New NIDA Director Unravels Neurochemistry of Addiction

Volkow has used positron emission tomography (PET) to scan the brains of normal control subjects and people who have abused various drugs to measure the levels of D2 receptors for dopamine, which has been associated with feelings of reward and pleasure and is implicated in drug abuse.

Her team at BNL found that cocaine abusers, and later methamphetamine abusers, not only had lower levels of the receptors but also lower brain glucose metabolism in the orbitofrontal cortex, the part of the brain responsible for “higher” cognitive functions (Psychiatric News, January 18, 2002).

This finding is significant, Volkow noted, because it was the first to point to the role of the frontal cortex in addiction and also because “this area of the brain has been shown by imaging to be involved in obsessive-compulsive behaviors.”

She spoke of studies in which researchers trained animals to press a lever for food. Normally, Volkow said, the animals stop pressing the lever when the food is gone. But when the researchers damaged the orbitofrontal cortex in the animals, they continued to press the lever, whether food—the reinforcer—was there or not.

“This reminds me of what many drug abusers have told me,” Volkow said. “They say, ‘I don’t understand why I take the drug. It is no longer pleasurable. I just can’t stop.’ ”

In prior studies, Volkow found that some healthy subjects had wide variability in their levels of D2 receptors, with some having levels as low as the cocaine abusers she studied. Her next question was this: What does it mean to have a low level of D2 receptors yet not be addicted to drugs?

To find the answer, Volkow measured the level of D2 receptors in 23 healthy men and gave them each a dose of methylphenidate, which drastically increases dopamine levels, and asked them to describe the drug’s effects on them.

Volkow said that those who found the stimulant pleasant had lower numbers of D2 receptors than those who described the experience as unpleasant. She postulated that the dopamine rush was so overwhelming for the people with high numbers of receptors that they found the drug aversive, but for those with a lower number of receptors, the dopamine levels stayed at a threshold where the experience was pleasurable. Her study appeared in the September 1999 issue of the American Journal of Psychiatry.

When one of Volkow’s colleagues at Brookhaven’s lab, Panayotis Thanos, Ph.D., used gene therapy techniques utilizing a virus to increase D2 receptor levels in one group of rats trained to press a lever to obtain alcohol, he found that the group drank 64 percent less than rats who received a placebo virus.

Volkow said she speculated initially that the number of D2 receptors a person has—and therefore, whether he or she may be vulnerable to substance abuse—is genetically determined. But it was not so simple, she discovered.

Volkow cited the work of Drake Morgan, Ph.D., and Michael Nader, Ph.D., at Wake Forest University School of Medicine, who in the February 2002 issue of Nature Neuroscience published data showing that environment played an important role in addiction for macaque monkeys.

The scientists measured the D2 receptor levels in a group of 20 monkeys in separate cages and found that their levels were similar. However, when the monkeys were housed together, D2 receptor levels increased by about 20 percent in the alpha, or dominant, monkeys.

In addition, the alpha monkeys were less likely to self-administer cocaine. Volkow acknowledged that in this case, the psychosocial stressors for the monkeys protected them from addiction, but chronic stress can have the opposite effect.

Besides the variations in D2 receptor levels, Volkow noted that dopamine transporters, which regulate the uptake of dopamine into neurons, may also factor into substance abuse. Several studies, Volkow noted, have found that rats reared in isolation have fewer dopamine transporters than rats reared by their mothers. When there are fewer transporters, the dopamine is released, but it is not removed from the terminal rapidly enough. Thus, the effects of certain drugs—for example, like cocaine—are heightened, making self-administration of the drugs more likely.

Volkow said a major investigative challenge before addiction researchers now is the interaction between stress, genes, biology, and drugs. “Predisposition does not mean predetermination, so a better understanding of how the environment influences addiction may lead to better interventions for drug abuse.” ▪