April 19, 2012

Yeast Cell Reaction To Zoloft Suggests Depression Cause, Drug Target Beyond Serotonin

A reaction to the antidepressant Zoloft that Princeton University researchers observed in yeast cells could help provide new answers to lingering questions among scientists about how antidepressants work, as well as support the idea that depression is not solely linked to the neurotransmitter serotonin.

In findings published this week in PLoS ONE, researchers based in the lab of Ethan Perlstein, a research fellow in Princeton's Lewis-Sigler Institute for Integrative Genomics, report that sertraline – trademarked as Zoloft – accumulated in the membranes of yeast cells. This accumulation occurred between the two lipid layers that make up the cellular membrane, causing a swelling and sharp curvature of the internal membrane.

Interestingly, Perlstein said, yeast cells lack serotonin, which is the primary target of antidepressants. Although the drugs are known to regulate serotonin, it is not completely understood how antidepressants interact with the body's brain cells and what effect, if any, this activity has on treating depression. Antidepressant accumulation has been observed in the membranes of human cells, the researchers report, but is considered benign.

But by observing a reaction to sertraline in an organism that does not contain the drug's conventional target, Perlstein and his co-authors have found significant evidence suggesting that antidepressants may have an active effect beyond regulating serotonin, he said.

If the membrane curvature the researchers found has therapeutic significance in treating depression, then the cell membrane could present an additional target for next-generation antidepressants.

"The serotonin transporter is one site where these drugs interact, but we show that's not all they do," Perlstein said. "These drugs have multiple effects on various targets in the cell – and one of the targets might be specific membranes themselves."

More immediately, Perlstein said, the activity of the drug in a serotonin-free organism supports existing research suggesting that depression might also be linked to diminished secretions of brain-derived neurotrophic factor (BDNF), a protein found in the brain.

"Our work provides some grounding for this alternative hypothesis of depression by suggesting that the serotonin-based theory might be an oversimplification and that the cause of depression is not a closed story," Perlstein said. "There is something else going on here."


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