Dexamethasone to target stress and immune system changes during early abstinence in individuals with Alcohol Use Disorder (AUD)

项目摘要 大约三分之一的美国人饮酒量足以被认为有依赖性的风险， 50%到90%的试图戒酒的酗酒者会复发，这凸显了更好的治疗方法的必要性。 开发药物和药物靶点。我们的研究计划表明， 酒精的特点是烦躁不安的状态，五分钟的心理压力暴露可以引起 过度的焦虑、消极情绪和渴望可以持续长达一个小时。之间的联系 这种对压力和复发因素的敏感反应也表明，压力诱导的渴望状态可能 是药物开发的最佳但尚未探索的目标。有鉴于此，试图描述 引发酒精渴望的生物学适应已经阐明了紧张性压力的离散变化 免疫系统功能，包括肾上腺敏感性（皮质醇和皮质醇/ ACTH比值）升高，以及 抑制抗炎细胞因子。因此，我们假设地塞米松（一种抗炎药） 糖皮质激素），可能能够通过操纵联合应激和 免疫系统增强我们提出了令人信服的初步数据来支持这一点。我们提出了一个概念证明， 一项双盲、交叉实验室研究，招募N=50名戒酒1个月的男性和女性 使用障碍（AUD）。我们将研究1.5mg地塞米松（DEX）与安慰剂（PBO）相比， 通过降低肾上腺敏感性，增加抗炎细胞因子， 水平和潜在的正常化免疫反应的压力。因此，我们的主要目标是确定 DEX与PBO是否可以减轻压力下的酒精渴望，消极情绪和焦虑（H1），以及 评估DEX与PBO对应激和免疫系统张力以及应激暴露后的影响（H2）。我们 还检查DEX相关的变化是否预测酒精渴望的减少（H3）。所有参与者将参加 在随机分配至DEX或PBO后，分为两个实验室阶段， 之间。在每个实验室会议期间，参与者将随机暴露于两个5分钟的个性化 想象条件（压力和放松），中间休息30分钟。主观焦虑，阴性 情绪和酒精渴望以及血浆促炎细胞因子（TNFα，TNFR 1，IL-6）抗 炎性细胞因子（IL-10、IL-1a）和下丘脑-垂体-肾上腺（HPA）轴标志物（皮质醇、ACTH） 将在基线、接触图像后立即和不同恢复时间点收集 直到图像后1小时。如果假设得到证实，使用DEX来参与关键压力和免疫 系统标记物将用于识别明确的药理学靶点，其支持被激发的酒精渴望。 研究结果还可能有助于开发一种概念上独特的治疗模式，鼓励使用 廉价、耐受性良好和广泛可用的药物，用于在产前（PRN）期间， 自我认同的脆弱性

PROJECT SUMMARY Approximately one third of Americans consume enough alcohol to be considered at risk for dependence and between 50 to 90% of alcoholics who attempt abstinence experience relapse, highlighting the need for better developed medications and medication targets. Our program of research has shown that early abstinence from alcohol is characterized by a dysphoric state where five minutes of psychological stress exposure can elicit exaggerated levels of anxiety, negative mood and craving that can persist for up to one hour. The link between this sensitized response to stress and relapse factors also suggests that the stress-induced craving state may be an optimal, yet under explored, target for medications development. In view of this, attempts to characterize the biological adaptations underlying provoked alcohol craving have elucidated discrete changes to tonic stress and immune system function, including elevated adrenal sensitivity (cortisol and cortisol / ACTH ratios), and suppressed anti-inflammatory cytokines. We therefore postulate that dexamethasone (an anti-inflammatory glucocorticoid), may be able to attenuate provoked alcohol craving by manipulating combined stress and immune system tone. We present compelling preliminary data to support this. We propose a proof of concept, double-blind, cross-over laboratory study to recruit N=50 one month abstinent men and women with alcohol use disorder (AUD). We will examine whether 1.5mgs dexamethasone (DEX) versus placebo (PBO) can decrease alcohol craving during stress by decreasing adrenal sensitivity, increasing anti-inflammatory cytokine levels and potentially normalizing the immune response to stress. Our primary aims are therefore to determine whether DEX Vs PBO can attenuate alcohol craving, negative mood and anxiety during stress (H1), as well as assess the effects of DEX Vs PBO on stress and immune system tone and following stress exposure (H2). We also examine whether DEX-related changes predict decreases in alcohol craving (H3). All participants will take part in two, laboratory sessions after being randomized to either DEX or PBO, with a 7-day washout period in between. During each laboratory session participants will be randomly exposed to two, 5-minute personalized imagery conditions (stress and relaxing) with a 30-minute break in between. Subjective anxiety, negative mood and alcohol craving as well as plasma pro-inflammatory cytokines (TNFα, TNFR1, IL-6,) anti- inflammatory cytokines (IL-10, IL-1a), and hypothalamic-pituitary-adrenal (HPA) axis markers (cortisol , ACTH) will be collected at baseline, immediately following exposure to imagery and at various recovery time-points until 1-hour post imagery. If hypotheses are confirmed, the use of DEX to engage key stress and immune system markers will serve to identify a clear pharmacological target underpinning provoked alcohol craving. Findings may also help develop a conceptually unique treatment paradigm which encourages the use of a cheap, well-tolerated and widely available medication for use on a pro re nata (PRN) basis, during periods of self-identified vulnerability.