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Issued: April 15, 2002
runews@rockefeller.edu
Contact: Office of Communications and Public Affairs (212) 327-7900

Nature's Own Antidote to Cocaine
Brain opiate may explain why some people are less susceptible to addiction

Kreek and colleagues found that individuals who inherit a "high-output" version of the gene that manufactures a brain opiate called dynorphin may be less likely to fall prey to the addictive powers of cocaine. Above is a partial DNA sequence of a high-output dynorphin gene containing three copies of a DNA "repeat." High-output forms of the dynorphin gene contain three or four copies of a repeated DNA unit, or repeat, within their promoter regions (the DNA in front of a gene's coding sequence that controls how much of the protein is made) and are thought to result in higher levels of dynorphin in the brain. Low-output versions contain of one or two copies of the repeat and are believed to result in lower brain levels of dynorphin.

Some people's brains may harbor their own built-in defense system against the addictive powers of cocaine. According to new research at The Rockefeller University, a naturally occurring brain opiate called dynorphin may, in certain individuals, serve as an antidote to counter the pleasurable, yet dangerous, effects of cocaine.

In the latest Neuropsychiatric Genetics section of the American Journal of Medical Genetics, Mary Jeanne Kreek, M.D., and Rockefeller University colleagues report that people carrying a "high-output" version of the dynorphin gene — one that is thought to result in higher levels of this protein in the brain — may be better protected against cocaine dependence or abuse than those carrying a "low-output" form.

"These results are preliminary, but do suggest that genetic differences in the gene that codes for dynorphin are correlated with individual variations of vulnerability to cocaine abuse," says Kreek, head of the Laboratory of Biology of Addictive Diseases at Rockefeller and senior physician at the Rockefeller Hospital.

"This kind of knowledge is important for the development of both preventative and drug-based treatment strategies for people suffering from cocaine addiction," she adds. Kreek, together with Rockefeller Professor Emeritus Vincent Dole and his late wife and colleague Marie Nyswander, pioneered methadone maintenance programs for the treatment of heroin addicts in the 1960s.

The new genetic association study compared DNA samples from 174 participants, including 83 people who had been previously diagnosed with cocaine dependence or abuse, and 91 "control" individuals with no prior history of any substance abuse. The results suggest that individuals who harbor the high-output form of the dynorphin gene have a significantly lower risk of becoming dependent upon or abusing cocaine than people with the low-output version. The p-value — a measure of statistical significance — for this study was .042 (values of .05 and lower are considered to be significant).

"We were very lucky to have well-characterized subjects for this study,"

Andrew C. Chen, a research associate (above), K. Steve LaForge, a laboratory manager, and other Rockefeller colleagues in the Kreek lab are homing in on genetic differences that may help explain why some people get hooked on cocaine, while others do not.

says Andrew Chen, M.D., Ph.D., first author of the study and a research associate at Rockefeller. "The subjects we looked at had been previously diagnosed using very stringent criteria - a fact that supports our findings."

Moreover, previous studies by Kreek and others suggest how this high-output version of the dynorphin gene might protect a person against addiction. Typically, snorting or injecting cocaine triggers a flood of dopamine and other neurotransmitters in the brain, and this, in turn, leads to its characteristic euphoric "high." But, according to the scientists, the brain compensates for this overabundance of dopamine by producing more of the opiate dynorphin, which then reduces levels of dopamine - in essence acting like an antitoxin to neutralize the destructive effects of cocaine. Consequently, higher levels of dynorphin in the brain might translate to increased protection against cocaine.

Because the scientists have demonstrated a possible neurobiological function for this particular genetic variant, it is referred to as a "functional variation."

"Knowing how this genetic variation could potentially modulate the effects of cocaine lends weight to our results," says Chen. "But, on the other hand, our sample size was relatively small, and further studies with more patients are needed to confirm these results."

Dynorphin is a member of the body's natural, or endogenous, opioid system. These molecules, by acting on their corresponding opioid receptors, are responsible for numbing pain, creating feelings of euphoria and increasing energy. They also play a role in the normal functioning of the gastrointestinal and immune systems, as well as modulate how the body deals with stress.

