Compound appears to block cravings for cocaine, JHU researchers find

Researchers at Johns Hopkins have unraveled the molecular foundations of cocaine's effects on the brain and identified a compound that appears to blocks cravings for the drug in cocaine-addicted mice. The compound, already proven safe for humans, is undergoing further animal testing in preparation for possible clinical trials for cocaine addicts, the researchers say.

"It was remarkably serendipitous that when we learned which brain pathway cocaine acts on, we already knew of a compound, CGP3466B, that blocks that specific pathway," said Solomon Snyder, a professor of neuroscience in the Institute for Basic Biomedical Sciences at the Johns Hopkins University School of Medicine. "Not only did CGP3466B help confirm the details of cocaine's action, but it also may become the first drug approved to treat cocaine addiction."

Details of the research appear today on the website of the journal Neuron.

Snyder, who won a 1978 Lasker Award for identifying the brain's own opiate receptors, and his team have studied the brain for decades. Twenty years ago, they discovered that the gas nitric oxide (NO) is a major player in the complex signaling network that lets our neurons coordinate activity with one another. Snyder and his team have since studied many of the proteins in that network that interact with nitric oxide.

In the most recent study, M.D./Ph.D. student Risheng Xu worked with other members of Snyder's team to investigate whether cocaine works through the NO signaling network, and if so, how. Using mice, they found that cocaine induces NO to react with GAPDH, a protein best known for regulating how cells store and use sugars. At low doses of cocaine, the GAPDH will stimulate the neuron, but at higher doses it activates the cell's self-destruct pathway.

"This explains why cocaine can have very different effects depending on the dosage," Xu says.

The team then performed experiments that indicated that CGP3466B, which blocks the reaction between NO and GAPDH, also blocks the effects of cocaine.