The two subtypes of corticosterone receptors in the rat brain play a pivotal role in the modulation of the stress response. Appropriate control of their gene expression is therefore critical for the maintenance of cellular and organism homeostasis. In this study, we investigated the contribution of gender and of the cellular environment of certain brain areas to the expression of both types of corticosteroid receptors, following restraint stress. Adult Wistar rats of both sexes were subjected to acute, chronic or to a combined chronic plus acute stress regimen, and the expression of glucocorticoid and mineralocorticoid receptors was evaluated in their hippocampus, hypothalamus, pituitary and frontal cortex, by using Northern blot analysis. Significant sex differences were observed in the first three brain areas examined as to the stress-induced expression of corticosteroid receptors. Among these, females showed a distinct mechanism of regulating glucocorticoid/mineralocorticoid receptor ratio in the hippocampus upon chronic stress, while the female hypothalamus was more prone than the male to changing corticosteroid receptor expression in response to restraint stress. In another set of experiments, we assessed the influence of ovarian steroids on stress-induced corticosteroid receptor expression in the above brain areas by analyzing ovariectomized rats exposed to short-term restraint. Our results showed that although ovarian steroids affect the stress-induced expression of receptor genes in a region-specific manner, their elimination does not appear to lead to the male pattern of expression. These findings provide further evidence for the existence of both regional and gender specificity in the regulation of brain and pituitary corticosteroid receptors following stress, and support the hypothesis of a distinct male and female neuroendocrine axis in response to stress.

1.
De Kloet ER, Vreugdenhil E, Oitzl MS, Joels M: Brain corticosteroid receptor balance in health and disease. Endocr Rev 1998;19:269–301.
2.
Yau JLW, Olsson T, Morris RGM, Meaney MJ, Seckl JR: Glucocorticoids, hippocampal corticosteroid receptor gene expression and antidepressant treatment: Relationship with spatial learning in young and aged rats. Neuroscience 1995;66:571–581.
3.
Liberzon I, Lopez JF, Flagel SB, Vazquez DM, Young EA: Differential regulation of hippocampal glucocorticoid receptors mRNA and fast feedback: Relevance to post-traumatic stress disorder. J Neuroendocrinol 1999;11:11–17.
4.
Liu D, Diorio J, Tannenbaum B, Caldji C, Francis D, Freedman A, Sharma S, Pearson D, Plotsky PM, Meaney MJ: Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal response to stress. Science 1997;277:1659–1662.
5.
Gomez F, Lahmame A, De Kloet ER, Armario A: Hypothalamic-pituitary-adrenal response to chronic stress in five inbred rat strains: Differential responses are mainly located at the adrenocortical level. Neuroendocrinology 1996;63:327–337.
6.
Herman JP, Adams D, Prewitt C: Regulatory changes in neuroendocrine stress-integrative circuitry produced by a variable stress paradigm. Neuroendocrinology 1995;61:180–190.
7.
Herman JP, Spencer R: Regulation of hippocampal glucocorticoid receptor gene transcription and protein expression in vivo. J Neurosci 1998;18:7462–7473.
8.
Kitraki E, Karandrea D, Kittas C: Long-lasting effects of stress on glucocorticoid receptor gene expression in the rat brain. Neuroendocrinology 1999;69:331–338.
9.
Makino S, Smith MA, Gold PW: Increased expression of corticotropin-releasing hormone and vasopressin messenger ribonucleic acid (mRNA) in the hypothalamic paraventricular nucleus during repeated stress: Association with reduction in glucocorticoid receptor mRNA levels. Endocrinology 1995;136:3299–3309.
10.
Sapolsky RM, Krey IC, McEwen BS: Stress down-regulates glucocorticoid receptors in a site-specific manner in the brain. Endocrinology 1984;114:287–292.
11.
Carey MP, Deterd CH, de Koning J, Helmerhorst F, De Kloet ER: The influence of ovarian steroids on hypothalamo-pituitary-adrenal regulation in the female rat. J Endocrinol 1995;144:311–321.
12.
Handa RJ, Burgess LH, Kerr JE, O’Keefe JA: Gonadal steroid hormone receptors and sex differences in the hypothalamo-pituitary-adrenal axis. Horm Behav 1994;28:464–476.
13.
McCormick CM, Smythe JW, Sharma S, Meaney MJ: Sex-specific effects of prenatal stress on hypothalamic-pituitary-adrenal responses to stress and brain glucocorticoid receptor density in adult rats. Brain Res Dev Brain Res 1995;84:55–61.
14.
Patchev VK, Almeida OFX: Gonadal steroids exert facilitating and ‘buffering’ effects on glucocorticoid-mediated transcriptional regulation of corticotropin-releasing hormone and corticosterone receptor genes in rat brain. J Neurosci 1996;16:7077–7084.
15.
McCormick CM, Furey BF, Child M, Sawyer MJ, Donohue SM: Neonatal sex hormones have ‘organizational’ effects on the hypothalamic-pituitary-adrenal axis of male rats. Brain Res Dev Brain Res 1998;105:295–307.
16.
Kerr JE, Beck SG, Handa RJ: Androgens modulate glucocorticoid receptor mRNA, but not mineralocorticoid receptor mRNA levels, in the rat hippocampus. J Neuroendocrinol 1996;8:439–447.
17.
Turner BB: Influence of gonadal steroids on brain corticosteroid receptors: A minireview. Neurochem Res 1997;22:1375–1385.
18.
Peiffer A, Lapointe B, Barden N: Hormonal regulation of type II glucocorticoid receptor messenger ribonucleic acid in rat brain. Endocrinology 1991;129:2166–2174.
19.
