'Inebriomics' taps genetics of alcoholism

Tiny nematode worms that get 'legless' more rapidly than their peers when they ingest alcohol have led a San Franciso team to the gene that is the major determinant of susceptibility to alcoholism in worms -- and probably in humans as well.

Australian researcher Dr Andrew Davies, whose research team at the University of California, San Francisco, made the discovery, told the Lorne Genome Conference at Phillip Island that the gene, called SLO-1, codes for a potassium channel -- a molecular 'valve' that regulates the flow of potassium ions into nerve cells in the brain.

The gene takes its name from 'slow', which accurately describes the behaviour of nematodes that have imbibed to the point where a worm in a legless state would blow 0.18 on a micro-breathalyzer, if only it had lungs.

Davies said C. elegans, named for its aesthetically pleasing sinuous motion on an agar plate, slows to a lethargic, erratic, flattened crawl after it has ingested alcohol. His 'inebriomics' team has also been able to distinguish high- and low-susceptibility genotypes by the fact that the reproductive performance of drunken worms is severely below par -- the worms, which are hermaphrodites, produce almost no eggs. It was once thought that alcohol's global effects on the body were due to alcohol increasing the fluidity of the phospholipids that form cell membranes, including nerve cell membranes.

But Davies said it had become clear in recent decades that genetic factors strongly influence susceptibility to alcoholism. The efficiency of the alcohol dehydrenase enzyme that breaks down alcohol in the liver varies between individuals, and there appears to be overlap between susceptibility to alcoholism and the tendency to disinhibition and impulsivity.

Deep drunk

Alcohol also has a more profound effect on mood in some individuals, indicating an overlap between alcoholism susceptibility genes and genes for susceptibility to mental disorders like manic depression.

But Davies' team decided to focus on genes involved in the most overt effect of exposure to alcohol: the pronounced variation in the intensity of individual responses to the same concentration of alcohol.

High responders are 'cheap drunks', low responders are less susceptible to alcohol's effects -- and in consequence, more likely to become alcoholics. Davies said low responders almost never become alcoholics.

The nematode, despite having only 302 neurons, compared with 100 billion in humans, has 118 different types of neurons, making it a good model for studying the genetics of alcoholism.

The effects of alcohol on the nervous system could involve as many as 30 different proteins, affecting either their activity or changing their localisation in neural tissues.

His team used a chemical mutagen to induce mutations in their nematodes, and found eight mutants with moderate to strong resistance to alcohol. Six turned out to have mutations in the Slo-1 gene, that give them more sprightly, sinuous motion -- they moved at around 65 per cent of normal speed, compared with less than 35 per cent for susceptibles. The egg-laying test independently fingered the Slo-1 gene as the major player in alcohol resistance.

Slo-1 mutant worms remain active because they have hyperactive neurotransmission -- their nerves continue to 'fire' more strongly, and for longer. That hyperactivity makes them much more sensitive to paralysis when exposed to the pesticide aldecarb, which inhibits neurotransmission.

Resistance is useful

Comparisons of the electrical activity of individual nerve cells in the resistant and wild-type worms showed that alcohol caused an increase in potassium flux back into the nerve after it 'fired', so it could recycle and fire again in a shorter time -- the source of the resistant worm's superior motility and mating performance.

In wild-type worms, the neurons fire and recycle more slowly, leading to the mental and physical lethargy familiar to any human who over-indulges.

So alcohol specifically activates the mutant Slo-1 potassium channel protein -- a fact confirmed when the alcohol resistant mutants were transfected with a wild-type SLO-1 gene, and slowed to a crawl.

Tellingly, the human version of the gene, hSLO-1, occurs in a chromosomal site that studies of families affected by alcoholism has already identified as a hot spot for an alcohol-susceptibility gene.

But even the SLO-1 mutants still move at only 65 per cent of the rate of sober worms, so Davies believes other genes abet the SLO-1 gene's contribution to alcoholism susceptibility.

The SLO-1 gene belongs to a class of potassium-channel genes known as BK genes. Could drugs that hyper-activate the normal BK channel prevent inebriation, and cure alcoholism?

Davies said BK agonists could possibly be used to save the lives of people who stop breathing because of acute alcohol poisoning, but they are unlikely to find favour among regular drinkers. Among other things, they cause urinary incontinence, erectile dysfunction and disturb the sense of balance.

Such side-effects are already familiar to the happiest during happy hour -- and are probably best experienced while drunk, not sober.