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This could be your brain on booze.

It's a truth that the Mothers Against Drunk Driving know all too well: Alcohol slows reflexes and impairs muscle coordination. But despite the great strides neuroscientists have made in the last few years in understanding the brain, the exact cause of alcohol's ability to intoxicate has remained a mystery.

Now, a group of researchers has uncovered clues that might explain why knocking back one nightcap too many can make it tough to walk a straight line. While studying the brains of a special breed of rats with a low tolerance for alcohol, Peter H. Seeburg and his colleagues at the University of Heidelberg in Germany have identified a molecule on the surface of nerve cells that responds abnormally to the sedative drug diazepam, better known by the trade name Valium. Because an experimental drug that can restore sobriety in drunken rats also appears to act through this same molecule, the researchers believe it may be the arbiter of alcohol's disabling effects in people as well as rats.

The molecule constitutes one of five subunits that together make up a nerve cell's receptor for GABA (gamma-aminobutyric acid), a body chemical that usually shuts off nerve-ceil activity. A region at the base of the brain known as the cerebellum controls motor coordination by using GABA as a molecular "off switch"to inactivate previously stimulated muscle nerves.

Seeburg's team found that so-called alcohol-non-tolerant rats have a mutant form of the alpha subunit of a GABA receptor. In the Jan. 28 NATURE, the researchers report that cells bearing this mutant subunit exhibit an enhanced sensitivity to diazepam. Moreover, they discovered that a drug known as R015-4513 -- which was once developed by the Swiss-based pharmaceutical company E Hoffmann-La Roche, Ltd. to reverse intoxication (SN: 12/6/86, p. 358) - could block this enhanced sensitivity by binding to the same site on the mutant subunit as diazepam.

Seeburg concludes that his team has "identified one of the little cog-wheels in the molecular machinery that brings about the loss of motor control in alcohol intoxication." He suggests that when the mutant subunit is exposed to alcohol, it perturbs the normal action of the GABA receptor, disrupting the cerebellum's fine control of muscle movement and causing individuals to stagger and fall. However, he admits that the finding rests only upon "converging lines of evidence."

Neuroscientist Stuart Cull-Candy of University College in London comments that the new finding sheds more light on the function of the different types of GABA receptors in the cerebellum than upon the brains reaction to alcohol. "The work strongly indicates that the GABA subunit can inhibit cerebellar processes," he says. However, in an editorial accompanying the new report, he and University College colleague Mark Farrant write, "Although the evidence is highly suggestive, there is as yet no proven link between mutation of [the alpha subunit of GABA] and the altered behavior of [alcohol-non-tolerant] rats."

Seeburg and his colleagues are now conducting experiments designed to demonstrate conclusively the alpha subunit's involvement in intoxication. They have begun determining whether the mutant GABA receptor subunit is more sensitive than its normal counterpart to alcohol. Although the results have so far turned up negative, he says, "In my view, all of the chips aren't in yet."
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Title Annotation:causes of intoxication
Author:Ezzell, Carol
Publication:Science News
Date:Jan 30, 1993
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