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.
Projective Narrative The objective of this proposal is to advance medication development for alcohol use disorder by examining the efficacy and mechanisms of action of minocycline, a neuroimmune modulator, as a potential treatment. This study has important clinical implications, as the available treatments for alcohol use disorder are only modestly effective and testing novel medications is a high research priority.
| Ray, Lara A; Bujarski, Spencer; Roche, Daniel James Olan et al. (2018) Overcoming the ""Valley of Death"" in Medications Development for Alcohol Use Disorder. Alcohol Clin Exp Res 42:1612-1622 |
