The effects of maternal SSRI exposure on the serotonin system, prefrontal protein expression and behavioral development in male and female offspring rats.

Fluoxetine (FLX), a commonly used selective serotonin reuptake inhibitor, is often used to treat depression during pregnancy. However, prenatal exposure to FLX has been associated with a series of neuropsychiatric illnesses. The use of a rodent model can provide a clear indication as to whether prenatal exposure to SSRIs, independent of maternal psychiatric disorders or genetic syndromes, can cause long-term behavioral abnormalities in offspring. Thus, the present study aimed to explore whether prenatal FLX exposure causes long-term neurobehavioral effects, and identify the underlying mechanism between FLX and abnormal behaviors. In our study, 12/mg/kg/day of FLX or equal normal saline (NS) was administered to pregnant Sprague-Dawley (SD) rats (FLX = 30, NS = 27) on gestation day 11 till birth. We assessed the physical development and behavior of offspring, and in vivo magnetic resonance spectroscopy (MRS) was conducted to quantify biochemical alterations in the prefrontal cortex (PFC). Ex vivo measurements of brain serotonin level and a proteomic analysis were also undertaken. Our results showed that the offspring (male offspring in particular) of fluoxetine exposed mothers showed delayed physical development, increased anxiety-like behavior, and impaired social interaction. Moreover, down-regulation of 5-HT and SERT expression were identified in the PFC. We also found that prenatal FLX exposure significantly decreased NAA/tCr with 1H-MRS in the PFC of offspring. Finally, a proteomic study revealed sex-dependent differential protein expression. These findings may have translational importance suggesting that using SSRI medication alone in pregnant mothers may result in developmental delay in their offspring. Our results also help guide the choice of outcome measures in identifying of molecular and developmental mechanisms.

Interleukin-18 levels in the hippocampus and behavior of adult rat offspring exposed to prenatal restraint stress during early and late pregnancy.

Exposure to maternal stress during prenatal life is associated with an increased risk of neuropsychiatric disorders, such as depression and anxiety, in offspring. It has also been increasingly observed that prenatal stress alters the phenotype of offspring via immunological mechanisms and that immunological dysfunction, such as elevated interleukin-18 levels, has been reported in cultures of microglia. Prenatal restraint stress (PRS) in rats permits direct experimental investigation of the link between prenatal stress and adverse outcomes. However, the majority of studies have focused on the consequences of PRS delivered in the second half of pregnancy, while the effects of early prenatal stress have rarely been examined. Therefore, pregnant rats were subjected to PRS during early/middle and late gestation (days 8-14 and 15-21, respectively). PRS comprised restraint in a round plastic transparent cylinder under bright light (6500 lx) three times per day for 45 minutes. Differences in interleukin-18 expression in the hippocampus and in behavior were compared between offspring rats and control rats on postnatal day 75. We found that adult male offspring exposed to PRS during their late prenatal periods had higher levels of anxiety-related behavior and depression than control rats, and both male and female offspring exhibited higher levels of depression-related behavior, impaired recognition memory and diminished exploration of novel objects. Moreover, an elevated level of interleukin-18 was observed in the dorsal and ventral hippocampus of male and female early- and late-PRS offspring rats. The results indicate that PRS can cause anxiety and depression-related behaviors in adult offspring and affect the expression of interleukin-18 in the hippocampus. Thus, behavior and the molecular biology of the brain are affected by the timing of PRS exposure and the sex of the offspring. All experiments were approved by the Animal Experimentation Ethics Committee at Kunming Medical University, China (approval No. KMMU2019074) in January 2019.