Mice on Prozac may help improve serotonin-based antidepressants

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Depressed mice, like depressed humans, often appear listless and antisocial, the result of aberrant levels of brain chemicals such as serotonin.

The most commonly prescribed antidepressant drugs, Prozac and other drugs of its class, act to normalize levels of serotonin. But by comparing mice that had been given Prozac with mice given an alternate drug, researchers from Rockefeller University have identified a new class of chemicals that could offer better control over serotonin and more effective treatments for the debilitating mental illness.

Serotonin is a neurotransmitter; it plays a key role in passing messages between cells in the brain by binding to and activating specific receptors located at the tips of neurons. There are seven different receptors, each with a specific expression pattern and function, on which serotonin works. But drugs like Prozac, which act by increasing serotonin levels, do not target any one receptor in particular.

The new research, however, from the lab of Nobel Prize winner Paul Greengard, finds that powerful antidepressant effects are seen even when only one receptor, called 5-HT 6 , is targeted.

"Using chemicals that either specifically activated or inhibited the 5-HT 6 receptor, we compared the biochemical and behavioral results with what we see with Prozac," says Greengard, Vincent Astor Professor and head of the Laboratory of Molecular and Cellular Neuroscience. In the brain, Prozac causes a number of recognizable changes that can be measured by researchers, including the activation of certain proteins. When the researchers compared the effects of their chemical, called EDMT, on those proteins against the effects of Prozac, they noted little difference.

They also compared how the mice behaved when they were given Prozac with how they behaved on EDMT. Using an experiment in which a mouse's level of depression can be assessed by its level of activity under duress, the research found that EDMT had an effect similar to that of Prozac. The study implies that much of Prozac's mechanism of action, which remains poorly understood despite the drug's nearly 20 years on the market, could be linked to its effect on 5-HT 6 .

"Our results show that the 5-HT 6 receptors play a large role in the antidepressant effects of serotonin reuptake inhibitors such as Prozac," says Greengard. "This suggests that if chemicals were developed that selectively activate the 5-HT 6 receptor, they might represent a new class of antidepressant drugs that could improve the therapeutic outcome of serotonin-based antidepressants."

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