The Effect of Corticotropin Releasing Hormone on Cortical Arousal

描述(申请人提供)：该R21项目建议开发一种新的用于临床研究的中枢促肾上腺皮质激素释放激素(CRH)受体功能的药理学-脑电探针。这项工作的长期目标是一种基于机制的治疗方法，用于治疗应激相关的精神障碍。血脑屏障对CRH的相对不通透性是测试有关人类中枢CRH功能的机制理论的障碍。这项工作的创新之处在于，它将CRH神经肽注射到嗅觉上皮细胞，以定量测试鼻内给药的CRH在健康对照组和抑郁症缓解期的药效学和药代动力学特性。我们的目标是进行两个平行的，安慰剂交叉的药效学研究，1.鼻腔和2.静脉注射CRH。我们主要感兴趣的是鼻腔CRH(与安慰剂相比)对定量测量大脑活动(事件相关脑电)和惊吓反射(EMG)的影响。来自我们实验室的初步人体数据与这种影响是一致的。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使抑郁障碍的机制研究成为可能。其次，药效学读数CRH功能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：R21提案的目标是测试健康成年男性和女性受试者的中枢CRH受体功能。该探头结合了鼻腔CRH挑战和大脑皮层活动的脑电测量。为了了解鼻腔探头的动力学，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.