Alcohol Use Disorder (AUD) causes more than 100 thousand preventable deaths in the U.S. each year. While there are several medications approved to treat AUD, they are limited by their modest efficacy and many patients do not benefit from them. Thus, development of new effective medication treatments for AUD is a high priority. Cumulating evidence points to an important interplay between alcohol and immune responses. While much is known about the effect of alcohol on the peripheral immune system, there is a growing body of evidence suggesting the importance of the effect of alcohol on central nervous system (CNS) immune function. Alcohol-induced immune activation has been reported following binge drinking, heavy drinking and chronic alcohol use. Alcohol exposure increases the CNS levels of cytokines (small proteins or peptides used for cell signaling), chemokines (small cytokines that attract other immune cells) and other neuroimmune factors, leading to a pro- inflammatory state in the CNS. Microglia, the intrinsic immune cells of the brain, plays a central role in mediating alcohol's action on the neuroimmune pathways. Evidence from animal studies suggests that the activation of microglia influences acute behavioral responses to alcohol, including heavy drinking, withdrawal, and the transition to dependence. Minocycline is a tetracycline derivative antibiotic that also inhibits microglia activation and release of pro-inflammatory cytokines, chemokines, and nitric oxide (NO) production. In animal studies, minocycline treatment reduced alcohol self-administration and attenuated alcohol-induced sedation. Further, in work done by our group, minocycline attenuated dextromethorphan-induced subjective effects in humans. This application is a proof of concept, pilot study to evaluate the safety and potential efficacy of minocycline as a treatment for AUD using a human laboratory paradigm. Minocycline's potential use for AUD has not been previously examined in human studies. This Phase I study will test minocycline's effects on acute responses to alcohol in heavy at risk drinkers. The outcomes of interest will include the subjective responses to alcohol, cognitive performance, and changes in plasma cytokine levels in response to alcohol. The results of this study may lead to development of minocycline as a potential treatment for AUD.

Public Health Relevance

AUD is one of the most important preventable causes of death in the U.S. However, the majority of alcohol addicted individuals do not benefit from the currently available pharmacotherapies. This application will examine the safety and potential efficacy of minocycline as a treatment for AUD. The results of this study may lead to development of a novel treatment to combat AUD.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Exploratory/Developmental Grants (R21)
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Health Services Research Review Subcommittee (AA)
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Bechtholt, Anita
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Yale University
Schools of Medicine
New Haven
United States
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