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Bar flies. Illustration of the inebriometer used to test flies' tolerance to ethanol.

Getting Drunk on the Fly

Chronic drinkers can usually handle a lot of booze and tend to be pretty relaxed when inebriated. Now, a newly discovered gene in flies called hangover may explain why these traits seem to go hand in hand.

Regular drinkers of ethanol--the type of alcohol found in frosty malted beverages--eventually require more and more drinks to feel tipsy. Such increased tolerance is seen as a warning sign of alcoholism. In 2000, behavioral geneticist Ulrike Heberlein of the University of California, San Francisco, found that mutations in a fruit fly gene that disrupts the synthesis of their version of the neurotransmitter noradrenaline dampen a fruit fly's ability to acquire tolerance to ethanol.

To find other genes involved in tolerance, Heberlein and her team intoxicated 400 flies, each with a random mutation in a single gene. First, the researchers dropped the flies into an ethanol vapor-infused inebriometer, a long vertical tube with platforms on which flies can land. As the flies get drunk, they fall from ledge to ledge until they literally hit bottom, dropping out the end of the tube. The faster a fly gets drunk, the quicker it ends up on the countertop.

The first round with the inebriometer yielded a number of mutant flies that hit the counter in the same amount of time as normal flies: 20 minutes. To test the tolerance of these mutants, the team dropped the bugs into the tube again. Normal flies take about 28 minutes to drop from the tube in the second round, but some of the mutant flies fell through in only 23 minutes, indicating their tolerance had been compromised. Upon closer examination of the flies, the researchers found a mutation in a previously uncharacterized gene, which they named hangover. Further tests indicated that hangover plays a role in a fly's response to stress. When researchers heat up normal flies, the insects ramp up various stress proteins. Stressed flies usually have heightened tolerance for ethanol, but not so for hangover mutants: Previous stress had no effect on the time it took them to fall through the inebriometer, suggesting hangover is required for the stress proteins to produce ethanol tolerance, the researchers report 11 August in Nature.

This work "gives us a gene and a pathway to link tolerance and the stress response," says molecular pharmacologist Leslie Morrow of the University of North Carolina, Chapel Hill. If the findings hold up in humans, they may shed light on why alcoholics tend to handle stress in a blunted fashion: an overactive hangoverlike gene. But she cautions that the inebriometer measures only one simple behavior--passing out--and that more complex aspects of tolerance, such as cognitive impairment, may involve additional genes.

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Heberlein's lab at University of California, San Francisco