Jefferson Scientists Find Evidence Of Greater Sensitivity To Addictive Drugs In Adolescence

Scientists led by Michelle Ehrlich, M.D., professor of neurology at Jefferson Medical College of Thomas Jefferson University in Philadelphia and a member of the Farber Institute for Neurosciences at Jefferson, and Ellen Unterwald, Ph.D., associate professor of pharmacology at the Temple University School of Medicine in Philadelphia, found a greater increase in a certain protein in the part of the adolescent mouse brain called the striatum following chronic exposure to drugs such as amphetamine or cocaine than they did in either very young mice or adults.

Such psychostimulant drugs affect the brain's striatum in different ways, potentially affecting both movement and locomotion, or the "reward" system. This "molecular adaptation," says Dr. Ehrlich, could be significant. "An increase in this protein may be important because it could also affect other molecules that could lead to long-lasting changes in the brain in response to psychostimulant drugs." The protein, called Delta FosB, is a transcription factor and plays a role in regulating gene expression. Earlier research by other scientists had shown increased amounts of Delta FosB in adult brains following chronic exposure to psychostimulants.

The team, which includes scientists at the Nathan Kline Institute in Orangeburg, New York, reports its findings November 1 in the Journal of Neuroscience.

"Periadolescence and adolescence are when addiction usually begins, so we will be looking to see if this increase is a clue to sensitivity to addiction and sensitivity to such drugs as therapeutic agents," says Dr. Ehrlich.

"Many molecules have been implicated in both therapeutic and addictive responses to psychostimulants," she notes. Dr. Ehrlich's team examined how the mice responded to cocaine and amphetamine. They looked at the effects of the drugs on Delta FosB in three different age groups: post-weanling, or day 22; adolescent, days 33-43; and adult, or about six weeks of age. Each group was given cocaine, amphetamine or saline.

They found that in the adult, Delta FosB was increased in the caudate nucleus, part of the striatum associated with motor activity, particularly hyperactivity and attention deficit syndrome. They did not see similar increases in the accumbens, another part of the striatum that is associated with reward from psychostimulants. In the post-weanling mice, there was an increased response in the caudate only to amphetamine.

When they looked at the adolescent mice, they found Delta FosB was made in increased amounts in both areas of the brain in response to the drugs.

"The implications are that there is an increased adaptation in the younger brain than in the older brain to these psychostimulants," she says.

The results raise several questions. "What are the behavioral correlates of this increase in protein activity?" says Dr. Ehrlich. "Does this make them more prone to self-administer psychostimulants, meaning these mice could be a model of addiction? Does this make them more prone to hyperactivity? Are they more tolerant of higher doses of medication? These questions are relevant to addiction and to therapeutic use of these medications in these age groups."

Dr. Ehrlich and her co-workers have begun looking at the causes of such adaptations in the brain. They are studying some of the specific molecules involved in new mouse models. "At this point, many of the drugs that are being used therapeutically and in the treatment of addiction are being targeted to very restricted molecules," she says. "The question is, would they be better targeted to other molecules?"