Scientists Identify Gene Involved in Sensitivity to Cocaine
Scientists have taken another step in unraveling the role genetics plays in addiction. A new study published in the May 14 issue of Nature found that mice lacking a specific gene were more attracted to cocaine than were mice who had the gene. Led by Dr. Rene' Hen, a team of Columbia University researchers found that mice lacking the gene for one of the receptors for the brain chemical serotonin were more motivated to take cocaine than were other mice. The researchers also observed that these mice were more sensitive to both the motor and the rewarding effects of cocaine than were their normal counterparts.
"More and more evidence suggests that an individual's genetic makeup is a major factor in determining his or her vulnerability to drug addiction. Research studies such as this move us closer to identifying the specific genes involved in addiction and closer to new strategies for drug abuse prevention and treatment," said Dr. Alan I. Leshner, director of the National Institute on Drug Abuse, National Institutes of Health, the agency that funded the study.
Previous studies have also suggested that responses to drugs of abuse are affected by the activity of the brain chemical serotonin (5-HT), although the exact role this substance plays in addiction is unknown. To test whether the ability to respond normally to serotonin is critical to taking drugs, the researchers bred a strain of mice lacking one of the brain's receptors for serotonin, called the 5-HT(1b) receptor. These kinds of genetically altered mice are referred to as knockout (KO) mice. The mice were taught to self-administer cocaine, and researchers determined their breakpoint--the point where the mice no longer take the drug. Dr. Hen and his colleagues observed that when self-administering cocaine, the KO mice had significantly higher breakpoints than did their wild type counterparts (WT mice). The KO mice worked longer to obtain cocaine than did their WT counterparts. Yet, when food was the reinforcer, both groups had the same breakpoint, showing, researchers say, that the KO mice were not merely hyperactive but were actually more attracted to the cocaine than were the WT mice.
When placed in an open field and given increasingly large doses of cocaine, KO mice were also more active than WT mice and engaged in cocaine-induced repetitive behavior at much lower dosages. All of these findings suggest that mice lacking the 5-HT(1b) receptor gene are more responsive to cocaine than are normal mice.
Looking at changes in the brains of KO mice that might explain their preference for cocaine, Dr. Hen and his team discovered elevated levels of an immediate early protein (FosB) that is increased by chronic cocaine exposure and thought to be critical for both the locomotor and rewarding effects of cocaine. The high breaking point of KO mice in the self-administration of cocaine and their increased locomotor response to the drug are also characteristic of mice that have been put on a chronic regimen of cocaine and become sensitized to it.
The researchers believe 5-HT(1b) KO mice may be similarly responsive to other abused drugs. The mice have already been shown to engage in increased self-administration of alcohol, and there is evidence that these KO mice may exhibit more impulsive-like behaviors than other mice, a trait the researchers say is often associated with drug abuse. "For these reasons," said Dr. Hen, "we believe the 5-HT(1b) receptor KO mice are a good model that could enable us to characterize the biochemical changes that might be responsible for the increased propensity to abuse drugs."
NIDA has mounted a major initiative to study the genetics of vulnerability to drug addiction. Because of the complexity of the drug addiction problem, NIDA's new genetics initiative will employ a variety of strategies, including both human and animal genetic mapping studies, to enhance the probability of success.
NIDA supports more than 85 percent of the world's research on the health aspects of drug abuse and addiction. The Institute also carries out a large variety of programs to ensure the rapid dissemination of research information and its implementation in policy and practice. Fact sheets on health effects of drugs of abuse and other topics can be ordered free of charge in English and
Spanish by calling NIDA Infofax at 1-888-NIH-NIDA (-644-6432) or 1-888-TTY-NIDA (-889-6432) for the deaf. These fact sheets and further information on the genetics initiative and other research funded by NIDA can be found on the Home page at http://www.nida.nih.gov.