The Addicted Brain
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James Worrell
If dopamine could be prevented from binding with receptors in the brain, one might suppose that addicts would not get a rush from drugs and would stop taking them. Yet as intuitive as that approach to therapy may seem—and it has intrigued researchers for more than 20 years—it hasn’t panned out. “The rat models all look great, and we’ve tried an impressive list of 50 or so drugs, including such dopamine antagonists as the haloperidol that schizophrenics take, but they don’t work for drug abuse,” says Elliot Stein, chief of the Neuroimaging Research Branch of the Intramural Research Program at the National Institute on Drug Abuse (NIDA) in Bethesda, Md.
That, Stein says, is because trying to block dopamine in an addict’s brain is akin to closing the barn door after the horse has bolted. Drug-induced dopamine surges have already caused a maladaptive form of learning and memory that initiates powerful cravings whenever a cue—the sight of drug paraphernalia, the friends an addict gets high with, a place of drug use or even a mood—triggers a drug association.
Normally, when there is a mismatch between reality and expectation, neurons fire, releasing dopamine. If you eat chocolate, have sex or take a drug and the world suddenly exceeds your expectations, you get a surge of dopamine. You learn to associate that surge not only with food, sex or drugs but also with other aspects of that experience. “Because drugs enhance this very powerful learning process, a drug user over-learns a response to the stimulus, so the mere sight of his drug buddy makes his brain scream cocaine,” says Stein.
But even with the horse out of the barn, as Stein puts it, it may be possible to help addicts unlearn responses to drug cues. The idea, says Nora Volkow, director of NIDA and the first researcher to conduct dopamine studies using positron-emission tomography scans, is to help an addict learn that items she associates with taking the drug—a $20 bill, say, which can be rolled up to snort cocaine—are no longer linked with the high she got when she was taking the drug. That, in turn, might curb the release of dopamine, beginning a new cycle of learning.
Because regulating the release and recycling of dopamine has proved so difficult, many researchers have shifted their target from learning circuitry to another circuit in the cortex that drives motivational behavior (the pathways are connected, but it is not known exactly how). That circuit is governed by two neurotransmitters, glutamate and gamma-aminobutyric acid (GABA), which both play major roles in modulating the intensity of dopamine response to drugs and other stimuli.
Glutamate-producing neurons in the prefrontal cortex descend into the nucleus accumbens, where the release of glutamate may excite either dopamine cells or GABA cells, which inhibit neurons from firing. Drugs of abuse confuse these pathways, thus leading to compulsive drug-seeking and the lack of inhibitory control that contribute to an addict’s relapse.
