Neurosteroids during development: implications for behavior and stress sensitivity

Exposure of developing female rats to estradiol during the perinatal period induces a long-lasting dysregulation of gonadal axis and alters brain and peripheral concentrations of steroid hormones. A single administration of beta-estradiol 3-benzoate (EB, 10 microg, s.c.) on the day of birth to female rats induced a marked and persistent decrease in the concentrations of allopregnanolone and progesterone in the cerebral cortex (86% and 94%, respectively, p<0.01), hypothalamus (55%, p<0.05 and 60%, p<0.001, respectively) and hippocampus (47%, p<0.05 and 76%, p<0.001, respectively) of adult female rats (Calza et al. 2010, Berretti et al. 2014). Neonatal EB treatment also increased dominant agonistic behaviors (duration: +142%, p<0.05, frequency: +121%, p<0.005) in the resident-intruder test and markedly decreased spontaneous female sexual behavior (lordosis: 91%, p<0.01, proceptivity: 99%, p<0.01), while locomotor activity, anxiety and mood-related behaviors, as well as seizures sensitivity were not affected. Neonatal administration of EB also altered the expression of specific subunits of the GABAA receptor (alpha1: +26%, p<0.05, alpha2: +22%, p<0.05, gamma2: +58%, p<0.05) and enhanced the sensitivity of adult rats to the anxiolytic and sedative-hypnotic effects of diazepam. Further, neonatal administration of EB increased sensitivity of adult rats to acute stress, as demonstrated by the greater enhancement in brain allopregnanolone levels following foot-shock stress (vehicle: +84%, p<0.05, EB: +421%, p<0.01). However, acute stress increased plasma corticosterone levels to a similar extent in vehicle- and EB-treated rats (+71% and +98%, respectively, p<0.001), suggesting that the greater sensitivity of EB-treated rats might not involve a dysregulation of the HPA axis. Indeed, the dexamethasone suppression test revealed that cerebrocortical, hypothalamic and plasma corticosterone levels were decreased to a similar extent in both EB- and vehicle-treated adult female rats, suggesting that the increased stress sensitivity in EB-treated rats is independent of HPA axis function. Finally, acute stress also induced a greater enhancement in extracellular concentrations of dopamine (4-fold, p<0.001) and norepinephrine (3-fold, p<0.001) in the prefrontal cortex of EB-treated rats compared to vehicle-treated rats, further suggesting that neonatal treatment with estradiol increases sensitivity to stress in adulthood. Overall, these results suggest that neonatal exposure to estradiol plays a major role in the regulation of brain allopregnanolone concentrations during development and in the expression of behavior and stress sensitivity in adult female rats. Thus, neonatal estradiol treatment may represent a useful animal model to study the role of allopregnanolone during development.