Neuropeptide Modulation of Stress: A Novel Approach to Cocaine Relapse

描述（由申请人提供）：该提案描述了一项两阶段初步研究：在第1阶段，将在5天住院期间检查鼻内施用血管加压素类似物去氨加压素（DDAVP）以增强可卡因依赖患者的应激敏感性和催产素以降低可卡因依赖患者的应激敏感性的安全性、耐受性和潜在功效。通过检查DDAVP的应激增强作用，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。这将与健康匹配的对照组进行比较，以评估加压素诱导的应激失调是否发生在可卡因依赖的人中。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，鼻内加压素可能是患者这种敏感性的简单测试。就其本身而言，鼻内催产素将被检查，看看它是否可以抵消鼻内DDAVP的应激增强作用，从而证明一些潜力，以减少可卡因依赖患者的应激相关复发的风险。压力敏感性将通过主观评分和压力激素ACTH的血清测量来评估。还将这些测量值与从匹配的对照受试者中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配到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对抗复发。本研究基于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CNS应激通路对加压素的敏感性，并增加了加压素从下丘脑和下丘脑传出通路向CNS应激中心的合成和释放。催产素系统，就其本身而言，在慢性应激的情况下，对CNS应激系统和HPA轴获得越来越多的调节作用：在可卡因依赖中，应激途径对催产素的敏感性增强，但催产素变得耗尽，创造了一个环境，其中外源性催产素可以发挥强大的调节作用。鼻内给药提供了一种可能的方便的方法，将这些小的神经肽传递到大脑，这将是本初步研究的一个主要部分的可行性。如果这项初步研究表明鼻内催产素降低可卡因依赖患者复发风险的可行性，它可以为这种方法的扩展研究奠定基础，以调节可卡因依赖患者的压力敏感性，并降低他们一旦戒断后的复发风险。

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.