Assessment of Pioglitazone to Address Stress Reactivity and Alcohol Use Disorder

摘要 酒精使用障碍（AUD）是一个严重的公共卫生问题。压力是现代社会的核心组成部分， 酒精使用理论和压力与许多人的饮酒密切相关。有许多 批准的AUD药物，但大多数人对这些药物没有反应， 药物解决了压力的作用。目前的提案似乎通过针对与压力有关的因素来影响酒精的使用。 通过过氧化物酶体增殖物激活受体（PPARs），这可能会影响压力 反应性、压力引起的酒精渴望和酒精使用。吡格列酮（Actos）靶向PPARγ，FDA- 被批准用于治疗糖尿病和代谢紊乱的个体。从两个人类 试验和动物研究表明，吡格列酮在治疗AUD方面具有很大的前景，包括 我们自己研究的初步数据。目前的建议将试图扩大我们的初步 针对患有AUD和压力升高的寻求治疗个体的酒精使用的发现，和/或 焦虑，具体目的如下：1）评估吡格列酮是否降低应激反应性和应激- 在人类实验室模型中诱导渴望;和2）评估吡格列酮是否改变每周的心理测量 压力/焦虑、渴望和饮酒的报告。目前建议的显著优点包括： 1)针对压力/焦虑和AUD升高的个体; 2）压力反应性的生物学评估 （心率、血压、唾液皮质醇）; 3）对酒精渴望的多维度评估 结合了相对新颖的行为经济测量（即，酒精需求，延迟折扣）;以及4） 包括强大的贝叶斯统计工具，非常适合较小的样本，如目前的 提议

ABSTRACT Alcohol use disorder (AUD) is significant public health concern. Stress is a central component in modern theories of alcohol use, and stress is intimately related to drinking for many individuals. There are a number of approved medications for AUD, but the majority of individuals do not respond to these medications and no medications address the role of stress. The current proposal looks affect alcohol use by targeting stress-related systems in the body through peroxisome proliferator-activated receptors (PPARs), which may effect stress reactivity, stress-induced alcohol craving, and alcohol use. Pioglitazone (Actos) targets PPARγ and is FDA- approved for treating individuals with diabetes and metabolic disorders. Promising results from both human trials and animal research suggest that pioglitazone holds great promising for addressing AUD, including preliminary data from our own research. The current proposal will attempt to expand on our preliminary findings targeting alcohol use among treatment-seeking individuals with AUD and elevated stress and/or anxiety with the following specific aims: 1) to assess if pioglitazone decreases stress reactivity and stress- induced craving in a human laboratory model; and 2) to assess if pioglitazone changes weekly psychometric reports of stress/anxiety, craving, and alcohol consumption. Notable strengths of the current proposal include: 1) targeting individuals with elevated stress/anxiety and AUD; 2) biological assessment of stress reactivity (heart rate, blood pressure, salivary cortisol); 3) a multi-dimensional assessment of alcohol craving incorporating relatively novel behavioral economic measures (i.e., alcohol demand, delay discounting); and 4) inclusion of powerful Bayesian statistical tools that are well suited for smaller samples, such as the current proposal.