Yale Bulletin and Calendar

March 23, 2001

Volume 29, Number 23

Study demonstrates role of
enzyme in cocaine addiction

Researchers at Yale and Rockefeller University 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," says 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 the March 15 issue of Nature, focuses on long-term neuroadaptive changes associated with drug addiction. One of these long-term changes, first identified by research scientist Jane Taylor of Yale, is the induction of stable delta-FosB proteins in nucleus accumbens, a brain region that mediates the drug's rewarding 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, Nestler and Taylor, other researchers on the study included James Bibb, Paul Greengard, Per Svenningsson, Akinori Nishi, Gretchen Snyder, Zachary Sagawa and Angus Nairn of Rockefeller University and Charles Ouimet from Florida State University.

-- By Karen Peart

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University's longstanding focus on humanities

Transformation brought about by Yale women

Fleury charts future of Yale Engineering

Study demonstrates role of enzyme in cocaine addiction

Foreign minister, law professor to debate the Taliban

Maynard Mack, world-renowned scholar of Shakespeare, dies

Richard Ruggles, noted economic statistician, dies

Yaledancers to perform spring concert at the Palace theater

The eyes will be the focus of two events hosted by Unite for Sight

Gemini Duo to present concert benefiting St. Thomas More

Conference looks at state's water conflicts

Memorial service is planned for Claude Palisca