Neuropeptide Modulation of Stress: A Novel Approach to Cocaine Relapse

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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.