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  • Print publication year: 2004
  • Online publication date: December 2009

9 - The endogenous cannabinoid system in schizophrenia


The human endogenous cannabinoid system is an appealing target in the investigation of schizophrenia. This is both because of clinical studies supporting the association between cannabis use and schizophrenia as well as the capacity of Δ9-tetrahydrocannabinol (Δ9-THC) to induce psychotic symptoms in non-psychotic individuals (see Chapters 3–5). Only since the recent elucidation of the endogenous cannabinoid system have direct investigations into its potential role in schizophrenia and other neuropsychiatric disorders become possible. The endocannabinoid system contains the cannabinoid CB1, CB1A and CB2 receptors; the endogenous cannabinoids (most importantly, anandamide, 2-arachidonylglycerol (2-AG) and palmitoylethanolamide), their respective synthetic and degradative enzymes and a transport process. This chapter provides an overview of the human endogenous cannabinoid system, focusing specifically on those aspects relevant to schizophrenia (see also Chapters 1 and 2 for a broader overview), and then reviews studies concerning this system in schizophrenia.

The human endogenous cannabinoid system

The Cannabinoid CB1 receptor in the brain

The first component of the human endogenous cannabinoid system to be identified was the CB1 receptor (Herkenham et al., 1990). The gene for this receptor is located on region q14–q15 of chromosome 6 (Hoehe et al., 1991) and encodes for a 472-amino-acid protein (Matsuda et al., 1990). This receptor has seven trans-membrane-spanning domains and interacts with guanine nucleotide-binding proteins (G proteins) as part of its signal transduction mechanism, placing it within the superfamily of G protein-coupled receptors.

