BNST GluN2B and CRF signaling in the antidepressant actions of ketamine

BNST GluN2B 和 CRF 信号在氯胺酮抗抑郁作用中的作用

• 批准号: 8717064
• 负责人: DANNY G WINDER
• 金额: $ 19.59万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8717064
• 关键词: Ablation; Adult; Affect; Affective; Amygdaloid structure; Anhedonia; Animal Model; Antidepressive Agents; Attention; Aversive Stimulus; Behavior; Behavioral; Brain region; Caloric Restriction; Catecholamines; Cells; Chronic; Clinical; Complement; Corticotropin Receptors; Corticotropin-Releasing Hormone; Data; Development; Disadvantaged; Dose; Drug effect disorder; Drug usage; Effectiveness; Enterobacteria phage P1 Cre recombinase; Figs - dietary; Genetic; Glutamate Receptor; Glutamates; Health; Injection of therapeutic agent; Ketamine; Knock-out; Label; Major Depressive Disorder; Measures; Mental Depression; Microspheres; Modeling; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor antagonist; Neurons; Neurotransmitters; Pharmacological Treatment; Play; Population; Process; Resistance; Rewards; Rodent Model; Role; Signal Transduction; Site; Stimulus; Structure of terminal stria nuclei of preoptic region; Synapses; System; Testing; Time; United States National Institutes of Health; Up-Regulation; Withdrawal; Work; alcohol exposure; diphtheria toxin receptor; enhancing factor; gamma-Aminobutyric Acid; in vivo; inhibitor/antagonist; insight; interest; novel; novel strategies; overexpression; public health relevance; receptor function; reuptake; synaptic function; therapeutic target; transmission process

DESCRIPTION (provided by applicant): Depression is a major health problem. Traditional pharmacological treatments have targeted the catecholamine systems with selective reuptake inhibitors, but these have the disadvantages that a) they take extended treatment to achieve efficacy, b) they often require continued dosing, and c) a significant proportion of the clinical population is treatment resistant. The glutamate neurotransmitter system has gained increased attention in the last several years with the advent of the use of the drug ketamine as an antidepressant. Ketamine, which is an antagonist of the NMDA class of glutamate receptors, is advantageous in that it is both rapidly acting and produces persistent effects after a single dose. Animal model studies suggest that ketamine works by producing homeostatic plasticity at glutamate synapses, however the key circuits modified to produce antidepressant actions are not clear. In this proposal we test the hypothesis that NMDA receptors in a region of the brain known as the bed nucleus of the stria terminalis play a key role in the antidepressant actions of ketamine. Moreover, we propose that this occurs via an interaction with the corticotropin receptor factor (CRF) system in this region.

描述（由申请人提供）：抑郁是一个主要的健康问题。传统的药理治疗方法针对选择性再摄取抑制剂的儿茶酚胺系统，但是这些缺点是a）他们采取扩展治疗以达到疗效，b）他们经常需要继续给药，c）c）很大一部分临床人群具有治疗性。在过去的几年中，随着使用药物氯胺酮作为抗抑郁药的出现，谷氨酸神经递质系统在过去几年中引起了人们的关注。氯胺酮是NMDA类谷氨酸受体的拮抗剂，其优势是，它既迅速起作用又产生单剂量后的持续作用。 动物模型研究表明，氯胺酮通过在谷氨酸突触下产生稳态可塑性而作出作用，但是对产生抗抑郁作用的关键电路尚不清楚。在该提案中，我们检验了以下假设：在大脑区域中，NMDA受体被称为基质末端的床核，在氯胺酮的抗抑郁作用中起关键作用。此外，我们建议这是通过与该区域中皮质激素受体因子（CRF）系统的相互作用发生的。