CHANCES ARE, WHAT’S INSIDE THOMAS STANTON’S SKULL BEARS little resemblance to a normal brain. Stanton, a 47-year-old medical supply technician at a Veterans Administration hospital in La Jolla, Calif., has been addicted to methamphetamines for 30 years, and the damage such abuse produces tends to be severe. According to Hans Breiter, a psychiatrist who has been studying addicts for 15 years, drugs of abuse significantly remodel brain structures and circuitry, making changes that become apparent when he analyzes magnetic resonance imaging scans. Breiter, whose research will eventually examine the brains of thousands of healthy and addicted subjects, has found in early tests that cocaine addicts who also abuse alcohol have decreased brain volume and diminished cortical thickness in regions that are important for judgment and decision-making. “Preliminary data suggest that parts of their brains are not communicating with other parts,” says Breiter, who directs the Phenotype Genotype Project in Addictions and Mood Disorders at the Massachusetts General Hospital.

For Stanton and other addicts, such brain alterations translate into a habit that’s extremely difficult to kick. Stanton started using meth in the Navy at age 17, when he needed a way to stay alert during long nights standing watch at sea. Since then, he’s been in and out of prison every few years, and though he has been clean for a year and a half, an earlier attempt to quit failed after five years, when loneliness and depression prompted a relapse. He now stays clear of former addict friends to avoid the temptation to get high. “Meth ruined my life, but there are days when I have to do everything in my power not to start again,” Stanton says.

One reason drugs are so alluring, no matter the cost, is well understood. Since the 1970s, scientists have known that the chemical dopamine, unleashed in the brain by all drugs of abuse, is responsible for the euphoria that draws people into addiction. But only recently have researchers discovered more about dopamine’s role—that it facilitates conditioned responses to drugs that result in compulsive abuse even when the drug itself no longer provides pleasure. When dopamine levels get out of kilter, other brain chemicals are also affected, producing profound changes in the circuitry involved with memory, inhibition, motivation and judgment. Treating addiction, scientists have found, requires much more than simply blocking the high.

DRUGS OF ABUSE ALTER A NUMBER OF NEUROTRANSMITTERS—the chemicals that transmit messages across synapses from neuron to neuron—but their effect on dopamine, which influences circuits that ferry signals of pleasure, awareness, judgment and motivation, may be the most crucial one in causing addiction. Dopamine encourages behavior essential to the survival of the species. It’s released when we eat, quench our thirst or have sex, making us want to repeat those activities. But taking any addictive drug also floods the brain with dopamine, and in much greater quantities than do natural rewards such as food or sex. Animal studies have shown that eating may boost dopamine levels by as much as 50% and that sex doubles them, whereas cocaine can produce triple the normal amount, and methamphetamine causes around a tenfold increase. Moreover, the dopamine surge from addictive drugs lasts longer than a natural high.

This effect begins at the base of the brain, in the ventral tegmental area, from which neurons send their long fibers into the nucleus accumbens, located in the midbrain, and into the frontal cortex. Dopamine attaches to cell receptors in the nucleus accumbens, initiating a cascade of biochemical events inside those neurons, which then pass the signal along to neurons in other brain regions. Normally dopamine is recycled back into the neuron that released it after transmitting its signal to the next neuron. But drugs of abuse disrupt that sequence, either releasing too much dopamine or interfering with its recycling. The chemical pools in the synapses and overwhelms the neurons, producing euphoria.

Because the brain can tolerate only so much dopamine, it may respond to repeated use of cocaine, for example, by reducing the number of a type of dopamine receptor called D2 in the nucleus accumbens. Many addicts have a marked decrease in D2 receptors, although it’s not clear whether they were born with fewer, whether drug use initiated a falloff, or both.

People who are addicted to drugs and have disrupted dopamine systems, including reduced D2 receptors, get fewer rewards from food and sex—for example, the brains of cocaine abusers are stirred by erotica to a much smaller degree than are the brains of healthy subjects—and so the dopamine rush from drugs often becomes the primary source of pleasure. And if repeated drug use further diminishes dopamine receptors, addicts need ever-increasing amounts of a drug to get high.

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.

