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Vol. 54, No. 4, 2006
Issue release date: April 2007
Section title: Original Paper
Editor's Choice -- Free Access
Neuropsychobiology 2006;54:231–246
(DOI:10.1159/000100778)

Neuropsychobiological Evidence for the Functional Presence and Expression of Cannabinoid CB2 Receptors in the Brain

Onaivi E.S.
Department of Biology, William Paterson University, Wayne, N.J., USA
email Corresponding Author

Abstract

For over a decade, until recently, it was thought that marijuana acts by activating brain-type cannabinoid receptors called CB1, and that a second type called CB2 cannabinoid receptor was found only in peripheral tissues. Neuronal CB2 receptors in the brain had been controversial. We reported the discovery and functional presence of CB2 cannabinoid receptors in the mammalian brain that may be involved in depression and drug abuse and this was supported by reports of identification of neuronal CB2 receptors that are involved in emesis. RT-PCR, immunoblotting, hippocampal cultures, immunohistochemistry, transmission electron microscopy, and stereotaxic techniques with behavioral assays were used to determine the functional expression of CB2 cannabinoid receptors in the rat brain and mouse brain exposed to chronic mild stress or treated with abused drugs. RT-PCR analyses supported the expression of brain CB2 receptor transcripts at levels much lower than those of CB1 receptors. In situ hybridization revealed CB2 mRNA in cerebellar neurons of wild-type but not of CB2 knockout mice. Abundant CB2 receptor immunoreactivity (iCB2) in neuronal and glial processes was detected in the brain. The effect of direct CB2 antisense oligonucleotide injection into the brain and treatment with JWH015 in motor function and plus-maze tests also demonstrated the functional presence of CB2 cannabinoid receptors in the central nervous system. In humans, there was a high incidence of Q63R polymorphism in the CB2 gene in Japanese alcoholics and depressed subjects. Contrary to the prevailing view that CB2 cannabinoid receptors are restricted to peripheral tissues and predominantly in immune cells, we demonstrated that CB2 cannabinoid receptors and their gene transcripts are widely distributed in the brain. This multifocal expression of iCB2 in the brain suggests that CB2 receptors may play broader roles than previously anticipated and may therefore be exploited as new targets in the treatment of depression and substance abuse.

© 2006 S. Karger AG, Basel


  

Key Words

  • CB2 cannabinoid receptor
  • CB2 gene
  • CB2 polyclonal antibody
  • CB2 knockout mice
  • CB2 electron micrograph from brain neurons

