Probing Inflammation and Reward Sensitivity in Alcohol Use Disorder

项目摘要/摘要 建议的博士前NRSA旨在研究神经炎症在调节奖赏中的作用 酒精使用障碍(AUD)的反应和负面情绪慢性酒精暴露已显示在 动物模型，以增加神经系统和全身炎症标志物。酒精性炎症 与慢性饮酒以及酒精的行为和神经毒性影响有关。然而， 关于炎症信号和AUD的文献绝大多数是临床前的，目前尚不清楚 关系可以推断为人类的关系。因此，有必要将其转化为临床标本。在人类身上， 上瘾通常被概念化为一种奖赏不足障碍。消极的情绪性也与AUD有关， 因此，患有AUD的人表现出更高水平的负面情绪，并伴有较高的 情绪障碍和AUD。神经炎症与负性情绪有关，如细胞因子 已经被证明在负面情绪的产生中起到了因果作用。此外，大脑激活对 注射致炎内毒素后，奖赏刺激减少。然而，两者之间的联系 AUD、炎症和行为结果尚未确定。 这项拟议的研究旨在通过研究炎症在糖尿病中的作用来填补这一文献空白。 AUD患者和少量饮酒健康人的临床样本中的负面情绪和奖励反应 控制。我们将通过实验引发全身性炎症反应，通过血浆中 促炎细胞因子。参与者将接受低剂量的内毒素，而内毒素已被证明会增加 细胞因子水平在生命体征没有明显变化的情况下，因此安全和尖锐地模仿低级别 炎症反应。在输注内毒素(或安慰剂)后的4小时内-在此期间 细胞因子水平在2小时达到峰值，4小时恢复到接近基线水平-参与者将接受以下评估 每小时一次的消极情绪和高峰期(2小时)的奖励反应。该项目的第一个目标是 对比对照组，研究神经炎症对AUD患者负性情绪的影响。第二个目标是 研究急性炎症对AUD和对照组奖赏反应的影响。这项提案的调查结果 将有助于阐明炎症在调节AUD情绪和奖赏反应中所起的作用。 除了这些研究目标外，拟议的F31将为我提供广泛的培训 心理神经免疫学和临床成瘾神经科学，重点是奖赏的心理生物学， 通过课程作业，与这些领域的专家合作，以及职业发展，包括演讲 在杂志俱乐部和会议上。这项培训将在劳拉·雷博士的成瘾实验室进行，该实验室利用 广泛的实验室技术，以了解物质使用障碍的原因和相关性。 该实验室位于加州大学洛杉矶分校，这是一个世界级的研究和培训环境。

Project Summary / Abstract The proposed predoctoral NRSA aims to examine the role of neuroinflammation in modulating reward response and negative mood in Alcohol Use Disorder (AUD). Chronic alcohol exposure has been shown in animal models to increase both neural and systemic markers of inflammation. Alcohol-induced inflammation has been linked to both chronic alcohol seeking and the behavioral and neurotoxic effects of alcohol. However, the literature on inflammatory signaling and AUD is overwhelmingly preclinical and it is unknown if this relationship can be extrapolated to humans. Therefore, translation to clinical samples is necessary. In humans, addiction is often conceptualized as a reward deficit disorder. Negative emotionality is also implicated in AUD, such that individuals with AUD demonstrate higher levels of negative mood, with a high comorbidity between mood disorders and AUD. Neuroinflammation is associated with negative emotionality, such that cytokines have been shown to play a causal role in the onset of negative mood. Further, brain activation in response to reward stimuli is decreased after inflammation-provoking endotoxin infusion. However, associations between AUD, inflammation, and behavioral outcomes have not yet been established. The proposed study aims to fill this gap in the literature by examining the role of inflammation in negative mood and reward response in a clinical sample of individuals with AUD and light-drinking healthy controls. We will experimentally provoke a systemic inflammatory response, measurable by plasma levels of proinflammatory cytokines. Participants will receive a low dose of endotoxin that has been shown to increase cytokine levels without significant changes in vital signs, therefore safely and acutely mimicking a low-grade inflammatory response. Over the course of 4 hours post-infusion of endotoxin (or placebo) – during which cytokine levels peak at 2 hours and return to near-baseline by hour 4 – participants will be assessed for negative mood at hourly intervals and reward response at peak (hour 2). The first aim of the project is to examine the effects of neuroinflammation on negative mood in AUD versus controls. The second aim is to examine the effects of acute inflammation on reward response in AUD and controls. This proposal’s findings will help to elucidate the role that inflammation plays in modulating mood and reward response in AUD. In addition to these study aims, the proposed F31 will provide me with a breadth of training in psychoneuroimmunology and clinical addictions neuroscience with a focus on the psychobiology of reward, through coursework, collaboration with experts in these fields, and career development including presentations at journal clubs and conferences. This training will take place in Dr. Lara Ray’s Addictions Lab, which utilizes a broad range of laboratory techniques to understand the causes and correlates of substance use disorders. This lab is located at UCLA, a world-class research and training environment.