March 2001

From Yale University

Enzyme involved in cocaine addiction identified by scientists at Yale and Rockefeller Universities

Researchers at Yale and Rockefeller Universities have found that an enzyme called Cdk5 regulates the action of dopamine, a chemical messenger associated with cocaine's "rush" and with addiction to cocaine and other drugs.

According to Jingshan Chen, assistant professor of psychiatry at Yale, the Cdk5-related process leads to changes in brain cells that are thought to play a key role in cocaine addiction.

"This work adds to our increasing understanding of the changes that cocaine causes in the brain at the molecular level to produce addiction," said Eric Nestler, who worked on the study while he was professor of pharmacology and neurobiology at Yale. "With this knowledge it should be possible to eventually develop more effective treatments for cocaine addiction."

The research, published in today's issue of Nature, focuses on long-term neuroadaptive changes associated with drug addiction. One of these long-term changes first identified by Jane Taylor at Yale, is the induction of stable delta-FosB proteins in nucleus accumbens, a brain region that mediates the drug'srewarding and reinforcing effects. Delta-FosB is a transcription factor, which means that it regulates expression of other genes.

Using a new technology called DNA array analysis, the team found that exposure to cocaine caused increased levels of delta-FosB in dopamine-sensitive brain cells. The delta-FosB then triggered an increase in Cdk5 levels. Genetically engineered transgenic mice or rats injected with cocaine for eight days showed elevated levels of Cdk5 compared with control animals.

Nestler said the cocaine-exposed rats also showed increases in motor activity after they were given cocaine. Rats that were treated with roscovitine, a drug that slows the action of Cdk5, displayed motor activity that was nearly double that of untreated rats.

"Since Cdk5 plays an important role in re-organization of cellular structures of neurons, we think that delta-FosB may mediate some long-term structural changes via Cdk5 and lead to drug addiction," said Chen.

Nestler said that chronic cocaine use normally causes sensitization, which progressively increases the degree of locomotor activity. When he and the team infused a Cdk5 inhibitor into the nucleus, cocaine's ability to produce sensitization was markedly enhanced. Therefore, the increase in Cdk5 induced by delta-FosB seems to represent a normal brake on the effects of cocaine.

"These findings indicate that cocaine-induced increases in Cdk5 levels may dull the brain's response to cocaine exposure," said Nestler, who is now Chair of the Department of Psychiatry at the University of Texas Southwestern Medical Center at Dallas. "This could contribute to a phenomenon observed in human addicts, who often report a diminishing pleasurable effect of cocaine with repeated use."

In addition to Chen and Nestler, other researchers on the study included Jane Taylor of Yale, James Bibb, Paul Greengard, Per Svenningsson, Akinori Nishi, Gretchen Snyder, Zachary Sagawa and Angus Nairn of the Rockefeller University; and Charles Ouimet from Florida State University.











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