Hypothalamic-Pituitary-Adrenal Response to Chronic Stress in Five Inbred Rat Strains: Differential Responses Are Mainly Located at the Adrenocortical Level

Abstract

The effects of chronic stress on the hypothalamic-pituitary-adrenocortical (HPA) axis were studied in five inbred rat strains, i.e. Brown Norway (BN), Fischer (FIS), Lewis (LEW), Spontaneously Hypertensive (SHR) and Wistar Kyoto (WKY). Previously, these rat strains had been shown to display clear behavioral differences in the forced swimming test that presumably measures depression-like behavior, BN and WKY being more passive than the other strains. Here we test the hypothesis that the differences in behavioral immobility might be associated with an abnormal HPA response to chronic immobilization (IMO) stress. In stress-naive rats under basal conditions (morning) there were no differences among strains in adrenal weight, serum adrenocorticotropin hormone (ACTH) and corticosterone (B) levels, corticotropin-releasing factor (CRF) mRNA in the hypothalamic paraventricular nucleus (PVN) and hippocampal glucocorticoid and mineralocorticoid receptor (GR and MR) mRNA. After chronic IMO, basal serum ACTH levels were increased in LEW, SHR and WKY, but not in BN or FIS rats, whereas basal B levels were increased in BN, FIS, SHR and WKY rats, but not in LEW. The increase in adrenal weight was also strain dependent and correlated negatively with chronic IMO-induced hypercorticosteronemia. These peripheral differences among strains were not observed at central levels. Thus, chronic IMO increased the CRF mRNA content in the PVN, analyzed by in situ hybridization, similarly in all strains. In addition, after chronic IMO no differences were found among strains in hippocampal GR mRNA and RM mRNA contents. Considering data from all strains together, chronic IMO reduced the GR mRNA (50-60%) content in the hippocampal CA1, CA3 and DG areas, and slightly diminished (11–13%) MR mRNA levels in CA1 and CA3 areas. The present results indicate that: (i) chronic IMO down-regulates GR mRNA in the hippocampus and slightly up-regulates CRF mRNA in the hypothalamic PVN similarly in all strains; (ii) after chronic IMO interstrain differences were observed in serum ACTH and B levels as well as adrenal hypertrophy; (iii) some changes are probably located at the adrenal level since changes in serum B level and adrenal weight were not related to changes in ACTH; (iv) in LEW and WKY rats, B hyporesponsiveness to chronic IMO might be linked to low adrenal sensitivity to ACTH, and (v) HPA axis changes induced by the chronic IMO procedure are not related to previously reported data on depressive-like behavior of BN and WKY in the forced swimming test.