A GABA Pathway to Faster Acting Antidepressants

描述（由申请人提供）：临床前和临床证据表明，GABA能缺陷是重度抑郁症（MDD）的重要因素。然而，这些缺陷存在的神经元回路和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压力的反应，一种具有结构、面孔和预测有效性的抑郁症啮齿动物模型，我们建议研究在定义的神经元回路中含有α 2和α 3的GABAA受体如何在从“正常”状态到“向下”（即抑郁）状态的行为转变中发挥作用，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交失败期间给予高度α 2特异性[或α 3特异性]激动剂是否可以防止[或促进]从“正常”状态向“低落”状态的转变。我们还将评估这种激动剂是否可以急性促进[或防止]从抑郁状态恢复到正常状态的过渡时，停止慢性社会失败。预期所提出的研究将证明α 2特异性激动产生急性抗抑郁样作用，并将为开发新型抗抑郁药提供概念验证。

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.