Prenatal paroxetine dysregulates monoamine homeostasis and affects placental hemodynamics in the rat fetoplacental unit

Résumé fourni par la source

Antidepressant use during pregnancy is increasingly common, with selective serotonin reuptake inhibitors (SSRIs) widely prescribed for maternal depression. However, growing evidence links prenatal SSRI exposure to adverse outcomes, including impaired placental functions, disrupted fetal development, and long-term neurobehavioral risks. Monoamines such as serotonin, dopamine, and norepinephrine are critical regulators of placental vascular tone, fetal programming, and neurodevelopment, making them highly susceptible to pharmacological disruption. Here, we investigated the effects of prenatal paroxetine on monoamine regulation, metabolite profiles, and fetoplacental hemodynamics in a pregnant rat model. Paroxetine was administered orally at two doses, 15 mg/kg (n = 10) or 50 mg/kg (n = 7) and compared to controls (n = 6). Gene expression of monoamine-related transporters and enzymes was quantified in placenta and fetal brain by qRT-PCR. Placental and fetal brain metabolomes were assessed via LC-MS, and Doppler ultrasound was used to evaluate uterine and fetal vascular parameters. At 15 mg/kg, paroxetine reduced fetal (2.03 ± 1.10 g vs. 2.27 ± 0.92 g) and placental weights (0.35 ± 0.08 g vs. 0.46 ± 0.05 g), downregulated placental expression of serotonin, dopamine, and norepinephrine transporters, disrupted tryptophan metabolism, and increased vascular resistance in umbilical arteries (2.10 ± 0.21 vs. 1.85 ± 0.05). Surprisingly, the 50 mg/kg dose attenuated many of these effects, suggesting non-linear pharmacological response, potentially due to transporter saturation and/or receptor desensitization. Importantly, gene expression and hemodynamic effects were consistent across sexes. These findings provide novel mechanistic insights into the impact of SSRIs on placental function and fetal development, underscoring the complexity of their pharmacokinetics and pharmacodynamics during pregnancy and emphasizing the need for careful dose consideration during pregnancy. Female rats were treated with oral paroxetine (15 or 50 mg/kg) for 7 pregestational days and throughout 20 days of gestation. On gestational day 20, Doppler ultrasound analysis was performed, and then placentas and fetal brains were collected for future analysis. The graphical abstract was created with BioRender. • Prenatal paroxetine disrupts placental monoamine signaling in a dose-dependent manner in pregnant rats. • Low-dose paroxetine increases uterine/umbilical resistance and reduces fetal growth. • High-dose paroxetine shows attenuated effects, suggesting nonlinear response. • These findings highlight risks of SSRI use for placental function during pregnancy. • Effects were consistent across fetal sexes, with no sex-specific differences observed.