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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：
9016574
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 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9016574
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 Neuronal Plasticity Neurons Nucleus Accumbens Pathway interactions Pharmaceutical Preparations Phenotype Play Pre-Clinical Model Preclinical Testing Property Reaction Regulation Research Rodent Model Role Series Serotonergic System Serotonin Stress Swimming System Testing Therapeutic Effect Wild Type Mouse Withdrawal Work antidepressant effect base dentate gyrus depressed patient depressive symptoms gamma-Aminobutyric Acid granule cell inhibitor/antagonist monoamine neuronal circuitry novel pre-clinical prevent receptor research study resilience response reuptake social stressor treatment response

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 α2- and α3-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 α2- specific [or α3-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 α2-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、面孔和预测效度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α2和α3的GABAA受体如何在从“正常”状态到“沮丧”（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α2特异性[或α3特异性]激动剂是否可以阻止[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。预期拟定的研究将证明α2特异性激动作用可产生急性抗抑郁药样作用，并将为开发新型抗抑郁药提供概念验证。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effect of genetic and pharmacological blockade of GABA receptors on the 5-HT2C receptor function during stress.

DOI：
10.1111/jnc.12929
发表时间：
2014-12
期刊：
Journal of neurochemistry
影响因子：
4.7
作者：
Martin CB;Gassmann M;Chevarin C;Hamon M;Rudolph U;Bettler B;Lanfumey L;Mongeau R
通讯作者：
Mongeau R

Corrigendum to "Prodepressant- and anxiogenic-like effects of serotonin-selective, but not noradrenaline-selective, antidepressant agents in mice lacking α2-containing GABAA receptors" [Behav. Brain Res. 332 (2017) 172-179].

勘误“血清素选择性的促抑郁和焦虑样作用，但不是去甲肾上腺素选择性，抗抑郁药在缺乏α2-含GABAA受体的小鼠中”[行为。