References

  1. Matsuda LA, Lolait TI, Bownstein MJ, Young AC, Bonner TI: Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990;346:561–564.
  2. Onaivi ES, Ishiguro H, Lin Z, Akinshola BE, Zhang PW, Uhl GR: Cannabinoid receptor genetics and behavior; in Onaivi ES (ed): Biology of Marijuana: From Gene to Behavior. Boca Raton, Taylor and Francis, 2002, pp 1–44.
  3. Munro S, Thomas KL, Abu-Shaar M: Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993;365:61–65.
  4. Meozzi PA, Patel S, Myers L, Leonard CM, Gardner E, Onaivi ES: Decreased alcohol consumption and enhanced cannabinoid CB2 receptor expression in mouse chronic mild stress model of depression. 7th Annu Undergraduate Res Symp Chem Biol Sci, Baltimore, 2004.
  5. Onaivi ES, Ishiguro H, Patel S, Meozzi PA, Myers L, Tagliaferro P, Leonard CM, Gardner E, Brusco A, Akinshola BE, Liu QR, Hope B, Uhl GR: Presence and functional expression of peripheral cannabinoid CB2 receptors in the brain. Coll Probl Drug Depend Annu Meet, Orlando, 2005.
  6. Onaivi ES, Ishiguro H, Gong JP, Patel S, Meozzi PA, Myers L, Tagliaferro P, Leonard CM, Gardner E, Brusco A, Akinshola BE, Liu QR, Hope B, Uhl GR: Peripheral cannabinoid CB2 receptors are expressed in the brain and involved in depression and substance abuse. ICRS Symp Cannabinoids, Vermont, 2005, p 66.
  7. Onaivi ES, Ishiguro H, Gong JP, Patel S, Meozzi PA, Myers L, Mora Z, Perchuk P, Tagliaferro P, Leonard CM, Gardner E, Brusco A, Akinshola BE, Liu QR, Hope B, Uhl GR: Presence and functional expression of CB2 cannabinoid receptors in brain that is involved in depression and substance abuse. Int Soc Neurochem/Eur Soc Neurochem Satellite Meet, Isola di San Servolo, Venice, 2005.
  8. Gong JP, Onaivi ES, Uhl GR: Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. ICRS Symp Cannabinoids, Vermont, 2005, p 91.
  9. Onaivi ES, Ishiguro H, Gong JP, Patel S, Meozzi PA, Myers L, Mora Z, Perchuk P, Tagliaferro P, Leonard CM, Gardner E, Brusco A, Akinshola BE, Liu QR, Hope B, Uhl GR: Presence and functional expression of CB2 cannabinoid receptors in the brain that is involved in depression and substance abuse. Int Narc Res Soc Meet, Annapolis, 2005.
  10. Gong JP, Onaivi ES, Uhl GR: Peripheral cannabinoid CB2 receptors: expression in neuronal patterns and localization in rat brain. Int Narc Res Soc Meet, Annapolis, 2005.
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  16. Carlisle SJ, Marciano-Cabral F, Staab A, Ludwick C, Cabral GA: Differential expression of the CB2 cannabinoid receptor by rodent macrophages and macrophage-like cells in relation to cell activation. Int J Immunopharmacol 2002;2:69–82.
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    External Resources

  59. Zhong L, Geng L, Njie Y, Feng W, Song ZH: CB2 cannabinoid receptors in trabecular meshwork cells mediate JWH015-induced enhancement of aqueous humor outflow facility. Invest Ophthalmol Vis Sci 2005;46:1988–1992.
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  62. Klein TW, Newton C, Larsen K, Lu L, Perkins I, Nong L: The cannabinoid system and immune modulation. J Leukocyte Biol 2003;74:486–496.
  63. Lee SF, Newton C, Widen R, Friedman H, Klein TW: Differential expression of cannabinoid CB2 receptor mRNA in mouse immune cell subpopulation and following B cell stimulation. J Pharmacol 2001;423:235–241.
  64. Buckley NE, McCoy KL, Mezey E, Bonner T, Zimmer A, Felder CC, Glass M, Zimmer A: Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB2 receptor. Eur J Pharmacol 2000;396:141–149.

  

Author Contacts

Emmanuel S. Onaivi, PhD
Department of Biology
William Paterson University
Wayne, NJ 07470 (USA)
Tel. +1 973 720 3453, Fax +1 973 720 2338, E-Mail Onaivie@wpunj.edu

  

Article Information

Received: January 2, 2006
Accepted after revision: December 17, 2006
Published online: March 15, 2007
Number of Print Pages : 16
Number of Figures : 7, Number of Tables : 0, Number of References : 64

  

Publication Details

Neuropsychobiology (International Journal of Experimental and Clinical Research in Biological Psychiatry, Pharmacopsychiatry, Biological Psychology/Pharmacopsychology and Pharmacoelectroencephalography)

Vol. 54, No. 4, Year 2006 (Cover Date: April 2007)

Journal Editor: Strik, W. (Bern)
ISSN: 0302–282X (print), 1423–0224 (Online)

For additional information: http://www.karger.com/NPS


Copyright / Drug Dosage / Disclaimer

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 or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
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 goverment 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.

