Researchers at Johns Hopkins and the National Institute on Drug Abuse have the first direct evidence that the brain's own natural opiate system is deeply involved in cocaine addiction and craving.
In a NIDA-supported study, investigators found proof that cocaine addiction causes a decrease in the amount of enkephalin and an increase in the number of the brain's receptors. The body's natural opiates, endorphins and enkephalins, work at the same sites in the brain as synthetic opiates, such as heroin.
"This is the first demonstration of a direct link between changes in the receptor sites in the brain that can be seen and measured by PET (positron emission tomography) scans, and the behavior of human drug abusers, namely the amount of craving for cocaine they experience," says James Frost, M.D., Ph.D., professor of radiology.
Scientists have long known that cocaine and opiates attach to different receptor sites in the brain. The new findings, based on PET scan studies of the brains of both cocaine-addicted and non-addicted individuals, also may lead to ways to predict if a recovering addict may start abusing drugs again, according to a report published in the November issue of Nature Medicine.
Frost's group, in collaboration with NIDA researchers, used PET to study changes in the number of mu receptors--a type of opiate receptor--in 10 cocaine-dependent men and seven nonaddicted controls by injecting them with an artificial drug that binds to these receptors. The drug, carfentanil, was made slightly radioactive so it would "light up" the area of the PET scan image where it attached to brain cells containing opiate receptors. The team found that the greater the binding to opiate receptors in the frontal cortex, anterior cingualate cortex, caudate and thalamus, the more severe the craving for cocaine. The increased binding to opiate receptor sites in the brains of cocaine abusers compared to controls lasted up to four weeks after withdrawal from the drug, the researchers report.
Chronic cocaine abuse causes the brain to reduce its production of enkephalins, Frost says. To compensate for the drop in enkephalin production, the brain produces more opiate receptors to "catch" as much of the remaining enkephalins as possible. This increase in the number of "empty" opiate receptors may produce the feeling of craving for cocaine, according to Frost.
"In order to get the brain to produce more enkephalins that will fill the receptors and stop the craving, the addict is driven to take more cocaine," Frost says. "This may be what keeps the drug abuser addicted.
This explains the finding by researchers at NIDA and elsewhere that the artificial substance buprenophine, which resembles heroin in its action, can reduce cocaine craving in some addicts, according to David A. Gorelick M.D., Ph.D., chief of the treatment branch at NIDA, and a co-author of the paper.
The new findings also suggest that researchers will be able to study the interaction of a variety of addictive drugs, such as cocaine, nicotine and alcohol, with the opiate system, according to Frost.
"By studying which receptor sites are active during a particular type of addiction, we'll be better able to determine how to treat it," he says.
Researchers first used PET to see where in the brain blood flow increased under various conditions, such as listening to music or reading, according to Frost. Then researchers at Hopkins pioneered the use of PET in the early 1980s to locate specific areas where drugs or natural nerve chemicals work, greatly extending the usefulness of this imaging technique.
To make PET scans, a physician injects into an individual a tracer drug--a drug that is "tagged" in such a way that it can be located in the body. For PET, the tracer drug is tagged with a small amount of radioactivity.
"Only a few micrograms of the tracer drug are administered so that PET images can be obtained without producing the drug's effects when it is injected," says Frost.
After the substance reaches the brain through the bloodstream, its radioactivity is used to create a map showing where the substance is concentrating in the brain. In the present study, the drug concentrated at opiate receptors.
The researchers are now studying whether changes in the binding to mu opiate receptors predict whether a person who has stopped abusing cocaine is at great risk of beginning again.
Other authors of the paper include Robin Stauffer (National Institute on Drug Abuse); Jon-Kar Zubieta, Hayden T. Ravert and Robert Dannals (Johns Hopkins).