-specific agonism generates an acute antidepressant-like effect and will provide proof-of-concept for the development of a novel class of antidepressant agents. PUBLIC HEALTH RELEVANCE: Currently available antidepressant drugs target monoaminergic or serotonergic systems, take several weeks to develop their therapeutic effects and do not work in all depressed patients; thus, there is an urgent need to develop antidepressants which have a rapid onset of action and/or which have targets distinct from those of the currently available drugs. We propose to examine the role of individual GABAA receptor subtypes in modulating transitions between "normal" and "down"/depressed states and expect that a2- and a3-containing GABAA receptors have opposing functions; specifically that a2-containing GABAA receptors will exert antidepressant-like actions whereas a3-containing GABAA receptors will have prodepressant-like effects, and that pharmacological agonism of a2-containing GABAA receptors will have an acute antidepressant-like action. By directing our research at previously unrecognized potential drug targets, we expect to provide proof-of-principle for the development of novel pharmacological agents with a more rapid onset of action.