Abstract

For over a decade, until recently, it was thought that marijuana acts by activating brain-type cannabinoid receptors called CB1, and that a second type called CB2 cannabinoid receptor was found only in peripheral tissues. Neuronal CB2 receptors in the brain had been controversial. We reported the discovery and functional presence of CB2 cannabinoid receptors in the mammalian brain that may be involved in depression and drug abuse and this was supported by reports of identification of neuronal CB2 receptors that are involved in emesis. RT-PCR, immunoblotting, hippocampal cultures, immunohistochemistry, transmission electron microscopy, and stereotaxic techniques with behavioral assays were used to determine the functional expression of CB2 cannabinoid receptors in the rat brain and mouse brain exposed to chronic mild stress or treated with abused drugs. RT-PCR analyses supported the expression of brain CB2 receptor transcripts at levels much lower than those of CB1 receptors. In situ hybridization revealed CB2 mRNA in cerebellar neurons of wild-type but not of CB2 knockout mice. Abundant CB2 receptor immunoreactivity (iCB2) in neuronal and glial processes was detected in the brain. The effect of direct CB2 antisense oligonucleotide injection into the brain and treatment with JWH015 in motor function and plus-maze tests also demonstrated the functional presence of CB2 cannabinoid receptors in the central nervous system. In humans, there was a high incidence of Q63R polymorphism in the CB2 gene in Japanese alcoholics and depressed subjects. Contrary to the prevailing view that CB2 cannabinoid receptors are restricted to peripheral tissues and predominantly in immune cells, we demonstrated that CB2 cannabinoid receptors and their gene transcripts are widely distributed in the brain. This multifocal expression of iCB2 in the brain suggests that CB2 receptors may play broader roles than previously anticipated and may therefore be exploited as new targets in the treatment of depression and substance abuse.

© 2006 S. Karger AG, Basel


  

Author Contacts

Emmanuel S. Onaivi, PhD
Department of Biology
William Paterson University
Wayne, NJ 07470 (USA)
Tel. +1 973 720 3453, Fax +1 973 720 2338, E-Mail Onaivie@wpunj.edu

  

Article Information

Received: January 2, 2006
Accepted after revision: December 17, 2006
Published online: March 15, 2007
Number of Print Pages : 16
Number of Figures : 7, Number of Tables : 0, Number of References : 64

  

Publication Details

Neuropsychobiology (International Journal of Experimental and Clinical Research in Biological Psychiatry, Pharmacopsychiatry, Biological Psychology/Pharmacopsychology and Pharmacoelectroencephalography)

Vol. 54, No. 4, Year 2006 (Cover Date: April 2007)

Journal Editor: Strik, W. (Bern)
ISSN: 0302–282X (print), 1423–0224 (Online)

For additional information: http://www.karger.com/NPS


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 1/2/2006
Accepted: 12/17/2006
Published online: 4/4/2007
Issue release date: April 2007

Number of Print Pages: 16
Number of Figures: 7
Number of Tables: 0

ISSN: 0302-282X (Print)
eISSN: 1423-0224 (Online)

For additional information: http://www.karger.com/NPS


Copyright / Drug Dosage

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 or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
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 goverment 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.

