A team of researchers led by scientists from the National Institute on Drug Abuse's Intramural Research Program has made a major advance in understanding the molecular basis of how cocaine produces its characteristic high, suggesting new targets for developing anti-addiction medicines. The findings, published in the April 24 issue of the Proceedings of the National Academy of Sciences, show that inactivating both the serotonin and dopamine transporters in the brains of mice dramatically reduces their experience of cocaine's rewarding, pleasurable effects. It has been known for some time that cocaine use affects the brain's dopamine system, but also that manipulating dopamine does not fully control cocaine's effects. Thus this study shows the critical importance of the serotonin system as well as the dopamine system in mediating cocaine's pleasurable effects.
"Currently, there is no medication that effectively blocks the brain's reward response to cocaine or that substantially relieves cocaine addiction, " says NIDA director Dr. Alan I. Leshner. "The finding that serotonin as well as dopamine plays a critical role in the development of cocaine addiction suggests a new biological target and approaches for developing such medications."
Dr. George Uhl, head of the NIDA research team, explains that his team studied genetically altered mice that were missing one or both copies of the dopamine transporter (DAT) and serotonin transporter (SERT) genes. They found that mice with even a single DAT gene copy and no SERT copies still experienced reward/reinforcement following cocaine administration. However, cocaine-induced reward/reinforcement behavior was totally blocked in mice with no DAT gene and either half-normal or absent SERT.
Dr. Uhl says, "These results demonstrate the dependence of cocaine reward on both DAT and SERT blockade. They define for the first time the brain molecular targets necessary for cocaine reward. They suggest that drugs acting on both dopamine and serotonin brain systems might be needed to effectively combat cocaine addiction."