Research Reveals How Prozac Triggers New Brain Cell Growth

By Kathleen Doheny
HealthDay Reporter

TUESDAY, May 16 (HealthDay News) -- Experts have long suspected that one way antidepressants such as Prozac, Paxil and Zoloft dispel depression is by stimulating the growth of new brain cells.

Now, researchers say they've zeroed in on just how that happens.

"It was clear that this generation of new neurons is important for the action of antidepressants," explained lead researcher Grigori Enikolopov, an associate professor at Cold Spring Harbor Laboratory in Cold Spring Harbor, N.Y.

His team report the findings in this week's online edition of the Proceedings of the National Academy of Sciences.

The researchers decided to look at how the use of selective serotonin reuptake inhibitor (SSRI) antidepressants -- the widely used class of drugs that includes Celexa, Paxil, Prozac and Zoloft -- might spur brain cell growth. To do so, they tracked the way in which stem cells -- undifferentiated cells that can grow into specialized cells -- became neurons in a special mouse model given the antidepressant Prozac (fluoxetine).

"Stem cells in the brain go through several steps before they become neurons," Enikolopov said. Examining the cascade of events, his team found that "cells which are born from the stem cells, called amplifying progenitors, are the cells being targeted by Prozac," he said. According to Enikolopov, Prozac zeroes in on these amplifying progenitors and increases their numbers. Within three to four weeks, his team noticed an increased number of mature neurons.

The Cold Spring researchers noted that about four years ago, other researchers found that animals that received Prozac showed a rise in neuron growth. Then, about two years ago, other experts found that this generation of new neurons is necessary for the drug to achieve its behavioral effect of lifting depression, Enikolopov said.

He believes the latest finding is another piece to add to the puzzle of how SSRI antidepressants work. However, it does not provide the entire answer. "What happens between having more neurons and decreasing depression, the changing of mood -- that is unanswered," he said.

His team used a new mouse strain that made it easy to identify and track these early progenitor cells. The work "defines a cellular target for antidepressants," Enikolopov said. "What has been known for 20, 30 years is that Prozac increases the level of serotonin [a neurotransmitter associated with good mood.]" But what wasn't known was why Prozac takes three or four weeks to start working.

"Alcohol, Valium, they work immediately," he says. "But these selective serotonin reuptake inhibitors, they need three or four weeks."

"Three to four weeks is basically comparable, in our schedule, of the 28 to 30 days it takes to go from a stem cell to a neuron," he pointed out.

Prozac first went on the market in 1987 in the United States as the first SSRI. These medications selectively target serotonin, inhibiting its reabsorption into the cell so there is more available.

Dennis Steindler, executive director of the McKnight Brain Institute at the University of Florida, Gainesville, applauded the Cold Spring work.

"The beauty of this study is, a new model has been generated," he said.

"This study is in essence a 'readout,' a neurogenic readout, whereby using this [mouse] model, the Enikolopov group found exactly the cell that increases its rate of proliferation," he said. "That leads to generating more neurons as a result of taking this drug."

"It could have been the stem cell, progenitor or a young neuron. They found it was the progenitor cell," Steindler said.

SOURCES: Grigori Enikolopov, Ph.D., associate professor, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.; Dennis Steindler, Ph.D., executive director, McKnight Brain Institute, University of Florida, Gainesville, Fla; May 15-19, 2006, Proceedings of the National Academy of Sciences Early Edition.

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