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）：有融合的临床前和临床证据，表明GABA能缺陷是主要抑郁症（MDD）的重要因素。但是，这些缺陷存在的神经元回路以及调节抑郁样行为的单个GABAA受体亚型是未知的。通过分析对慢性社会失败压力的反应，慢性社会失败压力是一种具有结构，面部和预测有效性的抑郁症模型，我们建议研究定义的神经元电路中如何在定义的神经元电路中含有A2-和A3的GABAA受体，在从一个行为过渡中起作用“正常”状态至“下降”（即沮丧）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给予的高度A2特异性[或A3特异性的激动剂是否可以防止[或促进）从“正常”状态到“下降”状态的过渡。我们还将评估这种激动剂是否可以急性地促进（或防止）在停止慢性社会失败后进行管理后，从沮丧状态恢复到正常状态。拟议的研究预计将证明A2特异性激动剂会产生急性抗抑郁药样作用，并将为开发新型抗抑郁药的发展提供概念验证。公共卫生相关性：目前可用的抗抑郁药靶向单胺能或血清素能系统，需要数周的时间来发展其治疗作用，并且在所有抑郁症患者中不起作用；因此，迫切需要开发抗抑郁药，这些抗抑郁药具有迅速发作的作用和/或具有与当前可用药物不同的靶标。我们建议检查单个GABAA受体亚型在调节“正常”和“下降”/抑郁状态之间的过渡中的作用，并期望含有A2-和A3的GABAA受体具有相反的功能；具体而言，含A2的GABAA受体将发挥抗抑郁药样作用，而含A3的GABAA受体将具有类似抑制剂的作用，并且含A2的GABAA受体的药理激动剂将具有急性抗抑郁药样的作用。通过将我们的研究定向以前未被认可的潜在药物靶标，我们期望为新型药理学剂的开发提供原则证明，并采取更快的作用。