MALE FISCHER-344 N-RATS SHOW A PROGRESSIVE CENTRAL IMPAIRMENT OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS WITH ADVANCING AGE/

We investigated the effects of aging on the regulation of hypothalamic -pituitary-adrenal function and hippocampal steroid receptors in a ser ies of in vivo and in vitro studies conducted in healthy intact 2-, 8- , 18-, and 24-month-old male Fischer 344/N rats. Basal plasma ACTH lev els were similar among age groups, and basal plasma corticosterone lev els showed a significant aging-associated decline. Two iv doses (2 and 20 mug/kg BW) of rat CRF elicited significantly greater and delayed A CTH and greater corticosterone responses in older rats, consistent wit h the pattern encountered in hypothalamic CRF deficiency. In contrast, the iv injection of a muscarinic agonist, arecoline, elicited similar ACTH and corticosterone responses in all age groups. An iv injection of ACTH-(1-24) evoked lower corticosterone responses in the older (18- and 24-month-old) than in the younger (2- and 8-month-old) groups of rats, consistent with an impairment of hypothalamic-pituitary-adrenal axis function in older animals. Steady state mRNA levels of mineraloco rticoid and glucocorticoid receptors were significantly decreased in t he hippocampus of the 8-, 18-, and 24-month-old rats, compatible with maturational, rather than senescent, changes. CRF mRNA levels in the p araventricular nucleus of the hypothalamus, CRF content, and in vitro secretion by whole explanted hypothalami were progressively and signif icantly reduced with age, whereas the steady state levels of arginine vasopressin mRNA were significantly increased with age. Steady state l evels of POMC mRNA were decreased, and ACTH content and in vitro secre tion by corticotrophs were increased with age in the anterior pituitar y. We conclude that male Fischer 344/N rats show a progressive hypotha lamic CRH deficiency with advancing age, which appears to be associate d with elevated production of arginine vasopressin in the hypothalamus .