Anti-inflammatory molecule reduces excessive alcohol consumption in female mice
· News-MedicalThe drugs that keep rheumatoid arthritis in check may one day help people stop drinking. A new Scripps Research study shows that an anti-inflammatory molecule, already approved by the U.S. Food and Drug Administration to treat autoimmune diseases, reduces excessive alcohol consumption in alcohol-dependent female mice.
Marisa Roberto, senior author, professor of translational medicine and the Paul and Cleo Schimmel Endowed Chair at Scripps ResearchThis disorder is, in part, driven by damage to our neuroimmune system. Targeting this system might be an exciting clinical avenue to follow up with in the coming years."
The new research revolves around a molecule called interleukin-6, or IL-6, which the body produces in response to stress, infection and injury. Best known for its role in driving inflammation in diseases like rheumatoid arthritis, IL-6 is produced not just by immune cells throughout the body but also cells in the brain, where it can directly influence brain circuit functions.
Previous research had already suggested that people who drink heavily tend to have elevated levels of IL-6 in their blood, and that a genetic variant in the IL-6 gene is associated with increased risk of alcohol use disorder. Due to these associations, Roberto's team wondered whether blocking IL-6 could reduce drinking behavior.
"GABA is an important brake signal that the brain uses to dampen the activity of neurons," explains co-first author Chloe Erikson, a postdoctoral fellow in the Roberto lab. "When this braking system gets weakened, over-excitation can result. That loss of inhibitory control plays a large role in alcohol use disorder-associated behaviors like alcohol consumption, craving and withdrawal."
Next, the group gave alcohol-dependent mice an antibody targeting the IL-6 receptor-the same class of drug used for rheumatoid arthritis. The antibody works by binding to the IL-6 receptor, preventing IL-6 from acting on cells throughout the body, including the brain. After receiving the treatment, alcohol-dependent female mice drank significantly less alcohol. Dependent males (in addition to non-dependent animals of either sex) showed no significant change, suggesting the drug wasn't broadly suppressing drinking but acting on a specific, dysregulated molecular pathway that drove drinking behavior in the females.
"In the human literature, we know that women are more prone to autoimmune diseases, so while the positive results in our female mice were surprising, they aligned with the clinical data," says co-first author Celsey St. Onge, also a Scripps Research postdoctoral fellow.
In addition to the mouse studies, the team analyzed postmortem brain tissue from 30 humans diagnosed with alcohol use disorder and 30 people without it. They identified 377 differentially expressed genes between the two groups. Among the strongest signals was IL-6, which was significantly elevated in those with alcohol use disorder, along with several other inflammation-related genes.
"There has been a substantial shift in the field in the past few years to classify alcohol use disorder as a whole-body disease," says Roberto. "With this neuroimmune angle, we add to a growing literature that drinking too much can take a serious toll on your health. It's our hope that classifying it as such can continue to destigmatize this complex disorder."
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