The Effect Of Prenatal Restraint Stress And Citalopram Exposure On Activity Of Hypothalamic-pituitary-adrenal Axis In Offspring Rats

[Background]:Maternal stress can disturb the normal fetal neurodevelopment progress and lead to negative neuroendocrine consequences for the offspring. Prenatal selective serotonin reuptake inhibitor (SSRI) exposure can also have an influence. These effects may be related to alterations in the hypothalamic-pituitary-adrenal (HPA) axis. The glucocorticoid receptor gene (NR3C1) has been shown to act as a repressor of transcription of the corticotropin releasing hormone (CRH) gene. And early life events disrupting the function of the HPA axis may be associated with epigenetic modification.[Purpose]:This study investigated the effect of maternal stress and/or SSRI treatment on the anxiety-like behavior, the HPA response to acute stress and potential mechanism.[Method]:Pregnant Sprague-Dawley rats dams were randomly assigned to four groups:(1) Restraint stress group; (2) Restraint stress+citalopram (10mg/Kg/day) group; (3) Citalopram (10 mg/Kg/day) group; and (4) Control group. Adolescent male and female offspring were used from each group.We use open field and elevated plus maze investigate the anxiety-like behavior; the real-time PCR and ELISA technique to test the expression of NR3C1 mRNA and HPA axis response to acute stress; also we use bisulfite sequencing PCR (BSP) technology to investigate the effect of maternal stress and/or SSRI treatment on the methylation rate of the corticotrophin-releasing hormone (CRH) promoter in the adolescent offspring of SD rats.[Result]:The results showed that prenatal citalopram treatment, regardless of maternal stress, increased the NR3C1 mRNA expression level in the hippocampus and inhibited the HPA axis response to acute stress. Maternal stress on its own decreased NR3C1 mRNA expression and resulted in an HPA axis response. We also confirm that prenatal citalopram treatment can reverse the maternal stress induced anxiety-like behavior. At last, the results also showed that prenatal stress is associated with the demethylation of the CRH promoter, and leads to anxiety-like behaviors in adolescent life stages, as well as hyper-responsiveness of the HPA axis. But prenatal citalopram treatment does not affect the methylation rate of CRH promoter in offspring rats.[Conclusion]:Together, these results imply that prenatal stress alters the normal HPA function, which may be via the epigenetic mechanism and down-regulation of NR3C1 expression; prenatal SSRI exposure may reverse the hyperactive HPA axis response induced by maternal stress via up-regulation of NR3C1 expression.