COMBINED DEXAMETHASONE CRH TEST IN RATS - HYPOTHALAMO-PITUITARY-ADRENOCORTICAL SYSTEM ALTERATIONS IN AGING/

Alterations of the hypothalamo-pituitary-adrenocortical (HPA) system a re well-known phenomena in human aging as well as under stressful cond itions and in psychiatric disorders. Among the various neuroendocrine function tests developed so far, the combined dexamethasone (DEX)/cort icotropin-releasing hormone (CRH) test, in which DEX-pretreated subjec ts receive a single dose of CRH, has proved to be the most sensitive m easure of subtle changes in HPA system regulation. To further explore the mechanisms underlying these neuroendocrine abnormalities in an ani mal model, a combined DEX/CRH test was established in young male Wista r rats. Five days before the experiment, the jugular vein was catheter ized under halothane anesthesia for subsequent drug infusion and blood sampling. DEX (30 mu g/kg) administered at 12.00 h, during the diurna l trough, suppressed the diurnal increase in circulating corticotropin (ACTH) and corticosterone between 18.00 and 20.00 h, during the acrop hase. Subsequent CRH (50 ng/kg) infused at 20.00 h provoked a minimal escape from DEX suppression, indicated by a slight increase in ACTH an d corticosterone secretion. Therefore, the combination of 30 mu g/kg D EX given at 12.00 h followed by pituitary-adrenal system stimulation w ith 50 ng/kg CRH at 20.00 h was defined as the standard DEX/CRH test p rocedure and was then used in young (3-6 months) and aged male Wistar rats (20-24 months). After DEX treatment, basal ACTH levels between 18 .00 and 20.00 h were significantly higher in aged than in young rats ( 77.6 +/- 23.2 vs. 19.9 +/- 0.9 pg/ml; p < 0.01), indicating resistance of the HPA system to the suppressive effect of DEX. In addition, the ACTH response to subsequent CRH was significantly higher in aged than in young animals (area under the concentration time curve: 3,670 +/- 2 ,230 vs. 294 +/- 112; p < 0.05). Thus, the HPA system appeared to be p rofoundly dysregulated in aged male Wistar rats. The elevated basal AC TH levels reflect glucocorticoid nonsuppression, suggesting negative f eedback impairment. This is further supported by the elevated ACTH res ponse to a subsequent CRH challenge, which, in addition, may indicate changes in the endogenous synergistic mechanisms of CRH with other cor ticotropic factors, for instance vasopressin. In summary, the DEX/CRH test revealed HPA system alterations in aging and can be applied in fu ture studies to further explore the mechanisms underlying the neuroend ocrine disturbances during (psycho) pathological states.