Based on high-throughput sequencing experiments conducted on animal models of alcohol exposure, scientists at the University of Illinois at Chicago (UIC) found that even small quantities of alcohol can induce immediate transcriptomic and epigenomic changes in the amygdala that alter accessibility to the genome.

The amygdala is the emotion center of the brain and plays a crucial role in the development of addiction. The study showed that the molecular changes in the amygdala underlie positive behavioral effects of alcohol such as feelings of deep relaxation (anxiolysis) and euphoria but also prime the genome to initiate and maintain alcohol use disorder (AUD).

Subhash Pandey, PhD, professor of psychiatry, director of the Center for Alcohol Research in Epigenetics at the College of Medicine at the University of Illinois, Chicago, is the senior author of the study. [Joshua Clark/University of Illinois Chicago]

The study led by Subhash Pandey, PhD, professor of psychiatry, director of the C

enter for Alcohol Research in Epigenetics in the UIC College of Medicine, was published in the journal Molecular Psychiatry “Unraveling the epigenomic and transcriptomic interplay during alcohol-induced anxiolysis“.

The investigators exposed Sprague-Dawley rats to low concentrations of alcohol and measured anxiety-like behavior as the rats explored an elevated plus-shaped maze where time spent in open, uncovered arms indicated low anxiety levels and time spent in enclosed arms denoted high levels of anxiety. Following euthanasia, the researchers analyzed brain tissue samples, using ATAC-seq (Assay for Transposase-Accessible Chromatin) and RNA-seq to identify epigenomic and transcriptomic changes that underlie changes in anxiety brought about by alcohol exposure in rats.

ATAC-seq showed alcohol increased global accessibility to the genome in the amygdala by inducing an “open” or “permissive” state in the normally tightly wound chromatin—represented by peaks in the sequencing output—that resulted in changes in gene transcription.

“We identified a candidate gene, Hif3a (Hypoxia-inducible factor 3, alpha subunit), that had ‘open’ chromatin regions associated with significantly increased active epigenetic histone acetylation marks and decreased DNA methylation at these regions,” the authors noted.

Through further investigations into the consequences of genetic and epigenetic modifications in the Hif3a gene, the authors revealed that mRNA levels of the gene in the amygdala increased following acute alcohol exposure but decreased during withdrawal after chronic alcohol exposure. Alcohol increased Hif3a expression, even after low doses of exposure, and reduced anxiety. Whereas many effects of alcohol are different among males and females, there was no difference in Hif3a expression levels between the two sexes 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,” said Pandey.

To parse out the behavioral consequences, the researchers knocked down Hif3a expression in the central nucleus of the amygdala in rats with or without alcohol exposure to validate its role in mediating anxiety. Acute alcohol in these rats did not show an increase in Hif3a mRNA levels and did not reduce anxiety levels in the animals as estimated by assays on the elevated plus maze. In control rats, when Hif3a was blocked, anxiety increased, mimicking withdrawal from chronic alcohol exposure. On the other hand, this also prevented the anti-anxiety effects of alcohol.

The researchers said that pathways involved in priming the brain for addiction and those associated with the highs of drinking, overlap. “This suggests that when the brain experiences the anti-anxiety effects of alcohol and the mood lift—the relaxation and the buzz—it is also being primed for alcohol use disorder,” said Pandey.

Although the data does not indicate that a single drink can result in addiction, Pandey clarified, it does provide an understanding of the increased vulnerability of some individuals to alcohol addiction over others. Pandey added that it’s important to know that low doses of ethanol created a priming for addiction. Therefore, social drinking or “pandemic drinking”  should not be assumed to be without risk.

“We’re seeing that dependent behaviors may not always be from long-term, high-quantity habits but a result of rapid epigenetic changes in the brain, which we show in this study may start happening even at low doses,” said Pandey. He believes insights gained in the current study could help understand the brain under the influence of alcohol addiction, which can then be leveraged to develop effective treatments for AUD.

The research was funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the U.S. Department of Veterans Affairs.

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