References

  1. Matsuda LA, Lolait TI, Bownstein MJ, Young AC, Bonner TI: Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990;346:561–564.
  2. Onaivi ES, Ishiguro H, Lin Z, Akinshola BE, Zhang PW, Uhl GR: Cannabinoid receptor genetics and behavior; in Onaivi ES (ed): Biology of Marijuana: From Gene to Behavior. Boca Raton, Taylor and Francis, 2002, pp 1–44.
  3. Munro S, Thomas KL, Abu-Shaar M: Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993;365:61–65.
  4. Meozzi PA, Patel S, Myers L, Leonard CM, Gardner E, Onaivi ES: Decreased alcohol consumption and enhanced cannabinoid CB2 receptor expression in mouse chronic mild stress model of depression. 7th Annu Undergraduate Res Symp Chem Biol Sci, Baltimore, 2004.
  5. Onaivi ES, Ishiguro H, Patel S, Meozzi PA, Myers L, Tagliaferro P, Leonard CM, Gardner E, Brusco A, Akinshola BE, Liu QR, Hope B, Uhl GR: Presence and functional expression of peripheral cannabinoid CB2 receptors in the brain. Coll Probl Drug Depend Annu Meet, Orlando, 2005.
  6. Onaivi ES, Ishiguro H, Gong JP, Patel S, Meozzi PA, Myers L, Tagliaferro P, Leonard CM, Gardner E, Brusco A, Akinshola BE, Liu QR, Hope B, Uhl GR: Peripheral cannabinoid CB2 receptors are expressed in the brain and involved in depression and substance abuse. ICRS Symp Cannabinoids, Vermont, 2005, p 66.
  7. Onaivi ES, Ishiguro H, Gong JP, Patel S, Meozzi PA, Myers L, Mora Z, Perchuk P, Tagliaferro P, Leonard CM, Gardner E, Brusco A, Akinshola BE, Liu QR, Hope B, Uhl GR: Presence and functional expression of CB2 cannabinoid receptors in brain that is involved in depression and substance abuse. Int Soc Neurochem/Eur Soc Neurochem Satellite Meet, Isola di San Servolo, Venice, 2005.
  8. Gong JP, Onaivi ES, Uhl GR: Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. ICRS Symp Cannabinoids, Vermont, 2005, p 91.
  9. Onaivi ES, Ishiguro H, Gong JP, Patel S, Meozzi PA, Myers L, Mora Z, Perchuk P, Tagliaferro P, Leonard CM, Gardner E, Brusco A, Akinshola BE, Liu QR, Hope B, Uhl GR: Presence and functional expression of CB2 cannabinoid receptors in the brain that is involved in depression and substance abuse. Int Narc Res Soc Meet, Annapolis, 2005.
  10. Gong JP, Onaivi ES, Uhl GR: Peripheral cannabinoid CB2 receptors: expression in neuronal patterns and localization in rat brain. Int Narc Res Soc Meet, Annapolis, 2005.
  11. Onaivi ES, Ishiguro H, Gong JP, Patel S, Meozzi PA, Myers L, Mora Z, Perchuk P, Tagliaferro P, Leonard CM, Gardner E, Brusco A, Akinshola BE, Liu QR, Hope B, Uhl GR: Discovery of the presence and functional expression of CB2 cannabinoid receptors in brain that is involved in depression and substance abuse. Soc Neurosci Abstr, Washington, 2005.
  12. Onaivi ES, Ishiguro H, Patel S, Meozzi PA, Myers L, Tagliaferro P, Hope B, Leonard CM, Uhl GR, Brusco A, Gardner E: Methods to study the behavioral effects and expression of CB2 cannabinoid receptors and its gene transcripts in chronic mild stress model of depression; in Onaivi ES (ed): Marijuana and Cannabinoid Research: Methods and Protocols. Totowa, Humana Press Inc, 2006, pp 291–298.
  13. Berdyshev EV: Cannabinoid receptors and the regulation of immune response. Chem Phys Lipids 2000;108:169–190.
  14. Suigiura T, Waku K: 2-Arachidonoylglycerol and cannabinoid receptors. Chem Phys Lipids 2000;108:89–106.
  15. Wilson RI, Nicoll R: Endogenous cannabinoids mediate retrograde signaling at hippocampal synapses. Nature 2001;410:588–592.
  16. Carlisle SJ, Marciano-Cabral F, Staab A, Ludwick C, Cabral GA: Differential expression of the CB2 cannabinoid receptor by rodent macrophages and macrophage-like cells in relation to cell activation. Int J Immunopharmacol 2002;2:69–82.
  17. Derocq JM, Segui M, Marchand J, Le Fur G, Casellas P: Cannabinoids enhance human B-cell growth at low nanomolar concentrations. FEBS Lett 1995;369:177–182.
  18. Galiegue S, Mary S, Marchand J, Dussossoy D, Carriere D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P: Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 1995;232:54–61.
  19. Griffin G, Wray EJ, Tao Q, McAllister SD, Rorrer WK, Aung M, Martin BR, Abood M: Evaluation of the cannabinoid CB2 receptor-selective antagonist, SR144528: further evidence for CB2 receptor absence in the rat central nervous system. Eur J Pharmacol 1999;377:117–125.
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