Some People Come Equipped With Addiction-Fighting Gene

Pharmacologically speaking, cocaine has been well characterized as one of the most—if not the most—addictive substances studied to date. Yet rare but consistent anecdotal accounts of “casual” cocaine use without addiction do exist. New research may now offer an explanation.

A report from the Laboratory of Biology of Addictive Diseases at Rockefeller University says that some people carry their own genetically based defense mechanism that helps to prevent the development of addictive behavior. The report appeared in the Neuropsychiatric Genetics section of the May 8 issue of the American Journal of Medical Genetics.

Mary Jeanne Kreek, M.D., a professor of psychiatry and director of the lab, presented evidence that a genetic variance that results in increased production of the naturally occurring brain opiate dynorphin may serve as an effective antidote to counter the pleasurable effects of cocaine.

Dynorphin, one of the body’s endogenous opiates, is thought to play a role in numbing pain, creating feelings of euphoria and well-being, and increasing energy. Endogenous opiates also help the body modulate its response to stress. Addictive opiates, such as heroin and morphine, as well as synthetic opiates like oxycodone (the active ingredient in OxyContin), mimic the actions of endogenous opiates in the body.

Kreek and her colleagues studied the association between the gene mutation coding for the “up-regulation” of dynorphin and dependence or abuse by analyzing DNA samples from 174 people, 83 of whom had been previously diagnosed with cocaine dependence or abuse, and 91 control subjects with no history of any substance abuse. Kreek is often referred to as “the mother of methadone” because she, along with Rockefeller Professor Emeritus Vincent Dole, M.D., and his now deceased wife, Marie Nyswander, pioneered methadone treatment for heroin addiction in the 1960s.

The current work was funded by grants from the National Institute on Drug Abuse and the National Institutes of Health.

The results of the study suggest that individuals who harbor the “high-output” form of the gene that codes for dynorphin have a significantly lower risk of becoming dependent on or developing addiction to cocaine compared with persons with the “low output,” more common, form of the gene.

“These results are preliminary but do suggest that genetic differences in the gene are correlated with individual variations of vulnerability to cocaine abuse,” Kreek said in a press release.

Previous studies from Kreek’s lab as well as others have indicated that cocaine triggers a flood of dopamine release in the brain, which in turn leads to its characteristic high. This onslaught of dopamine can be toxic to brain tissues, causing permanent damage, Kreek said.

In apparent response to increasing levels of dopamine, dynorphin production picks up as well. Kreek and her colleagues believe that dynorphin acts like an “antitoxin” to neutralize the destructive effects of cocaine. As such, a person who carries a gene that leads to increased baseline levels of dynorphin in the brain might then be “protected” against cocaine-induced brain damage.

Studies have shown that the dynorphin gene is present as a “multiple” or “repeat”—that is, individuals may have one, two, three, or four copies. Having more copies of the gene presumably leads to increased levels of dynorphin.

Kreek’s lab showed that there is a definite correlation between having three or four copies of the repeat and having a significantly lowered risk of becoming addicted to cocaine.

“Knowing how this genetic variation could potentially modulate the effects of cocaine lends weight to our results,” commented lead author Andrew Chen, M.D., Ph.D., a research associate professor at Rockefeller. Chen cautioned, however, that the team’s sample size was small, and further follow-up work needs to be done to confirm the results.

An abstract of the study, “Potentially Functional Polymorphism in the Promoter Region of Prodynorphin Gene May Be Associated With Protection Against Cocaine Dependence or Abuse,” is posted on the Web at www3.interscience.wiley.com/cgi-bin/abstract/93514787/START. ▪