Development of minocycline as a neuroimmune therapy for alcohol use disorder

项目总结/摘要 这个K 01指导研究科学家发展奖旨在准备候选人， 成为一名独立的研究者，使用心理神经免疫学和神经成像技术， 开发治疗酒精使用障碍（AUD）的药物酒精使用障碍是一个严重的公共卫生问题， 严重影响生活质量并造成相当大的经济负担。尽管这个问题普遍存在， 目前批准用于治疗AUD的药物很少，并且可用的药物具有 最好是中等效果。因此，AUD的药物开发仍然是最优先的研究事项， 新分子靶点和新化合物的鉴定对于AUD的治疗是必不可少的。最近 有证据表明，神经免疫系统可能是AUD的一种新的治疗靶点。 米诺环素是一种神经免疫调节剂，可减少酒精消耗，酒精相关炎症， 酒精引起的啮齿类动物神经毒性。然而，米诺环素对神经炎症和 AUD患者的神经认知功能尚不清楚。因此，本K 01的研究目标 应用是表征神经免疫系统在AUD中的作用，并识别生物行为学特征。 米诺环素可能是一种有效的AUD药物治疗机制。我们将推进药物治疗 通过进行随机、双盲和安慰剂对照的正电子发射， 断层扫描（PET）成像研究，检查米诺环素对神经炎症、酒精提示 反应性、神经认知功能和酒精使用。在拟议的研究中，不寻求治疗 目前诊断为DSM-5 AUD的个体（N = 24）将随机接受200 mg 二甲胺四环素或安慰剂，持续28天，并完成两次实验室检查。第一实验室 在开始给药方案之前（第0天）立即进行第二次治疗， 每天服药28天后完成。在每一次实验中，参与者将 完成线索反应范例、神经认知表现任务和PET成像会话。 将通过使用放射性示踪剂N-（2，5-二甲氧基-苄基）-N-（5-甲氧基-苄基）-N-（2-甲氧基-苄基）- 氟-2-苯氧基苯基）乙酰胺（[11 C]-DAA 1106），其标记活化的小胶质细胞 在大脑里。此外，将在给药第0、7、14、21和28天采集血样，以测量 促炎标志物的循环水平，以确定特定的免疫信号传导途径 AUD的潜在神经炎症。本研究的成功完成将有助于药物治疗 通过评估新化合物和检查神经免疫系统的效用来开发AUD 作为AUD的治疗靶点。PI的培训目标是获得以下方面的专业知识：1）神经成像，2） 成瘾的心理神经免疫学，以及3）临床试验研究的当代统计方法 同时继续发展和完善职业发展所需的专业技能。

Project Summary/Abstract This K01 Mentored Research Scientist Development Award is designed to prepare the candidate to become an independent investigator in using psychoneuroimmunology and neuroimaging techniques to develop medications for alcohol use disorder (AUD). Alcohol use disorder is a critical public health issue that severely affects quality of life and produces a sizable economic burden. Despite this pervasive problem, there are few currently approved pharmacotherapies for the treatment of AUD, and those that are available have moderate efficacy at best. Therefore, medication development for AUD remains a top research priority, and the identification of new molecular targets and novel compounds is essential for the treatment of AUD. Recent evidence suggests that the neuroimmune system may represent one such novel treatment target for AUD. Minocycline is a neuroimmune modulator that reduces alcohol consumption, alcohol-related inflammation, and alcohol-induced neurotoxicity in rodents. However, the effects of minocycline on neuroinflammation and neurocognitive function in individuals with an AUD are unknown. Thus, the research objective of this K01 application is to characterize the role of the neuroimmune system in AUD and identify the biobehavioral mechanisms by which minocycline may be an effective AUD pharmacotherapy. We will advance medication development for AUD by conducting a randomized, double blind, and placebo-controlled positron emission tomography (PET) imaging study examining the effects of minocycline on neuroinflammation, alcohol cue reactivity, neurocognitive function, and alcohol use in AUD. In the proposed study, non-treatment seeking individuals with a current DSM-5 AUD diagnosis (N = 24) will be randomized to receive either 200 mg of minocycline or placebo on a daily basis for 28 days and complete two laboratory sessions. The first laboratory session will be performed immediately before commencing the medication regimen (day 0) and the second will be completed after taking the medication daily for 28 days. Within each laboratory session, participants will complete a cue reactivity paradigm, neurocognitive performance tasks, and a PET imaging session. Neuroinflammation will be assessed by using PET imaging with the radiotracer N-(2,5-dimethoxy-benzyl)-N-(5- fluoro-2-phenoxyphenyl) acetamide labeled with carbon-11 ([11C]-DAA1106), which labels activated microglia in the brain. Additionally, blood samples will be drawn on days 0, 7, 14, 21, and 28 of treatment to measure circulating levels of proinflammatory markers in order to identify the specific immune signaling pathways underlying neuroinflammation in AUD. The successful completion of this study will contribute to medication development for AUD by evaluating a novel compound and examining the utility of the neuroimmune system as a treatment target for AUD. The training goals for the PI are to gain expertise in 1) neuroimaging, 2) the psychoneuroimmunology of addiction, and 3) contemporary statistical approaches to clinical trial research while continuing to develop and refine the professional skills necessary for career advancement.