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      The Serotonin Transporter is Required for Stress-Evoked Increases in Adrenal Catecholamine Synthesis and Angiotensin II AT 2 Receptor Expression

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          Abstract

          High numbers of serotonin transporter (SERT) binding sites and high serotonin (5-HT) content are expressed in the adrenal medulla of wild-type (SERT+/+) mice. Acute restraint stress increases adrenomedullary 5-HT, norepinephrine (NE) and epinephrine (E) release, adrenomedullary tyrosine hydroxylase (TH) mRNA, and angiotensin II AT<sub>2</sub> receptor expression. There are no alterations in adrenal catecholamine content during restraint. In littermate SERT–/– mice, which do not express SERT binding sites, the basal adrenomedullary 5-HT content is significantly reduced and does not increase after stress. The stress-induced increase in plasma E is higher in SERT–/– than in SERT+/+ animals. In SERT–/– mice, the stress-induced increase in expression of TH mRNA does not occur, and as a consequence, adrenal E content decreases, and adrenal E and NE content are lower than that of SERT+/+ mice during restraint. In addition, instead of increased expression, stress induces a profound decrease in the number of adrenomedullary AT<sub>2</sub> receptors in SERT–/– mice. Our results indicate that SERT is necessary for the stress-induced increase in adrenomedullary catecholamine synthesis and AT<sub>2</sub> receptor expression. These data further indicate a close relationship between the adrenomedullary 5-HT and angiotensin II systems, and an important role of adrenomedullary AT<sub>2</sub> receptors in catecholamine synthesis and release during stress.

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          Most cited references 12

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          Exaggerated adrenomedullary response to immobilization in mice with targeted disruption of the serotonin transporter gene.

          This study examined whether serotonin transporter (5-HTT) gene knockout influences adrenomedullary, sympathoneural, or hypothalamo-pituitary-adrenal responses to acute immobilization. In conscious, cannulated mice, arterial plasma concentrations of catecholamines, ACTH, and corticosterone were measured at baseline and after 15 min of immobilization. Tissue levels of serotonin (5-HT), catecholamines, and hormones were also measured in pituitary and adrenal glands. At baseline, adrenal and pituitary 5-HT concentrations in knockout (5-HTT(-/-)) mice were markedly lower than those in littermate control (5-HTT(+/+)) mice, whereas the groups did not differ in levels of catecholamines or hormones in plasma or tissue. Immobilization increased plasma levels of catecholamines, ACTH, and corticosterone in all genotypes. 5-HTT(-/-) mice had exaggerated responses of plasma epinephrine to immobilization and significant reductions in adrenal epinephrine, norepinephrine, and 5-HT contents compared with values in littermate controls. Pituitary ACTH was significantly reduced after immobilization in 5-HTT(-/-) mice only, but increases in plasma ACTH and corticosterone levels did not differ between genotypes. The results suggest that one 5-HTT function is to restrain adrenomedullary activation in response to immobilization. Exaggerated adrenomedullary responses seem to be an autonomic correlate of the anxiety-like behaviors in 5-HTT knockout mice.
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            The use of 14C-labeled tissue paste standards for the calibration of 125I-labeled ligands in quantitative autoradiography.

            The relationship between the exposure of Ultrofilm to 5-30-microns slices of 14C-labeled or 125I-labeled brain paste standards was characterized using quantitative autoradiography. After exposing these slices to Ultrofilm for 24, 48 or 72 h, the autoradiograms from the 14C-labeled brain pastes were used to generate standard curves with computerized densitometry. These autoradiographic standard curves were then used to estimate the level of radioactivity present in brain paste slices containing known amounts of 125I, which also had been exposed to the film for the same length of time. The relationship between the calculated concentration of 125I and the radioactivity of 125I as determined by direct gamma counting of slices scraped from slides was a direct linear one. The use of 14C-labeled, as opposed to 125I-labeled, standards obviates the major disadvantage of using 125I-radioligands for quantitative autoradiographic studies.
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              The AT2 receptor: fact, fancy and fantasy.

              The angiotensin AT2 receptor subtype was recently cloned and pharmacologically characterized but its function still remains elusive and controversial. It is a member of the G-protein coupled receptor superfamily with a minimal sequence homology with the AT1 receptor, responsible for the known effect of angiotensin II. The AT2 receptor displays a totally different signaling mechanisms from the AT1 receptor and involves various phosphatases. It is expressed at low density in adult tissues but up-regulated in pathological circumstances. Clearly, the AT2 receptor has antiproliferative properties and therefore opposes the growth promoting effect linked to the AT1 receptor stimulation. It is also reported that the AT2 receptor regulates ionic fluxes, affects differentiation and nerve regeneration, has anti-angiogenic and anti-fibrotic properties and stimulates apoptosis. However, the results, although suggestive, are sometimes equivocal. Obviously, the AT2 receptor plays a role in the pathogenesis and remodeling of cardiovascular and renal diseases. A more extensive knowledge of the AT2 receptor could therefore contribute to the understanding of the clincial beneficial effects of the AT1 receptor antagonists.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2003
                October 2003
                31 October 2003
                : 78
                : 4
                : 217-225
                Affiliations
                aSection on Pharmacology and bLaboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, Bethesda, Md., USA
                Article
                73705 Neuroendocrinology 2003;78:217–225
                10.1159/000073705
                14583654
                © 2003 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, Tables: 2, References: 44, Pages: 9
                Categories
                Transgenic Models in Neuroendocrinology

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