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Pathway to Addiction

Researchers have the first strong evidence that a brain chemical called serotonin plays an important role in drug addiction. A report in tomorrow's Nature shows that genetically engineered mice whose brain cells lack a receptor for serotonin appear to be especially vulnerable to the effects of cocaine. Further studies of the mice may help scientists track down at least a few of the genes that predispose people to addictions.

Neuroscientist René Hen of Columbia University and his colleagues used a standard test to gauge the animals' craving for cocaine. They trained the mice to press a lever to receive an injection of the drug and monitored how hard they were willing to work to receive a hit. The "knockout" mice lacking the serotonin-1B receptor pressed the lever far more often than normal mice--and eventually received twice as many injections. Moreover, the brains of the knockout mice resembled those of normal mice already "sensitized" to cocaine. After repeated exposure to the drug, mouse brains express higher amounts of certain long-lasting proteins, called chronic FRAs. Those proteins were abundant in knockout mice that had never been given cocaine. The animals--which are more aggressive and impulsive than normal mice, but have no other obvious developmental problems--will also drink twice as much alcohol as normal mice.

Although scientists have known that cocaine blocks the transmitter that mops up serotonin after it's been used to signal nerve cells, the neurotransmitter's role in addiction has largely been ignored, says pharmacologist Francis White of the Finch University of Health Sciences/The Chicago Medical School. One reason, he says, is that serotonin's 14 known receptors make it hard to tease out and study individual effects. Although serotonin has been implicated in depression, obsessive-compulsive behaviors, eating disorders, and aggressiveness, the brain chemical dopamine--which is part of the brain's reward system--has gotten almost all of the attention in addiction studies, White says.

Hen hopes the mice might provide "a model of vulnerability," which will help researchers pinpoint the changes in the brain that determine how people respond to drugs. He says his team is now working to determine exactly which brain pathways and regions are affected by the missing serotonin-1B receptor.