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Clozapine decreases [3H] CP 55940 binding to the cannabinoid1 receptor in the rat nucleus accumbens

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Abstract

Antipsychotic drugs are effective in the treatment of cannabis-induced psychosis, but only clozapine appears effective in the treatment of comorbid schizophrenia and cannabis use. The unique effects of clozapine on cannabis use could, therefore, be due to an as yet unidentified interaction between clozapine and the endogenous cannabinoid system. To address this hypothesis, we used in situ radioligand binding and quantitative autoradiography with the selective cannabinoid CB1 receptor agonist, (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (side chain-2,3,4(N)-3H) ([3H]CP 55940) to measure the density of the CB1 receptor in frontal cortex, hippocampus, nucleus accumbens and striatum from rats treated with a variety of antipsychotic drugs. Clozapine significantly decreased [3H]CP 55940 binding in the nucleus accumbens compared with vehicle after 1 (35.0±14.0 vs. 71.2±8.5 fmol/mg estimated tissue equivalent (ete); P=0.03) and 3 months (42.3±4.0 vs. 71.1±16.3 fmol/mg ete; P<0.04) of treatment, an effect not observed with haloperidol, chlorpromazine or olanzapine. In rats treated with clozapine for 3 months and then left for 1 month without treatment, [3H]CP 55940 binding was not different in the nucleus accumbens (100.5±22.2 vs. 100.9±25.4 fmol/mg ete; P>0.10). By contrast, there were significant increases in accumbal [3H]CP 55940 binding in rats treated with haloperidol (136.5±14.2 fmol/mg ete; P<0.05), chlorpromazine (137.4±12.7 fmol/mg ete; P<0.05) and olanzapine (144.7±10.1 fmol/mg ete; P<0.01). These data indicate that in the nucleus accumbens clozapine differs from other antipsychotic drugs in its effects on [3H]CP 55940 binding. If these results can be extrapolated into humans, then this effect of clozapine on the CB1 receptor may be a mechanism that makes it uniquely effective in schizophrenia and comorbid cannabis use.

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References

  • Abood ME, Martin BR (1996) Molecular neurobiology of the cannabinoid receptor. Int Rev Neurobiol 39:197–221

    CAS  PubMed  Google Scholar 

  • Ameri A (1999) The effects of cannabinoids on the brain. Prog Neurobiol 58:315–348

    CAS  PubMed  Google Scholar 

  • Berk M, Brook S, Trandafir AI (1999) A comparison of olanzapine with haloperidol in cannabis-induced psychotic disorder: a double-blind randomized controlled trial. Int Clin Psychopharmacol 14:177–180

    CAS  PubMed  Google Scholar 

  • Berrendero F, Sepe N, Ramos JA, Di Marzo V, Fernandez-Ruiz JJ (1999) Analysis of cannabinoid receptor binding and mRNA expression and endogenous cannabinoid contents in the developing rat brain during late gestation and early postnatal period. Synapse 33:181–191

    CAS  PubMed  Google Scholar 

  • Breivogel CS, Childers SR (1998) The functional neuroanatomy of brain cannabinoid receptors. Neurobiol Dis 5:417–431

    CAS  PubMed  Google Scholar 

  • Bymaster FP, Perry KW, Nelson DL, Wong DT, Rasmussen K, Moore NA, Calligaro DO (1999) Olanzapine: a basic science update. Br J Psychiatry 174:36–40

    Google Scholar 

  • Chambers RA, Krystal JH, Self DW (2001) A neurobiological basis for substance abuse comorbidity in schizophrenia. Biol Psychiatry 50:71–83

    CAS  PubMed  Google Scholar 

  • Chopra GS, Smith JW (1974) Psychotic reactions following cannabis use in East Indians. Arch Gen Psychiatry 30:24–27

    CAS  PubMed  Google Scholar 

  • Dean B, Sundram S, Bradbury R, Scarr E, Copolov D (2001) Studies on [3H]CP-55940 binding in the human central nervous system: regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use. Neuroscience 103:9–15

    CAS  PubMed  Google Scholar 

  • Drake RE, Xie H, McHugo GJ, Green AI (2000) The effects of clozapine on alcohol and drug use disorders among patients with schizophrenia. Schizophr Bull 26:441–449

    CAS  PubMed  Google Scholar 

  • Fukudome Y, Ohno-Shosaku T, Matsui M, Omori Y, Fukaya M, Tsubokawa H, Taketo MM, Watanabe M, Manabe T, Kano M (2004) Two distinct classes of muscarinic action on hippocampal inhibitory synapses: M2-mediated direct suppression and M1/M3-mediated indirect suppression through endocannabinoid signalling. Eur J Neurosci 19:2682–2692

    PubMed  Google Scholar 

  • Geary WA, Toga AW, Wooten GF (1985) Quantitative film autoradiography for tritium: methodological considerations. Brain Res 337:99–108

    CAS  PubMed  Google Scholar 

  • Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, Rice KC (1990) Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A 87:1932–1936

    CAS  PubMed  Google Scholar 

  • Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC (1991) Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 11:563–583

    CAS  PubMed  Google Scholar 

  • Howlett AC (1995) Pharmacology of cannabinoid receptors. Ann Rev Pharmacol Toxicol 35:607–634

