Preclinical study reveals role of estrogen in binge drinking in women

Preclinical study reveals role of estrogen in binge drinking in women

The hormone estrogen regulates binge drinking in women, causing them to consume large amounts of alcohol in the first 30 minutes after drinking, according to a preclinical study led by scientists at Weill Cornell Medicine. The study shows, presumably for the first time, that circulating estrogen increases binge alcohol consumption in women and contributes to known gender differences in this behavior.

The results were published in the journal on December 30Nature communicationcould lead to new approaches to treating alcohol use disorders.

We know much less about what influences alcohol drinking behavior in women because most studies on alcohol consumption have been conducted in men.”

Dr. Kristen Pleil, senior author, associate professor of pharmacology

But women also consume too much and are more susceptible to the negative health effects of alcohol than men.

Recent studies suggest that women increased their heavy drinking more than men during the pandemic lockdown. This behavior has important consequences for women's health, said Dr. Pleil, “because many studies show that this drinking pattern increases the harmful effects of alcohol.” In fact, women had many more alcohol-related hospital visits and complications than men during and after the pandemic.

Peak estrogen levels are associated with increased alcohol consumption

In a 2021 study, Drs. Pleil and her team found that a specific subpopulation of neurons in a brain region called the bed nucleus of the stria terminalis (BNST) was more excitable in female mice than in males. This increased activity correlated with their binge drinking behavior.

But what makes this neural circuit more excitable in women? "Estrogen has such strong effects on so many behaviors, particularly in women," said Dr. Pleil. “So it makes sense that it also modulates drinking.”

To assess the possible involvement of estrogen, researchers, including lead author Dr. Lia Zallar, who was a graduate student in the Pleil lab at the time of the research, was tasked with monitoring hormone levels during the estrous cycle of female mice. Then they served the alcohol. They found that when a woman has high estrogen levels in her blood, she drinks much more than on days when her estrogen is low.

This increased bingeing behavior was reflected in increased activity of the same neurons in the BNST. "When a woman takes her first sip from the bottle of alcohol, these neurons go crazy," said Dr. Pleil. “And when she has high estrogen levels, they get even crazier.” This additional increase in neural activity causes the mice to attack the bottle even more, especially within the first 30 minutes of providing the alcohol, a behavior that Dr. Pleil referred to as “front loading”.

Surprising discovery: Cell surface receptors enable estrogen to act quickly

Although researchers suspected that estrogen would have an impact on drinking, they were surprised by its mechanism of action. This steroid hormone typically regulates behavior by binding to receptors, which then travel to the cell nucleus, where they alter the activity of certain genes - a process that can take hours. Dr. However, Pleil and her team realized that something other than estrogen, infused directly into the BNST, excited the neurons and triggered binge drinking within minutes.

So the researchers tested estrogen that had been engineered so that it couldn't enter cells and bind to nuclear receptors - a feat of chemical engineering pioneered by Dr. Jacob Geri, assistant professor of pharmacology at Weill Cornell Medicine. They found that when estrogen promotes binge eating, the hormone binds to receptors on the surface of neurons and directly modulates cell-cell communication there.

“We believe this is the first time that anyone has shown that endogenous estrogen produced by the ovaries can use such a rapid behavioral control mechanism during a normal estrous cycle,” said Dr. Pleil. This rapid action causes alcohol to rise to the top when estrogen levels are high.

The team identified the estrogen receptor that mediates this effect and found that it is expressed in the excited BNST neurons and in neurons from other brain regions that excite them. The researchers are now studying the signaling mechanisms for this effect and are also investigating whether the same system regulates alcohol consumption in men.

“All the infrastructure is there in men too: the estrogen receptors and the basic circuit organization,” said Dr. Pleil. The only difference is the source of estrogen, which in men without an ovarian source is based on the local conversion of testosterone to estrogen in the brain.

Inhibiting the enzyme that synthesizes estrogens could represent a novel treatment for selectively reducing alcohol consumption when hormone levels rise. An FDA-approved version of such an inhibitor is currently used to treat women with estrogen-sensitive cancers.

"Combining this drug with compounds that modulate the downstream effects of chemicals produced by BNST neurons could potentially provide a new, targeted approach to treating alcohol use disorders," said Dr. Pleil.

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