Dopamine is very much involved in how this circuit learns and adapts, but once the infrastructure of the circuit gets changed through drug use, it’s really GABA and glutamate that drive drug-seeking behavior,” says Peter Kalivas, professor and chair of the department of neurosciences at the Medical University of South Carolina at Charleston.

That’s why, instead of targeting dopamine, some researchers are testing what happens when GABA transmission is enhanced with anticonvulsants or muscle relaxants, or the production of glutamate is inhibited. The trick is to get a therapeutic effect without causing lethargy, cognitive slowing or loss of motivation. Kalivas is encouraged by the results of experiments with rats and a promising Phase I human study with cocaine addicts in which an antioxidant compound, N-acetylcysteine, inhibited cravings for cocaine and dampened activity in addicts’ prefrontal cortices—home to glutamate and GABA activity—when the addicts were shown drug cues. “Our guess is that this won’t be a cure but that it will help restore some cognitive function,” says Kalivas, “though it may not help the hard-core addict who is extremely cognitively impaired.”

Yet another approach may be to amplify the dopamine response to non-drug-related stimuli, assuming researchers can find the right dopamine receptors to target. “If you can increase drug abusers’ sensitivity to natural reinforcers like sex and food, then they have alternative behaviors to help them feel good,” says Volkow.

EVEN AS THEY CRAVE THE RUSH of their next hit, some addicts realize there’s a cost to getting high. That’s the executive brain talking—specifically, the anterior cingulate. But the executive brain, associated with decision-making and judgment, gradually loses sway as addiction takes hold. “The end stage of drug abuse is the disconnection—functionally or even structurally—of the primitive limbic brain from the more developed frontal cortical brain,” explains psychiatrist and neurologist Walter Ling, director of the Integrated Substance Abuse Programs at the University of California at Los Angeles.

To test the breakdown of the brain’s executive function, NIDA’s Stein compared brain images of cocaine addicts with those of a control group as the subjects pressed a button to identify patterns in a rapidly changing sequence of letters. When a subject made a mistake, the anterior cingulate, which monitors and recognizes errors, did not light up on the scan nearly as brightly among cocaine users as it did among members of the control group. “The ability of the cocaine addict’s brain to recognize an error was severely impeded,” says Stein. “Just saying no to drugs clearly doesn’t work for addicts because their brains are significantly impaired in coping with the conflict that arises when the no signal meets the yes signal brought on by a drug cue.”

But when the addicts were high on cocaine during this experiment, the rush of dopamine allowed their usually sluggish cingulates to approach normal levels. That suggests that a drug that increases dopamine might enhance compromised dopamine levels in the anterior cingulate and other areas and perhaps restore some of the dysfunctional dopamine circuitry. Stein also thinks that the brain’s cognitive circuitry can be bolstered by the rehabilitation of the anterior cingulate in the same way that therapy helps stroke victims relearn how to speak and move. “If we think of the anterior cingulate as a muscle that has atrophied, maybe we can use biofeedback to give people information about their cingulate activity and ask them to try to increase it, much as we might give feedback on muscle performance,” says Stein, who is writing a protocol for a clinical trial to test his idea.

To be ultimately effective, addiction treatment must prevent relapse, so identifying those at high risk for relapse is vital, says Martin P. Paulus, associate chief of psychiatry at the San Diego Veterans Administration Hospital and professor of psychiatry at the University of California at San Diego. He uses brain images of methamphetamine abusers shortly after they have stopped using the drug to predict those likely to fall off the wagon. “If we have an objective measure of brain function that indicates probability of relapse,” says Paulus, “then we can appropriate resources to those who most need them.” In Paulus’s study, slightly lower levels of activity in the prefrontal cortex during decision-making tasks predicted with considerable accuracy those addicts who would relapse during the first two years after treatment.

Whether the brains of addicts can ever return to normal is an open question. “It seems to be highly variable,” says Volkow of NIDA, who has been following methamphetamine and cocaine addicts after sobriety. “Some brains recover, while others don’t. It probably depends on how long someone has been taking the drug, how frequently and the age at which he or she began. The earlier you start, the greater the likelihood the brain changes will be longer lasting.”