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）：抑郁症是一个主要的健康问题。传统的药物治疗采用选择性再摄取抑制剂来靶向儿茶酚胺系统，但这些治疗方法的缺点是：a）需要延长治疗时间才能达到疗效，b）通常需要持续给药，c）很大一部分临床人群对治疗有抵抗力。随着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受到了越来越多的关注。氯胺酮是 NMDA 类谷氨酸受体的拮抗剂，其优点在于它既能快速起效，又能在单次剂量后产生持久的作用。 动物模型研究表明，氯胺酮通过在谷氨酸突触处产生稳态可塑性来发挥作用，但经修改以产生抗抑郁作用的关键电路尚不清楚。在本提案中，我们测试了这样的假设：大脑中称为终纹床核的区域中的 NMDA 受体在氯胺酮的抗抑郁作用中发挥着关键作用。此外，我们认为这是通过与该区域的促肾上腺皮质激素受体因子（CRF）系统相互作用而发生的。