Researchers Identify An Enzyme That Regulates The Action Of Chronic Cocaine

Cocaine addiction develops through repeated exposure to the drug. In response, the brain attempts to maintain equilibrium by countering the effects of repeated drug administration. Chronic exposure to cocaine can set a series of chemical reactions in motion that lead to changes in the expression pattern of certain genes that then "feed back" to block the effects of cocaine. This succession of events appears to underlie the adaptive changes occurring in the addictive brain.

"By finding new inhibitors to this pathway, we might find compounds that have a palliative effect, removing the craving for cocaine similar to the way methadone removes the craving for heroin," says Research Associate James Bibb, senior author on the paper.

Cdk5 regulates certain effects of chronic cocaine by controlling the signaling of a neurotransmitter called dopamine. Dopamine is involved in fine motor control, reward and reproductive behavior, but abnormalities in dopamine signaling are associated with several neurological and psychiatric disorders, including substance abuse. When dopamine is released in the brain, it binds to a receptor and starts a cascade of biochemical events. Cdk5 is important to this process because it activates a key molecule involved in dopamine signaling called DARPP-32.

"We had shown earlier that DARPP-32 is a major player in the mechanisms by which dopamine produces its effects in the brain," says Greengard, Vincent Astor Professor and director of the Zachary and Elizabeth Fisher Center for Research on Alzheimer's Disease at Rockefeller. In the current study, the laboratory was looking for causes and co-factors of addiction.

Cdk5 became an appealing target for this research when co-author Eric Nestler, now at Univeristy of Texas Southwestern Medical Center in Dallas, first found that expression of the Cdk5 gene goes up in mice genetically altered to serve as a model for drug abuse. In subsequent behavioral studies conducted by Jane Taylor in the Psychiatry Department at Yale University, the effects of a drug, roscovitine, which inhibits Cdk5, were assessed in rats that were also exposed repeatedly to cocaine. The results indicated that cocaine-induced increases in Cdk5 levels serve to dampen responses to subsequent drug exposure. The Nature paper also shows that repeated exposure to cocaine enhanced the biochemical pathway between Cdk5 and DARPP-32 resulting in reduced sensitivity of the dopamine receptors involved in mediating the behavioral effects of cocaine.

Other coauthors on the paper include Per Svenningsson, Akinori Nishi, Gretchen Snyder, Zachary Sagawa, and Angus Nairn from Rockefeller University, Jingshan Chen from the Department of Psychiatry at Yale University, and Charles Ouimet from the Program in Neuroscience at Florida State University.

Funding for the research was provided by National Institute for Drug Abuse and the National Institute for Mental Health. Greengard is Vincent Astor Professor and head of the Laboratory of Molecular and Cellular Neuroscience at The Rockefeller University. He shared the 2000 Nobel Prize in Physiology or Medicine for his discovery of how dopamine and a number of other transmitters in the brain exert their action in the nervous system.

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 whom are on campus. At present, 32 faculty are elected members of the U.S. National Academy of Sciences, including the president, Arnold J. Levine, Ph.D. 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.