Prenatal exposure to chronic mild stress increases corticosterone levels in the amniotic fluid and induces cognitive deficits in female offspring, improved by treatment with the antidepressant drug amitriptyline

Abstract

Prenatal stress and associated in utero exposure to elevated levels of stress hormones can adversely affect the development of the central nervous system, thereby increasing the risk of mental illnesses in later life. Here, we examined the impact of prenatal exposure to chronic mild stress (CMS) on locomotion, anxiety-related behaviour, cognition and hippocampal serotonergic neurotransmission in juvenile and adult B6D2F2 mice, and whether antidepressant treatment in adulthood could reverse the observed behavioural disturbances. Pregnant B6D2F1 female mice were either subjected to CMS or left undisturbed until parturition. Three-week and 7-week-old male and female offspring were assessed in the open-field, novel object recognition and contextual fear conditioning tests. Hippocampal levels of serotonin and its major metabolite were then quantified using high-performance liquid chromatography. Some prenatally-stressed adult females were treated with amitriptyline (20mg/kg/day in drinking water) for 10 days, from the day prior to onset of behavioural testing. In a separate experiment, amniotic fluid was collected from stressed and non-stressed dams on gestational (G) days 13 and 18 to quantify levels of corticosterone. We found that prenatal CMS specifically impaired learning and memory performance in adult females. Amitriptyline elevated hippocampal serotonin levels and attenuated these cognitive deficits. Corticosterone levels in the amniotic fluid were increased by CMS on G13 but by G18, the levels in non-stressed dams reached those of stressed dams. These results suggest that female mice are particularly vulnerable to the adverse developmental effects of prenatal stress which can be improved by appropriate treatment strategies including antidepressants.