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Chronic brain glucocorticoid receptor blockade enhances the rise in circadian and stress-induced pituitary-adrenal activity.
Endocrinology 1996; 137(11):4935-43E

Abstract

This study examined the hypothesis that experimentally induced corticosteroid resistance in the brain would lead to adaptations in the activity of the hypothalamic-pituitary-adrenal (HPA) axis similar to the endocrine features of the endogenous resistance accompanying the pathogenesis of depression. For this purpose, the glucocorticoid antagonist RU 38486 (aGC) was infused intracerebroventricularly (i.c.v.) (100 ng/h) via Alzet minipumps for several days. During this chronic receptor blockade, parameters for basal and stress-induced HPA activity were measured in a longitudinal study design. Chronic i.c.v. infusion of the aGC did not affect basal morning levels of ACTH and corticosterone. During the afternoon phase of the circadian cycle, the aGC caused gradual and sequential changes in the HPA axis. After aGC infusion, the circadian rise of ACTH levels was enhanced in the afternoon of day 1, but was normal on subsequent days. For corticosterone, basal afternoon levels towards the diurnal peak were increased at days 1, 3, and 4 in aGC-treated rats. On day 2, in contrast, corticosterone levels did not differ from vehicle-infused controls. Paraventricular CRH messenger RNA, as measured at day 4, was not altered by aGC treatment. After 10 days of aGC treatment, the adrenal weight was increased, and the sensitivity of adrenocortical cells in vitro to ACTH was enhanced. Corticosteroid receptor binding in vitro in hippocampus, hypothalamus, and pituitary was not different between the aGC and vehicle-treated rats. In a second series of experiments, the HPA responsiveness to the stress of a novel environment at day 2 in the morning was increased after chronic aGC infusion, at a time basal hormone levels were not affected. The data show that 1) chronic i.c.v. infusion of aGC readily enhances the amplitude of circadian corticosterone changes, presumably by increasing the adrenocortical sensitivity to ACTH; 2) chronic aGC-treated animals show an enhanced ACTH and corticosterone response to stress, which is delayed in termination; 3) corticosteroid receptor expression, basal CRH messenger RNA, and ACTH levels are not altered after prolonged chronic aGC treatment. It is concluded that, over a period of a few days, aGC-induced corticosteroid resistance triggers a sequelae of pituitary-adrenal adaptations ultimately resulting in hypercorticism. Paradoxically, however, this hypercorticism develops because of increased peak levels of corticosteroid hormone rather than through elevated trough levels as is commonly observed during depressive illness.

Authors+Show Affiliations

Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands. AVH@CHDR.LeidenUniv.NLNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

8895366

Citation

van Haarst, A D., et al. "Chronic Brain Glucocorticoid Receptor Blockade Enhances the Rise in Circadian and Stress-induced Pituitary-adrenal Activity." Endocrinology, vol. 137, no. 11, 1996, pp. 4935-43.
van Haarst AD, Oitzl MS, Workel JO, et al. Chronic brain glucocorticoid receptor blockade enhances the rise in circadian and stress-induced pituitary-adrenal activity. Endocrinology. 1996;137(11):4935-43.
van Haarst, A. D., Oitzl, M. S., Workel, J. O., & de Kloet, E. R. (1996). Chronic brain glucocorticoid receptor blockade enhances the rise in circadian and stress-induced pituitary-adrenal activity. Endocrinology, 137(11), pp. 4935-43.
van Haarst AD, et al. Chronic Brain Glucocorticoid Receptor Blockade Enhances the Rise in Circadian and Stress-induced Pituitary-adrenal Activity. Endocrinology. 1996;137(11):4935-43. PubMed PMID: 8895366.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Chronic brain glucocorticoid receptor blockade enhances the rise in circadian and stress-induced pituitary-adrenal activity. AU - van Haarst,A D, AU - Oitzl,M S, AU - Workel,J O, AU - de Kloet,E R, PY - 1996/11/1/pubmed PY - 1996/11/1/medline PY - 1996/11/1/entrez SP - 4935 EP - 43 JF - Endocrinology JO - Endocrinology VL - 137 IS - 11 N2 - This study examined the hypothesis that experimentally induced corticosteroid resistance in the brain would lead to adaptations in the activity of the hypothalamic-pituitary-adrenal (HPA) axis similar to the endocrine features of the endogenous resistance accompanying the pathogenesis of depression. For this purpose, the glucocorticoid antagonist RU 38486 (aGC) was infused intracerebroventricularly (i.c.v.) (100 ng/h) via Alzet minipumps for several days. During this chronic receptor blockade, parameters for basal and stress-induced HPA activity were measured in a longitudinal study design. Chronic i.c.v. infusion of the aGC did not affect basal morning levels of ACTH and corticosterone. During the afternoon phase of the circadian cycle, the aGC caused gradual and sequential changes in the HPA axis. After aGC infusion, the circadian rise of ACTH levels was enhanced in the afternoon of day 1, but was normal on subsequent days. For corticosterone, basal afternoon levels towards the diurnal peak were increased at days 1, 3, and 4 in aGC-treated rats. On day 2, in contrast, corticosterone levels did not differ from vehicle-infused controls. Paraventricular CRH messenger RNA, as measured at day 4, was not altered by aGC treatment. After 10 days of aGC treatment, the adrenal weight was increased, and the sensitivity of adrenocortical cells in vitro to ACTH was enhanced. Corticosteroid receptor binding in vitro in hippocampus, hypothalamus, and pituitary was not different between the aGC and vehicle-treated rats. In a second series of experiments, the HPA responsiveness to the stress of a novel environment at day 2 in the morning was increased after chronic aGC infusion, at a time basal hormone levels were not affected. The data show that 1) chronic i.c.v. infusion of aGC readily enhances the amplitude of circadian corticosterone changes, presumably by increasing the adrenocortical sensitivity to ACTH; 2) chronic aGC-treated animals show an enhanced ACTH and corticosterone response to stress, which is delayed in termination; 3) corticosteroid receptor expression, basal CRH messenger RNA, and ACTH levels are not altered after prolonged chronic aGC treatment. It is concluded that, over a period of a few days, aGC-induced corticosteroid resistance triggers a sequelae of pituitary-adrenal adaptations ultimately resulting in hypercorticism. Paradoxically, however, this hypercorticism develops because of increased peak levels of corticosteroid hormone rather than through elevated trough levels as is commonly observed during depressive illness. SN - 0013-7227 UR - https://www.unboundmedicine.com/medline/citation/8895366/Chronic_brain_glucocorticoid_receptor_blockade_enhances_the_rise_in_circadian_and_stress_induced_pituitary_adrenal_activity_ L2 - https://academic.oup.com/endo/article-lookup/doi/10.1210/endo.137.11.8895366 DB - PRIME DP - Unbound Medicine ER -