Neuropeptide Modulation of Stress: A Novel Approach to Cocaine Relapse

描述(申请人提供)：这项建议描述了一项两阶段的初步研究：在第一阶段，它将检查在5天的住院期间，鼻腔内应用加压素类似物去氨加压素(DDAVP)来增强可卡因依赖患者的安全性、耐受性和潜在疗效，以及催产素来降低可卡因依赖患者的应激敏感性。通过检测DDAVP的应激增强效应，我们将评估它是否可以作为一种应激挑战来测试可卡因依赖患者的应激敏感性。这将与健康的匹配对照组进行比较，以评估血管加压素诱导的应激失调是否发生在有可卡因依赖的人身上。由于高应激敏感性已被证明可以预测可卡因依赖患者的复发，鼻内注射加压素可能是对患者这种敏感性的简单测试。就其本身而言，将检查鼻内催产素，以确定它是否可以抵消鼻内DDAVP的应激增强效应，从而展示出一些降低可卡因依赖患者应激相关复发风险的潜力。应激敏感性将通过主观评分和血清应激激素ACTH的测量来评估。这些测量也将与从匹配的对照受试者获得的数据进行比较。在第一阶段之后，接下来是为期六周的门诊第二阶段，在此期间，可卡因依赖患者被随机分成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缓或抗复发。本研究的基础是可卡因依赖引起的慢性应激增加了下丘脑-垂体-肾上腺(HPA)轴和中枢应激通路对加压素的敏感性，并增加了从下丘脑和下丘脑传出通路到中枢应激中心的加压素合成和释放。在慢性应激的情况下，催产素系统对中枢应激系统和HPA轴的调节作用越来越强：在可卡因依赖的情况下，应激途径对催产素的敏感性增强，但催产素变得枯竭，从而创造了外源性催产素可以发挥强大调节作用的环境。鼻腔给药提供了一种可能的便捷方法，将这些小神经肽输送到大脑，其可行性将是这一初步研究的主要部分。如果这项初步研究表明，鼻内注射催产素可以降低可卡因依赖患者的复发风险，那么它可能为这种方法的扩大研究奠定基础，以调节可卡因依赖患者的应激敏感性，并在他们戒烟后降低他们的复发风险。

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.