University Of Virginia Researchers Link Cocaine Addiction Responses To Biological Clock Genes

"This exciting new research has given us a clue to the specific genetic mechanisms that influence vulnerability to addiction," says Alan I. Leshner, director of the National Institute on Drug Abuse, which funded the study with the National Institute of General Medical Sciences.

"Once it is clear, these mechanisms could become the basis for predicting who is most at risk for addiction and thus become a major aid in preventing this national health problem."

Besides enabling the potential development of drugs to treat cocaine addiction, this research holds out the prospect that so-called "clock" genes -- which are involved in setting and maintaining the body's internal clock -- might have other, as yet undiscovered, roles in the body and brain. These studies also hold hope for discovering common biological abnormalities underlying sleep/wake disturbances and mood disorders.

"This study opens up the field of drug studies to thinking how a totally unexpected set of genes functions in response to drugs," says Jay Hirsh, professor of biology at U.Va. and senior author of the report. For several years he has been seeking to understand the genetics of behavioral responses to cocaine.

Hirsh and his team, which includes doctoral student Rozi Andretic and technician Sarah Chaney, use fruit flies as their genetic models for humans. Fruit flies and humans have many genetic similarities; therefore the flies can be used as a tool to study the complex biological processes underlying drug abuse. Genetics researchers have long been able to manipulate genes in fruit flies for investigations of nervous system pathways.

The flies used by Hirsh's team were mutated to lack certain circadian genes. These insects did not become sensitized to cocaine, a process in which repeated doses of the drug produce increasingly severe responses. Flies containing functional circadian genes did become sensitized to cocaine. This indicates that certain circadian genes not only play a critical role in regulating the biological clock, but they may also function in ways that allow susceptibility to drug addiction.

For this study, cocaine was administered as an aerosol, and the insects' responses were closely monitored and videotaped for comparison. "We may come to see drug addicts more in terms of their genes, than as people who are not in control of their behavior. Apparently genes may be determining behavior in the case of drug abuse."

For the past several years, Hirsh has used the fruit fly to probe some of the brain's molecular mysteries, such as the circuitry involved in learning, memory, and muscle movement. While researching core communications pathways in the nervous systems of fruit flies, Hirsh and his colleagues reasoned that by testing the effects of cocaine on fruit flies, they might be able to better understand the molecular underpinnings of cocaine-induced behavior and addiction.

Last year, the team initially showed that normal fruit flies respond to crack cocaine in manners strikingly similar to vertebrates, developing sensitized responses to repeated doses of cocaine. The work laid the foundation for the current studies elaborating the possible molecular bases for cocaine addiction in people, including other recently published findings in the current online issue of Current Biology, (http://www.biomednet.com/library/abstract/JCUB.bb9p35) that implicate tyramine, one of the body's naturally occurring molecules, as the likely perpetrator of cocaine sensitization in fruit flies.