Paroxetine Treatment During Prenatal Depression Leads to Sex‐Dependent Behavioural Changes, Antioxidant and Neurochemical Impairments in Offspring of Mice

Prenatal depression significantly increases the risk of adverse neurodevelopmental outcomes in children. While selective serotonin inhibitors (SSRIs) like paroxetine are often prescribed during pregnancy, their effects on the developing brain are not fully understood. This study examined sex-dependent effects of prenatal paroxetine exposure on behaviour, oxidative stress and neurochemical parameters in offspring of dams exposed to chronic unpredictable mild stress (CUMS), a validated model of prenatal depression. Pregnant Swiss mice underwent CUMS from gestational Days 13-19 due to gestational timing and observable sensitivity, receiving paroxetine (2.5 or 5 mg/kg, p.o.) or saline (10 mL/kg) with n = 6 per group. After birth, the offspring underwent behavioural testing at infancy (postnatal days [PND] 25-30), adolescence (PND 35-40) and adulthood (PND 85-90). The prefrontal cortex, hippocampus and striatum were analysed for oxidative stress markers, and neurochemical parameters (serotonin, dopamine, and glutamic acid decarboxylase), and corticosterone levels were measured. Results indicated that combined prenatal paroxetine exposure induced significant sex-specific alterations in behaviour throughout the life course, especially affecting anxiety and depression modulated by dose-dependent administration. Additionally, it enhanced locomotion in later life and reduced anxiety compared to the control group. Paroxetine increases antioxidant activities and decreases pro-oxidants, with some differences in MDA levels across various brain regions when compared to the control CUMS. Male offspring had higher corticosterone release, while females had lower levels compared to CUMS-exposed offspring. Males had decreased GAD enzymes in the hippocampus and striatum; females had low striatal GAD but increased levels in the hippocampus compared to CUMS-exposed offspring, along with sex-dependent regional changes with paroxetine, which increases dopamine and serotonin in the prefrontal cortex, striatum and hippocampus. Our findings indicate that prenatal paroxetine exposure during depression may affect offspring neurodevelopment, causing sex-dependent behavioural, antioxidant and neurochemical impairments.