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Marijuana and Madness
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Amara, S. G. and Kuhar, M. J. (1993). Neurotransmitter transporters: recent progress. Annu. Rev. Neurosci., 16, 73–93
Ameri, A. (1999). The effects of cannabinoids on the brain. Progr. Neurobiol., 58, 315–348
Beltramo, M., Stella, N., Calignano, al. (1997). Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science, 277, 1094–1097
Bisogno, T., Berrendero, F., Ambrosino, al. (1999). Brain regional distribution of endocannabinoids: implications for their biosynthesis and biological function. Biochem. Biophys. Res. Commun., 256, 377–380
Bonnin, A., Miguel, R., Castro, J. G., Ramos, J. A. and Fernandez-Ruiz, J. J. (1996). Effects of perinatal exposure to delta 9-tetrahydrocannabinol on the fetal and early postnatal development of tyrosine hydroxylase-containing neurons in rat brain. J. Mol. Neurosci., 7, 291–308
Breivogel, C. S., Griffin, G., Di, M. V. and Martin, B. R. (2001). Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. Mol. Pharmacol., 60, 155–163
Buhler, B., Hambrecht, M., Loffler, W., an, H. W. and Hafner, H. (2002). Precipitation and determination of the onset and course of schizophrenia by substance abuse – a retrospective and prospective study of 232 population-based first illness episodes. Schizophr. Res., 54, 243–251
Comings, D. E., Muhleman, D., Gade, al. (1997). Cannabinoid receptor gene (CNR1): association with ⅰ.ⅴ. drug use. Mol. Psychiatry, 2, 161–168
Cravatt, B. F., Giang, D. K., Mayfield, S. al. (1996). Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature, 384, 83–87
Dawson, E. (1995). Identification of a polymorphic triplet marker for the brain cannabinoid receptor gene: use in linkage and association studies of schizophrenia. Psych. Gen., 5, s50–s51
Dean, B., Sundram, S., Bradbury, R., Scarr, E. and 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
Dean, B., Bradbury, R. and Copolov, D. L. (2003). Cannabis-sensitive dopaminergic markers in postmortem CNS: changes in schizophrenia. Biol. Psychiatry, 53, 585–592
Devane, W. A., Hanus, L., Breuer, al. (1992). Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science, 258, 1946–1949
Di Marzo, V., Fontana, A., Cadas, al. (1994). Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature, 372, 686–691
Di Marzo, V., Breivogel, C. S., Tao, al. (2000). Levels, metabolism, and pharmacological activity of anandamide in CB(1) cannabinoid receptor knockout mice: evidence for non-CB(1), non-CB(2) receptor-mediated actions of anandamide in mouse brain. J. Neurochem., 75, 2434–2444
Dinh, T. P., Carpenter, D., Leslie, F. al. (2002). Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc. Natl Acad. Sci. USA, 99, 10819–10824
Egertova, M. and Elphick, M. R. (2000). Localisation of cannabinoid receptors in the rat brain using antibodies to the intracellular C-terminal tail of CB. J. Comp. Neurol., 422, 159–171
Elphick, M. R. and Egertova, M. (2001). The neurobiology and evolution of cannabinoid signalling. Philos. Trans. R. Soc. Lond. B Biol. Sci., 356, 381–408
Emrich, H. M., Leweke, F. M. and Schneider, U. (1997). Towards a cannabinoid hypothesis of schizophrenia: cognitive impairments due to dysregulation of the endogenous cannabinoid system. Pharmacol. Biochem. Behav., 56, 803–807
Felder, C. C., Nielsen, A., Briley, E. al. (1996). Isolation and measurement of the endogenous cannabinoid receptor agonist, anandamide, in brain and peripheral tissues of human and rat. FEBS Lett., 393, 231–235
Gadzicki, D., Muller-Vahl, K. and Stuhrmann, M. (1999). A frequent polymorphism in the coding exon of the human cannabinoid receptor (CNR1) gene. Mol. Cell Probes, 13, 321–323
Giuffrida, A., Parsons, L. H., Kerr, T. al. (1999). Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nature Neurosci., 2, 358–363
Glass, M., Faull, R. L. and Dragunow, M. (1993). Loss of cannabinoid receptors in the substantia nigra in Huntington's disease. Neuroscience, 56, 523–527
Glass, M., Dragunow, M. and Faull, R. L. (1997). Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the foetal, neonatal and adult human brain. Neuroscience, 77, 299–318
Glass, M., Dragunow, M. and Faull, R. L. (2000). The pattern of neurodegeneration in Huntington's disease: a comparative study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations in the human basal ganglia in Huntington's disease. Neuroscience, 97, 505–519
Goparaju, S. K., Ueda, N., Yamaguchi, H. and Yamamoto, S. (1998). Anandamide amidohydrolase reacting with 2-arachidonoylglycerol, another cannabinoid receptor ligand. FEBS Lett., 422, 69–73
Hambrecht, M. and Hafner, H. (2000). Cannabis, vulnerability, and the onset of schizophrenia: an epidemiological perspective. Aust. NZ J. Psychiatry, 34, 468–475
Harrison, P. J. (1999). The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain, 122 (Pt 4), 593–624
Herkenham, M., Lynn, A. B., Little, M. al. (1990). Cannabinoid receptor localization in brain. Proc. Natl Acad. Sci. USA, 87, 1932–1936
Hernandez, M. L., Garcia-Gil, L., Berrendero, F., Ramos, J. A. and Fernandez-Ruiz, J. J. (1997). Delta 9-tetrahydrocannabinol increases activity of tyrosine hydroxylase in cultured fetal mesencephalic neurons. J. Mol. Neurosci., 8, 83–91
