BioEd Online

A gene that helps flies deal with stress also makes them tolerant to repeated alcohol intake, scientists have found. The researchers say that humans probably have a similar gene, which could help to explain some cases of alcoholism and possibly even lead to a treatment.

High alcohol tolerance, the ability to resist the effects of alcohol after continued drinking, is one of the factors that can lead to alcohol dependence and addiction. Highly tolerant people tend to drink more than others simply because they don't get the same kick from a given dose.

Both tolerance and the tendency to develop alcoholism are known to be partly inherited. But only a few of the genes responsible have been identified. Because genetic studies in humans are difficult, Ulrike Heberlein's team at the University of California in San Francisco turned to the fruit fly Drosophila melanogaster.

To measure ethanol tolerance in flies, the researchers placed the flies in a column containing several platforms. When they were exposed to ethanol vapour, the flies tended to lose their balance and fall off their platform to the next one down, until they finally landed with a drunken bump at the bottom of the column. The sooner the flies hit the bottom, the drunker they were.

Stressed out

The researchers checked the ethanol tolerance of tens of thousands of flies whose genomes had been damaged at random locations.

Normal flies took about 20 minutes to reach the bottom of the column. When the researchers exposed the same flies to a repeated dose of ethanol four hours later, the flies had developed a tolerance against the ethanol and took 8 minutes longer to hit the bottom.

But mutants lacking a gene dubbed hangover reached the bottom of the column just 23 minutes after exposure to the second dose, the scientists report in Nature¹. This indicates that hangover mutants have a lower tolerance, the researchers say.

The mutant flies also died younger and coped less well than normal flies with other kinds of stress, such as excessive heat. The hangover gene codes for a type of protein that turns on other genes. Humans have many genes like this, Heberlein adds, making it likely that one of them is equivalent to hangover. She suggests it might turn on genes that activate the cellular response to stress.

From mice to men

Paula Hoffman, who studies alcohol tolerance in mice at the University of Colorado, Denver, agrees that humans probably have the equivalent gene. Hoffman says a similar gene is switched on in mice when they are given alcohol, although she doesn't know why. "It's nice to see that these things seem to be parallel in different organisms," Hoffman says.

Hangover is the second known gene responsible for ethanol tolerance. Five years ago, Heberlein's group showed that a gene for a neurotransmitter called octopamine, which helps flies memorize rewarding experiences, is also important. Flies lacking both these genes have almost no alcohol tolerance.

Such genes could be used to help identify people at risk of becoming alcoholics. The ultimate goal, Heberlein says, is to identify potential drug targets to treat alcoholism. "Once you understand how tolerance works," she says, "you can potentially interfere with it pharmacologically."