Alcohol use and abuse often begins in adolescence where many factors collide to promote excessive intake. Most striking though is that those who drink during adolescence - specifically before age 15 - are four times more likely to develop an alcohol use disorder in adulthood. This suggests that alcohol impacts the adolescent brain in such a way to make it more susceptible to developing an alcohol use disorder. Indeed, the adolescent brain is more susceptible to brain damage due to alcohol, which has led several groups to examine subsequent neuroinflammatory signaling in alcohol use disorders. A hallmark of neuroinflammation is microglial activation. Microglia are one of the three types of non-neuronal, glia cells in the brain that act as the brain?s immune system, but their role in alcohol use disorders is poorly understood. Microglia display a full spectrum of phenotypes from beneficial to cytotoxic and the phenotype of these microglia after alcohol exposure has not been defined. Further, microglia may become ?primed? by an event, then upon subsequent challenge they aggressively over-respond, a phenomenon intertwined with their phenotype. Microglia priming appears to be more evident in development, where early life exposure to immune insult has long-term consequences on a variety of adult outcomes. Thus, the priming or activation of microglia by alcohol during adolescent development may result in long term consequences. Therefore, the overarching hypothesis of this proposal is that young adolescents are more to susceptible to microglia priming by alcohol versus adults and that alcohol priming produces long term effects on alcohol-induced neuropathology and addiction-relevant behavior. We will test this hypothesis through three specific aims that (1) determine the adolescent?s susceptibility to alcohol-induced effects on microglia, (2) examine whether adolescents have a greater susceptibility to alcohol priming microglia and (3) elucidate the role of microglia priming in addiction-relevant behavior. By understanding the events that prime the adolescent brain to be susceptible to developing an alcohol use disorders, better interventions and treatments can be developed so that we can reduce the incidence of alcohol use disorders.

Public Health Relevance

Alcohol use and abuse often begins in adolescence despite the adolescent brain?s susceptibility to the damaging effects of alcohol. This grant explores a potential mechanism of that susceptibility: developmental vulnerability to the effect of alcohol on microglia, one of three types of non-neuronal, glial cells, and how that vulnerability contributes to the brain and behavioral pathologies associated with the development of alcohol use disorders.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Regunathan, Soundar
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University of Kentucky
Schools of Pharmacy
United States
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Maggio, Sarah E; Saunders, Meredith A; Nixon, Kimberly et al. (2018) An improved model of ethanol and nicotine co-use in female P rats: Effects of naltrexone, varenicline, and the selective nicotinic ?6?2* antagonist r-bPiDI. Drug Alcohol Depend 193:154-161
Maggio, Sarah E; Saunders, Meredith A; Baxter, Thomas A et al. (2018) Effects of the nicotinic agonist varenicline, nicotinic antagonist r-bPiDI, and DAT inhibitor (R)-modafinil on co-use of ethanol and nicotine in female P rats. Psychopharmacology (Berl) 235:1439-1453