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Probing Inflammation and Reward Sensitivity in Alcohol Use Disorder

探索酒精使用障碍中的炎症和奖励敏感性

基本信息

批准号：
10460601
负责人：
Elizabeth Burnette
金额：
$ 2.74万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-03 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10460601
关键词：
Acute Alcohol consumption Alcohol dependence Alcoholic beverage heavy drinker Alcohols Anhedonia Animal Model Anxiety Attenuated Behavioral Biological Blood specimen Body Weight Brain Chronic Clinical Clinical Trials Collaborations Depressed mood Disease Dose Emotional Emotions Endotoxins Environment Escherichia coli Functional disorder Genes Hour Human Individual Inflammation Inflammatory Inflammatory Response Infusion procedures Interleukin-6 Intravenous Intravenous infusion procedures Journals Knock-out Laboratories Learning Light Link Literature Magnetic Resonance Imaging Measurable Mediating Mood Disorders Moods Mus National Research Service Awards Neuroimmune Neurosciences Participant Phase Phenotype Placebos Plasma Play Psychoneuroimmunology Questionnaires Randomized Regulation Research Training Rewards Role Saline Sampling Self Administration Signal Transduction Stimulus Substance Use Disorder TNF gene Techniques Testing Time Training Training Activity Translations addiction alcohol effect alcohol exposure alcohol seeking behavior alcohol use disorder behavioral outcome career career development chronic alcohol ingestion comorbidity comparison group cytokine depressive symptoms disorder control double-blind placebo controlled trial drinking experience inflammatory marker insight negative mood neuroinflammation neurotoxic novel pre-clinical pre-doctoral preclinical study preference psychobiology reinforcer relating to nervous system response response biomarker sex substance use symposium systemic inflammatory response

项目摘要

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.

项目总结/摘要拟议的博士前NRSA旨在研究神经炎症在调节奖励中的作用酒精使用障碍（AUD）的反应和消极情绪。慢性酒精暴露已被证明，动物模型，以增加炎症的神经和全身标志物。酒精性炎症与慢性酒精寻求以及酒精的行为和神经毒性作用有关。然而，在这方面，关于炎症信号传导和AUD的文献绝大多数是临床前的，关系可以推断到人类。因此，翻译成临床样本是必要的。在人类中，成瘾通常被认为是一种奖赏缺乏症。负面情绪也与澳元有关，因此，AUD患者表现出更高水平的负面情绪，情绪障碍和AUD。神经炎症与消极情绪有关，例如细胞因子已经被证明在消极情绪的发生中起着因果作用。此外，大脑激活响应于在引起炎症的内毒素输注后，奖赏刺激减少。然而， AUD、炎症和行为结果尚未确定。这项拟议的研究旨在通过检查炎症在以下方面的作用来填补文献中的这一空白：在患有AUD和轻度饮酒的健康个体的临床样本中，对照我们将通过实验激发全身炎症反应，通过血浆中的促炎细胞因子参与者将接受低剂量的内毒素，细胞因子水平没有生命体征的显著变化，因此安全和急性模拟低级别炎症反应。在输注内毒素（或安慰剂）后4小时内-在此期间细胞因子水平在2小时达到峰值，并在4小时恢复到接近基线水平-将评估参与者的每小时间隔的负面情绪和高峰（第2小时）的奖励反应。该项目的第一个目标是检查神经炎症对AUD与对照组的负面情绪的影响。第二个目标是检查急性炎症对AUD和对照组中奖赏反应的影响。本提案的结论将有助于阐明炎症在调节AUD情绪和奖励反应中所发挥的作用。除了这些研究目标，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，重点是奖励的心理生物学，通过课程，与这些领域的专家合作，以及包括演示在内的职业发展在杂志俱乐部和会议上。该培训将在劳拉·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因素。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。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder.

DOI：
10.1007/s40265-021-01670-3
发表时间：
2022-03
期刊：
Drugs
影响因子：
11.5
作者：
Burnette EM;Nieto SJ;Grodin EN;Meredith LR;Hurley B;Miotto K;Gillis AJ;Ray LA
通讯作者：
Ray LA

Alcohol use disorder (AUD) is associated with enhanced sensitivity to cellular lipopolysaccharide challenge.

酒精使用障碍（AUD）与细胞脂多糖挑战的敏感性增强有关。