Identifying Molecular Mechanisms in Alcohol Use Disorders: TLR4 Methylation and Cytokine Expression

Karoly, Hollis C.

Graduate Thesis Or Dissertation

Identifying Molecular Mechanisms in Alcohol Use Disorders: TLR4 Methylation and Cytokine Expression Public Deposited

Analytics

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Citeable URL: https://scholar.colorado.edu/concern/graduate_thesis_or_dissertations/zp38wc72r

Abstract

Alcohol use disorders (AUDs) are associated with significant morbidity, mortality and socioeconomic costs in the United States. Despite decades of research, the best treatments are only modestly successful, in part due to the neurobiological complexity of AUDs. Although the molecular mechanism(s) driving the effects of alcohol on the brain and body are not fully understood, human and animal studies have converged to underscore the role of neuroinflammation. Alcohol increases inflammation via binding to Toll-like Receptor 4 (TLR4) receptors on immune cells. Chronic alcohol-induced, TLR4-mediated inflammatory signaling may lead to cellular damage. One hypothesized consequence of alcohol-induced immune signaling disruptions is neuronal cell death in frontal control regions of the brain, consistent with inhibitory deficits observed in AUD. This study explores inflammation as a molecular mechanism underlying cognitive deficits in AUD.We collected N=82 subjects (mean age=29.91(4.5), range 25-40), including n=43 heavy drinkers and n=39 light drinkers. In addition to administering a battery of questionnaires measuring psychological variables, substance use and other health behaviors, we measured circulating and LPS-stimulated pro-inflammatory cytokines (IL-6, IL-8, IL-1β) and the damage-associated molecular pattern (DAMP) molecule HMGB1, TLR4 promoter methylation, and cognitive performance. We hypothesized that alcohol consumption would be associated with increased circulating and stimulated cytokines and HMGB1, greater TLR4 methylation and lower cognitive performance. We further hypothesized that inflammatory cytokines would mediate the relationship between alcohol consumption and cognition.Contrary to these hypotheses, no group differences emerged for inflammation or cognitive performance. When alcohol was examined as a continuous predictor, a significant relationship emerged between alcohol consumption and circulating and stimulated IL-6 and between cannabis use and circulating IL-1β. Follow-up analyses indicated that cannabis use moderates the relationship between alcohol and circulating IL-6, such that individuals who did not use cannabis in the 90 days prior to the study showed a strong correlation between alcohol and IL-6, whereas those who did use cannabis did not demonstrate any association. Future work should explore the interaction between alcohol and cannabis on peripheral inflammation, ideally with the inclusion of structural or functional brain imaging to examine how potential changes in peripheral inflammation impact neural control circuitry.

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