Elucidating the Effects of Neuroimmune Modulation on Neural Substrates of Alcohol Cue and Stress Reactivity

摘要 酒精使用障碍（AUD）是一种慢性复发性疾病，具有重大的公共卫生影响。发展 治疗AUD的有效药物是一个关键的研究优先事项。新分子的鉴定 靶点和针对这些靶点的化合物的开发代表了药物治疗的关键目标 发展一个有希望的治疗目标是调节神经免疫功能。慢性酒精 消费诱导促炎状态，例如AUD患者增加 神经炎症压力暴露也会引起大脑的炎症反应， 对酒精的行为反应该建议是基于最近的迹象表明，异丁司特（IBUD）， 靶向神经营养因子信号传导和神经免疫功能的神经免疫调节剂，代表了一种神经免疫调节剂。 治疗AUD的潜在有效药物。在啮齿类动物中，IBUD减少了酒精摄入量， 减轻压力诱发的复发。在一项人类实验室研究中，IBUD改善了情绪弹性， 酒精提示和压力暴露以及酒精渴望的降低。这些结果表明 IBUD是一种很有前途的酒精成瘾药物治疗。然而，IBUD的作用机制并不 完全理解这个NRSA应用程序的目的是促进我作为一个临床神经科学家的发展 专注于AUD的药物开发。该申请提出增加一种新的神经成像 申办者（Lara Ray博士）新资助的R01方案，一项为期12周的双盲安慰剂对照研究 异丁司特治疗AUD的随机临床试验。这项研究将探讨神经免疫的影响， 通过IBUD对寻求治疗中酒精线索和心理社会压力的神经反应的调节 个人AUD 64名目前患有AUD的寻求治疗的受试者将完成1次神经成像 作为R01试验第4周随访访视的一部分。在这次访问中，与会者将完成两个 神经影像范例评估视觉酒精线索和心理社会压力的神经反应。 在为期12周的试验期间，参与者将每两周完成一次饮酒报告。具体而言，目标1测试 假设IBUD会减弱奖励回路中对酒精线索的神经反应， 安慰剂目的2检验IBUD将减少扩展杏仁核中的神经激活的假设， 与安慰剂相比，前额皮质对心理社会压力的影响。探索性目标测试的假设， IBUD治疗的个体，对酒精线索具有较低神经腹侧纹状体激活的参与者将具有 更好的饮酒效果。目前的研究代表了一个重要的步骤：1）识别神经 IBUD作为AUD治疗的作用机制，2）我作为AUD治疗的科学发展和成熟度， 一位独立的临床和翻译酒精研究人员，对药物开发感兴趣。

ABSTRACT Alcohol use disorder (AUD) is a chronic relapsing disease with a major public health impact. The development of efficacious medications to treat AUD is a crucial research priority. The identification of novel molecular targets and the development of compounds for these targets represents a critical goal in medications development. One promising treatment target is the modulation of neuroimmune function. Chronic alcohol consumption induces a proinflammatory state, such that individuals with AUD have increased neuroinflammation. Stress exposure also induces an inflammatory response in the brain and sensitizes behavioral responses to alcohol. This proposal is based on recent indications that ibudilast (IBUD), a neuroimmune modulator that targets neurotrophin signaling and neuroimmune function, represents a potentially efficacious medication for the treatment of AUD. In rodents, IBUD reduced alcohol intake and attenuated stress-induced relapse. In a human laboratory study, IBUD improved mood resilience during alcohol cue and stress exposure and decreased tonic levels of alcohol craving. These results indicate the IBUD is a promising alcohol addiction pharmacotherapy. However, the mechanisms of IBUD’s actions are not fully understood. The objective of this NRSA application is to foster my development as a clinical neuroscientist with a focus on medications development for AUD. This application proposes to add a novel neuroimaging protocol to the Sponsor’s (Dr. Lara Ray) newly funded R01, a 12-week, double-blind, placebo-controlled randomized clinical trial of ibudilast for AUD. The proposed study will investigate the effect of neuroimmune modulation through IBUD on neural response to alcohol cues and psychosocial stress in treatment-seeking individuals with AUD. Sixty-four treatment seeking participants with current AUD will complete 1 neuroimaging visit as part of the Week 4 follow-up visit for the R01 trial. During this visit participants will complete two neuroimaging paradigms evaluating neural responses to visual alcohol cues and psychosocial stress. Participants will complete bi-weekly reports of their drinking during the 12-week trial. Specifically, Aim 1 tests the hypothesis that IBUD will attenuate neural response to alcohol cues in reward circuitry compared to placebo. Aim 2 tests the hypothesis that IBUD will reduce neural activation in the extended amygdala and prefrontal cortex to psychosocial stress compared to placebo. The Exploratory Aim tests the hypothesis that in IBUD-treated individuals, participants with lower neural ventral striatal activation to alcohol cues will have better drinking outcomes. The present study represents an important step in: 1) identifying the neural mechanisms underlying IBUD’s actions as an AUD treatment and 2) my scientific development and maturity as an independent clinical and translational alcohol researcher with an interest in medications development.