Minimolecule may explain how antidepressants work

Prozac increases levels of a microRNA

Scientists have uncovered a new chemical process that may explain how antidepressants like Prozac work. The newly found mechanism also suggests why the drugs take weeks to start helping and may one day point to new therapies for depression.

A team from Paris has found that fluoxetine, commonly known as Prozac, increases the amount of a particular microRNA called miR-16 in the brain. A microRNA is a small piece of RNA that prevents the translation of messenger RNA into protein.

The miR-16 microRNA slows the formation of a cleaner-upper protein called the serotonin transporter. The protein clears away serotonin, a chemical that helps brain cells communicate and alleviates depression, from the space between brain cells.

With less of the cleaner-upper to gobble up serotonin in the brain, there’s more serotonin in the spaces between brain cells, and depression symptoms lessen for some patients. The results are published in the Sept. 17 Science.

“It’s an exciting development,” says pharmacologist Alan Frazer of the University of Texas Health Science Center at San Antonio. “As far as I know, it’s the first demonstration of a microRNA able to affect serotonin transporter expression.”

Scientists knew that Prozac and other drugs like it, called selective serotonin reuptake inhibitors or SSRIs, somehow blocked the action of the serotonin transporter and left more serotonin in the brain. But exactly how the drugs worked, and why they took so long to have an effect, was a mystery.

Researchers were studying the effects of SSRI treatment in the mouse brain and noticed that treated mice had fewer serotonin transporters than untreated mice. But the transporters’ blueprints, called messenger RNAs, were still around at normal levels. The researchers suspected that a microRNA might ultimately be responsible for preventing the creation of the transporter during SSRI treatment.

Using a computer program, the team found the miR-16 microRNA could bind to the messenger RNA encoding the serotonin transporter and prevent its translation into a protein. When mouse brain cells were treated with Prozac, the drug increased the production of miR-16 in mouse brain cells. In turn, miR-16 decreased the amount of serotonin transporter that took up serotonin. This means the drug doesn’t act on the serotonin transporter directly, but acts on the intermediate microRNA instead.

Results also showed that after some time, Prozac worked through miR-16 to cause a set of brain cells that don’t normally produce serotonin to produce the brain chemical, raising the overall level in the brain. This effect took longer and could explain the delay in Prozac’s ability to alleviate depression.

Finally, the researchers found that mice could be treated with miR-16 instead of Prozac and still experience antidepressant benefits.

“We think that miR-16 can be seen as a new target for antidepressant action,” says cellular biologist Sophie Mouillet-Richard of the French National Institute of Health and Medical Research.

The findings may also help treat patients more effectively with SSRIs, says neuroscientist Olivier Berton of the University of Pennsylvania in Philadelphia.

“Only a proportion of the patients that are receiving these drugs are responding, and there is a very high rate of relapse,” says Berton. “By looking at this new mechanism in screening, that could be a way to predict which patients are going to respond or not to the treatment.”

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