Glucocorticoid-targeting of the adenylyl cyclase signaling pathway in the cerebellum of young vs. aged rats.
Glucocorticoids exacerbate aging-induced cell death, but relatively little is known about other CNS effects in senescence. We examined noradrenergic/adenylyl cyclase signaling in the cerebellum, which is a brain region that is susceptible to deterioration of synaptic function in aging. Aged control rats had increased total cyclase catalytic activity, but showed deficits in basal adenylyl cyclase. Deficits resolved when G-proteins were stimulated with GTP, GTP and fluoride, or GTP and isoproterenol, despite reductions in beta-receptors. In young rats, long-term dexamethasone infusions evoked the same types of changes that had been seen in aging, including induction of cyclase catalytic activity and enhanced G-protein responsiveness. The same dexamethasone regimens given to aged rats failed to cause stimulation of these processes in the cerebellum, but did so in a peripheral tissue (kidney). These data indicate homology between the cellular events involved in noradrenergic signaling during aging and after glucocorticoid administration to young animals; the absence of glucocorticoid effects in the elderly cohort supports a convergent mechanism with aging. Given the high incidence of HPA axis dysregulation in the elderly, and particularly in elderly depression, effects of glucocorticoids on cell signaling may contribute to disrupted function and to altered drug reactivity.
Box 3813, Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. t.slotkin@duke.edu
T A
TA
Slotkin
J
J
Zhang
E C
EC
McCook
F J
FJ
Seidler
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000375:Aging / Q000502:physiology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002531:Cerebellum / Q000201:enzymology*; D005576:Colforsin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D005459:Fluorides / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology; D008297:Male; D008345:Manganese / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D000318:Adrenergic beta-Agonists; D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D005576:Colforsin; D008345:Manganese; D003907:Dexamethasone; D006160:Guanosine Triphosphate; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D005459:Fluorides