Alcohol remains one of the most consumed products in the world, but also one of the deadliest. Alcohol consumption represents a major public health issue in France, where it is the cause of 49,000 deaths per year. Faced with this scourge, the medications available are few in number and provide only limited help, which leaves many patients in failure.
A team from Boston University Chobanian and Avedisian School of Medicine has just shed light on a new avenue: drugs that stimulate alpha-2 receptors
of the brain, already used for other indications, reduce excessive alcohol consumption in mice and improve certain cognitive performances. These results open up interesting perspectives for the management of alcohol dependence.
Alpha-2 receptors and alcohol: a new possible barrier to dependence
Alcohol use disorder is more than just a strong urge to drink. Over time, it is accompanied by cognitive deficits: poor memory, fragile attention, difficulty adapting to unexpected events… These functions depend on the prefrontal cortex, an area which helps to plan, resist impulses and take a step back, and which is damaged by chronic consumption.
Adrenergic receptors alpha-2 act a bit like a brake button on the noradrenaline system, involved in stress and impulsivity. Two drugs targeting these receptors were tested: clonidine, an old molecule used in cardiology, and guanfacine, already prescribed for attention deficit disorder with or without hyperactivity (ADHD). The idea: to see if reinforcing this chemical braking helps to regain control over alcohol.
Less consumption and better memory with guanfacine in mice
The researchers first exposed mice to a 20% ethanol solution, offered intermittently for several weeks, to mimic “binge drinking” type consumption. They then administered clonidine or guanfacine and measured the amount of alcohol drunk, side effects and the impact on other rewards like sugar. Both molecules reduced consumption well, but clonidine caused strong sedation and dangerous drops in body temperature.
There guanfacineit reduced the alcohol ingested without these risks, and without reducing either sucrose intake or overall fluid intake, suggesting a targeted effect on alcohol, without altering the feeling of pleasure. During acute withdrawal, guanfacine also improved performance on a memory task dependent on prefrontal cortex functions and frequently impaired by chronic alcohol consumption, with no effect on spatial memory, suggesting a targeted improvement in executive functions.
“By demonstrating that selective stimulation of alpha-2 receptors reduces excessive alcohol consumption and improves certain cognitive aspects in models exposed to alcohol, our study highlights a promising and potentially safe avenue to help people reduce their harmful alcohol consumption. We hope that this work will accelerate the development of treatments to regain control of consumption and improve the daily functioning of people suffering from alcohol-related disorders.“, explained Pietro Cottone, professor of pharmacology, physiology and biophysics and of psychiatry at Boston University.
From mouse to patient: a still experimental avenue
The team also observed that two large norepinephrine-producing brain centers remained continuously activated after prolonged exposure to alcohol, as if the stress system remained stuck in alert mode. Selectively stimulate the
alpha-2 receptors could help rebalance this circuit, reducing the pressure to drink while supporting the functioning of the prefrontal cortex. However, all of this remains based on animal models.
From a clinical perspective, guanfacine has a major advantage: it is already authorized for other uses. “As guanfacine is already approved for other uses, this work could accelerate clinical trials compared to developing an entirely new drug,” added Valentina Sabino, professor of pharmacology, physiology and biophysics and psychiatry at the university and co-senior author of the study.
Although these results are promising, human clinical trials are needed to verify whether these effects are confirmed in humans. For the moment, this treatment should not be used for self-medication but only within the framework of trials and specialized medical monitoring.
In the meantime, this discovery reminds us that when it comes to addiction, better understanding the brain remains one of the strongest keys to hoping to regain control.