Researchers supported by the National Institute on Drug Abuse (NIDA) have identified a process in the brain that may underlie addiction to cocaine and other drugs of abuse. Their research indicates that repeated exposure to cocaine causes a change at the level of gene expression that leads to altered levels of a specific brain protein called cyclin-dependent kinase 5 (Cdk5). The same group of researchers previously found that Cdk5 regulates the action of dopamine, a chemical messenger in the brain associated with the cocaine's pleasurable "rush" and with addiction to cocaine and other drugs. The Cdk5-related process leads to changes in brain cells that are thought to play a key role in cocaine addiction.
Dr. James Bibb, Dr. Paul Greengard, and colleagues at the Rockefeller University in New York City, together with Dr. Eric Nestler at the University of Texas Southwest Medical Center in Dallas, report their findings in the March 15 issue of the journal Nature.
"This research provides a valuable insight into the step-by-step molecular adaptations that the brain makes in response to drugs," says NIDA Director Dr. Alan I. Leshner. "These adaptations result in long term changes at the cellular level that are involved in the development of addiction."
Dr. Bibb and his colleagues found that, in dopamine-sensitive brain cells of rodents, exposure to cocaine causes gene-mediated increases in levels of delta-FosB, a protein that in turn triggers increases in Cdk5 levels. Mice genetically engineered to "overexpress" delta-FosB as well as rats injected with cocaine for 8 days showed elevated levels of Cdk5 compared with rats injected with a saline solution. The cocaine-exposed rats also exhibited increases in motor activity following cocaine administration, consistent with cocaine's stimulant actions. In rats treated daily with roscovitine, a compound that inhibits the action of Cdk5, motor activity one hour after cocaine exposure was nearly double that of rats that were not treated with the Cdk5 inhibitor. These behavioral findings indicate that cocaine-induced increases in Cdk5 levels may dampen the brain's response to cocaine exposure, which would lead cocaine abusers to use more of the drug to achieve the desired effect.
"These results suggest that delta-FosB-mediated changes in Cdk5 levels and the resulting alterations in dopamine signaling in brain cells contribute to adaptive changes in the brain related to cocaine addiction," Dr. Bibb says.
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