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Simple Model Gives Insight Into SSRI's Cellular Effects

By Anette Breindl
Science Editor

Using yeast as a model system, scientists have gained new insights into the effects of selective serotonin reuptake inhibitors (SSRIs) on cells.

SSRIs are a major class of antidepressants including Prozac (fluoxetine, Eli Lilly and Co.) and Celexa (citalopram, Forest Laboratories Inc.). They were developed as a way to increase serotonin signaling, which is reduced in depression. They do so, at least in part, by preventing serotonin that is released by neurons from being recycled back into those neurons. As a result, the transmitter stays in the synapse for longer, activating its receptors.

"I'm not saying that that's not correct," Ethan Perlstein told BioWorld Today. "But I don't think that that's the whole story" of how SSRIs treat depression.

The most glaring piece of evidence that there is more to the story is the time it takes for SSRIs to work. While their effect on serotonin levels is near-immediate, it takes chronic administration for weeks or months for them to achieve their real goal: to make patients feel better.

Perlstein, who is at Princeton University's Lewis-Sigler Institute for Integrative Genomics, and his team published another piece of the puzzle in the April 18, 2012, issue of PLoS ONE. They looked at the effects of SSRIs by studying a model organism that lacks that target, serotonin and its transporters, altogether: Saccharomyces cerevisiae or brewer's yeast.

Though it makes beer, which is sometimes used as a misguided home remedy for depression, yeast is clearly not the place to study the psychological effects of antidepressants. But Perlman is not the first to put it to use for studying brain disorders. Some scientists have used it successfully to understand physical aspects of proteins that contribute to neurodegenerative disease. (See BioWorld Today, Nov. 7, 2007.)

Perlstein's lab uses yeast to look at the effects of therapeutic drugs on basic aspects of cell physiology by testing whether they affect growth. He said that growth is a simple phenotype – "in some ways, deceptively simple," because effects in many different pathways can ultimately lead to changes in growth.

For their study of SSRIs, they chronically administered Zoloft (sertraline, Pfizer Inc.) to yeast cells. Because yeast does not use serotonin for signaling, it has no serotonin transporters, either. But the drug nevertheless was able to enter cells – in fact, in earlier studies Perlstein and colleagues had shown it was toxic to them at high enough doses, which was unexpected, since the common wisdom is that it is not possible to overdose on selective serotonin reuptake inhibitors because they are not toxic to cells.

"That's why [SSRI's] got so big," Perlstein said. "But here it was, killing yeast cells."

In the work now published in PLoS ONE, the researchers looked at the fate of SSRIs in yeast cells in greater detail by radiolabeling Zoloft and looking at where, exactly, it ended up in the cells.

They found that most of it ended up in the cell membrane. "Yeast cells are accumulating this drug in their membranes," Perlstein said – to an extent that "the membranes sort of drown in the drug."

That accumulation led to what is technically known as "curvature stress" – basically, overloaded membranes bulged inward. That in turn set off autophagy as a protective response in the affected cells.

Perlstein contended the work supported the idea that SSRIs work partly by stimulating the growth of new cells in the brain. Growing cells need (among other things) bigger membranes, and membrane transport is coupled to cell growth via signaling pathways.

When SSRIs accumulate in membranes, they might stimulate such pathways directly. But given the sheer amount of cell membrane that exists in the brain, as well as the pathways such as autophagy trying to maintain membrane homeostasis, it is easily possible that effects of SSRIs that occur via their accumulation in membranes might take some time to appear.

Perlstein said that he and his colleagues want to look at the time course of Zoloft's effects in more details. "We need to get a better grip, in yeast cells, on chronic vs. acute administration" of the drug, he said.

But they also want to make sure that their work is not just about how Zoloft cheers up yeast. They are currently replicating the experiments now published in PLoS ONE in rat neuronal cell lines.