Sex differences in long-term behavioral alterations, especially anxiety, following prenatal fluoxetine exposure in C57BL/6 mice

Evidence demonstrates that psychiatric disorders during pregnancy are detrimental to the offspring. Many disorders are treated with SSRIs and increasing numbers of pregnant women now receive these drugs during gestation. The long-term neurobehavioral consequences of prenatal SSRI exposure require further evaluation. This study examined the effects of prenatal fluoxetine exposure in mice in an extensive battery of behaviors related to neurodevelopment, mood, social, and repetitive behaviors. C57BL/6J dams were administered fluoxetine at a low (0.6 mg/kg/day) or high (6 mg/kg/day) dose or saline from embryonic days 8 to 18. Juvenile mice were tested for changes in ultrasonic vocalizations and neuromotor development. In adulthood, offspring were tested for changes in behaviors related to anxiety, depression, social, and repetitive behaviors. Prenatal exposure to fluoxetine impaired surface righting reflex at P5, and sex-dependently reduced the frequency of ultrasonic vocalizations in juvenile males but not females. In adulthood, both males and females prenatally exposed to high, but not low, doses of fluoxetine exhibited an increase in repetitive behaviors in the marble burying task and a decrease in sucrose preference. Males, but not females, exposed to fluoxetine exhibited increased anxiety-related behaviors in the elevated plus maze. Prenatal fluoxetine exposure did not affect other adult behaviors including social preference, self-grooming, passive avoidance and open field activity. These findings suggest males are more sensitive than females to disruptions in serotonin balance during prenatal development and highlight the need for additional systematic and mechanistic studies to evaluate the impact of fluoxetine exposure during other periods of gestation.