A GABA Pathway to Faster Acting Antidepressants

GABA 通往更快起效的抗抑郁药的途径

基本信息

批准号：
8616813
负责人：
Uwe Rudolph
金额：
$ 39.5万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-07 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8616813
关键词：
Acute Address Agonist Anhedonia Animals Antidepressive Agents Anxiety Back Behavior Behavioral Behavioral Paradigm Behavioral inhibition Benzodiazepines Chronic Clinical Complex Conflict (Psychology)Depressed mood Desipramine Development Diazepam Dopamine D1 Receptor Dopamine D2 Receptor Drug Targeting Exhibits Exposure to Face Fluoxetine Functional disorder Genetic Imipramine In complete remission Individual Knock-out Knockout Mice Ligands Major Depressive Disorder Mental Depression Modeling Molecular Monitor Mood Disorders Mus Neurobiology Neurons Nucleus Accumbens Pathway interactions Patients Pharmaceutical Preparations Phenotype Play Pre-Clinical Model Preclinical Testing Property Reaction Regulation Research Rodent Model Role Series Serotonin Stress Swimming System Testing Therapeutic Effect Wild Type Mouse Withdrawal Work base dentate gyrus depressive symptoms gamma-Aminobutyric Acid granule cell inhibitor/antagonist monoamine novel pre-clinical prevent receptor research study resilience response reuptake social stressor

项目摘要

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.

描述（由申请人提供）：临床前和临床证据一致表明，GABA 能缺陷是重度抑郁症 (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个体 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，我们建议研究特定神经元回路中含有 a2 和 a3 的 GABAA 受体如何在从“正常”状态到“沮丧”（即抑郁）状态，反之亦然。使用一种新颖的遗传药理学方法，我们将进一步评估在社交失败期间施用高度a2特异性[或a3特异性]激动剂是否可以阻止[或促进]从“正常”状态到“低落”状态的转变。我们还将评估在慢性社会失败停止后服用这种激动剂是否可以急剧促进（或阻止）从抑郁状态恢复到正常状态。拟议的研究预计将证明α2特异性激动作用会产生急性抗抑郁样作用，并将为开发一类新型抗抑郁药提供概念验证。