Alcohol Use Disorder Triggers Brain Inflammation

There is a continuous, vicious cycle between changes in the brain and changes in behavior in people with alcohol use disorder (AUD). AUD can disrupt the brain’s signaling pathways, which can make drinking worse. Recently, researchers at Scripps Research have learned new information regarding the immune system’s function in this cycle. On February 28, 2023, they published a study in the journal Brain, Behavior, and Immunity stating that mice with alcohol dependence have greater amounts of the immunological signaling molecule interleukin 1 (IL-1). However, in these animals, the IL-1 pathway plays a distinct role, leading to inflammation in crucial regions of the brain that are known to be involved in decision-making.

“These inflammatory changes to the brain could explain some of the risky decision-making and impulsivity we see in people with alcohol use disorder,” says senior author Marisa Roberto, Ph.D., the Schimmel Family Chair of Molecular Medicine and a professor of neuroscience at Scripps Research. “In addition, our findings are incredibly exciting because they suggest a potential way to treat alcohol use disorder with existing anti-inflammatory drugs targeting the IL-1β pathway.”

Uncontrolled and obsessive drinking is the hallmark of AUD, which also includes alcohol abuse, dependence, and binge drinking. Many connections between the immune system and AUD have already been found by researchers, many of which centre on IL-1. For example, AUD is more common among people with specific mutations in the gene that codes for the IL-1 protein. Moreover, increased levels of IL-1 have been discovered in the brains of AUD patients during autopsy.

“We suspected that IL-1β was playing a role in AUD, but the exact mechanisms in the brain have been unclear,” says first author Florence Varodayan, Ph.D., an assistant professor at Binghamton University and former postdoctoral fellow in the Roberto lab.

In the latest research, Roberto, Varodayan, and their associates compared mice who were alcohol-dependent to those that drank either modest amounts or none at all. They found that the medial prefrontal cortex (mPFC), a region of the brain involved in controlling emotions and behaviors, contained around twice as much IL-1 in the alcohol-dependent group.

The team went on to demonstrate that the IL-1 signaling in the alcohol-dependent group was not only altered fundamentally, but also enhanced. IL-1 triggered an anti-inflammatory signaling pathway in mice that had not been exposed to alcohol as well as in animals that had consumed moderate doses of alcohol. Gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter known to control neuronal activity in the brain, was consequently decreased due to this.

In contrast, IL-1 activated pro-inflammatory signalling and increased GABA levels in alcohol-dependent mice, presumably contributing to some of the alterations in brain activity linked to AUD. Importantly, the alcohol-dependent mice’s altered IL-1 signalling lasted during alcohol abstinence.

The U.S. Food and Drug Administration has already given the go-ahead for medications that inhibit the activity of IL-1 to treat rheumatoid arthritis and other inflammatory diseases. To find out whether these already-available medications could be helpful in treating AUD, more research is required.

“We plan to follow up on this study with more work on exactly how targeting specific components of the IL-1β pathway might be useful in treating alcohol use disorder,” says Roberto.

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