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      Homologous Upregulation of sst2 Somatostatin Receptor Expression in the Rat Arcuate Nucleus in vivo

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          Abstract

          In vitro studies using various cell systems have provided conflicting results regarding homologous regulation of somatostatin (SRIH) receptors, and information on whether SRIH regulates the expression of its own receptors in vivo is lacking. In the present study we examined, by in situ hybridization, the effects of pretreatment with the sst2-preferring SRIH analog, octreotide, in vivo, on mRNA levels of two SRIH receptor subtypes, sst1 and sst2, in rat brain and pituitary. <sup>125</sup>I-[DTrp<sup>8</sup>]-SRIH binding was also measured in these regions. Three hours after the iv injection of 50 µg octreotide to conscious adult male rats, there was a 46% increase (p < 0.01) in the labeling density of sst2 mRNA-expressing cells in the hypothalamic arcuate nucleus compared to normal saline-pretreated controls, but not in any of the other brain regions examined. Computer-assisted image analysis revealed that 3 h exposure to octreotide significantly (p < 0.01) augmented both the number and labeling density of sst2 mRNA-expressing cells in the arcuate nucleus, compared to those in saline-treated controls. By contrast, within the anterior pituitary gland, in vivo exposure to octreotide did not affect the expression of sst2 mRNA. No changes in sst1 mRNA-expressing cells were observed after octreotide treatment in any of the regions measured, indicating that the observed effects were homologous, i.e. specific of the receptor subtype stimulated. Octreotide pretreatment was also without effect on the density of <sup>125</sup>I-[DTrp<sup>8</sup>]-SRIH binding in either the arcuate nucleus or pituitary. These results demonstrate, for the first time, that SRIH preexposure in vivo upregulates the expression of a subtype of its own receptors, sst2, within the central nervous system. They further suggest that pretreatment with SRIH in vivo does not cause sst2 receptor desensitization in arcuate nucleus and pituitary. Such homologous regulatory mechanisms may play an important role in the neuroendocrine control of growth hormone (GH) secretion by the arcuate nucleus.

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          Immunohistochemical distribution of somatostatin-like immunoreactivity in the central nervous system of the adult rat.

          The localization and distribution of somatostatin (growth hormone release-inhibiting hormone; somatotropin release-inhibiting factor) have been studied with the indirect immunofluorescence technique of Coons and collaborators and the immunoperoxidase method of Sternberger and coworkers using specific and well-characterized antibodies to somatostatin, providing semiquantitative, detailed maps of somatostatin-immunoreactive cell profiles and fibers. Our results demonstrate a widespread occurrence of somatostatin-positive nerve cell bodies and fibers throughout the central nervous system of adult, normal or colchicine-treated, albino rats. The somatostatin cell bodies varied in size from below 10 micron up to 40 micron in diameter and could have only a few or multiple processes. Dense populations of cell somata were present in many major areas including neocortex, piriform cortex, hippocampus, amygdaloid complex, nucleus caudatus, nucleus accumbens, anterior periventricular hypothalamic area, ventromedial hypothalamic nucleus, nucleus arcuatus, medial to and within the lateral lemniscus, pontine reticular nuclei, nucleus cochlearis dorsalis and immediately dorsal to the nucleus tractus solitarii. Extensive networks of nerve fibers of varying densities were also found in most areas and nuclei of the central nervous system. Both varicose fibers as well as dot- or "dust-like" structures were seen. Areas with dense or very dense networks included nucleus accumbens, nucleus caudatus, nucleus amygdaloideus centralis, most parts of the hypothalamus, nucleus parabrachialis, nucleus tractus solitarii, nucleus ambiguus, nucleus tractus spinalis nervi trigemini and the dorsal horn of the spinal cord. One exception is the cerebellum which only contained few somatostatin-positive cell bodies and nerve fibers. It should be noted that somatostatin-positive cell bodies and fibers did not always conform to the boundaries of the classical neuroanatomical nuclei, but could often be found in areas between these well-established nuclei or occupying, in varying concentrations, only parts of such nuclei. It was difficult to identify with certainty somatostatin-immunoreactive axons in the animals studied. Some pathways could, however, be demonstrated, but further experimental studies are necessary to elucidate the exact projections of the somatostatin-immunoreactive neurons in the rat central nervous system.
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            Rapid identification of subtype-selective agonists of the somatostatin receptor through combinatorial chemistry.

            Nonpeptide agonists of each of the five somatostatin receptors were identified in combinatorial libraries constructed on the basis of molecular modeling of known peptide agonists. In vitro experiments using these selective compounds demonstrated the role of the somatostatin subtype-2 receptor in inhibition of glucagon release from mouse pancreatic alpha cells and the somatostatin subtype-5 receptor as a mediator of insulin secretion from pancreatic beta cells. Both receptors regulated growth hormone release from the rat anterior pituitary gland. The availability of high-affinity, subtype-selective agonists for each of the somatostatin receptors provides a direct approach to defining their physiological functions.
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              Somatostatin Receptor Desensitization in NG108-15 Cells

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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2001
                July 2001
                06 July 2001
                : 74
                : 1
                : 33-42
                Affiliations
                Departments of aPediatrics and bNeurology and Neurosurgery, McGill University, Montreal, Que., Canada; cINSERM, Centre Paul-Broca, Paris, France
                Article
                54668 Neuroendocrinology 2001;74:33–42
                10.1159/000054668
                11435756
                cc43a3cd-54ab-40d8-b96e-e95d70994fe0
                © 2001 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.

                History
                Page count
                Figures: 4, Tables: 2, References: 52, Pages: 10
                Categories
                Regulation of Hypothalamic Neurons

                Endocrinology & Diabetes,Neurology,Nutrition & Dietetics,Sexual medicine,Internal medicine,Pharmacology & Pharmaceutical medicine
                Autoradiography,Somatostatin receptors,Arcuate nucleus,Octreotide,In situ hybridization,Somatostatin,Growth hormone

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