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The neurons that produce this molecular messenger are surprisingly rare. Clustered in loose knots buried deep in the brain, they number a few tens of thousands of nerve cells out of an estimated total of 100 billion. But through long, wire-like projections known as axons, these cells influence neurological activity in many regions, including the nucleus accumbens, the primitive structure that is one of the brain's key pleasure centers. At a purely chemical level, every experience humans find enjoyable whether listening to music, embracing a lover or savoring chocolate amounts to little more than an explosion of dopamine in the nucleus accumbens, as exhilarating and ephemeral as a firecracker.
Dopamine, like most biologically important molecules, must be kept within strict bounds. Too little dopamine in certain areas of the brain triggers the tremors and paralysis of Parkinson's disease. Too much causes the hallucinations and bizarre thoughts of schizophrenia. A breakthrough in addiction research came in 1975, when psychologists Roy Wise and Robert Yokel at Concordia University in Montreal reported on the remarkable behavior of some drug-addicted rats. One day the animals were placidly dispensing cocaine and amphetamines to themselves by pressing a lever attached to their cages. The next they were angrily banging at the lever like someone trying to summon a stalled elevator. The reason? The scientists had injected the rats with a drug that blocked the action of dopamine.
In the years since, evidence linking dopamine to drugs has mounted. Amphetamines stimulate dopamine-producing cells to pump out more of the chemical. Cocaine keeps dopamine levels high by inhibiting the activity of a transporter molecule that would ordinarily ferry dopamine back into the cells that produce it. Nicotine, heroin and alcohol trigger a complex chemical cascade that raises dopamine levels. And a still unknown chemical in cigarette smoke, a group led by Brookhaven chemist Joanna Fowler reported last year, may extend the activity of dopamine by blocking a mopping-up enzyme, called MAO B, that would otherwise destroy it.
The evidence that Volkow and her colleagues present in the current issue of Nature suggests that dopamine is directly responsible for the exhilarating rush that reinforces the desire to take drugs, at least in cocaine addicts. In all, 17 users participated in the study, says Volkow, and they experienced a high whose intensity was directly related to how extensively cocaine tied up available binding sites on the molecules that transport dopamine around the brain. To produce any high at all, she and her colleagues found, cocaine had to occupy at least 47% of these sites; the "best" results occurred when it took over 60% to 80% of the sites, effectively preventing the transporters from latching onto dopamine and spiriting it out of circulation.
Scientists believe the dopamine system arose very early in the course of animal evolution because it reinforces behaviors so essential to survival. "If it were not for the fact that sex is pleasurable," observes Charles Schuster of Wayne State University in Detroit, "we would not engage in it." Unfortunately, some of the activities humans are neurochemically tuned to find agreeable eating foods rich in fat and sugar, for instance have backfired in modern society. Just as a surfeit of food and a dearth of exercise have conspired to turn heart disease and diabetes into major health problems, so the easy availability of addictive chemicals has played a devious trick. Addicts do not crave heroin or cocaine or alcohol or nicotine per se but want the rush of dopamine that these drugs produce.
Dopamine, however, is more than just a feel-good molecule. It also exercises extraordinary power over learning and memory. Think of dopamine, suggests P. Read Montague of the Center for Theoretical Neuroscience at Houston's Baylor College of Medicine, as the proverbial carrot, a reward the brain doles out to networks of neurons for making survival-enhancing choices. And while the details of how this system works are not yet understood, Montague and his colleagues at the Salk Institute in San Diego, California, and M.I.T. have proposed a model that seems quite plausible. Each time the outcome of an action is better than expected, they predicted, dopamine-releasing neurons should increase the rate at which they fire. When an outcome is worse, they should decrease it. And if the outcome is as expected, the firing rate need not change at all.