Addictive opiates, which include heroin, morphine and other analgesics such as codeine, are structurally similar to the opioids produced naturally in the body and thus bind to and stimulate the same receptors, subsequently triggering these drugs' well-known effects. Cocaine, on the other hand, acts primarily on the brain's "reward" circuits; it increases levels of dopamine and other neurotransmitters at specific areas of the brain.

Yet, research in the last few years has shown that cocaine, like heroin, also acts on the endogenous opioid system - including dynorphin. Studies in rats by Kreek and others have shown that cocaine, while directly inducing a surge in dopamine in the brain, causes a rise in dynorphin levels. Furthermore, Kreek and her colleagues have demonstrated directly in rats and indirectly in humans that administration of dynorphin results in a decrease in the amount of dopamine in the brain.

Together, these studies imply that dynorphin rises after cocaine administration as a means to counteract the effects of cocaine. Under natural circumstances, however, this rise in dynorphin may not be enough to safeguard a person against addiction.

These findings led Kreek and other to speculate that subtle variations, also called polymorphisms, in the gene that instructs brain cells to manufacture dynorphin may explain why some individuals tend to be more resistant to cocaine addiction after experimenting with the drug. Recently, Alexander Zimprich and colleagues at the Otto-von-Guericke University, Magdeburg, Germany have discovered such a variation within this gene.

Zimprich found that a specific piece of the DNA making up this dynorphin gene is present in one, two, three or four copies in different individuals. Furthermore, because this variable region is located in the "promoter" region of the gene (the DNA in front of a gene's coding sequence that controls how much of the protein is made), having more copies of it may lead to higher levels of dynorphin in the brain. Specifically, the researchers demonstrated in cells that genes containing three or four copies of this DNA "repeat" produce more dynorphin than those with one or two.

Kreek's lab has now taken this work one step further by showing a correlation in humans between having three and four copies of the repeat and not being addicted to cocaine. Yet Chen cautions that more studies are imperative in order to confirm their results. In addition to having a small overall sample size, he says that the study did not equally represent each of the major ethnic groups. For example, the Hispanic group contained only 22 individuals.

Ideally, genetic risks should be calculated for each ethnic group separately, in addition to as a whole, to avoid the problems of ethnic or cultural stratification — a phenomenon that occurs when a polymorphism is more frequent in one ethnic population but mistakenly taken to be correlated only with a trait or disease common to that group.

Chen explains, "For example, if you were to look for an association between the trait of using chopsticks and a putative polymorphism without considering that Asian people potentially could harbor this polymorphism in higher frequencies, you might end up concluding that this particular genetic variation causes people in general to use chopsticks.

"Because of this and other limitations of smaller sample sizes, we are planning further studies with more patients."

Cocaine addiction is a serious public health problem around the world and, in particular, the United States. According to the National Household Survey on Drug Abuse, about 1.8 million Americans were chronic cocaine abusers in 1998. Like all addictions, cocaine addiction is a complex disease influenced by many genes, in addition to other behavioral, psychological and environmental factors. However, unlike heroin and other addictive diseases, there are no current pharmaceutical-based treatment programs for cocaine addiction.

The research was supported by grants from the National Institute of Drug Abuse and the National Institutes of Health.

John D. Rockefeller founded Rockefeller University in 1901 as The Rockefeller Institute for Medical Research. Rockefeller scientists have made significant achievements, including the discovery that DNA is the carrier of genetic information. The University has ties to 21 Nobel laureates, six of which are on campus. Rockefeller University scientists have received this award for two consecutive years: neurobiologist Paul Greengard, Ph.D., in 2000 and cell biologist Günter Blobel, M.D., Ph.D., in 1999, both in Physiology or Medicine. At present, 33 faculty are elected members of the U.S. National Academy of Sciences. Celebrating its Centennial anniversary in 2001, Rockefeller - the nation's first biomedical research center - continues to lead the field in both scientific inquiry and the development of tomorrow's scientists.