Fluorescent staining of persistently activated noradrenergic neurons in the locus coeruleus nucleus of the brain.

Research

Study Finds Alpha-2 Receptor Drugs Reduce Heavy Alcohol Drinking

Findings point to alpha-2 adrenergic receptors as a key modulator of heavy drinking and alcohol-related cognitive problems, highlighting dysregulated noradrenergic circuitry as a critical contributor to alcohol addiction.

Alcohol use is widespread and alcohol use disorder (AUD) causes substantial harm. AUD affects 29 million individuals and causes more than 140,000 deaths annually in the U.S. alone. Individuals with AUD also often struggle with cognitive deficits, particularly in memory, attention, and cognitive flexibility, which can further undermine recovery. Current drug options are limited, and only modestly effective, so more efficacious and better-tolerated options are urgently needed.

Researchers at Boston University Chobanian & Avedisian School of Medicine report for the first time that guanfacine, a selective alpha-2 adrenergic drug already used clinically for ADHD, reduces heavy alcohol consumption and improve certain alcohol-related cognitive deficits in an experimental model, without the sedation and dangerous drops in body temperature seen with older alpha-2 drugs such as clonidine.

The hope is that this work will accelerate development of treatments that restore control over drinking and improve everyday functioning for people with alcohol use disorder.

Pietro Cottone, PhD

“By showing that selective stimulation of alpha-2 receptors reduces heavy drinking and improves aspects of cognition in alcohol-exposed models, our study points to a promising and potentially safe way to help people cut down on harmful drinking. The hope is that this work will accelerate development of treatments that restore control over drinking and improve everyday functioning for people with alcohol use disorder,” says co-corresponding author Pietro Cottone, PhD, associate professor of pharmacology, physiology & biophysics and psychiatry at the school.

The models were given intermittent access to 20% ethanol over several weeks to produce heavy drinking. Researchers then examined how two drugs that stimulate alpha-2 adrenergic receptors -clonidine and the more selective drug guanfacine- affected alcohol intake, side effect risk, reward specificity, and alcohol-related cognitive function.

Because guanfacine is already approved for other uses, this work could accelerate clinical testing compared with developing a brand-new drug.

Valentina Sabino, PhD

Clonidine reduced drinking but also worsened alcohol’s side effects, increasing sedation and lowering body temperature, while guanfacine reduced alcohol intake without these risks. Further, unlike clonidine, guanfacine did not suppress sucrose consumption or overall fluid intake, indicating that it selectively reduced alcohol drinking without dampening normal reward. During acute withdrawal, guanfacine also improved performance on a memory task that depends on prefrontal cortex function and is commonly impaired by chronic alcohol exposure, with no effect on spatial memory, pointing to a targeted improvement in executive cognitive function. The researchers also found that prolonged heavy drinking left two major norepinephrine-producing brain centers chronically activated, linking long-term changes in this system to compulsive drinking and impaired cognition. The study suggests that alcohol addiction dysregulates norepinephrine systems and that selectively stimulating alpha‑2 adrenergic receptors may restore balance -reducing the drive to drink while improving prefrontal cognitive functions.

According to the researchers, guanfacine or similar drugs could potentially be repurposed to help people with AUD reduce heavy drinking and improve cognitive deficits. “Because guanfacine is already approved for other uses, this work could accelerate clinical testing compared with developing a brand-new drug,” adds co-corresponding author Valentina Sabino, PhD, professor of pharmacology, physiology & biophysics and psychiatry at the school.

While these results are promising, human trials are needed to see if the effects translate to people.

These findings appear online in the journal eNeuro.