New study shows how heavy drinking increases brain inflammation
The researchers found higher than normal levels of the immune signaling molecule interleukin 1β (green) in neurons (circled in red) in the brains of alcohol-dependent mice. Credit: Scripps Study.
A group of researchers at Scripps have uncovered results that suggest a new potential target for drug development to treat alcohol use disorders.
People with alcohol use disorder (AUD) experience an endless vicious cycle of brain and behavioral changes. AUD can disrupt communication pathways in the brain, leading to escalation of drinking behavior and further aggravation of the condition.
Scientists at Scripps Research have uncovered new insights into the role of the immune system in the alcohol disorder (AUD) cycle. In a study published in the journal Brain, Behavior, and Immunity, they found that levels of the immune signaling molecule interleukin 1β (IL-1β) are elevated in the brains of alcohol-dependent mice. In addition, the IL-1β pathway works differently in these mice, leading to inflammation in critical decision-making areas of the brain.
“These inflammatory changes in the brain may explain some of the risky decisions and impulsivity we see in people with alcohol use disorders,” says senior author Marisa Roberto, Ph.D., Schimmel Family Chair of Molecular Medicine and Professor of Neuroscience at Scripps Research. . “In addition, our results are incredibly interesting because they offer a potential treatment for alcohol use disorder with existing anti-inflammatory drugs that target the IL-1β pathway.”
AUD is characterized by uncontrolled and compulsive drinking and encompasses a range of conditions including alcohol abuse, addiction, and heavy drinking. Researchers have previously found numerous links between the immune system and AUD, many of which involve IL-1β. For example, people with certain mutations in the gene encoding the IL-1β molecule are more likely to develop AUD. In addition, higher levels of IL-1β in the brain have been found in autopsies of people with AUD.
“We suspected that IL-1β plays a role in AUD, but the exact mechanisms in the brain were unclear,” says first author Florence Varodayan, Ph.D., assistant professor at Binghamton University and former researcher at the Roberto Laboratory.
In the new study, Roberto, Varodayan and colleagues compared alcohol-addicted mice with animals that drink moderate amounts of alcohol or no alcohol at all. They found that the alcohol-dependent group had about twice as much IL-1β in the medial prefrontal cortex (mPFC), a part of the brain that plays a role in regulating emotions and behavior.
The team then showed that IL-1β signaling in the alcohol-dependent group was not only elevated, but fundamentally different. In mice that were not exposed to alcohol, as well as mice that drank moderate amounts of alcohol, IL-1β activated an anti-inflammatory signaling pathway. In turn, this lowered levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), a signaling molecule known to regulate nerve activity in the brain.
However, in alcohol-dependent mice, IL-1β instead activated pro-inflammatory signaling and increased GABA levels, which likely contributed to some of the AUD-related changes in brain activity. Notably, these changes in IL-1β signaling in alcohol-dependent mice persisted even during alcohol withdrawal.
Drugs that block IL-1β activity have already been approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis and other inflammatory conditions. More work is needed to determine whether these existing drugs may be useful in the treatment of AUD.
“We plan to continue this study by doing more work on exactly how targeting specific components of the IL-1β pathway might be beneficial for the treatment of alcohol use disorders,” says Roberto.
Reference: “Persistent ethanol intake induces a pro-inflammatory switch in the regulation of interleukin-1β GABAergic signaling in the medial prefrontal cortex of male mice” F.P. Varodayana, A.R. Panga, T.D. Davis, P. Gandhi, M. Baggio, M.K. Chiosses, Y. A. Blednov, M. D. Burkart, S. Edwards, A. J. Roberts, and M. Roberto, February 28, 2023, Brain, Behavior, and Immunity.
DOI: 10.1016/j.bbi.2023.02.020
The study was funded by the National Institutes of Health, the Schimmel Family Chair, the Pearson Center for Alcohol and Drug Addiction Research, and the Scripps Research Institute Animal Modeling Center.
