Long-lasting deficient dexamethasone suppression of hypothalamic-pituitary-adrenocortical activation following peripheral CRF challenge in socially defeated rats

The present study focuses on the long-term changes in the regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis following two short-lasti ng episodes of intensive stress in the rat stress model of social defeat an d the possible similarities with HPA functioning in human affective disorde rs. Male Wistar rats experienced social defeats on 2 consecutive days by an aggressive male conspecific. The long-term effect of these defeats on rest ing and ovine corticotropin-releasing factor (oCRF; intravenous (i.v.) 0.5 mu g/kg) induced levels of plasma ACTH and corticosterone (CORT) were measu red 1 and 3 weeks later. In a second experiment the glucocorticoid feedback regulation of HPA function was tested in a combined dexamethasone (DEX)/CR F test (DEX; 25 mu g/kg s.c., 90 min before oCRF injection, 0.5 mu g/kg). T he oCRF challenges were performed between 11.00 and 13.00 h (about three ho urs after start of the light phase). One week after defeat the ACTH respons e to CRF was significantly enhanced in defeated rats as compared to control s. Three weeks after defeat the ACTH response was back to control levels. T he increased ACTH response 1 week after the stressor was not reflected in h igher CORT levels. Neither were baseline ACTH and CORT levels affected by t he prior stress exposure. DEX pretreatment inhibited pituitary adrenocortic al activity, reflected both in reduced baseline and response values of ACTH and CORT. The ACTH response to CRF following DEX administration was signif icantly higher in defeated rats as compared to controls both at one and thr ee weeks after defeat. A reduced DEX suppression of baseline secretion of A CTH appeared 3 weeks after defeat. The same tendency was apparent in respon se and baseline values of CORT. The differences in CORT between socially st ressed and control treated rats, however, did not reach significance. The p ossible role of changes in glucocorticoid-(GR) and mineralocorticoid recept or (MR) binding in the altered regulation of HPA activity following defeat were studied in brain and pituitary of male Wistar rats 1 and 3 weeks after defeat. One week after defeat OR-binding decreased in hippocampus and hypo thalamus. No changes were observed in OR-binding in the pituitary nor in MR -binding in any of the regions analysed. Three weeks after defeat OR-bindin g recovered in hippocampus and hypothalamus but at this time MR-binding in hippocampal tissue was seriously decreased. In a fourth experiment vasopres sin (AVP) and CRF stores in the external zone of the median eminence (ZEME) were measured by quantitative immunocytochemistry one and three weeks afte r defeat and compared with controls. Social defeat failed to induce a chang e in the immunocytochemical stores of AVP or CRF. The present findings show that in rats short-lasting stressors like defeat induce long-lasting, temp oral dynamic changes in the regulation of the HPA axis. Since these changes in time are reflected in GRs and MRs in different brain areas an altered c orticosteroid receptor binding might play an important role in the affected HPA activity following defeat.