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      Mineralo- and Glucocorticoid Receptor mRNAs Are Differently Regulated by Corticosterone in the Rat Hippocampus and Anterior Pituitary

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          Abstract

          In most cell lines and animal tissues, glucocorticoid receptors undergo downregulation after exposure to corticosterone. However, corticosterone treatment has not shown a consistent effect on mineralocorticoid (MR) and glucocorticoid receptors (GR) in the hippocampus, and it has been rarely assessed in the anterior pituitary. In this study we investigated dose-dependent effects of corticosterone on MR and GR mRNAs in the hippocampus and anterior pituitary. Adrenalectomized rats substituted with corticosterone in drinking fluid were injected subcutaneously with vehicle or 1, 10, 50, 100, or 200 mg of corticosterone, and sacrificed 4 h later. In the hippocampus we found a progressive decrease in MR and GR mRNAs with increasing doses of corticosterone. This was significant with 50 and 100 mg corticosterone for MR mRNA and with 10–200 mg corticosterone for GR mRNA at plasma corticosterone levels above 30 µg/dl. The anterior pituitary did not show significant changes at any dose. A time-course with 2 mg of corticosterone (non-response dose range at 4 h) revealed a significant decrease in MR and GR mRNAs in the hippocampus 8 h after the subcutaneous injection. In the anterior pituitary both mRNAs showed an increase that was significant 24 h after injection for MR and from 8 to 24 h for GR. In the hippocampus, adrenalectomy (absence of corticosterone) induced a significant increase in MR and GR mRNAs on day 3, but not on days 1, 8 and 21 after adrenalectomy. In the anterior pituitary there were no significant changes at any time after adrenalectomy. In summary, we have found an in vivo corticosterone dose- and time-dependent downregulation of MR and GR mRNAs in the hippocampus, whereas anterior pituitary MRs and GRs seem relatively insensitive to the excess or the absence of corticosterone, suggesting the lack of an autoregulatory effect in this tissue. Significant mRNA changes appearing later in time could suggest a secondary response via a glucocorticoid-induced gene product. Corticosteroid receptor downregulation in the hippocampus could prevent overstimulation or tissue damage when plasma corticosterone is high, while increased corticosteroid receptors in the anterior pituitary could buffer the excessive brain drive on the pituitary during chronic stress or pathological conditions associated with increased plasma glucocorticoids, such as depression.

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          Most cited references 20

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          A new method of total RNA isolation by a single extraction with an acid guanidinium thiocyanate-phenol-chloroform mixture is described. The method provides a pure preparation of undegraded RNA in high yield and can be completed within 4 h. It is particularly useful for processing large numbers of samples and for isolation of RNA from minute quantities of cells or tissue samples.
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              Molecular mechanisms of glucocorticoid action and resistance.

               J Cidlowski,  M Schaaf (2002)
              The actions of glucocorticoid hormones are mediated by an intracellular receptor, the glucocorticoid receptor (GR). The mechanism of action of this ligand-inducible transcription factor is discussed, focusing on mechanisms of glucocorticoid resistance. Three mechanisms are highlighted: ligand-induced down-regulation of the receptor, the dominant-negative inhibition by the beta-isoform of the receptor, and repression by the transcription factor NF-kappa B. It has been shown that these mechanisms can significantly inhibit glucocorticoid signaling, and could therefore seriously decrease the efficacy of glucocorticoids used clinically.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2004
                May 2004
                10 June 2004
                : 79
                : 4
                : 174-184
                Affiliations
                aDepartment of Pharmacology, Psychopharmacology Unit, and bDepartment of Pediatrics, Geneva University Hospital, Geneva, Switzerland
                Article
                78099 Neuroendocrinology 2004;79:174–184
                10.1159/000078099
                15153751
                © 2004 S. Karger AG, Basel

                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.

                Page count
                Figures: 3, References: 49, Pages: 11
                Categories
                Adrenocorticotropin and Adrenal Steroids

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