ADDICTED

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Why? The mice, says Caron, a biochemist at Duke University's Howard Hughes Medical Institute laboratory, are high on dopamine. They lack the genetic mechanism that sponges up this powerful stuff and spirits it away. Result: there is so much dopamine banging around in the poor creatures' synapses that the mice, though drug-free, act as if they were strung out on cocaine.

For years scientists have suspected that genes play a critical role in determining who will become addicted to drugs and who will not. But not until now have they had molecular tools powerful enough to go after the prime suspects. Caron's mice are just the most recent example. By knocking out a single gene--the so-called dopamine-transporter gene--Caron and his colleagues may have created a strain of mice so sated with dopamine that they are oblivious to the allure of cocaine, and possibly alcohol and heroin as well. "What's exciting about our mice," says Caron, "is that they should allow us to test the hypothesis that all these drugs funnel through the dopamine system."

Several dopamine genes have already been tentatively, and controversially, linked to alcoholism and drug abuse. Inherited variations in these genes modify the efficiency with which nerve cells process dopamine, or so the speculation goes. Thus, some scientists conjecture, a dopamine-transporter gene that is superefficient, clearing dopamine from the synapses too rapidly, could predispose some people to a form of alcoholism characterized by violent and impulsive behavior. In essence, they would be mirror images of Caron's mice. Instead of being drenched in dopamine, their synapses would be dopamine-poor.

The dopamine genes known as D2 and D4 might also play a role in drug abuse, for similar reasons. Both these genes, it turns out, contain the blueprints for assembling what scientists call a receptor, a minuscule bump on the surface of cells to which biologically active molecules are attracted. And just as a finger lights up a room by merely flicking a switch, so dopamine triggers a sequence of chemical reactions each time it binds to one of its five known receptors. Genetic differences that reduce the sensitivity of these receptors or decrease their number could diminish the sensation of pleasure.

The problem is, studies that have purported to find a basis for addiction in variations of the D2 and D4 genes have not held up under scrutiny. Indeed, most scientists think addiction probably involves an intricate dance between environmental influences and multiple genes, some of which may influence dopamine activity only indirectly. This has not stopped some researchers from promoting the provocative theory that many people who become alcoholics and drug addicts suffer from an inherited condition dubbed the reward-deficiency syndrome. Low dopamine levels caused by a particular version of the D2 gene, they say, may link a breathtaking array of aberrant behaviors. Among them: severe alcoholism, pathological gambling, binge eating and attention-deficit hyperactivity disorder.