Serotonin-deficient mice brains are more vulnerable to social stress and do not respond to a standard antidepressant, fluoxetine (Prozac), which works by boosting serotonin transmission between neighboring neurons, revealed a Duke study. These results may help explain why some people with depression seem unresponsive to treatment with selective serotonin reuptake inhibitors (SSRIs), the most common antidepressant drugs available in the market today. It also points to several possible therapeutic strategies to explore for treatment-resistant depression.
Senior author Marc Caron said, "The results are very exciting because they establish in a genetically defined animal model of serotonin deficiency, that low serotonin could be a contributing factor to the development of depression in response to psychosocial stress and can lead to the failure of SSRIs to alleviate symptoms of depression."
AdvertisementDuring the study, researchers used a transgenic mouse strain called Tph2KI that has only 20-40 percent of normal levels of serotonin in its brain. Tph2KI mice harbor an extremely rare mutation that was first identified in a small group of people with major depression. In the new study, researchers tested the responses of these mice to a type of psychosocial stress- social defeat stress.
Researchers found that a 3-week treatment with Prozac following the exposure to stress alleviated depression-like symptoms in normal mice, but not mutant mice. Caron said, "Prozac and other SSRIs work by blocking the ability of cells to recapture serotonin, so it makes sense that the drugs would be less effective in animals with abnormally low levels of serotonin to begin with."
The study is published in the Proceedings of the National Academy of Sciences.