Neuropeptide Modulation of Stress: A Novel Approach to Cocaine Relapse

压力的神经肽调节：可卡因复吸的新方法

基本信息

批准号：
8637428
负责人：
Wilfred Noel Raby
金额：
$ 20.25万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8637428
关键词：
Abstinence Admission activity Adrenal Glands Affect Agonist Animal Model Anterior Pituitary Gland Automobile Driving Binding Brain Chronic Chronic stress Clinical Trials Cocaine Cocaine Abuse Cocaine Dependence Control Groups Corticotropin Corticotropin-Releasing Hormone Corticotropin-Releasing Hormone Receptors DDAVP Data Desmopressin Development Double-Blind Method Efferent Pathways Endocrine Environment Gender Gene Expression Glucocorticoids Homeostasis Hormones Hospitals Human Hyperactive behavior Hypothalamic structure Inpatients Intranasal Administration Investigation Measurement Measures Methods Neurons Neuropeptides Outpatients Oxytocin Oxytocin Receptor Pathway interactions Patients Pattern Penetration Pharmaceutical Preparations Phase Physiological Pituitary Gland Pituitary-Adrenal System Placebos Psychostimulant dependence Randomized Receptor Gene Regulation Relapse Reporting Risk Safety Serum Site Staging Stress Stress Tests System Testing Time Vasopressins Withdrawal analog base biological adaptation to stress cocaine use craving density disorder later incidence prevention novel strategies paraventricular nucleus prevent primary outcome public health relevance randomized placebo controlled trial receptor receptor density response stressor volunteer

项目摘要

DESCRIPTION (provided by applicant): This proposal describes a two phase preliminary study: In phase 1, It will examine the safety, tolerability, and potential efficacy of the intranasl administration of the Vasopressin analog Desmopressin (DDAVP) to enhance, and of Oxytocin to reduce stress sensitivity in cocaine dependent patients during a 5-day inpatient admission. By examining DDAVP for its stress enhancing effects, we will evaluate if it could serve as a stress challenge to test stress sensitivity in cocaine dependent patients. This will be compared to a healthy matched control group to assess if vasopressin-induced stress dysregulation take place in humans with cocaine-dependence. As high stress sensitivity has been shown to predict relapse in cocaine dependent patients, intranasal Vasopressin could be a simple test of this sensitivity in patients. For its part, intranasal Oxytocin will be examined to see if it can counteract the stress-enhancing effect of intranasal DDAVP, and thus demonstrate some potential to reduce the risk of stress-related relapse for cocaine-dependent patients. Stress sensitivity will be assessed by subjective ratings and serum measurements of the stress hormone ACTH. These measures will also be compared to data obtained from matched control subjects. Following phase 1, a six-week outpatient phase 2 follows, during which cocaine-dependent patients are randomized to a double-blind clinical trial of intranasal Oxytocin or placebo, to test if intranasal Oxytocin can delay or counter relapse. This study is based on the findings that chronic stress, as is caused by cocaine dependence, increases the sensitivity of Hypothalamo-pituitary-adrenal (HPA) axis and CNS stress pathways to Vasopressin, and increases the synthesis and release of Vasopressin from the hypothalamus and hypothalamic efferent pathways to CNS stress centers. Oxytocin systems, for their part, acquire an increasing moderating effect on CNS stress systems and the HPA axis in situations of chronic stress: in cocaine dependence, the sensitivity of stress pathways to Oxytocin is enhanced, but Oxytocin becomes depleted, creating a environment where exogenous Oxytocin could exert a strong regulatory effect. Intranasal administration provides a possible convenient method to deliver these small neuropeptides to the brain, and the feasibility of this will be a major part of this preliminary study. Should this preliminary study show the feasibility of intranasal Oxytocin to reduce the relapse risk of cocaine dependent patients, it could set the stage for an expanded investigation of this method to regulate stress sensitivity in cocaine-dependent patients, and reduce their relapse risk once they become abstinent.

描述（由申请人提供）：该提案描述了一项两阶段的初步研究：在第1阶段，它将检查加压素类似物类似物的内部纳米肌在可加油依赖性患者中降低cocaine coccaine依赖患者的安全性，耐受性和潜在的疗效，以增强和催产剂，以降低cocaine依赖患者的压力敏感性。通过检查DDAVP的压力增强效应，我们将评估它是否可以作为对可卡因依赖性患者的压力敏感性的压力挑战。将其与健康匹配的对照组进行比较，以评估与可卡因依赖性的人类中加压素诱导的应激失调。由于已经显示出高应力敏感性可以预测可卡因依赖性患者的复发，因此鼻内加压素可能是对患者这种敏感性的简单测试。就其部分而言，将检查鼻内催产素，以查看它是否可以抵消鼻内DDAVP的应激增强作用，因此证明了降低可卡因依赖性患者应激相关复发风险的潜力。应力敏感性将通过主观等级和应力激素ACTH的血清测量评估。这些措施也将与从匹配的对照对象获得的数据进行比较。在第1阶段之后，接下来是六周的门诊阶段2，在此期间可卡因依赖性患者被随机分为鼻内催产素或安慰剂的双盲临床试验，以测试鼻内催产素是否可以延迟或反复发。这项研究基于以下发现，即可卡因依赖性所致慢性应激，增加了甲状腺 - 肾上腺肾上腺（HPA）轴和CNS对加压素的应激途径的敏感性，并增加了下丘脑和下丘脑效能的加压素的合成和释放。就催产素系统而言，在慢性压力的情况下，对CNS应激系统和HPA轴的调节作用越来越不断增加：在可卡因依赖性中，应激途径对催产素的敏感性得到了增强，但是催产素的敏感性被耗尽，从而耗尽，从而创造出强大的氧气质蛋白会产生强大的效应。鼻内给药提供了一种可能的方便方法，可以将这些小神经肽输送到大脑，这将是这项初步研究的主要部分。如果这项初步研究表明鼻内催产素降低可卡因依赖患者的复发风险的可行性，它可能为这种方法扩大研究以扩大研究以调节可卡因依赖性患者的压力敏感性，并降低他们的复发风险。