Prenatal fluoxetine modifies the behavioral and hormonal responses to stress in male mice: role for glucocorticoid insensitivity

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Women with major depressive disorder during pregnancy often use selective serotonin reuptake inhibitors (SSRIs) antidepressants. These drugs readily cross the placental barrier and impact the developing fetal brain. Recently, we reported that prenatal fluoxetine (FLX), an SSRI antidepressant drug, altered corticosterone and behavioral responses to stress in female mouse offspring. The present study assessed the effects of prenatal FLX on these responses in males. The results showed that prenatal FLX significantly augmented the corticosterone response to acute stress in young prepubescent mice. The corticosterone response to continuous stress was not affected by prenatal FLX irrespective of age. In addition, continuous stress reduced general activity, and anxiety-like and depressive-like behaviors in adult animals prenatally exposed to FLX, but not in controls. The dexamethasone suppression test showed that prenatal FLX induced a state of glucocorticoid insensitivity in adult males, indicating that the negative feedback control of the hypothalamic–pituitary–adrenal axis response to stress was disrupted. Together, these findings indicate that prenatal FLX altered hormonal and behavioral responses to stress and suggest a role for the development of glucocorticoid insensitivity in these effects. These findings may aid understanding of the limitations and precautions that should be taken in the use of SSRIs by pregnant women.

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