Acute stress imposed during adolescence has minimal effects on hypothalamic-pituitary-adrenal (HPA) axis sensitivity in adulthood in female Sprague Dawley rats

Abstract

Adolescence is a developmental epoch marked by maturation of stress-responsive systems including the Hypothalamic-Pituitary-Adrenal (HPA) axis. Emerging evidence has found sex-specificity in the long term behavioral and neural effects of stressors experienced during this sensitive period, though most studies have utilized chronic stress exposures that span much of the adolescent period. Using Sprague-Dawley rats, we examined how a single exposure to inescapable footshock (80 shocks, 5 s, 1.0 mA, 90 s variable ITI) applied during early adolescence (PND 29-31) affected the corticosterone (CORT) response to a later restraint stress challenge in adulthood. We found that females, but not males, displayed a marginally enhanced CORT response when challenged with restraint in adulthood. To further probe intrinsic sensitivity of the HPA axis in adolescent stressed females, subsequent studies utilized exogenous CRH and ACTH challenges to probe sensitivity of the pituitary and adrenal glands respectively, demonstrating that neither gland appears to be sensitized to hormone challenge as a result of adolescent stress history in females. A final experiment examined negative feedback regulation of the HPA axis through systemic administration of dexamethasone, showing that corticosteroid receptor-mediated negative feedback mechanisms were also intact in females with a history of adolescent stress. Together, these findings report that intrinsic regulatory elements of the HPA axis are fully intact in females exposed to footshock in adolescence, and that adolescent exposure to footshock had appreciably modest long-lasting effects on HPA axis sensitivity. These findings are discussed within the general context of stress resilience and vulnerability.

Keywords: Acth; Adolescence; Corticosterone; Corticotrophin-releasing hormone; Female; Sex differences; Stress.

Figure 1.

Experiment 1 design (A). Male and female subjects were exposed to footshock in early adolescence. In adulthood, they were then exposed to 60 minutes of restraint, and tail blood was collected at key time points for CORT (B and C) and progesterone (D and E) plasma concentrations. A trend for a main effect of adolescent shock was found in the CORT response in females.

Figure 2.

Experiment 2 design (B). Female subjects were exposed to footshock in early adolescence, and in adulthood were exposed to a CRH challenge. Serum was collected and analyzed for concentrations of key HPA axis hormones. The vehicle control group had reduced ACTH at baseline (B), CRH injection induced an increase in CORT regardless of stress history in adolescence (C), and no effects were seen in progesterone (D). * indicates a main effect of CRH injection, and different letters indicate differences between groups.

Figure 3.

Experiment 3 design (B). Female subjects were exposed to footshock in early adolescence, and in adulthood were exposed to an ACTH challenge. Serum was collected and analyzed for concentrations of ACTH (B), CORT (C), and progesterone (D). ACTH injection induced increases in ACTH and CORT concentrations regardless of adolescent stress history, while progesterone was lower in the control group that did not receive shock or ACTH compared to all other groups. * indicates a main effect of ACTH injection, and different letters indicate differences between groups.

Figure 4.

Experiment 4 design (B). Female subjects were exposed to footshock in early adolescence, and in adulthood were exposed to a dexamethasone suppression test. Serum was collected and analyzed for concentrations of ACTH (B), CORT (C), and progesterone (D). DEX successfully suppressed both ACTH and CORT in the adolescent stress history group, indicating that HPA axis negative feedback remained intact. * indicates a main effect of DEX injection.