Even low doses of alcohol cause changes in brain circuitry

How many drinks are too many?

According to a recent rodent study, even minute amounts of alcohol can cause epigenomic and transcriptomic changes in brain circuits in a region essential for the development of addiction.

The pathways involved in preparing the brain for addiction are also linked to the highs that accompany drinking, such as euphoria and anxiolysis, a state of relaxed but alert sedation, according to researchers at the University of Illinois at Chicago.

Subhash Pandey, Director of the UIC Center for Research in Alcohol Epigenetics. Credit: Joshua Clark/University of Illinois, Chicago

“This suggests that when the brain experiences alcohol’s anti-anxiety and mood-elevating effects — the relaxation and high — it is also preparing it for an alcohol use disorder,” said study senior author Subhash Pandey, Joseph A. Flaherty Endowed Professor of Psychiatry and Director of the Center for Alcohol Research in Epigenetics at the UIC College of Medicine.

Pandey notes that while the research doesn’t imply that a drink causes addiction in individuals, it does provide some insight into why certain people are more prone to alcohol use disorders.

“We see that addictive behaviors don’t always stem from long-term, quantitative habits, but are a result of rapid epigenetic changes in the brain that we show in this study, which can occur even at low doses,” Pandey said. who is also a Senior Research Career Scientist at the Jesse Brown Veterans Affairs Medical Center.

An article published in the magazine Molecular Psychiatry describes Pandey’s experiments studying rats under control and alcohol exposure conditions.

In the experiments, rodents were exposed to low concentrations of alcohol and the researchers watched them navigate a maze. Then the researchers started

” data-gt-translate-attributes=”[{” attribute=””>RNA sequencing to examine brain tissue samples they had obtained after euthanasia and searched for patterns in gene expression.

When the samples were analyzed, the researchers discovered that a gene known as hypoxia inducible factor 3 alpha subunit, or Hif3a for short, was connected to behaviors such as how long rats remained in parts of the maze with enclosed (high anxiety) or open arms (low anxiety).

Alcohol increased Hif3a expression, even after low doses of exposure, and reduced anxiety. And, while many effects of alcohol are different among males and females, there was no difference between the two in this study.

“We saw that low doses, what we consider ‘social drinking,’ changes the gene expression in the amygdala, a brain region that regulates anxiety. In other words, it creates an epigenetic pathway for addiction,” Pandey said.

Pandey and his colleagues also set up additional experiments in which they blocked the gene in the amygdala of rats with or without alcohol exposure to validate its role in mediating anxiety. When Hif3a was blocked, anxiety was increased in control rats, mimicking withdrawal from chronic alcohol exposure. On the other hand, this also prevented the anti-anxiety effects of alcohol.

The researchers showed why, too. Hif3a’s chromatin — bundles of

One thing the study does not suggest, however, is what level of alcohol exposure was safe for rodents. Instead, Pandey said, it’s important to know that low doses created priming for addiction. For people, he thinks the takeaway is simple — don’t assume social drinking or even “pandemic drinking” is without risk.

“Alcohol use disorder is complex and challenging to overcome. The information we learned from this study helps us to understand better what is happening in the brain and, one day, may be leveraged to develop better treatments and pharmaceuticals,” Pandey said.

Reference: “Unraveling the epigenomic and transcriptomic interplay during alcohol-induced anxiolysis” by Harish R. Krishnan, Huaibo Zhang, Ying Chen, John Peyton Bohnsack, Annie W. Shieh, Handojo Kusumo, Jenny Drnevich, Chunyu Liu, Dennis R. Grayson, Mark Maienschein-Cline and Subhash C. Pandey, 12 September 2022, Molecular Psychiatry.
DOI: 10.1038/s41380-022-01732-2

The study was funded by the National Institute on Alcohol Abuse and Alcoholism and the U.S. Department of Veterans Affairs.