Bad buzz

Hormones may make men and women experience alcohol differently

New research in mice explains the alcohol gender imbalance.

Men and women have strikingly different patterns of alcohol use and suffer varying consequences of excessive drinking. Women drink less than men but are more likely to suffer bodily harm and illness related to alcohol.

In a new study in mice, researchers uncovered a key mechanism driving this puzzling gender imbalance: fluctuating estrogen.

The sex hormone estrogen can make drinking alcohol more rewarding to female mice over males, scientists report. Meanwhile, reducing certain estrogen receptors in the brain can diminish binge drinking behavior in female — and not male — mice.

The study, published Monday in the Journal of Neuroscience, builds on a growing body of research suggesting hormonal differences may explain why, for women, problematic drinking can spiral into severe drinking.

"Women more rapidly transition from problematic alcohol drinking to having an alcohol use disorder and to suffer from the negative health effects of alcohol, such as increased cancer risk, liver damage, heart disease, and brain damage," co-author Amy Lasek, a psychiatrist at the University of Illinois tells Inverse. Lasek has spent years researching the neurobiological basis for sex differences in drug abuse.

"If alcohol drinking is higher during times when estrogen levels are elevated, this can contribute to both the health risks of alcohol drinking and increase the likelihood of developing severe alcohol drinking problems."

While the new study was conducted in mice, the findings may lead to breakthrough, sex-based treatments for alcohol use disorder in humans, the researchers say.

Reward and reinforcement — Estrogen has "potent effects" on the dopamine system and increases the vulnerability of females to develop addiction to substances like alcohol, the researchers write. Dopamine, often called the "feel-good neurotransmitter," carries information between brain cells and helps regulate mood, motivation, and reward.

Estrogen influences the dopamine system and drinking in two ways: The hormone can make neurons sensitive to alcohol and release more dopamine. High estrogen levels are also associated with upped alcohol consumption and binge drinking.

Until now, researchers hadn't pinpointed exactly which estrogen receptors in the brain are pivotal to this process. To answer that question, Lasek and her team examined male and female mice and activated estrogen receptors mice's ventral tegmental area (VTA). This brain region is involved in drug reward and reinforcement. Then, they tracked how the activation influenced alcohol’s effects on the brain.

"These results indicate that different brain mechanisms cause binge drinking in females and males."

Activating the estrogen receptor ERα caused neurons to fire more often than normal in response to alcohol. Increased neuron firing releases more dopamine and could translate to a greater feeling of reward when drinking, making abuse more likely when estrogen levels rise.

The scientists then reduced the number of estrogen receptors in the VTA of both male and female mice, and saw how mice exhibited drinking-related behavior. Knocking out the estrogen receptors decreased binge drinking behavior in female mice but had no effect on male mice — even though there is estrogen in their brains too.

Taken together, the research suggests estrogen receptors, specifically ERα in the VTA brain region, can fuel binge drinking in female mice.

While male mice have estrogen receptors in this brain region, the receptors do not appear to be important for binge drinking, Lasek explains. Why this is isn't known, but Lasek says it is possible that the estrogen receptors in females may be more sensitive to activation when estrogen levels change.

"These results indicate that different brain mechanisms cause binge drinking in females and males," Lasek says. "This is important because it means that different approaches might be needed to reduce binge drinking in men and women."

An "alarming" rise in drinking — Binge drinking is the most common, costly, and deadly pattern of excessive alcohol use in the United States, according to the Centers for Disease Control.

Binge drinking is defined as a pattern of drinking that brings a person’s blood alcohol concentration (BAC) to 0.08 g/dl or above. This typically happens when men consume 5 or more drinks or women consume 4 or more drinks in about 2 hours.

Men are more than twice as likely than women to binge drink, but in the past decade, women are drinking more than ever. Over the past ten years, rates of alcohol use disorder have increased in women by 84 percent relative to a 35 percent increase in men.

Effective treatment options for alcohol use disorder are desperately needed, the study team explains. Their research suggests that taking a targeted, sex-based approach could be helpful.

Currently, there are drugs that block estrogen receptors called selective estrogen receptor modulators (SERMS) that are used for breast cancer treatment.

"However, SERMS have significant side effects like hot flashes, fatigue, and mood swings so, unfortunately, using a SERM to block estrogen receptors in otherwise healthy women to reduce alcohol drinking is not a good option," Lasek says.

What's left to be found are the specific signaling pathways by which estrogen receptors act in the brain, leading to increased binge drinking and the feeling of reward. The discovery of these pathways, Lasek explains, will likely lead to a more targeted method to reduce binge drinking in women without negative side effects.

Abstract: Elevations in estrogen (17E-estradiol, E2) are associated with increased alcohol drinking by women and experimentally in rodents. E2 alters the activity of the dopamine system, including the ventral tegmental area (VTA) and its projection targets, which plays an important role in binge drinking. A previous study demonstrated that during high E2 states, VTA neurons in female mice are more sensitive to ethanol excitation. However, the mechanisms responsible for the ability of E2 to enhance ethanol sensitivity of VTA neurons have not been investigated. In this study, we used selective agonists and antagonists to examine the role of estrogen receptor subtypes (ERα and ERβ) in regulating the ethanol sensitivity of VTA neurons in female mice and found that ERα promotes the enhanced ethanol response of VTA neurons. We also demonstrated that enhancement of ethanol excitation requires the activity of the metabotropic glutamate receptor, mGluR1, which is known to couple with ERα at the plasma membrane. To investigate the behavioral relevance of these findings, we administered lentivirus expressing short hairpin RNAs targeting either ERα or ERβ into the VTA and found that knockdown of each receptor in the VTA reduced binge-like ethanol drinking in female, but not male, mice. Reducing ERα in the VTA had a more dramatic effect on binge-like drinking than reducing ERβ, consistent with the ability of ERα to alter ethanol sensitivity of VTA neurons. These results provide important insight into sex-specific mechanisms that drive excessive alcohol drinking.
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