Interleukin 1, an immune signaling molecule, was discovered in neurons from alcohol-dependent rats at higher levels than usual. Scripps Research
People with alcohol use disorder (AUD) go through a permanent vicious cycle of changes in their brain and behavior. AUD can alter communication pathways in the brain, leading to an increase of drinking behavior and further aggravation of the condition.
Scientists at Scripps Research have discovered new insights on the role of the immune system in the addiction cycle. Moreover, the IL-1 pathway operates differently in these mice, causing inflammation in critical brain areas that are involved in decision making.
Marisa Roberto, Ph.D., the Schimmel Family Chair of Molecular Medicine and a professor of neuroscience at Scripps Research, believes that these neuroinflammatory changes could be to blame for some of the dangerous decisions and impulsivity seen in people with alcohol dependence. "In addition, our findings are extremely exciting because they highlight a potential way to treat alcohol dependence with existing anti-inflammatory medications targeting the IL-1 pathway."
AUD is characterized by uncontrolled and compulsive drinking. It also includes a wide range of ailments, including alcohol dependency, and binge drinking. Many studies have previously discovered numerous connections between the immune system and AUD—many of them centered around IL-1.
"We suspected that IL-1 was involved in AUD, but the exact mechanisms in the brain have been unclear," says the first author Florence Varodayan, an assistant professor at Binghamton University and a former postdoctoral fellow in the Roberto lab.
Roberto, Varodayan, and their colleagues studied the effects of alcohol on mice and animals that consumed little or no alcohol at all. They found that the alcohol-dependent group had roughly twice as much IL-1 in the medial prefrontal cortex (mPFC), a part of the brain that regulates emotions and behaviors.
The team then showed that IL-1 signaling in the alcohol-dependent group was not only enhanced, but also fundamentally different. IL-1 activated an anti-inflammatory signaling pathway in mice that had not been exposed to alcohol, as well as in mice who had drunk moderate amounts of alcohol, and this reduced levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) molecule known to regulate neural activity in the brain.
IL-1 instead activated pro-inflammatory signaling and increased GABA levels in alcohol-dependent mice, likely contributing to some of the changes in brain activity associated with AUD. Notably, these changes in IL-1 signaling in alcohol-dependent mice lasted long after withdrawal.
The Food and Drug Administration of the United States has already approved drugs that block the activity of IL-1 for the treatment of rheumatoid arthritis and other inflammation. More research is needed to establish whether these existing medicines are beneficial for the treatment of AUD.
Roberto stated that "we intend to continue investigating this project by looking into further how specific components of the IL-1 pathway might be beneficial in treating alcohol use disorder."
F.P. Varodayan, A.R. Pahng, P. Gandhi, M. Bajo, M.Q. Steinman, Y.A. Blednov, M.D. Burkart, S. Edwards, A.J. Roberts, and M. Roberto, 28 February 2023, Brain, Behavior, and Immunity. DOI: 10.1016/j.bbi.2023.02.020
The National Institutes of Health, The Schimmel Family Chair, The Pearson Center for Alcoholism and Addiction Research, and The Scripps Research Institute's Animal Models Core Facility provided funding for the study.
