A malfunctioning enzyme may be a reason that binge drinking increases the odds of alcoholism, according to a study by scientists at the Stanford University School of Medicine.

The scientists identified a previously unsuspected job performed by the enzyme, ALDH1a1, in mice. The discovery could help guide the development of medications that extinguish the urge to consume alcohol, said Jun Ding, PhD, assistant professor of neurosurgery.

Ding is the senior author of the study, published Oct. 2 in Science. The study’s lead author is postdoctoral scholar Jae-Ick Kim, PhD.

Alcoholism is an immense national and international health problem. More than 200 million people globally, including 18 million Americans, suffer from it. Binge drinking substantially increases the likelihood of developing alcoholism. As many as one in four American adults report having engaged in binge drinking in the past month.

Existing medications for treating alcoholism have had mixed results. Disulfiram (Antabuse) and similar substances, for example, work by inducing unpleasant side effects — including shortness of breath, nausea, vomiting and throbbing headaches — if the person taking it consumes alcohol. “But these drugs don’t reduce the craving — you still feel a strong urge to drink,” Ding said.

In the new study, Ding and his associates showed that blocking ALDH1a1 activity caused mice’s consumption of and preference for alcohol to rise to levels equivalent to those observed in mice that had experienced several rounds of the equivalent of binge drinking. Restoring ALDH1a1 levels reversed this effect.

Previous studies have shown that mutations in the gene for ALDH1a1 are associated with alcoholism, but the reasons for this have been obscure. A key finding in the new study is that in certain nerve cells strongly implicated in addictive behaviors, ALDH1a1 is an essential piece of a previously unknown biochemical assembly line for the manufacture of an important neurotransmitter called GABA. Neurotransmitters are chemicals that bind to receptors on nerve cells, promoting or inhibiting signaling activity in those cells.

GABA is the brain’s main inhibitory neurotransmitter. It was previously thought that GABA was made in mammalian brains only via a different biochemical assembly line that doesn’t involve ALDH1a1.

An alternative assembly line

While GABA is produced widely throughout the brain, the novel GABA-production assembly line identified by Ding’s group was observed only in a group of nerve cells known to play a powerful role in addiction. The new finding has potentially great clinical significance because a drug that could increase GABA synthesis through this alternative assembly line — by boosting ALDH1a1 levels in the brain — could potentially restore the balance in neural circuitry that’s been thrown out of kilter by excessive alcohol consumption without dangerously elevating GABA levels elsewhere in the brain.