How heavy alcohol consumption increases brain inflammation

The findings by a Scripps Research team point toward a potential new drug target for treating alcohol use disorder (AUD).
AUD is characterised by uncontrolled and compulsive drinking, and it encompasses a range of conditions including alcohol abuse, dependence and binge drinking. Researchers have previously discovered numerous links between the immune system and AUD, many of them centred around IL-1β. People with certain mutations in the gene that codes for the IL-1β molecule, for instance, are more prone to developing AUD. In addition, autopsies of people who had AUD have found higher levels of IL-1β in the brain.
Scientists at Scripps Research have uncovered new details about the immune system’s role in this cycle. They reported in the journal Brain, Behavior and Immunity on Feb. 28, 2023, that the immune signalling molecule interleukin 1β (IL-1β) is present at higher levels in the brains of mice with alcohol dependence and the IL-1β pathway takes on a different role in these animals, causing inflammation in critical areas of the brain known to be involved in decision-making.
The researchers compared alcohol-dependent mice with animals drinking moderate or no alcohol at all and 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 behaviours.
IL-1β signalling in the alcohol-dependent group was not only increased, but also fundamentally different. In mice that had not been exposed to alcohol, as well as in mice that had drunk moderate amounts of alcohol, IL-1β activated an anti-inflammatory signalling pathway. In turn, this lowered levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), a signalling molecule known to regulate neural activity in the brain. However, in alcohol-dependent mice, IL-1β instead activated pro-inflammatory signalling and boosted levels of GABA, likely contributing to some of the changes in brain activity associated with AUD. Notably, these changes in IL-1β signalling in the alcohol-dependent mice persisted even during alcohol withdrawal.
Drugs that block the activity of IL-1β are already approved by the US Food and Drug Administration to treat rheumatoid arthritis and other inflammatory conditions. More work is needed to determine whether these existing drugs could have utility in treating AUD.
Source: F.P. Varodayan, A.R. Pahng, T.D. Davis, P. Gandhi, M. Bajo, M.Q. Steinman, W.B. Kiosses, Y.A. Blednov, M.D. Burkart, S. Edwards, A.J. Roberts, M. Roberto, Chronic ethanol induces a pro-inflammatory switch in interleukin-1β regulation of GABAergic signalling in the medial prefrontal cortex of male mice, Brain, Behavior, and Immunity, Volume 110, 2023, Pages 125-139, ISSN 0889-1591