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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.
The more science unmasks the powerful biology that underlies addiction, the brighter the prospects for treatment become. For instance, the discovery by Fowler and her team that a chemical that inhibits the mopping-up enzyme MAO B may play a role in cigarette addiction has already opened new possibilities for therapy. A number of well-tolerated MAO B-inhibitor drugs developed to treat Parkinson's disease could find a place in the antismoking arsenal. Equally promising, a Yale University team led by Eric Nestler and David Self has found that another type of compound one that targets the dopamine receptor known as D1 seems to alleviate, at least in rats, the intense craving that accompanies withdrawal from cocaine. One day, suggests Self, a D1 skin patch might help cocaine abusers kick their habit, just as the nicotine patch attenuates the desire to smoke.
Like methadone, the compound that activates D1 appears to be what is known as a partial agonist. Because such medications stimulate some of the same brain pathways as drugs of abuse, they are often addictive in their own right, though less so. And while treating heroin addicts with methadone may seem like a cop-out to people who have never struggled with a drug habit, clinicians say they desperately need more such agents to tide addicts particularly cocaine addicts over the first few months of treatment, when the danger of relapse is highest.