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

地塞米松可针对酒精使用障碍 (AUD) 患者早期戒酒期间的压力和免疫系统变化

• 批准号: 10350207
• 负责人: Helen Cecilia Fox
• 金额: $ 22.93万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10350207
• 关键词: Abstinence; Adrenal Glands; Alcohol dependence; Alcohols; American; Animals; Anti-Inflammatory Agents; Anxiety; Attenuated; Biological Adaptation; Blood Pressure; Chronic stress; Cocaine; Consumption; Corticotropin; Data; Dependence; Development; Dexamethasone; Double-Blind Method; Exposure to; FDA approved; Glucocorticoids; Health; Heart Rate; Hour; Human; Hydrocortisone; Hypothalamic structure; Imagery; Immune; Immune response; Immune system; Individual; Inflammatory; Inflammatory Response; Injections; Intake; Interleukin-10; Interleukin-6; Laboratories; Laboratory Study; Link; Measures; Morbidity - disease rate; Motivation; Mus; Participant; Pharmaceutical Preparations; Pharmacology; Pituitary Gland; Placebos; Plasma; Property; Psychological Stress; Public Health; Randomized; Recombinant Interleukin-10; Recording of previous events; Recovery; Relapse; Research; Risk; SP1 gene; Severities; Stress; TNF gene; TNFRSF1A gene; Time; Up-Regulation; Woman; alcohol abstinence; alcohol abuse therapy; alcohol craving; alcohol measurement; alcohol seeking behavior; alcohol use disorder; anakinra; base; binge drinking; biological adaptation to stress; craving; cytokine; drinking; effective therapy; experience; hypothalamic-pituitary-adrenal axis; immune system function; individualized medicine; inflammatory marker; men; negative mood; placebo group; pre-clinical research; primary outcome; problem drinker; programs; recruit; relapse prediction; response; screening; secondary outcome; stress state

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.

项目总结 大约三分之一的美国人消费了足够的酒精，被认为有依赖和 50%到90%试图戒酒的酒鬼会复发，这突显了需要更好的戒酒方法 开发了药物和用药靶点。我们的研究计划表明，早期禁欲 酒精的特点是烦躁不安，五分钟的心理压力暴露可能会引发 过度的焦虑、消极情绪和渴望会持续长达一个小时。两者之间的联系 这种对压力和复发因素的敏感化反应也表明，压力诱导的渴望状态可能 成为药物开发的最佳目标，但仍未得到探索。有鉴于此，试图刻画 引发酒精渴求的生物适应已经阐明了紧张性压力的离散变化。 和免疫系统功能，包括肾上腺敏感性增加(皮质醇和皮质醇/ACTH比率)，以及 抑制抗炎细胞因子。因此，我们假设地塞米松(一种抗炎药物 糖皮质激素)，可能能够通过操纵联合应激和 免疫系统音调。我们提供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， 双盲交叉实验室研究招募N=50名一个月戒酒的男性和女性 使用障碍(澳元)。我们将研究1.5毫克地塞米松(DEX)与安慰剂(PBO)是否可以 通过降低肾上腺敏感度、增加抗炎细胞因子来减少应激时的酒精渴求 并潜在地使对压力的免疫反应正常化。因此，我们的主要目标是确定 DEX与PBO是否可以缓解酒精渴求、负面情绪和压力时的焦虑(H1)，以及 评估DEX和PBO对压力和免疫系统张力的影响，以及随后的应激暴露(H2)。我们 还要检查与DEX相关的变化是否可以预测酒精渴求的减少(H3)。所有参与者都将参加 第二部分，在随机分为DEX或PBO后的实验室会议，为期7天的洗涤期 在两者之间。在每个实验室课程期间，参与者将随机接触到两个5分钟的个性化培训 想象条件(压力和放松)，中间有30分钟的休息时间。主观焦虑，消极的 情绪和酒精渴求以及血浆促炎症细胞因子(肿瘤坏死因子α，肿瘤坏死因子受体，白介素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、暴露于图像后立即和在不同的恢复时间点收集 直到1小时后的图像。如果假设得到证实，使用DEX进行关键的应激和免疫 系统标记物将用来识别一个明确的药理靶点，以支持引发的酒精渴望。 这些发现还可能有助于开发一种概念上独特的治疗范例，该范例鼓励使用 价格便宜、耐受性好、可广泛获得的药物，可在以下情况下使用 自我确认的漏洞。