Gene ID Could Aid Alcoholism Fight

Thanks to research with worms, scientists say they've found the gene responsible for the intoxicating effects of alcohol.

"We have identified the mechanism that explains the intoxicating effect of alcohol," says lead researcher Dr. Steven McIntire, who adds the discovery could one day lead to a treatment for alcoholism.

The research by McIntire, an assistant professor of neurology at the University of California, San Francisco, and his colleagues appears in the Dec. 12 issue of Cell.

In experiments with small round worms called Caenorhabditis elegans, McIntire's team identified an ion channel -- specifically the BK potassium channel, which is controlled by a single gene -- as the mechanism through which alcohol acts on the brain.

When the channel was exposed to alcohol, the worms wiggled and moved in a way that indicated they were intoxicated. However, in worms that did not have the gene, exposure to alcohol had no effect, the researchers found.

This mechanism is thought to be similar throughout the animal kingdom, because all species -- from worms to mice to humans -- become intoxicated at similar alcohol concentrations, McIntire notes.

While previous studies have identified a number of genes that can influence how alcohol affects behavior, this is the first finding that a single gene and the protein it controls are responsible for intoxication, he adds.

To confirm their finding, the researchers reasoned that since activation of the BK channel with alcohol is the major cause of intoxication, artificially activating the channel without alcohol should also result in intoxication.

They used worms where the BK channels opened more often than usual without alcohol exposure, just as normal channels do when exposed to alcohol. Worms with abnormal BK channels acted just as intoxicated, without exposure to alcohol, as normal worms did when exposed to alcohol, the researchers say.

McIntire suspects the mechanisms that function in the worms he studied would be the same in humans.

In mammals, BK channels are active in nerve, muscle and gland tissue. They control neurotransmitter release, muscle contraction and hormonal secretion, and the channel may be involved in hormonal or non-behavioral effects of alcohol as well, the researchers say.

McIntire notes that in human cell cultures, this gene responds to alcohol in the same way as it does in the C. elegans worms his team studied.

"Once we start to understand the molecular mechanisms of action on the brain, then we have a basis for the development of therapeutics to alter the effects of alcohol and treat alcoholism," he says.

In the next phase of its research, the team hopes to identify the site on the BK channel where alcohol exerts its effects, McIntire says.

After that, McIntire's group will start drug studies in mammals in an attempt to alter the actions of alcohol. McIntire believes that by altering sensitivity to alcohol, there is a probability that mechanisms that cause dependence on alcohol can be changed.

Basically, McIntire says, if you take away the intoxication, you take away the desire and hence the dependence.

Steven Treistman, a professor of neurobiology and director of the neuroscience program at the University of Massachusetts, agrees -- and disagrees.

Treistman admits to a certain bias because he and his colleagues have been working on the effects of alcohol on the BK channel in mammals for many years. "Obviously this channel is a very important component of how alcohol works in the brain," he says.

However, the process in humans is more complex. "A worm isn't a human," he says. Treistman believes the BK channel probably controls a very small part of the behavioral pattern that we call intoxication in a person.

"Other genes have been identified that are very important in turning on and turning on drug-related behavior," he notes. While Treistman agrees the BK channel has to be a target in controlling the effects of alcohol, he says it's not the only target.

Other ion-controlling genes, such as those that control the calcium channels, may also be sensitive to alcohol, he says. "Knocking out any one of these genes may be sufficient to block the response to alcohol," Treistman adds.

By Steven Reinberg