The Effect of Corticotropin Releasing Hormone on Cortical Arousal

描述（由申请人提供）：本R21项目拟开发一种适用于临床研究的中央促肾上腺皮质激素释放激素（CRH）受体功能的新型药理学-脑电图探针。这项工作的长期目标是基于机制的治疗方法，以压力相关的精神疾病。血脑屏障对CRH的相对不渗透性是检验人类中枢CRH功能机制理论的障碍。这项工作的新颖之处在于其将CRH神经肽施用于嗅觉上皮，以便定量测试健康对照组和缓解抑郁症患者鼻内给药CRH的药效学和药代动力学特性。我们的目标是进行两项平行、安慰剂交叉的药效学研究。鼻内和2。静脉CRH。我们主要对鼻内CRH（相对于安慰剂）对脑活动（事件相关脑电图）和惊吓反射（EMG）定量测量的影响感兴趣。我们实验室的初步人体数据与这种效应一致。这项研究的公共卫生相关性是双重的。首先，获得CRH功能的药效学探针将允许抑郁症的机制研究。其次，CRH功能的药效学读数可能有助于定量指导未来基于抗CRH受体的治疗。公共卫生相关性：本R21提案的目的是在健康成年男性和女性受试者中测试中枢CRH受体功能的探针。该探针结合了鼻内CRH挑战和脑皮层活动的脑电图测量。为了了解鼻内探针的动力学，还将进行静脉CRH挑战，以提供比较数据。

DESCRIPTION (provided by applicant): This R21 project proposes to develop a novel pharmacological-EEG probe of central corticotropin- releasing hormone (CRH) receptor function suitable for clinical research. The long-term objective of this work is a mechanism-based treatment approach to stress related psychiatric disorders. The relative impermeability of the blood brain barrier to CRH is an obstacle to testing mechanistic theories regarding central CRH function in humans. The novelty of this work lies in its administration of the CRH neuropeptide to the olfactory epithelium in order to quantitatively test pharmacodynamic and pharmacokinetic properties of intranasally administered CRH in healthy controls and remitted depressives. We aim to conduct two parallel, placebo-crossover pharmacodynamic studies of 1. intranasal and 2. intravenous CRH. We are primarily interested in the effect of intranasal CRH (vs. placebo) on a quantitative measurement of brain activity (event related EEG) and startle reflex (EMG). Preliminary human data from our laboratory are consistent with such effects. The public health relevance of the study is two-fold. Firstly, obtaining a pharmacodynamic probe of CRH function will permit mechanistic investigations of depressive disorder. Secondly, a pharmacodynamic readout CRH function may help to quantitatively guide future anti-CRH receptor based treatments. PUBLIC HEALTH RELEVANCE: The objective of this R21 proposal is to test a probe of central CRH receptor function in healthy adult male and female subjects. The probe combines intranasal CRH challenge with EEG measures of brain cortical activity. In order to understand the kinetics of the intranasal probe, an intravenous CRH challenge will also be performed, to provide comparison data.