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，对公众健康有重大影响。最新进展 寻找治疗AUD的有效药物是一个至关重要的研究重点。新分子的鉴定 靶点和用于这些靶点的化合物的开发是药物治疗中的一个重要目标 发展。一个有希望的治疗靶点是神经免疫功能的调节。慢性酒精 消费会导致促炎状态，从而使患有澳门氏症的人增加 神经炎。压力暴露还会在大脑中诱导炎症反应，并使 对酒精的行为反应。这项建议是基于最近的迹象表明异丁司特(IBUD)，一个 针对神经营养因子信号和神经免疫功能的神经免疫调节剂，代表一种 治疗AUD的潜在有效药物。在啮齿动物中，IBUD减少了酒精摄入量和 减轻应激导致的复发。在一项人体实验室研究中，IBUD改善了患者在 酒精暗示和压力暴露，以及减少酒精渴望的滋补水平。这些结果表明， IBUD是一种很有前途的酒精成瘾药物疗法。然而，IBUD的作用机制并不是 完全理解。这个NRSA应用程序的目的是促进我作为临床神经学家的发展 专注于澳元病的药物开发。这个应用程序建议添加一种新的神经成像 赞助商(劳拉·雷医生)新资助的R01方案，为期12周，双盲，安慰剂对照 异丁司特治疗AUD的随机临床试验。这项拟议的研究将调查神经免疫的影响 IBUD对寻求治疗中对酒精线索和心理社会应激的神经反应的调节 患有澳门氏症的个人。目前患有AUD的64名寻求治疗的参与者将完成1次神经成像 作为R01试验第四周后续访问的一部分进行访问。在这次访问期间，参与者将完成两个 评估对视觉酒精线索和心理社会压力的神经反应的神经成像范例。 参与者将在为期12周的试验期间完成每两周一次的饮酒报告。具体来说，AIM 1测试 IBUD将减弱奖赏回路中对酒精线索的神经反应的假设与 安慰剂。目的2验证IBUD将减少杏仁核和杏仁核神经活动的假设 与安慰剂相比，前额叶皮质对心理社会压力的影响。探索性的目标检验了这样的假设： IBUD治疗的个体，对酒精刺激有较低神经腹侧纹状体激活的参与者将有 更好的饮酒结果。本研究代表了在以下方面的重要步骤：1)识别神经 IBUD作为AUD治疗的作用机制和2)我的科学发展和成熟度 对药物开发感兴趣的独立临床和转化性酒精研究人员。

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.