Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-848d4c4894-cjp7w Total loading time: 0 Render date: 2024-06-13T17:59:41.736Z Has data issue: false hasContentIssue false

Chapter 18 - Post-mortem Studies of the Brain Cannabinoid System in Schizophrenia

from Part VI - Cannabinoids and Schizophrenia: Aetiopathology and Treatment Implications

Published online by Cambridge University Press:  12 May 2023

By
Suresh Sundram ,
Brian Dean  and
David Copolov
Edited by
Deepak Cyril D'Souza ,
David Castle  and
Sir Robin Murray
Deepak Cyril D'Souza
Affiliation:
Staff Psychiatrist, VA Connecticut Healthcare System; Professor of Psychiatry, Yale University School of Medicine
David Castle
Affiliation:
University of Tasmania, Australia
Sir Robin Murray
Affiliation:
Honorary Consultant Psychiatrist, Psychosis Service at the South London and Maudsley NHS Trust; Professor of Psychiatric Research at the Institute of Psychiatry
Get access

Summary

Post-mortem human brain tissue provides a valuable resource to probe the mechanisms underlying associations between cannabis and schizophrenia and how the endocannabinoid system may be dysregulated in the disorder. Although the endocannabinoid system has been variously examined, the majority of studies have focused on its stable components, in particular, the cannabinoid CB1 receptor in brain regions relevant to schizophrenia. Its widespread distribution throughout the human CNS and localization to GABA containing inhibitory interneurons and excitatory glutamate pyramidal neurons add relevance to its potential role in schizophrenia. The weight of evidence supports an increase in cannabinoid CB1 receptor density in prefrontal cortical and striatal regions without a commensurate increase in mRNA expression and a possible increase in the endogenous ligand, 2-arachidonoylglycerol. These changes in tissue from people without a history of cannabis use suggests the endocannabinoid system may be implicated in schizophrenia, although potential confounds of treatment and other factors need to be considered.

Keywords

endocannabinoid systemcannabinoid CB1 receptorpost-mortem human brain tissueschizophreniaprefrontal cortex
Type
Chapter
Information
Marijuana and Madness , pp. 178 - 188
Publisher: Cambridge University Press
Print publication year: 2023

