Laboratory studies on oxytocin for treatment of alcohol dependence

描述（由申请人提供）：本R21提案的目的是为未来研究神经肽催产素（OT）作为酒精使用障碍（AUD）的新治疗方法的应用提供基础。对OT作为酒精治疗的兴趣源于其在适应性过程中的作用，包括奖励、联想学习、记忆和应激反应。对其使用的支持是基于对成瘾动物模型的研究，这些研究表明，OT减少了酒精强化，减弱了药物耐受性，减少了戒断症状。OT通过与下丘脑-垂体-肾上腺（HPA）轴以及多巴胺中边缘奖励和促肾上腺皮质激素释放因子（CRF）应激系统的相互作用发挥其作用。鉴于压力、饮酒和复发之间的紧密联系，以及酗酒者中已知的hpa轴活性失调，OT对应激系统的影响引起了人们的高度关注。临床前和临床证据都表明，OT可能有助于使迟钝的应激反应正常化，并减轻酒精戒断相关的高皮质醇症、负面情绪和戒断症状。在重度饮酒者中使用金标准实验室程序，我们将在双盲安慰剂控制条件下检查鼻内OT给药对皮质醇应激反应的影响以及预测酒精使用和滥用的不同措施。目的1将研究催产素对酒精戒断的影响，包括症状严重程度、酒精渴望、皮质醇和负面情绪。目的2将研究催产素对社会压力反应的影响。目的3将检验催产素对饮酒动机的影响。目的4将研究催产素对酒精敏感性的影响。这些初步数据将为OT治疗饮酒问题的潜力提供关键信息，并将为确定未来全面研究和临床试验的样本量提供基础。

DESCRIPTION (provided by applicant): The goal of this R21 proposal is to provide the foundation for future research to examine the utility of the neuropeptide oxytocin (OT) as a new treatment for alcohol use disorders (AUD). Interest in OT as an alcohol treatment stems from its role in adaptive processes including reward, associative learning, memory, and stress responses. Support for its use is based on studies in animal models of addiction showing that OT reduced alcohol reinforcement, attenuated drug tolerance, and decreased withdrawal symptoms. OT exerts its effects via interactions with the hypothalamic-pituitary-adrenal (HPA) axis, as well as dopamine mesolimbic reward and corticotrophin-releasing factor (CRF) stress systems. OT effects on stress systems are of high interest given the strong link between stress, alcohol drinking and relapse, and known dysregulation of HPA-axis activity in heavy drinkers. Both preclinical and clinical evidence provide evidence that OT may help to normalize blunted stress responses, and attenuate alcohol withdrawal associated hypercortisolism, negative mood and withdrawal symptoms. Using gold-standard laboratory procedures in heavy drinkers, we will examine the effects of intranasal OT administration on cortisol stress responses and different measures predictive of alcohol use and misuse under double-blind placebo controlled conditions. Aim 1 will examine the effects of oxytocin on alcohol withdrawal, including symptom severity, alcohol craving, cortisol and negative mood. Aim 2 will examine the effects of oxytocin on response to social stress. Aim 3 will examine the effects of oxytocin on motivation to drink. Aim 4 will examine the effects of oxytocin on alcohol sensitivity. These preliminary data will provide critical information on the potential of OT as a treatment for alcohol drinking problems and will provide the basis for determination of sample sizes for future comprehensive research and clinical trials.