Serotonin homeostasis in the materno-fetal interface at term: role of transporters (SERT/SLC6A4 and OCT3/SLC22A3) and monoamine oxidase A (MAO-A) in uptake and degradation of serotonin by human and rat term placenta.

AIM: Serotonin is crucial for proper fetal development, and the placenta has been described as a 'donor' of serotonin for the embryo/fetus. However, in later stages of gestation the fetus produces its own serotonin from maternally-derived tryptophan and placental supply is no longer needed. We propose a novel model of serotonin homeostasis in the term placenta with special focus on the protective role of organic cation transporter 3 (OCT3/SLC22A3). METHODS: Dually perfused rat term placenta was employed to quantify serotonin/tryptophan transport and metabolism. Placental membrane vesicles isolated from human term placenta were used to characterize serotonin transporters on both sides of the syncytiotrophoblast. RESULTS: We obtained the first evidence that serotonin is massively taken up from the fetal circulation by OCT3. This uptake is concentration-dependent and inhibitable by OCT3 blockers of endogenous (glucocorticoids) or exogenous (pharmaceuticals) origin. Population analyses in rat placenta revealed that fetal sex influences placental extraction of serotonin from fetal circulation. Negligible fetal serotonin levels were detected in maternal-to-fetal serotonin/tryptophan transport and metabolic studies. CONCLUSION: We demonstrate that OCT3, localized on the fetus-facing membrane of syncytiotrophoblast, is an essential component of feto-placental homeostasis of 5-HT. Together with 5-HT degrading enzyme, monoamine oxidase-A, this offers a protective mechanism against local vasoconstriction effects of 5-HT in the placenta. However, this system may be compromised by OCT3 inhibitory molecules, such as glucocorticoids or antidepressants. Our findings open new avenues to explore previously unsuspected/unexplained complications during pregnancy including prenatal glucocorticoid excess and pharmacotherapeutic risks of treating pregnant women with OCT3 inhibitors.