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

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.