Have you ever noticed how some people remain sober and standing, even after having drunk enough alcohol to send most people snoozing under the table?

These people are alcoholics, and the condition runs in families. "Sons and daughters of alcoholics are less sensitive to the biochemical, motor and perceptual changes induced by intoxicating levels of ethanol relative to children without a family history of alcoholism." So say Todd E. Thiele of the University of Washington, Seattle, and colleagues, in a new report in the Journal of Neuroscience1. "Furthermore, these children have an increased risk for developing alcoholism," they add.

This is not just a product of social conditioning: the causes seem to be strongly genetic. Thiele and colleagues demonstrate this by breeding mice with behaviour that is remarkably like that of alcoholism. The mice lack a gene encoding a specific segment (one of six) of an enzyme called 'Protein Kinase A'. The enzyme helps to communicate chemical signals from the environment to the cell machinery responsible for turning genes on and off.

The mice live as long as usual and appear to grow and behave normally. But, needless to say, they suffer from deficits in those aspects of biochemistry that involve Protein Kinase A (including brain chemistry). This makes them leaner than usual, gives them movement problems and brings other, subtle metabolic and behavioural effects.

Such consequences include the ability to voluntarily consume more alcohol than their fellows, and recover far more rapidly from alcohol-induced stupor. And not only do these mice drink more alcohol, they choose to drink significantly stronger alcohol solutions.

This seems purely behavioural. For example, there is no evidence that these alcoholic mice digest alcohol differently from other mice, and they get no benefit from the calories in alcohol -- they still eat as much food as other mice do. And they don't drink just for the taste: there is evidence that mice perceive alcohol as bittersweet, yet the genetically modified mice drink no more quinine- or sucrose-laced water than do other mice.

There is other evidence for a genetic basis for sensitivity to alcohol: work on flies has isolated a gene that encodes a protein involved in similar biochemical functions to those described in the mice. Mutations in this gene produce flies that are more sensitive than usual to the effects of alcohol.

Interestingly, Thiele and colleagues recently showed that mice lacking a substance called 'Neuropeptide Y' drink a lot of alcohol and are resistant to alcohol-induced sedation2. Neuropeptide Y is an important brain chemical, and appears to be involved in the same biochemical pathway as Protein Kinase A.

A picture appears to be emerging from the work -- gross genetic upset to this pathway (in parts of the brain yet to be identified conclusively) leads to behaviour which, in humans, is seen as alcoholic. It could be that alterations or variations in the biochemical behaviour of this pathway contribute to alcoholism in humans.