June 03, 2025

Females may be more biochemically sensitive to alcohol-long before dependence sets in Scripps Research's insights into sex-based differences in brain chemistry could guide personalized treatment strategies for alcohol use disorder.

June 03, 2025

LA JOLLA, CA Alcohol affects everyone differently, but new research reveals that biological sex may play a bigger role than previously thought. In a preclinical study published in Biological Psychiatry on April 4, 2025, Scripps Research scientists uncovered distinct differences in how the brains of female rats respond to alcohol and found early evidence that the effectiveness of certain medications varies depending on drinking history and sex. This emerging research could help guide more personalized treatment strategies for alcohol use disorder (AUD), particularly for women who may be more biochemically sensitive to alcohol's effects and for individuals in earlier stages of harmful alcohol use.

The research team focused on the noradrenergic system: a brain network that triggers the body's fight-or-flight response and helps regulate stress, attention and emotional processing. This system controls the chemical norepinephrine (also commonly known as noradrenaline).

Their findings build on previous work from the lab of Marisa Roberto, a professor of neuroscience at Scripps Research, who led the new study as well.

We previously studied the noradrenergic system only in male rats and saw that it was dysregulated following chronic alcohol exposure, says Roberto, the senior author. This time, we wanted to study whether the same changes occur in females.

As anticipated, the researchers observed those alterations in the female brain, but the changes appeared much earlier than expected. Even in female rats with limited alcohol exposure, norepinephrine changed how strongly brain cells communicated modifying the strength of signals between them. In males, this effect only emerged after alcohol dependence had developed.

This suggests that the female noradrenergic system may be more sensitive at baseline, but additional research is needed to confirm and better understand this potential sex-based difference, highlights co-first author Alexia Anjos-Santos, a visiting PhD candidate at Scripps Research. Early sensitivity may help explain why women are more vulnerable to alcohol's long-term effects, such as anxiety and depression, as shown in clinical studies.

To investigate this further, the team zeroed in on the central amygdala: a brain region that processes stress and alcohol-related signals, and is strongly influenced by norepinephrine. The researchers found that FDA-approved drugs targeting two specific norepinephrine receptors 1 and could reduce alcohol consumption in different ways.

Both 1 and receptors help regulate the brain's responses to stress, emotional arousal and other physiological challenges. One of the tested drugs, prazosin, is an 1-blocker that's approved to treat high blood pressure and enlarged prostates, and it's often prescribed off-label to reduce PTSD-related nightmares. The second drug is a -blocker known as propranolol, which is approved for preventing migraines and treating high blood pressure, chest pain, heart attacks and essential tremors.

Prazosin lowered drinking in both non-dependent and dependent female rats, while propranolol only worked after dependence had set in.

These are critical takeaways, says Roberto. Our results, along with existing clinical literature, suggest that 1 receptor-specific medications like prazosin could help reduce alcohol cravings as well as stress-related symptoms like anxiety even in people with milder patterns of alcohol use.

Therefore, the team's findings could inform tailored treatment strategies for AUD.

-blocking therapies might be beneficial for more severe AUD, especially when the body's stress systems are highly activated, explains co-first author Chloe Erikson, a postdoctoral fellow at Scripps Research. And this may be the case for both sexes, but blocking 1 receptors seems more effective in females with either mild or heavy alcohol use.

To explore whether these findings could translate to humans, the researchers also analyzed postmortem brain tissue from women with and without AUD. The team found that while the central amygdala itself didn't show obvious changes, two connected brain areas the basolateral amygdala and the prefrontal cortex had lower levels of 1 receptor gene expression in women with AUD.

While alcohol targets many parts of the brain, the interplay between these regions may be especially important, says Roberto. She cautions, however, that the human sample size was small, and some confounding variables (like age, smoking status and AUD family history) may have influenced the results.

This study adds to a growing body of evidence suggesting that men and women may respond differently to alcohol as well as to medications designed to treat AUD.

Overall, our studies point to sex differences at the preclinical level in the noradrenergic system that may very well contribute to differences in treatment efficacy at the clinical level, notes Roberto.

Next, the research team plans to explore whether stress-related medications like prazosin and propranolol could mitigate other symptoms of AUD such as anxiety, depression and pain sensitivity.

This knowledge could also help explain why different treatments reduce drinking at various stages of AUD including before dependence develops, adds Roberto.

In addition to Anjos-Santos, Erikson and Roberto, authors of the study, Noradrenaline modulates central amygdala GABA transmission and alcohol drinking in female rats, are Francisco J Flores-Ramirez, Larry Rodriguez, Valentina Vozella, Vittoria Borgonetti, Bryan Cruz, Cristina Zalfa, Kiley Hughes, Pauravi Gan

LINK:	https://www.scripps.edu/news-and-events/press-room/2025/20250603-rober...
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