Development of minocycline as a neuroimmune therapy for alcohol use disorder

开发米诺环素作为酒精使用障碍的神经免疫疗法

• 批准号: 9371790
• 负责人: Daniel Roche
• 金额: $ 18.72万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2018-03-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9371790
• 关键词: Acetamides; Acute; Affect; Alcohol consumption; Alcohol-Induced Neurotoxicity; Alcohols; Attenuated; Back; Behavioral; Binding; Biological; Blood specimen; Brain; Carbon; Career Mobility; Cells; Chronic; Clinical; Clinical Trials; Cognitive; Cues; DSM-V; Data; Development; Diagnosis; Double-Blind Method; Economic Burden; Economics; Environment; Goals; Heavy Drinking; Image; Immune; Immune signaling; Impaired cognition; Individual; Inflammation; Interview; Label; Laboratories; Maintenance; Measures; Mentored Research Scientist Development Award; Mentors; Microglia; Minocycline; Mitochondria; Molecular Target; National Institute on Alcohol Abuse and Alcoholism; Neurocognitive; Neurocognitive Deficit; Neuroimmune; Neuroimmune system; Participant; Performance; Pharmaceutical Preparations; Pharmacotherapy; Placebo Control; Placebos; Positron-Emission Tomography; Proteins; Psychoneuroimmunology; Public Health; Quality of life; Randomized; Regimen; Research; Research Personnel; Research Priority; Rewards; Rodent; Role; Sampling; Self Administration; Serum; Severities; Signal Pathway; Signaling Molecule; Task Performances; Techniques; Testing; Tetracyclines; TimeLine; Training; addiction; alcohol abuse therapy; alcohol cue; alcohol exposure; alcohol response; alcohol use disorder; attenuation; behavioral response; biobehavior; cost; craving; cue reactivity; design; drug efficacy; effective therapy; experience; imaging study; improved; neuroimaging; neuroinflammation; neurotoxicity; novel; pre-clinical; preclinical study; radiotracer; reduced alcohol use; skills

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.

项目摘要/摘要 K01指导研究科学家发展奖旨在帮助候选人准备 成为使用精神神经免疫学和神经成像技术的独立研究人员 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，并产生相当大的经济负担。尽管存在这个普遍存在的问题，但 目前被批准用于治疗AUD的药物疗法很少，而可用的药物疗法有 最好的效果是中等。因此，AUD的药物开发仍然是研究的重中之重， 识别新的分子靶点和新的化合物对于AUD的治疗是至关重要的。近期 有证据表明，神经免疫系统可能代表了AUD的一个新的治疗靶点。 米诺环素是一种神经免疫调节剂，可减少酒精摄入量、酒精相关炎症和 酒精对啮齿动物的神经毒性作用。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，这款K01的研究目标是 应用是表征神经免疫系统在AUD中的作用并确定其生物行为 米诺环素可能是一种有效的药物治疗机制。我们将推进药物治疗 通过进行随机、双盲和安慰剂控制的正电子发射来开发AUD 断层扫描(PET)成像研究米诺环素对神经炎症、酒精提示的影响 AUD的反应性、神经认知功能和酒精使用。在拟议的研究中，不寻求治疗 目前患有DSM-5和UD诊断的患者(N=24)将随机接受200毫克的 每日服用米诺环素或安慰剂，共28天，并完成两个实验室疗程。第一个实验室 会议将在药物治疗方案开始前立即进行(第0天)，第二次将 在连续28天每日服药后完成。在每个实验室课程中，参与者将 完成线索反应范例、神经认知操作任务和正电子发射计算机断层扫描。 神经炎症将通过使用放射性示踪剂N-(2，5-二甲氧基苄基)-N-(5- 碳-11标记的([11C]-DAA1106)乙酰胺，标记激活的小胶质细胞 在大脑里。此外，将在治疗的第0、7、14、21和28天抽取血样进行检测。 循环中促炎症标志物的水平以确定特定的免疫信号通路 AUD潜在的神经炎症。这项研究的成功完成将有助于药物治疗 通过评估一种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1)神经成像方面的专业知识，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。