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Aging and glucocorticoids: effects on cell signaling mediated through adenylyl cyclase.

Publication ,  Journal Article
Slotkin, TA; Thai, L; McCook, EC; Saleh, JL; Zhang, J; Seidler, FJ
Published in: J Pharmacol Exp Ther
November 1996

Abnormalities of hypothalamus-pituitary-adrenal axis regulation are common in the elderly and excess glucocorticoids have been implicated in the loss of neural function in aging. In the current study, we examined cell signaling mediated through adenylyl cyclase in brain regions, heart and liver of young and aged rats given continuous infusions of dexamethasone (10 or 50 micrograms/kg/day) for 26 days. Aged control animals showed significant deficits in total adenylyl cyclase activity (assessed with forskolin-Mn++) in the brain regions and the heart; superimposed on this change, the striatum and the heart displayed interference with the response mediated either at the level of G-protein coupling to cyclase (striatum) or neurotransmitter receptor coupling to G-proteins (heart). Administration of dexamethasone to young rats did not reproduce the effects of aging on any of the measures of adenylyl cyclase, despite the fact that the higher dose produced Cushingoid effects. The same dexamethasone regimens given to aged rats produced alterations in G-protein coupling mechanisms in the cortex and in serotonergic-mediated cyclase responses in the striatum, and also decreased basal enzyme activity in the heart. In contrast to the brain regions and the heart, the liver showed unique effects of aging and dexamethasone. Total adenylyl cyclase activity, the enzymatic response to beta adrenergic stimulation and the number of beta adrenergic receptors were all elevated in aged animals as compared to the younger cohort. Dexamethasone decreased both hepatic beta receptor numbers and isoproterenol responsiveness in young animals, but increased receptor binding in aged animals. These data indicate that the defects associated with aging in the central nervous system and the cardiac cell signaling mediated through adenylyl cyclase are not a result of glucocorticoid excess; however, central and peripheral tissues respond differently to glucocorticoids in aged vs. young animals. Given the high incidence of hypothalamus-pituitary-adrenal axis dysregulation in the elderly, and particularly in elderly depression, effects of glucocorticoids on cell signaling may contribute to disruption of cell function and to hypo- or hyper-reactivity to drugs, such as antidepressants, that act by altering synaptic transmission.

Duke Scholars

Published In

J Pharmacol Exp Ther

ISSN

0022-3565

Publication Date

November 1996

Volume

279

Issue

2

Start / End Page

478 / 491

Location

United States

Related Subject Headings

  • Receptors, Adrenergic, beta
  • Rats, Sprague-Dawley
  • Rats
  • Pharmacology & Pharmacy
  • Male
  • Liver
  • Heart
  • Glucocorticoids
  • GTP-Binding Proteins
  • Dexamethasone
 

Citation

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Slotkin, T. A., Thai, L., McCook, E. C., Saleh, J. L., Zhang, J., & Seidler, F. J. (1996). Aging and glucocorticoids: effects on cell signaling mediated through adenylyl cyclase. J Pharmacol Exp Ther, 279(2), 478–491.
Slotkin, T. A., L. Thai, E. C. McCook, J. L. Saleh, J. Zhang, and F. J. Seidler. “Aging and glucocorticoids: effects on cell signaling mediated through adenylyl cyclase.J Pharmacol Exp Ther 279, no. 2 (November 1996): 478–91.
Slotkin TA, Thai L, McCook EC, Saleh JL, Zhang J, Seidler FJ. Aging and glucocorticoids: effects on cell signaling mediated through adenylyl cyclase. J Pharmacol Exp Ther. 1996 Nov;279(2):478–91.
Slotkin, T. A., et al. “Aging and glucocorticoids: effects on cell signaling mediated through adenylyl cyclase.J Pharmacol Exp Ther, vol. 279, no. 2, Nov. 1996, pp. 478–91.
Slotkin TA, Thai L, McCook EC, Saleh JL, Zhang J, Seidler FJ. Aging and glucocorticoids: effects on cell signaling mediated through adenylyl cyclase. J Pharmacol Exp Ther. 1996 Nov;279(2):478–491.

Published In

J Pharmacol Exp Ther

ISSN

0022-3565

Publication Date

November 1996

Volume

279

Issue

2

Start / End Page

478 / 491

Location

United States

Related Subject Headings

  • Receptors, Adrenergic, beta
  • Rats, Sprague-Dawley
  • Rats
  • Pharmacology & Pharmacy
  • Male
  • Liver
  • Heart
  • Glucocorticoids
  • GTP-Binding Proteins
  • Dexamethasone