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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：
8371318
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/8371318
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 Delivery Systems 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. 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.

描述（由申请人提供）：越来越多的临床前和临床证据表明，gaba能缺陷是重度抑郁症（MDD）的一个重要因素。然而，这些缺陷存在的神经元回路和调节抑郁样行为的个体GABAA受体亚型尚不清楚。通过分析啮齿类动物对慢性社会失败应激的反应，我们提出研究a2-和a3- GABAA受体在特定神经回路中如何在从“正常”状态到“下降”（即抑郁）状态的行为转变中发挥作用。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”状态过渡到“下降”状态。我们还将评估这种激动剂是否能在慢性社会失败停止后迅速促进[或阻止]从抑郁状态向正常状态的转变。拟议的研究有望证明a2特异性激动作用产生急性抗抑郁样作用，并将为开发一类新型抗抑郁药物提供概念证明。