Aging is associated in the 344/N Fischer rat with decreased stress responsivity of central and peripheral catecholaminergic systems and impairment of the hypothalamic-pituitary-adrenal axis.
The effects of acute stress on various indices of sympatho-adrenal, sympathoneural functions and hypothalamic-pituitary-adrenal (HPA) axis were examined both at central and peripheral sites in healthy, intact male Fischer 344/N rats of increasing age. Extracellular fluid (ECF) levels of norepinephrine (NE), its metabolites dihydroxyphenylglycol (DHPG), and methoxyhydroxyphenylglycol (MHPG), and of the dopamine metabolite dihydroxyphenylacetic acid (DOPAC), were measured 24 h after implantation of a microdialysis probe in the paraventricular nucleus (PVN) of the hypothalamus, and samples collected at 30-min. intervals during immobilization (IMMO). ECF levels of NE, DHPG, MHPG, and DOPAC were at baseline similar in both age groups, and all increased significantly in response to IMMO. The IMMO-induced increases in ECF levels of NE and MHPG were, however, significantly smaller in old than in young rats. Plasma levels of the dihydroxyphenylalanine (DOPA), -NE, epinephrine (EPI), DHPG, MHPG, dopamine (DA), DOPAC and HVA, were determined in different groups of young and old rats, cannulated in the tail artery, at baseline, and after 5, 30, 60, and 120 min of IMMO. Basal levels of DOPA, DHPG, MHPG, DA, DOPAC, HVA, NE and EPI were significantly higher in old than in young rats, and increased in plasma during IMMO. However, the magnitude of the increase in the majority of these compounds was significantly smaller in old than in young rats. Basal plasma levels of ACTH were similar among age groups, and basal plasma levels of corticosterone showed a significant aging-associated decline. Two i.v. doses (2 and 20 micrograms/kg BW) of rat CRF elicited significantly greater and delayed ACTH, and greater corticosterone responses in older rats, consistent with the pattern encountered in hypothalamic CRF deficiency. An i.v. injection of ACTH 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 secondary adrenocortical atrophy in older animals. Steady-state mRNA levels of mineralocorticoid and glucocorticoid receptors were significantly decreased in the hippocampus of the 8-, 18-, and 24-month-old rats, compatible with maturational rather than senescent changes. CRF mRNA levels in the paraventricular nucleus of the hypothalamus, and levels of POMC mRNA in the anterior pituitary were significantly reduced with age. In conclusion, in this strain of rats, aging is associated with diminished responsiveness of central, and peripheral catecholaminergic systems to acute stress, and progressive hypothalamic CRH deficiency.
Cizza
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G
Developmental Endocrinology Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892-1262, USA.
Gold
P W
PW
Chrousos
G P
GP
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000375:Aging; D000818:Animals; D002395:Catecholamines / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D015870:Gene Expression; D006624:Hippocampus / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology*; D007103:Immobilization; D008125:Locus Coeruleus / Q000378:metabolism; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011965:Receptors, Glucocorticoid / Q000235:genetics; D018161:Receptors, Mineralocorticoid / Q000235:genetics; D013312:Stress, Physiological / Q000378:metabolism*
D002395:Catecholamines; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D009638:Norepinephrine