Does endotoxin administration increase alcohol consumption in individuals with AUD?

项目摘要 这NIH小研究补助金计划（父R 03）申请建议支持早期阶段 调查员Terril Verplaetse博士，在神经炎症领域建立一个新的研究项目， 酒精研究神经免疫功能是一个关键系统，与负强化饮酒和 酒精使用障碍（AUD）。研究发现，压力和长期饮酒 增加小胶质细胞的活性，这是神经炎症的标志。然而，神经炎症对酒精的作用 使用行为不太清楚。内毒素，也称为脂多糖（LPS），是众所周知的诱导 神经炎症和急性应激。在临床前研究中，LPS增加自愿乙醇摄入量。{{{To我们 知识，激发研究，以检查神经炎症引起的饮酒尚未开发， 人与人之间，此外，在过去十年中，女性的AUD比率相对于男性增加了84%。 在男性中增加了35%。压力和更大的神经免疫反应与酒精的使用有关， 妇女和男子，但在妇女中发挥特别关键的作用。因此，此应用程序将生成数据， 计算性别和内毒素（vs.安慰剂）给药对饮酒的相互作用的效应量 行为和潜在的机制，内毒素对女性和男性饮酒的影响。的目标 这项拟议中的研究是为了检查神经炎症在女性和男性急性饮酒中的作用， 研究神经炎症对酒精自身作用的潜在机制的性别差异， 局研究人群将是符合AUD DSM-5标准的个体。该项目的特点是 一个经过充分验证的人类实验室范例，它模拟了饮酒行为的两个关键特征： 抵制饮酒（即，减少开始饮用的时间）和随后的自由饮用（即，毫升 酒精消耗）。为了确定内毒素（与安慰剂相比）是否会增加我们的主要结局， 开始饮酒和女性和男性的酒精消费量，个人将完成一个单一的 在2小时酒精之前给予LPS（与安慰剂相比;{双盲}）的实验室阶段 自我管理会议（具体目标1）。我们还将评估内毒素与 酒精对AUD患者的影响（具体目标2）。其他分析将检查以下方面的潜在性别差异： 内毒素（相对于安慰剂）对饮酒行为影响的潜在机制（例如，外周细胞因子， 渴望，主观中毒，情绪，压力，心率，血压，皮质醇，ACTH，{和性别 激素）（具体目标3）。采取 总之，这一提议将为评估神经炎症对酒精的作用提供有价值的数据- 动机的行为，并将有丰富的应用，以告知新的药物治疗 针对AUD患者神经炎症通路的策略，包括性别适当的治疗。

PROJECT SUMMARY This NIH Small Research Grant Program (Parent R03) application proposes support for early stage investigator Terril Verplaetse, Ph.D., to establish a new research program in the area of neuroinflammation and alcohol research. Neuroimmune function is a key system linked to negative reinforcement drinking and to the development of alcohol use disorder (AUD). Stress and chronic alcohol consumption have been found to increase microglial activity, a marker of neuroinflammation. However, the role of neuroinflammation on alcohol use behavior is less clear. Endotoxin, also called lipopolysaccharide (LPS), is well-known to induce neuroinflammation and acute stress. In preclinical studies, LPS increases voluntary ethanol intake. {{{To our knowledge, a provocation study to examine neuroinflammation-induced drinking has not been developed in humans with AUD.}}}. Further, rates of AUD have increased in women by 84% over the past ten years relative to a 35% increase in men. Stress and greater neuroimmune response are associated with alcohol use for both women and men but play an especially critical role in women. Thus, this application will generate data to calculate effect sizes for the interaction between sex and endotoxin (vs. placebo) administration on drinking behavior and potential mechanisms underlying endotoxin effects on drinking in women vs. men. The goal of this proposed research is to examine the role of neuroinflammation on acute drinking in women and men and to investigate sex differences in potential mechanisms underlying the role of neuroinflammation on alcohol self- administration. The study population will be individuals meeting DSM-5 criteria for AUD. This project features a well-validated human laboratory paradigm that models two critical features of drinking behavior; the ability to resist drinking (i.e., reducing time to initiate drinking) and subsequent ad-libitum drinking (i.e., milliliters of alcohol consumed). To determine whether endotoxin (vs. placebo) increases our primary outcomes of time to initiate drinking and amount of alcohol consumed in women and men, individuals will complete a single laboratory session in which LPS (vs. placebo; {{{double-blinded}}}) is administered prior to a 2-hour alcohol self-administration session (Specific Aim 1). We will also evaluate the safety of endotoxin in combination with alcohol in individuals with AUD (Specific Aim 2). Additional analyses will examine potential sex differences in mechanisms underlying endotoxin (vs. placebo) effects on drinking behavior (e.g., peripheral cytokines, craving, subjective intoxication, mood, stress, heart rate, blood pressure, cortisol, ACTH, {{{and sex hormones}}}) over the course of the 2-hour alcohol self-administration session (Specific Aim 3). Taken together, this proposal will provide valuable data for evaluating the role of neuroinflammation on alcohol- motivated behavior and will have abundant applications to inform novel pharmacotherapeutic treatment strategies targeting neuroinflammatory pathways in individuals with AUD, including sex-appropriate treatments.