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Dopamine in Striatum Linked To Action of SSRIs

It looks as if SSRI antidepressants might affect the neurotransmitter dopamine as well as serotonin, at least in the striatal region of the brain.

The striatum, a large cluster of nerve cells tucked away within the depths of each hemisphere of the brain and heavily dependent on the neurotransmitter dopamine, is crucial for motion control, reward, and emotion. And new research suggests that the SSRI antidepressants may have some part to play with this region.

Studies have suggested that depression might involve the striatum. For example, the concentration of dopamine and the density of striatal dopamine transporters were found to be abnormal in patients with major depressive disorder. Previous research has suggested that the actions of antidepressants are influenced by dopamine and by the interplay of serotonin and dopamine.

John Dani, Ph.D., a professor of neuroscience at Baylor College of Medicine, and colleagues treated striatal slices from mouse brains with the SSRI antidepressant fluoxetine. They found that such treatment tricked transporters on striatal nerves that use dopamine as their neurotransmitter into ferrying serotonin instead of dopamine into striatal nerve terminals. Further, serotonin carried into these terminals was subsequently discharged along with dopamine. When the researchers injected mice with fluoxetine, it seemed to lead to the same serotonin "freeloader" phenomena in the striatum that fluoxetine treatment had produced in vitro. The researchers reported their findings in the April 7 Neuron.

In an accompanying editorial, David Sulzer, Ph.D., an associate professor of psychiatry at Columbia University, and Robert Edwards, M.D., a professor of neurology at the University of California, San Francisco, said, "The evidence that antidepressants induce serotonin accumulation by dopamine neurons has now been significantly advanced.... [However,] it is not yet known if such serotonin release by dopamine neurons contributes to the therapeutic effect of these agents."

Dani and his coworkers think that it might. "We can conclude...that the extremely dense dopamine transporters in the striatum are able to transport serotonin into dopamine terminals when extracellular serotonin is elevated," they said in their report. "Normally, this process may be of little significance because of its low efficiency and the low extracellular serotonin concentration. However, it may play a functional role when serotonin is elevated for prolonged times during treatment with SSRI-type antidepressants."

The study was funded by the National Alliance for Research on Schizophrenia and Depression and the National Institutes of Health.

An abstract of "Corelease of Dopamine and Serotonin From Striatal Dopamine Terminals" is posted online at <www.neuron.org/content/article/abstract?uid=PIIS0896627305001261>.

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