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期初步研究：在第一阶段，它将检查鼻腔内给药抗利尿激素类似物去氨加压素（DDAVP）增强和催产素降低可卡因依赖患者5天住院期间的应激敏感性的安全性、耐受性和潜在疗效。通过检测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，以评估抗利尿激素诱导的应激失调是否发生在可卡因依赖人群中。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，鼻内催产素将被检测，看它是否能抵消鼻内DDAVP的压力增强作用，从而证明它有可能降低可卡因依赖患者因压力而复发的风险。应激敏感性将通过主观评分和应激激素ACTH的血清测量来评估。这些测量还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配到鼻内催产素或安慰剂的双盲临床试验中，以测试鼻内催产素是否可以延缓或对抗复发。本研究基于可卡因依赖引起的慢性应激增加下丘脑-垂体-肾上腺（HPA）轴和中枢神经系统应激通路对抗利尿激素的敏感性，并增加下丘脑和下丘脑输出通路对中枢神经系统应激中心的抗利尿激素的合成和释放。就催产素系统而言，在慢性应激情况下，其对中枢神经系统应激系统和下丘脑轴的调节作用日益增强：在可卡因依赖中，应激通路对催产素的敏感性增强，但催产素逐渐耗尽，创造了外源性催产素可以发挥强大调节作用的环境。鼻内给药为将这些小神经肽输送到大脑提供了一种可能的方便方法，其可行性将是本初步研究的主要部分。如果本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，则可为该方法调节可卡因依赖患者的压力敏感性，降低其戒断后的复发风险的扩展研究奠定基础。

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.