The antidepressant Zoloft affects cell membranes in yeast, which lack the brain chemical the drug targets.
Yeast on antidepressants. I’m Bob Hirshon and this is Science Update.
So-called SSRI antidepressants, like Prozac and Zoloft, are widely used. Yet it’s still not clear exactly how they work. They’re designed to target a brain chemical called serotonin, which promotes well being. But evolutionary pharmacologist Ethan Perlstein, of Princeton University’s Lewis-Sigler Institute, gave small doses of Zoloft to yeast, which don’t use serotonin at all.
We found these membrane changes, that to us were consistent with the idea that the membranes were actually soaking up the Zoloft, and by doing so, it changed their structures. The membranes seemed to actually distort.
Perlstein says the Zoloft appears to cause minor damage to the membrane, which the cell then repairs and strengthens similar to the way we build muscles from exercise. Since brain chemicals like serotonin are packaged in membranes, it’s possible that this contributes to the drugs’ therapeutic effect. I’m Bob Hirshon for AAAS, the Science Society.
Making Sense of the Research
In 1987, the FDA approved the anti-depressant drug Prozac, the first selective serotonin reuptake inhibitor, or SSRI. Today, Prozac and other SSRIs, including Zoloft, Paxil, Celexa, and Lexapro, are the most widely prescribed psychiatric drugs. SSRIs affect the transmission of serotonin, a key brain chemical in mental health.
Like other brain signaling chemicals, or neurotransmitters, serotonin stimulates certain neurons, or brain cells, to release electrical signals. This happens in the gap between two neurons, called a synapse. As it's understood now, SSRIs prolong this activity by preventing serotonin from being quickly re-absorbed back into the neuron from which it came.
However, the details of exactly how SSRIs work remain unclear. The brain is extremely complex, and there is probably a lot more to SSRIs than we currently understand. Perlstein decided to do this particular experiment because a typical dose of the anti-depressant Zoloft (generic name: sertraline) kills yeast. He wondered if this was basically an overdose, and whether smaller doses would have a different effect.
When he gave yeast cells very small quantities of Zoloft, he did find a potentially beneficial effect. The yeast's cell membranes became distorted, a sign of minor damage that triggers autophagy (the process by which cells consume and recycle damaged material). The end result seems to be that the membranes are actually strengthened, just as exercising causes minor damage to muscle tissue that's then rebuilt stronger than before.
That's especially interesting because yeast don't have any serotonin in their systems, nor do they have receptors that bind to serotonin. So the main action of an SSRI like Zoloft would have no effect on yeast. On the other hand, human cells have membranes, so the drug's effect on yeast probably occurs in human patients in some form.
It's not yet clear that strengthening cell membranes would actually improve a patient's mood. But within a cell, neurotransmitters like serotonin are packaged in little membranes called vesicles. It's possible that strengthening these vesicles could allow more serotonin to get where it needs to go. Since this strengthening process would take time, that could explain why SSRIs take weeks to become fully effective—a longstanding mystery, since blocking the reuptake of serotonin should happen immediately.
Now try and answer these questions:
- What is an SSRI?
- Why was it surprising that Zoloft affected yeast?
- How might this apply to its effect on humans?
- How might this help explain why SSRIs take weeks to work?
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