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Predisposition to Addiction Found in Cocaine Study

A lack of dopamine receptors in a specific brain region could trigger increased compulsions, such as drug addiction
cocaine addiction



© ISTOCKPHOTO/CHRISTOPHER O'DRISCOLL

A new study shows that brain circuitry makes some people more susceptible to becoming addicts. Researchers found that a pocket near the top of the brain stem may be key in determining whether someone is likely to engage in compulsive behavior or become hooked on drugs like cocaine, which is currently abused by an estimated two million Americans. The finding could help prevent addiction by predicting those predisposed to such behavior and could also lead to new ways to treat it.

Researchers at the University of Cambridge in England report in this week's Science that a lower number of specific types of receptors that bind the neurotransmitter dopamine—a chemical central to the brain's reward system—in the front (or ventral) section of the striatum (a midbrain region implicated in planning and movement as well as executive function) correlates to increased impulsive behavior in rats. In addition, they found that the more impulsive animals, when given the option, consumed more cocaine than the calmer rats did.

"Our data provide a link between impulsivity and compulsivity," says lead author Jeffrey Dalley, an experimental psychologist at Cambridge's Behavioral and Clinical Neuroscience Institute. "We have formulated a strong working hypothesis that dopamine dysfunction in the ventral striatum mediates impulsivity and encourages increased intake of cocaine. Increasing use of cocaine eventually affects the entire striatum, including the dorsal [or hind section of the] striatum, which is heavily implicated in compulsive habit-based learning."

At the outset of the experiment, the researchers tested the visual attention and anticipatory behavior of rats, and segregated the most impulsive animals. They then gave six impulsive rats, along with six laid-back ones PET (positron emission tomography) scans that focused on the striatum. The scientists specifically probed the nucleus accumbens, a ventral (front) section of the striatum associated with pleasure processing, to determine the number of D2 dopamine receptors there. (Previous studies have shown a dip in the number of the D2 family of dopamine receptors in cocaine-addicted monkeys.) The Cambridge team found that impulsive rats had 10 percent fewer receptors in their ventral striatum. Next, the rats were hooked up to a catheter and allowed to self-administer cocaine. (This is typically done by the rat depressing a lever.) Researchers observed that all of the rats consumed some amount of the drug, but that the impulsive ones consumed it at twice the rate of the normal (or less impulsive) animals

The findings suggest that a lack of D2-family receptors may predict both the risk of anticipatory impulsivity as well as a predisposition to behaviors like drug and other addictions such as compulsive gambling and shopping. "This is probably one of several 'vulnerability' markers, for future drug addiction," Dalley says. "What determines the final 'tipping' point is obviously very complex [involving] genes and environment, etc."

Steven Grant, a researcher at the National Institute on Drug Abuse, says that the new findings will help untangle a "chicken and egg problem" with human addiction studies: Previous research found a correlation between the D2-family receptors and drug abuse, but it was unclear whether fewer receptors contributed to addiction or if chronic drug use led to a drop in the number of receptors. "This allows us a framework to interpret the human studies," says Grant.

Diana Martinez, a research psychiatrist at the Columbia University Medical Center in New York City, disagrees that the study has direct human implications. "We have done the same study in actual cocaine dependent subjects and we have seen no predictive value of D2/3 receptor binding potential," she says. Martinez adds that, "lower quantities of these receptors have also been reported in a number of human traits that are not generally associated with impulsivity: social phobia, obsessive-compulsive disorder, social detachment and increased age."

The real value of the new research may be that these receptors can provide new and more effective therapies for current addicts, says Michael Nader, a physiologist and pharmacologist at the Wake Forest University School of Medicine in Winston-Salem, N.C. "This identifies a target," he says. "If you have low D2 levels you're more vulnerable; if you change the environment, you can increase those levels." He suggests that treatments that stimulate production of D2 receptors could be beneficial.

"Most licensed treatments are substitution therapies"such as methadone in the case of heroin addiction"so they maintain the addicted state, but more safely," says Dalley. "We feel that newer treatments should aim to prevent relapse." He notes that the behavior of the impulsive study rats normalized after they went through withdrawal from cocaine. "The potential here," he says, "is [in] treatments that retard the return of impulsivity in post-cocaine addicts, [which] may be an important contributor to relapse."

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