Estrogen Drives Binge Drinking in Females

A recent preclinical study led by scientists at Weill Cornell Medicine has uncovered a significant link between the hormone estrogen and binge drinking behavior in females. This study, published in Nature Communications on December 30, provides compelling evidence that estrogen plays a crucial role in regulating binge drinking, particularly the tendency of females to consume large amounts of alcohol within the first 30 minutes of drinking—a behavior often referred to as “pregaming.” This groundbreaking research sheds light on the neurobiological mechanisms driving alcohol consumption in females and opens up new avenues for understanding sex differences in alcohol use and its associated health risks.

The study establishes a key finding: estrogen increases alcohol consumption in females and contributes to the known sex differences in binge drinking behavior. According to Dr. Kristen Pleil, an associate professor of pharmacology at Weill Cornell Medicine and the senior author of the study, there has been a long-standing gap in understanding how alcohol consumption differs between males and females. Most research on alcohol use has traditionally focused on males, but this study highlights that females are more vulnerable to the harmful effects of alcohol and are prone to binge drinking, often in ways that differ from male patterns.

During the pandemic lockdown, women, in particular, were found to increase their alcohol consumption at higher rates than men, which had significant health consequences. Studies have shown that women experienced more alcohol-related hospital visits and complications than men during and after the pandemic. This pattern of drinking is concerning because it not only increases the risk of alcohol use disorder but also exacerbates the negative health effects associated with alcohol, such as liver disease, cardiovascular problems, and mental health issues.

The current study builds upon previous research conducted by Dr. Pleil and her team in 2021, which identified a subpopulation of neurons in the bed nucleus of the stria terminalis (BNST)—a brain region involved in emotional regulation—that showed heightened activity in female mice compared to their male counterparts. This increased neuronal excitability in the BNST was found to correlate with binge drinking behavior in females. The next logical question for the researchers was what causes these neurons to become more excitable in females. The answer, according to Dr. Pleil, lies in estrogen, a hormone with well-documented effects on various behaviors, particularly in females.

To investigate estrogen’s role, the researchers monitored the hormone levels in female mice throughout their estrous cycle, which is analogous to the menstrual cycle in humans. They then offered the mice alcohol and observed their drinking patterns. The results were striking: when estrogen levels were high, the female mice consumed significantly more alcohol compared to when estrogen levels were low. This increase in alcohol consumption was mirrored by enhanced activity in the same neurons in the BNST that had been implicated in binge drinking behavior.

Dr. Pleil and her team were particularly interested in the precise mechanism by which estrogen influences binge drinking. Estrogen is traditionally known to exert its effects by binding to estrogen receptors inside cells, which then travel to the nucleus and alter gene activity—a process that typically takes hours. However, the researchers observed that when estrogen was introduced directly into the BNST, it triggered binge drinking behavior within minutes, a much faster response than what is typically expected for a steroid hormone. This raised the question: how could estrogen be acting so rapidly?

The researchers soon discovered a surprising mechanism. Estrogen was binding to receptors located on the surface of the neurons, rather than inside the cells as previously thought. These surface receptors allowed estrogen to directly modulate the communication between neurons, triggering the enhanced neuronal activity that drove binge drinking behavior. This finding represents a major breakthrough, as it is the first time that estrogen has been shown to act so quickly to influence behavior during the normal estrous cycle.

The team also identified the specific estrogen receptor that mediates this rapid effect, finding it expressed not only in the excitatory BNST neurons but also in neurons from other brain regions that interact with the BNST. This receptor appears to play a critical role in regulating alcohol consumption, particularly during the initial “front-loading” phase, when females consume large quantities of alcohol shortly after it is made available.

The implications of these findings are significant, both for understanding alcohol consumption patterns in females and for developing potential treatments for alcohol use disorder. According to Dr. Pleil, the discovery opens up the possibility of using drugs that target estrogen signaling to reduce alcohol consumption during times when estrogen levels are high, such as during certain phases of the menstrual cycle. One potential treatment could involve inhibiting the enzyme responsible for synthesizing estrogens, which is already used in clinical settings to treat estrogen-sensitive cancers in women. When combined with other treatments that target the downstream effects of the BNST neurons, such a strategy could offer a novel approach for selectively reducing binge drinking in females.

In addition to its potential therapeutic applications, the study also raises important questions about how alcohol consumption is regulated differently in males and females. Although the researchers have identified a key role for estrogen in females, they also note that the basic neural circuitry and estrogen receptors are present in males. In males, the primary source of estrogen is not the ovaries but the conversion of testosterone into estrogen within the brain. The researchers are now investigating whether the same mechanisms that regulate drinking behavior in females also play a role in males, which could lead to a more comprehensive understanding of alcohol use across sexes.

Reference: Lia J. Zallar et al, Rapid nongenomic estrogen signaling controls alcohol drinking behavior in mice, Nature Communications (2024). DOI: 10.1038/s41467-024-54737-6