Ahima RS, Lawson ANL, Osei SYS, Harlan RE: Sexual dimorphism in regulation of type II corticosteroid receptor immunoreactivity in the rat hippocampus. Endocrinology 1992;131:1409–1416.
20.
Jones BC, Sarrieua A, Reed CL, Azar MR, Mormede P: Contribution of sex and genetics to neuroendocrine adaptation to stress in mice. Psychoneuroendocrinology 1998;23:505–517.
21.
Meaney MJ, Diorio J, Francis D, Widdowson J, LaPlante P, Caldji C, Sharma S, Seckl JR, Plotsky PM: Early environmental regulation of forebrain glucocorticoid receptor gene expression: Implications for adrenocortical responses to stress. Dev Neursci 1996;18:49–72.
22.
Kitraki E, Bozas E, Philippidis H, Stylianopoulou F: Aging-related changes in IGF-II and c-fos gene expression in the rat brain. Int J Dev Neurosci 1993;11:1–9.
23.
Chomczynski P, Sacchi N: Single-step method of RNA isoaltion by guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987;162:156–159.
24.
Tritos N, Kitraki E, Philippidis H, Stylianopoulou F: Neurotransmitter modulation of glucocorticoid receptor mRNA levels in the rat hippocampus. Neuroendocrinology 1999;69:324–330.
25.
Arizza JL, Simerly WB, Swanson LW, Evans RM: The neuronal mineralocorticoid receptor as a mediator of the glucocorticoid response. Neuron 1988;1:887–900.
26.
McCullagh N, Nelder J: Generalized Linear Models. New York, Chapman and Hall, 1989.
27.
Herman JP: Regulation of adrenocorticosteroid receptor mRNA expression in the central nervous system. Cell Mol Neurobiol 1993;13:349–371.
28.
Swanson LW, Simmons DM: Differential steroid hormone and neural influences on peptide mRNA levels in CRH cells of the paraventricular nucleus: A hybridization histochemical study in the rat. J Comp Neurol 1989;285:413–435.
29.
Kant GJ, Lenox RH, Bunnell BN, Mougey EH, Pennington LL, Meyerhoff J: Comparison of stress response in male and female rats: Pituitary cyclic AMP and plasma prolactin, growth hormone and corticosterone. Psychoneuroendocrinology 1983;8:421–428.
30.
Burchfield SR, Woods SC, Elich MS: Pituitary adreno-cortical response to chronic intermittent stress. Physiol Behav 1980;24:297–302.
31.
Young EA: Sex differences in response to exogenous corticosterone: A rat model of hypercortisolemia. Mol Psychiatry 1996;1:313–319.
32.
Armario A, Restrepo C, Castellanos JM, Balasch J: Dissociation between adrenocorticotropin and corticosterone response to restraint after previous chronic exposure to stress. Life Sci 1985;36:2085–2092.
33.
Aguilera G: Corticotropin-releasing hormone, receptor regulation and the stress response. TEM 1998;9:329–336.
34.
Dallman MF, Akana SF, Scribner KA, Bradbury MJ, Walter C-D, Strack AM, Cascio CS: Mortyn Jones Memorial Lecture. Stress feedback and facilitation in the hypothalamo-pituitary-adrenal axis. J Neuroendocrinol 1992;4:517–526.
35.
Marti O, Gavalda A, Gomez F, Armario A: Direct evidence for chronic stress-induced facilitation of the adrenocorticotropin response to a novel acute stressor. Neuroendocrinology 1994;60:1–7.
36.
Herman JP, Watson SJ: Stress regulation of mineralocorticoid receptor heteronuclear RNA in rat hippocampus. Brain Res 1995;677:243–249.
37.
Oitzl MS, Van Haarst AD, Sutanto W, De Kloet ER: 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;20:655–675.
38.
Castren M, Patchev VK, Almeida OFX, Holsboer F, Trapp T, Castren E: Regulation of rat mineralocorticoid receptor expression in neurons by progesterone. Endocrinology 1995;136:3800–3806.
39.
Juptner M, Jussofie A, Hiemke C: Effects of ovariectomy and steroid replacement on GABAA receptor binding in female rat brain. J Steroid Biochem Mol Biol 1991;38:141–147.
40.
Ferrini M, De Nicola AF: Estrogen up-regulate type I and type II glucocorticoid receptors in brain regions from ovariectomized rats. Life Sci 1991;48:2593–2601.
41.
Halasz I, Rittenhouse PA, Zorrilla EP, Redei E: Sexually dimorphic effects of maternal adrenalectomy on hypothalamic corticotropin-releasing factor, glucocorticoid receptor and anterior pituitary POMC mRNA levels in rat neonates. Brain Res Dev Brain Res 1997;100:198–204.
42.
Turner BB: Sex difference in glucocorticoid binding in the rat pituitary is estrogen dependent. Life Sci 1990;46:1399–1406.
43.
Peiffer A, Barden N: Estrogen-induced decrease of glucocorticoid receptor messenger ribonucleic acid concentration in rat anterior pituitary gland. Mol Endocrinol 1987;1:435–440.
44.
De Kloet ER, Burbach JPA, Mulder GH: Localization and role of transcortin-like molecules in the anterior pituitary. Mol Cell Endocrinol 1977;7:261–273.
45.
Hammond GL: Molecular properties of corticosteroid binding globulin and sex-steroid binding proteins. Endocr Rev 1990;11:65–79.
46.
Turner BB, Weaver DA: Sexual dimorphism of glucocorticoid binding in rat brain. Brain Res 1985;343:16–23.
47.
Patchev VK, Hayashi S, Orikasa C, Almeida OFX: Implications of estrogen-dependent brain organization for gender differences in hypothalamo-pituitary-adrenal regulation. FASEB J 1995;9:419–423.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.