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      Identification of Endocannabinoids and Cannabinoid CB 1 Receptor mRNA in the Pituitary Gland

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          Abstract

          Most data on effects of natural and synthetic cannabinoids on anterior pituitary hormone secretion point out to a primary impact on the hypothalamus. There is also some evidence, however, of possible direct actions of these compounds on the anterior pituitary, although the presence of cannabinoid receptors in the pituitary has not been documented as yet. In the present study, we evaluated the presence of cannabinoid CB<sub>1</sub> receptor-mRNA transcripts in the pituitary gland by in situ hybridization. We observed CB<sub>1</sub> receptor-mRNA transcripts in the anterior pituitary and to a lesser extent in the intermediate lobe whereas they were absent in the neural lobe. We then examined whether CB<sub>1</sub> receptor-mRNA levels in both pituitary lobes responded to chronic activation by a specific agonist, as did receptors located in adjacent hypothalamic nuclei and in other brain regions. Daily administration of CP-55,940 for 18 days produced a small, but statistically significant paradoxical increase in CB<sub>1</sub> receptor-mRNA levels in the anterior pituitary, with no changes in the intermediate lobe, in contrast to reduced CB<sub>1</sub> receptor-mRNA levels observed in the ventromedial hypothalamic nucleus (VMN), and to decreased CB<sub>1</sub> receptor binding in the VMN and the arcuate nucleus. The time-course of up-regulation of CB<sub>1</sub> receptor-mRNA transcripts in the anterior lobe was biphasic; daily administration of Δ<sup>9</sup>-tetrahydrocannabinol produced an early and marked decrease in CB<sub>1</sub> receptor-mRNA levels after 1 and 3 days, followed by normalization after 7 days and by a small increase after 14 days. We also checked whether endogenous cannabinoid ligands are present in the anterior pituitary and the hypothalamus. Although anandamide itself was detected only in trace amounts, concentrations of its precursor N-arachidonoyl-phosphatidyl-ethanolamine and of 2-arachidonoyl-glycerol were found in both tissues, suggesting that endocannabinoids may be synthetized in the anterior pituitary. In summary, CB<sub>1</sub> receptors and corresponding ligands seem to be expressed in cells of the anterior and intermediate lobes of the pituitary, but the response of CB<sub>1</sub> receptor-mRNA transcripts in the anterior lobe to chronic agonist activation is different than the desensitization observed in hypothalamic nuclei.

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          Most cited references 12

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          The cannabinoid receptor: biochemical, anatomical and behavioral characterization.

          The actions of the active principle of marihuana, delta 9-tetrahydrocannabinol, are mimicked by synthetic cannabinoid agonists showing high potency and enantio-selectivity in behavioral assays. These drugs have been used to characterize cannabinoid receptor binding, biochemistry and pharmacology, leading to a better understanding of the effects of cannabinoids in the CNS of humans and experimental animals.
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            Distribution of neuronal cannabinoid receptor in the adult rat brain: A comparative receptor binding radioautography and in situ hybridization histochemistry

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              Chronic cannabinoid administration alters cannabinoid receptor binding in rat brain: a quantitative autoradiographic study.

              The active ingredient of marijuana is (-)-delta 9-tetrahydrocannabinol (delta 9-THC). delta 9-THC and other natural and synthetic cannabinoids such as CP-55,940 inhibit spontaneous activity and produce catalepsy in animals in a receptor-mediated fashion. Tolerance develops to the motor effects of delta 9-THC after repeated administration. To test the hypothesis that tolerance is mediated by changes in cannabinoid receptor binding characteristics, we used quantitative in vitro autoradiography of [3H]CP-55,940 binding to striatal brain sections from rats treated either chronically or acutely with delta 9-THC, CP-55,940, or the inactive natural cannabinoid cannabidiol. In the chronic conditions, rats were given daily i.p. injections of delta 9-THC (10 mg/kg), cannabidiol (10 mg/kg), or CP-55,940 (1, 3, or 10 mg/kg) for 2 weeks and sacrificed 30 min after the last injection. In the acute condition, animals received a single dose (10 mg/kg) prior to sacrifice. Rats developed tolerance to the inhibitory effects of delta 9-THC and CP-55,940, assayed in an open field on days 1, 7, and 14. Cannabidiol had no effect on behavior. Densitometry of [3H]CP-55,940 binding to brain sections showed that delta 9-THC- and CP-55,940-treated animals had homogeneous decreases in binding in all structures measured at the selected striatal levels. Cannabidiol had no effect on binding. Analysis of binding parameters showed that alterations in the acute condition were attributed to changes in affinity (KD), whereas the major changes in the chronic condition were attributed to a lowering of capacity (Bmax). The effects in the 1, 3, and 10 mg/kg CP-55,940 conditions were dose-dependent and paralleled the behavioral data showing that the animals given the highest dose developed the greatest degree of tolerance. The data suggest that tolerance to cannabinoids results at least in part from agonist-induced receptor down-regulation.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                1999
                August 1999
                16 August 1999
                : 70
                : 2
                : 137-145
                Affiliations
                aDepartamento de Bioquímica y Biología Molecular, Facultad de Medicina y bDepartamento de Farmacología, Facultad de Farmacia, Unidad Cartográfica Cerebral, Instituto Pluridisciplinar, Universidad Complutense de Madrid, Spain cDepartment of Human Morphology and Developmental Biology, School of Medicine, Semmelweis University, Budapest, Hungary, and dIstituto per la Chimica di Molecole di Interesse Biologico, CNR, Arco Felice, Naples, Italy
                Article
                54468 Neuroendocrinology 1999;70:137–145
                10.1159/000054468
                10461028
                © 1999 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: 48, Pages: 9
                Categories
                Pituitary Receptors

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