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: 10246351
• 负责人: Daniel Roche
• 金额: $ 17.66万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246351
• 关键词: Acetamides; Acute; Affect; Alcohol consumption; Alcohol-Induced Neurotoxicity; Alcohols; Antibiotics; 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; Environment; Goals; Heavy Drinking; 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; 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; Signal Transduction; 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 estimate; craving; cue reactivity; design; drug efficacy; effective therapy; efficacy evaluation; 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.

项目概要/摘要 K01 指导研究科学家发展奖旨在帮助候选人做好准备 成为使用心理神经免疫学和神经影像技术的独立研究者 开发治疗酒精使用障碍（AUD）的药物。酒精使用障碍是一个重要的公共卫生问题 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， 目前批准的治疗 AUD 的药物疗法很少，并且可用的药物疗法有 效果充其量是中等。因此，AUD 的药物开发仍然是研究的首要任务，并且 新分子靶点和新化合物的鉴定对于 AUD 的治疗至关重要。最近的 有证据表明，神经免疫系统可能是 AUD 的此类新治疗靶点之一。 米诺环素是一种神经免疫调节剂，可减少饮酒、酒精相关炎症和 酒精引起的啮齿动物神经毒性。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，本次K01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 米诺环素可能成为有效的 AUD 药物疗法的机制。我们将提前用药 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) 成像研究检查米诺环素对神经炎症、酒精提示的影响 反应性、神经认知功能和酒精使用（澳元）。在拟议的研究中，不寻求治疗 当前 DSM-5 AUD 诊断的个体 (N = 24) 将被随机分配接受 200 毫克 每天服用米诺环素或安慰剂，持续 28 天，并完成两次实验室检查。第一个实验室 疗程将在开始药物治疗方案（第 0 天）之前立即进行，第二次疗程将在 每日服药 28 天后完成。在每次实验室会议中，参与者将 完成提示反应范式、神经认知表现任务和 PET 成像会话。 将使用放射性示踪剂 N-(2,5-二甲氧基-苄基)-N-(5-) 的 PET 成像来评估神经炎症 氟-2-苯氧基苯基)乙酰胺用碳-11 ([11C]-DAA1106) 标记，可标记激活的小胶质细胞 在大脑中。此外，将在治疗第 0、7、14、21 和 28 天抽取血样进行测量 促炎标记物的循环水平，以确定特定的免疫信号传导途径 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 通过评估新型化合物并检查神经免疫系统的效用来开发 AUD 作为 AUD 的治疗目标。 PI 的培训目标是获得 1) 神经影像学方面的专业知识，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。