Hillard, C. J. (2000). Endocannabinoids and vascular function. J. Pharmacol. Exp. Ther., 294, 27–32
Hoehe, M. R., Caenazzo, L., Martinez, M. al. (1991). Genetic and physical mapping of the human cannabinoid receptor gene to chromosome 6q14–q15. New Biol., 3, 880–885
Hoffman, A. F. and Lupica, C. R. (2000). Mechanisms of cannabinoid inhibition of GABA(A) synaptic transmission in the hippocampus. J. Neurosci., 20, 2470–2479
Howlett, A. C., Barth, F., Bonner, T. al. (2002). International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol. Rev., 54, 161–202
Khantzian, E. J. (1997). The self-medication hypothesis of substance use disorders: a reconsideration and recent applications. Harvard Rev. Psychiatry, 4, 231–244
Leroy, S., Griffon, N., Bourdel, M. al. (2001). Schizophrenia and the cannabinoid receptor type 1 (CB1): association study using a single-base polymorphism in coding exon 1. Am. J. Med. Genet., 105, 749–752
Leweke, F. M. (2002). Elevated CSF endocannabinoid levels in schizophrenic patients versus controls. Int. J. Neuropsychopharmacol., 5 [S1], s47
Leweke, F. M., Schneider, U., Thies, M., Munte, T. F. and Emrich, H. M. (1999a). Effects of synthetic delta9-tetrahydrocannabinol on binocular depth inversion of natural and artificial objects in man. Psychopharmacology (Berl.), 142, 230–235
Leweke, F. M., Giuffrida, A., Wurster, U., Emrich, H. M. and Piomelli, D. (1999b). Elevated endogenous cannabinoids in schizophrenia. Neuroreport, 10, 1665–1669
Mailleux, P., Parmentier, M. and Vanderhaeghen, J. J. (1992). Distribution of cannabinoid receptor messenger RNA in the human brain: an in situ hybridization histochemistry with oligo-nucleotides. Neurosci. Lett., 143, 200–204
Matsuda, L. (1997). Molecular aspects of cannabinoid receptors. Crit. Rev. Neurobiol., 11, 143–166
Matsuda, L. A., Lolait, S. J., Brownstein, M. J., Young, A. C. and Bonner, T. I. (1990). Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature, 346, 561–564
Meltzer, H. Y. and Stahl, S. M. (1976). The dopamine hypothesis of schizophrenia: a review. Schizophr. Bull., 2, 19–76
Perlstein, W. M., Carter, C. S., Noll, D. C. and Cohen, J. D. (2001). Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia. Am. J. Psychiatry, 158, 1105–1113
Pistis, M., Porcu, G., Melis, M., Diana, M. and Gessa, G. L. (2001). Effects of cannabinoids on prefrontal neuronal responses to ventral tegmental area stimulation. Eur. J. Neurosci., 14, 96–102
Porter, A. C. and Felder, C. C. (2001). The endocannabinoid nervous system: unique opportunities for therapeutic intervention. Pharmacol. Ther., 90, 45–60
Rakhshan, F., Day, T. A., Blakely, R. D. and Barker, E. L. (2000). Carrier-mediated uptake of the endogenous cannabinoid anandamide in RBL- 2H3 cells. J. Pharmacol. Exp. Ther., 292, 960–967
Sakurai-Yamashita, Y., Kataoka, Y., Fujiwara, M., Mine, K. and Ueki, S. (1989). Delta 9-tetrahydrocannabinol facilitates striatal dopaminergic transmission. Pharmacol. Biochem. Behav., 33, 397–400
Schlicker, E. and Kathmann, M. (2001). Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol. Sci., 22, 565–572
Schneider, U., Leweke, F. M., Niemcyzk, al. (1996). Impaired binocular depth inversion in patients with alcohol withdrawal. J. Psychiatr. Res., 30, 469–474
Schneider, U., Borsutzky, al. (2002). Reduced binocular depth inversion in schizophrenic patients. Schizophr. Res., 53, 101–108
Shire, D., Carillon, C., Kaghad, al. (1995). An amino-terminal variant of the central cannabinoid receptor resulting from alternative splicing. J. Biol. Chem., 270, 3726–3731
Sipe, J. C., Chiang, K., Gerber, A. L., Beutler, E. and Cravatt, B. F. (2002). A missense mutation in human fatty acid amide hydrolase associated with problem drug use. Proc. Natl Acad. Sci. USA, 99, 8394–8399
Stella, N., Schweitzer, P. and Piomelli, D. (1997). A second endogenous cannabinoid that modulates long-term potentiation. Nature, 388, 773–778
Sundram, S., Bradbury, R., Copolov, D. L. and Dean, B. (2000). Clozapine differentially and reversibly alters cannabinoid CB1 receptor binding in the rat nucleus accumbens. Int. J. Neuropsychopharmacol., 3 [S1], S132
Tsai, S. J., Wang, Y. C. and Hong, C. J. (2000). Association study of a cannabinoid receptor gene (CNR1) polymorphism and schizophrenia. Psychiatr. Genet., 10, 149–151
Ujike, H., Takaki, M., Nakata, al. (2002). CNR1, central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia. Mol. Psychiatry, 7, 515–518
Voruganti, L. N., Slomka, P., Zabel, P., Mattar, A. and Awad, A. G. (2001). Cannabis induced dopamine release: an in-vivo SPECT study. Psychiatry Res., 107, 173–177
Westlake, T. M., Howlett, A. C., Bonner, T. I., Matsuda, L. A. and Herkenham, M. (1994). Cannabinoid receptor binding and messenger RNA expression in human brain: an in vitro receptor autoradiography and in situ hybridization histochemistry study of normal aged and Alzheimer's brains. Neuroscience, 63, 637–652
Wilson, R. I. and Nicoll, R. A. (2001). Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature, 410, 588–592
Wilson, R. I. and Nicoll, R. A. (2002). Endocannabinoid signaling in the brain. Science, 296, 678–682
Yang, H. Y., Karoum, F., Felder, al. (1999). GC/MS analysis of anandamide and quantification of N-arachidonoylphosphatidylethanolamides in various brain regions, spinal cord, testis, and spleen of the rat. J. Neurochem., 72, 1959–1968