Princeton University researchers observed a self-degradation response to the antidepressant Zoloft in yeast cells that could help provide new answers to lingering questions about how antidepressants work. Five minutes after Zoloft treatment, a yeast cell (A) shows elevated activity, particularly in the vacuole (B), a cell component that recycles damaged or dead cellular material. In the cell vesicle (C), Zoloft resulted in the formation of a black membrane whorl, a thick buildup of membrane layers, on the internal membrane. An image from another yeast cell vesicle (D) shows the internal membrane has become a crescent-shaped bulge as the vesicle enters autophagy and begins to break down. Twenty minutes after Zoloft treatment, a cell vacuole (E) exhibits an unknown, active swirl of membrane growth not seen in the untreated cells that could be part of the final degradation process. (Image by Ethan Perlstein)
Princeton University researchers have observed a self-degradation response to the antidepressant Zoloft in yeast cells that 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 in the journal PLoS ONE, researchers based in the lab of Ethan Perlstein, an associate research scholar in Princeton’s Lewis-Sigler Institute for Integrative Genomics and senior lecturer in molecular biology , report that sertraline — trademarked as Zoloft — accumulated in the internal membranes of baker’s yeast cells.
This buildup caused a swelling and sharp curvature in the membranes of vesicles, bubble-like cell components with a hand in cell metabolism, movement and energy storage. The vesicles then went into autophagy, a protective response in which cells recycle excess or damaged membrane.
But yeast cells lack serotonin, which is the primary target of antidepressants, Perlstein said. 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 engage in pharmacological activity beyond regulating serotonin. Perlstein worked with co-first authors Jingqui Chen and Daniel Korostyshevsky, as well as Sean Lee, all three senior research specialists in Perlstein’s lab.
Although antidepressants 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, Perlstein said. Antidepressant accumulation has been observed in the membranes of human cells, the researchers report, but is considered benign.
If, however, 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.
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 that regulates brain-cell growth.
Perlstein explains his findings as follows:
"The key finding of this paper is that the antidepressant sertraline/Zoloft accumulates within an organism lacking serotonin and induces autophagy, which is a protective mechanism cells use to recycle excess or damaged cell membrane. Specifically, we observed distortions, bulging and buckling in the membrane layer of vesicles inside cells treated with sertraline.
"We saw these effects in the yeast species Saccharomyces cerevisiae, or baker’s yeast. Despite it being a simple, single-cell organism, the basic cellular ’plumbing’ of yeast has been preserved by evolution in more complex organisms, including humans.
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