    CAS  Google Scholar 

  • Howlett AC, Champion TM, Wilken GH, Mechoulam R (1990) Stereochemical effects of 11-OH-delta 8-tetrahydrocannabinol-dimethylheptyl to inhibit adenylate cyclase and bind to the cannabinoid receptor. Neuropharmacology 29:161–165

    CAS  PubMed  Google Scholar 

  • Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG (2002) International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 54:161–202

    CAS  PubMed  Google Scholar 

  • Kapur S, Seeman P (2001) Does fast dissociation from the dopamine D(2) receptor explain the action of atypical antipsychotics?: a new hypothesis. Am J Psychiatry 158:360–369

    CAS  PubMed  Google Scholar 

  • Koob GF, Sanna PP, Bloom FE (1998) Neuroscience of addiction. Neuron 21:467–476

    CAS  PubMed  Google Scholar 

  • Liu P, Bilkey DK, Darlington CL, Smith PF (2003) Cannabinoid CB1 receptor protein expression in the rat hippocampus and entorhinal, perirhinal, postrhinal and temporal cortices: regional variations and age-related changes. Brain Res 979:235–239

    CAS  PubMed  Google Scholar 

  • Mailleux P, Vanderhaeghen J-J (1993) Dopaminergic regulation of cannabinoid receptor mRNA levels in the rat caudate-putamen: an in situ hybridization study. J Neurochem 61:1705–1712

    CAS  PubMed  Google Scholar 

  • National Health and Medical Research Council (1997) Australian Code of Practice for the Care and Use of Animals for Scientific Purposes. Commonwealth Department of Health and Family Services, Canberra, pp 1–82

    Google Scholar 

  • Oviedo A, Glowa J, Herkenham M (1993) Chronic cannabinoid administration alters cannabinoid receptor binding in rat brain: a quantitative autoradiographic study. Brain Res 616:293–302

    CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic Press Australia, Sydney

    Google Scholar 

  • Regier DA, Farmer ME, Rae DS, Locke BZ, Keith SJ, Judd LL, Goodwin FK (1990) Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) study. JAMA 264:2511–2518

    CAS  PubMed  Google Scholar 

  • Rodriguez de Fonseca F, Gorriti MA, Fernandez-Ruiz JJ, Palomo T, Ramos JA (1994) Downregulation of rat brain cannabinoid binding sites after chronic delta 9-tetrahydrocannabinol treatment. Pharmacol Biochem Behav 47:33–40

    CAS  PubMed  Google Scholar 

  • Sim-Selley LJ (2003) Regulation of cannabinoid CB1 receptors in the central nervous system by chronic cannabinoids. Crit Rev Neurobiol 15:91–119

    CAS  PubMed  Google Scholar 

  • Weickert CS, Kleinman JE (1998) The neuroanatomy and neurochemistry of schizophrenia. Psychiatr Clin North Am 21:57–75

    CAS  PubMed  Google Scholar 

  • Weiner DM, Meltzer HY, Veinbergs I, Donohue EM, Spalding TA, Smith TT, Mohell N, Harvey SC, Lameh J, Nash N, Vanover KE, Olsson R, Jayathilake K, Lee M, Levey AI, Hacksell U, Burstein ES, Davis RE, Brann MR (2004) The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine. Psychopharmacology (Berl) 177:207–216

    CAS  Google Scholar 

  • Zorn SH, Jones SB, Ward KM, Liston DR (1994) Clozapine is a potent and selective muscarinic M4 receptor agonist. Eur J Pharmacol 269:R1–R2

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

S.S. was the Lilly Psychiatry Research Fellow of the Royal Australian and New Zealand College of Psychiatrists and the Woods Family Trust Fellow of The Mental Health Research Institute of Victoria. B.D. is a recipient of a Young Investigators award from the National Alliance for Research in Schizophrenia and Affective Disorders. The authors gratefully acknowledge the assistance of Elizabeth Scarr, Geoffrey Pavey, Robyn Bradbury, Tabasum Hussain, Lee Naylor and Fiona-Marie Parkin.

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Authors and Affiliations

  1. The Mental Health Research Institute of Victoria, Locked Bag 11, Parkville, Victoria, 3052, Australia

    Suresh Sundram, David Copolov & Brian Dean

  2. Northern Psychiatry Research Centre, University of Melbourne, Melbourne, Victoria, Australia

    Suresh Sundram

  3. Department of Psychiatry, University of Melbourne, Melbourne, Victoria, Australia

    Suresh Sundram & Brian Dean

  4. Department of Psychological Medicine, Monash University, Melbourne, Victoria, Australia

    David Copolov

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  1. Suresh Sundram
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  2. David Copolov
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  3. Brian Dean
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Correspondence to Suresh Sundram.

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Sundram, S., Copolov, D. & Dean, B. Clozapine decreases [3H] CP 55940 binding to the cannabinoid1 receptor in the rat nucleus accumbens. Naunyn Schmied Arch Pharmacol 371, 428–433 (2005). https://doi.org/10.1007/s00210-005-1074-2

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  • DOI: https://doi.org/10.1007/s00210-005-1074-2

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