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Corticosterone, brain mineralocorticoid receptors (MRs) and the activity of the hypothalamic-pituitary-adrenal (HPA) axis: the Lewis rat as an example of increased central MR capacity and a hyporesponsive HPA axis.
Psychoneuroendocrinology 1995; 20(6):655-75P

Abstract

In this study we report a series of differences in brain and peripheral elements regulating the hypothalamic-pituitary-adrenal (HPA) axis between male LEW and Wistar rats. We found: (i) differential properties of mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) in the brain (hippocampus, hypothalamus) and pituitary: LEW rats displayed an increased capacity of MRs in the hippocampus and hypothalamus and a decreased capacity of glucocorticoid receptors GRs in the pituitary. The binding affinity (Kd) for MRs and GRs in the hippocampus was comparable. (ii) Lower concentrations of corticotropin releasing hormone (CRH) mRNA were detected in the nucleus paraventricularis of the hypothalamus of LEW rats. (iii) Adrenal weight was similar in LEW and Wistar rats; however, LEW rats had about 30% less adrenocortical cells. Subjecting adrenocortical cells to increasing doses of ACTH1-24 in vitro resulted in about a 60% smaller release of corticosterone in LEW rats. (iv) LEW rats escaped dexamethasone suppression showing increased basal levels of endogenous ACTH, but responded with a comparable release of corticosterone to the IV injection of 5 ng ACTH1-24. (v) LEW rats responded to a variety of stimuli: adrenalectomy under ether anaesthesia, a novel environment, a tail nick and restraint or an immunological challenge, with lower circulating ACTH and corticosterone plasma levels than Wistar rats. (vi) Evening levels of ACTH and corticosterone were lower in LEW than Wistar rats but did not differ in the morning. Blockade of brain MRs in the evening by a central injection of the specific MR antagonist RU28318 in LEW rats resulted in increased circulating levels of ACTH and corticosterone. (vii) Levels of corticosteroid-binding proteins were lower in one-day adrenalectomized LEW rats, indicating higher levels of free corticosterone. (viii) LEW rats had a smaller thymus than Wistar rats. Taken together, the receptor binding data correspond to a decreased neuroendocrine responsiveness of LEW rats to stress. We suggest that the shift in the central MR/GR balance of LEW rats, i.e. augmented MR-mediated effects of corticosterone, is the central regulating mechanism of the hyporeactive HPA axis in this rat strain. Lower levels of CRH mRNA in the hypothalamus and lower levels of ACTH and corticosterone in response to various stimuli, as well as the hyporesponsive adrenals to exogenous ACTH, are apparently the consequences of the life-long suppressive action of corticosterone via central MRs.

Authors+Show Affiliations

Leiden/Amsterdam Center for Drug Research, Division of Medical Pharmacology, University of Leiden, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

8584606

Citation

Oitzl, M S., et al. "Corticosterone, Brain Mineralocorticoid Receptors (MRs) and the Activity of the Hypothalamic-pituitary-adrenal (HPA) Axis: the Lewis Rat as an Example of Increased Central MR Capacity and a Hyporesponsive HPA Axis." Psychoneuroendocrinology, vol. 20, no. 6, 1995, pp. 655-75.
Oitzl MS, van Haarst AD, Sutanto W, et al. Corticosterone, brain mineralocorticoid receptors (MRs) and the activity of the hypothalamic-pituitary-adrenal (HPA) axis: the Lewis rat as an example of increased central MR capacity and a hyporesponsive HPA axis. Psychoneuroendocrinology. 1995;20(6):655-75.
Oitzl, M. S., van Haarst, A. D., Sutanto, W., & de Kloet, E. R. (1995). Corticosterone, brain mineralocorticoid receptors (MRs) and the activity of the hypothalamic-pituitary-adrenal (HPA) axis: the Lewis rat as an example of increased central MR capacity and a hyporesponsive HPA axis. Psychoneuroendocrinology, 20(6), pp. 655-75.
Oitzl MS, et al. Corticosterone, Brain Mineralocorticoid Receptors (MRs) and the Activity of the Hypothalamic-pituitary-adrenal (HPA) Axis: the Lewis Rat as an Example of Increased Central MR Capacity and a Hyporesponsive HPA Axis. Psychoneuroendocrinology. 1995;20(6):655-75. PubMed PMID: 8584606.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Corticosterone, brain mineralocorticoid receptors (MRs) and the activity of the hypothalamic-pituitary-adrenal (HPA) axis: the Lewis rat as an example of increased central MR capacity and a hyporesponsive HPA axis. AU - Oitzl,M S, AU - van Haarst,A D, AU - Sutanto,W, AU - de Kloet,E R, PY - 1995/1/1/pubmed PY - 1995/1/1/medline PY - 1995/1/1/entrez SP - 655 EP - 75 JF - Psychoneuroendocrinology JO - Psychoneuroendocrinology VL - 20 IS - 6 N2 - In this study we report a series of differences in brain and peripheral elements regulating the hypothalamic-pituitary-adrenal (HPA) axis between male LEW and Wistar rats. We found: (i) differential properties of mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) in the brain (hippocampus, hypothalamus) and pituitary: LEW rats displayed an increased capacity of MRs in the hippocampus and hypothalamus and a decreased capacity of glucocorticoid receptors GRs in the pituitary. The binding affinity (Kd) for MRs and GRs in the hippocampus was comparable. (ii) Lower concentrations of corticotropin releasing hormone (CRH) mRNA were detected in the nucleus paraventricularis of the hypothalamus of LEW rats. (iii) Adrenal weight was similar in LEW and Wistar rats; however, LEW rats had about 30% less adrenocortical cells. Subjecting adrenocortical cells to increasing doses of ACTH1-24 in vitro resulted in about a 60% smaller release of corticosterone in LEW rats. (iv) LEW rats escaped dexamethasone suppression showing increased basal levels of endogenous ACTH, but responded with a comparable release of corticosterone to the IV injection of 5 ng ACTH1-24. (v) LEW rats responded to a variety of stimuli: adrenalectomy under ether anaesthesia, a novel environment, a tail nick and restraint or an immunological challenge, with lower circulating ACTH and corticosterone plasma levels than Wistar rats. (vi) Evening levels of ACTH and corticosterone were lower in LEW than Wistar rats but did not differ in the morning. Blockade of brain MRs in the evening by a central injection of the specific MR antagonist RU28318 in LEW rats resulted in increased circulating levels of ACTH and corticosterone. (vii) Levels of corticosteroid-binding proteins were lower in one-day adrenalectomized LEW rats, indicating higher levels of free corticosterone. (viii) LEW rats had a smaller thymus than Wistar rats. Taken together, the receptor binding data correspond to a decreased neuroendocrine responsiveness of LEW rats to stress. We suggest that the shift in the central MR/GR balance of LEW rats, i.e. augmented MR-mediated effects of corticosterone, is the central regulating mechanism of the hyporeactive HPA axis in this rat strain. Lower levels of CRH mRNA in the hypothalamus and lower levels of ACTH and corticosterone in response to various stimuli, as well as the hyporesponsive adrenals to exogenous ACTH, are apparently the consequences of the life-long suppressive action of corticosterone via central MRs. SN - 0306-4530 UR - https://www.unboundmedicine.com/medline/citation/8584606/Corticosterone_brain_mineralocorticoid_receptors__MRs__and_the_activity_of_the_hypothalamic_pituitary_adrenal__HPA__axis:_the_Lewis_rat_as_an_example_of_increased_central_MR_capacity_and_a_hyporesponsive_HPA_axis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/0306453095000037 DB - PRIME DP - Unbound Medicine ER -