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      Histaminergic Neurons Are Involved in the Orexigenic Effect of Orexin-A

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          Abstract

          Orexin-A is an orexigenic peptide expressed mainly in the hypothalamus. Orexin-A increases and anti-orexin-A antibodies decrease food intake. However, the exact mechanism by which orexin-A exerts its orexigenic action is not fully elucidated. The histaminergic system is known to play a role in feeding behavior and we hypothesized that it could be involved in the orexigenic effect of orexin-A. To study this, we used histamine knockout animals and pharmacological blockade of the histaminergic system and studied the effect of orexin-A on feeding behavior and gene expression of neuropeptide Y (NPY). Orexin-A was administered intracerebroventricularly and food intake measured in wild-type, histamine H<sub>1</sub>-receptor knockout or histidine decarboxylase knockout mice. Additionally, we administered orexin-A to wild-type mice with pharmacologically blocked H<sub>1</sub>-receptors or pharmacologically stimulated autoinhibitory H<sub>3</sub>-receptors. By quantitative real-time PCR we measured the effect of orexin-A on NPY mRNA expression in wild-type and knockout mice. Orexin-A dose-dependently stimulated food intake when administered to wild-type mice in doses up to 0.03 µg. Orexin-A in a dose of 0.01 µg increased food intake 10-fold in wild-type mice, whereas no increase in food intake was seen in either knockout mice or pharmacologically manipulated mice. Orexin-A increased NPY mRNA 4-fold in wild-type mice, whereas no change was observed in knockout mice. We conclude that the orexigenic effect of orexin-A is dependent on an intact histaminergic neuronal system and seems to involve an H<sub>1</sub>-receptor mechanism.

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          Most cited references 40

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          Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors that Regulate Feeding Behavior

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            The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity.

            We describe a hypothalamus-specific mRNA that encodes preprohypocretin, the putative precursor of a pair of peptides that share substantial amino acid identities with the gut hormone secretin. The hypocretin (Hcrt) protein products are restricted to neuronal cell bodies of the dorsal and lateral hypothalamic areas. The fibers of these neurons are widespread throughout the posterior hypothalamus and project to multiple targets in other areas, including brainstem and thalamus. Hcrt immunoreactivity is associated with large granular vesicles at synapses. One of the Hcrt peptides was excitatory when applied to cultured, synaptically coupled hypothalamic neurons, but not hippocampal neurons. These observations suggest that the hypocretins function within the CNS as neurotransmitters.
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              Distribution of orexin receptor mRNA in the rat brain.

              The expression pattern of mRNA encoding two orexin receptors (OX1R and OX2R) in the rat brain was examined. OX1R and OX2R exhibited marked differential distribution. Within the hypothalamus, OX1R mRNA is most abundant in the ventromedial hypothalamic nucleus whereas OX2R is predominantly expressed in the paraventricular nucleus. High levels of OX1R mRNA were also detected in tenia tecta, the hippocampal formation, dorsal raphe, and locus coeruleus. OX2R mRNA is mainly expressed in cerebral cortex, nucleus accumbens, subthalamic and paraventricular thalamic nuclei, anterior pretectal nucleus. The presence of orexin receptor mRNA in the hypothalamus is in support of its proposed role in feeding regulation. Broad central distribution of orexin receptors may indicate additional functions for orexins.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2005
                February 2006
                22 February 2006
                : 82
                : 2
                : 70-77
                Affiliations
                aDepartment of Medical Physiology, bCluster for Molecular Imaging, University of Copenhagen; Departments of cSurgery C, and dClinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Copenhagen, Denmark, and eResearch Center for Allergy and Immunology, RIKEN Institute, Yokohama, Japan
                Article
                90982 Neuroendocrinology 2005;82:70–77
                10.1159/000090982
                16415597
                © 2005 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: 5, Tables: 1, References: 48, Pages: 8
                Categories
                Original Paper

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