BNST GluN2B and CRF signaling in the antidepressant actions of ketamine

描述（由申请人提供）：抑郁症是一个主要的健康问题。传统的药理学治疗已经用选择性再摄取抑制剂靶向了儿茶酚胺系统，但是这些具有以下缺点：a）它们需要延长治疗以实现功效，B）它们通常需要持续给药，以及c）相当大比例的临床人群是治疗抗性的。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得到了越来越多的关注。氯胺酮是NMDA类谷氨酸受体的拮抗剂，其优势在于它在单次给药后既快速起效又产生持续作用。 动物模型研究表明，氯胺酮通过在谷氨酸突触上产生稳态可塑性来发挥作用，然而，改变以产生抗抑郁作用的关键电路尚不清楚。在这个建议中，我们测试的假设，NMDA受体在一个区域的大脑被称为床核的终纹发挥关键作用的氯胺酮的抗抑郁作用。此外，我们建议，这是通过与该地区的促肾上腺皮质激素受体因子（CRF）系统的相互作用。

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.