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Atwood, B. K., and Mackie, K. (2010). CB2: A cannabinoid receptor with an identity crisis. Br J Pharmacol, 160, 467–479.CrossRefGoogle ScholarPubMed
Bagher, A. M., Laprairie, R. B., Kelly, M. E. M., et al. (2013). Co-expression of the human cannabinoid receptor coding region splice variants (hCB₁) affects the function of hCB₁ receptor complexes. Eur J Pharmacol, 721, 341–354.Google Scholar
Basavarajappa, B. S., and Hungund, B. L. (2002). Neuromodulatory role of the endocannabinoid signaling system in alcoholism: An overview. Prostaglandins Leukot Essent Fatty Acids, 66, 287–299.CrossRefGoogle ScholarPubMed
Benito, C., Tolon, R. M., Pazos, M. R., et al. (2008). Cannabinoid CB2 receptors in human brain inflammation. Br J Pharmacol, 153, 277–285.Google Scholar
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.Google Scholar
Castillo, P. E., Younts, T. J., Chávez, A. E., et al. (2012). Endocannabinoid signaling and synaptic function. Neuron, 76, 70–81.Google Scholar
D’Souza, D. C., Abi-Saab, W. M., Madonick, S., et al. (2005). Delta-9-tetrahydrocannabinol effects in schizophrenia: Implications for cognition, psychosis, and addiction. Biol Psychiatry, 57, 594–608.Google Scholar
Dalton, V. S., Long, L. E., Weickert, C. S., et al. (2011). Paranoid schizophrenia is characterized by increased CB1 receptor binding in the dorsolateral prefrontal cortex. Neuropsychopharmacology, 36, 1620–1630.CrossRefGoogle ScholarPubMed
Dean, B., Sundram, S., Bradbury, R., et al. (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.CrossRefGoogle ScholarPubMed
Deng, C., Han, M., and Huang, X. F. (2007). No changes in densities of cannabinoid receptors in the superior temporal gyrus in schizophrenia. Neurosci Bull, 23, 341–347.Google Scholar
Di Marzo, V., Breivogel, C. S., Tao, Q., et 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.Google Scholar
Eggan, S. M., Hashimoto, T., and Lewis, D. A. (2008). Reduced cortical cannabinoid 1 receptor messenger RNA and protein expression in schizophrenia. Arch Gen Psychiatry, 65, 772–784.Google Scholar
Eggan, S. M., Stoyak, S. R., Verrico, C. D., et al. (2010). Cannabinoid CB1 receptor immunoreactivity in the prefrontal cortex: Comparison of schizophrenia and major depressive disorder. Neuropsychopharmacology, 35, 2060–2071.Google Scholar
Elphick, M. R., and Egertova, M. (2001). The neurobiology and evolution of cannabinoid signalling. Phil Trans R Soc Lond B, 356, 381–408.Google Scholar
Garani, R., Watts, J. J., and Mizrahi, R. (2021). Endocannabinoid system in psychotic and mood disorders, a review of human studies. Prog Neuropsychopharmacol Biol Psychiatry, 106, 110096.CrossRefGoogle ScholarPubMed
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.Google Scholar
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.Google Scholar
Guillozet-Bongaarts, A. L., Hyde, T. M., Dalley, R. A., et al. (2014). Altered gene expression in the dorsolateral prefrontal cortex of individuals with schizophrenia. Mol Psychiatry, 19, 478–485.Google Scholar
Herkenham, M., Lynn, A. B., Little, M. D., et al. (1990). Cannabinoid receptor localization in brain. Proc Natl Acad Sci USA, 87, 1932–1936.Google Scholar
Hoehe, M. R., Caenazzo, L., Martinez, M. M., et al. (1991). Genetic and physical mapping of the human cannabinoid receptor gene to chromosome 6q14–q15. New Biol, 3, 880–885.Google ScholarPubMed
Howlett, A. C., and Abood, M. E. (2017). CB1 and CB2 receptor pharmacology. Adv Pharmacol, 80, 169–206.CrossRefGoogle Scholar
Ishiguro, H., Horiuchi, Y., Ishikawa, M., et al. (2010). Brain cannabinoid CB2 receptor in schizophrenia. Biol Psychiatry, 67, 974–982.CrossRefGoogle ScholarPubMed
Jenko, K. J., Hirvonen, J., Henter, I. D., et al. (2012). Binding of a tritiated inverse agonist to cannabinoid CB1 receptors is increased in patients with schizophrenia. Schizophr Res, 141, 185–188.CrossRefGoogle ScholarPubMed
Katona, I., Urbán, G. M., Wallace, M., et al. (2006). Molecular composition of the endocannabinoid system at glutamatergic synapses. J Neurosci, 26, 5628–5637.Google Scholar
Koethe, D., Llenos, I. C., Dulay, J. R., et al. (2007). Expression of CB1 cannabinoid receptor in the anterior cingulate cortex in schizophrenia, bipolar disorder, and major depression. J Neural Transm, 114, 1055–1063.Google Scholar
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 oligonucleotides. Neurosci Lett, 143, 200–204.CrossRefGoogle Scholar
Marco, E. M., Granstrem, O., Moreno, E., et al. (2007). Subchronic nicotine exposure in adolescence induces long-term effects on hippocampal and striatal cannabinoid-CB1 and mu-opioid receptors in rats. Eur J Pharmacol, 557, 37–43.Google Scholar
Matsuda, L. A. (1997). Molecular aspects of cannabinoid receptors. Crit Rev Neurobiol, 11, 143–166.Google Scholar
Matsuda, L. A., Lolait, S. J., Brownstein, M. J., et al. (1990). Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature, 346, 561–564.CrossRefGoogle ScholarPubMed
Mechoulam, R., and Hanus, L. (2000). A historical overview of chemical research on cannabinoids. Chem Phys Lipids, 108, 1–13.Google Scholar
Morrison, P. D., and Murray, R. M. (2020). Cannabis points to the synaptic pathology of mental disorders: How aberrant synaptic components disrupt the highest psychological functions. Dialogues Clin Neurosci, 22, 251–258.CrossRefGoogle Scholar
Muguruza, C., Lehtonen, M., Aaltonen, N., et al. (2013). Quantification of endocannabinoids in postmortem brain of schizophrenic subjects. Schizophr Res, 148, 145–150.CrossRefGoogle ScholarPubMed
Muguruza, C., Morentin, B., Meana, J. J., et al. (2019). Endocannabinoid system imbalance in the postmortem prefrontal cortex of subjects with schizophrenia. J Psychopharmacol, 33, 1132–1140.Google Scholar
Newell, K. A., Deng, C., and Huang, X. F. (2006). Increased cannabinoid receptor density in the posterior cingulate cortex in schizophrenia. Exp Brain Res, 172, 556–560.CrossRefGoogle ScholarPubMed
Nunez, E., Benito, C., Pazos, M. R., et al. (2004). Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: An immunohistochemical study. Synapse, 53, 208–213.Google Scholar
Palkovits, M., Harvey-White, J., Liu, J., et al. (2008). Regional distribution and effects of postmortem delay on endocannabinoid content of the human brain. Neuroscience, 152, 1032–1039.Google Scholar
Pertwee, R. G. (2010). Receptors and channels targeted by synthetic cannabinoid receptor agonists and antagonists. Curr Med Chem, 17, 1360–1381.Google Scholar
Piomelli, D. (2003). The molecular logic of endocannabinoid signalling. Nat Rev Neurosci, 4, 873–884.Google Scholar
Price, M. R., Baillie, G. L., Thomas, A., et al. (2005). Allosteric modulation of the cannabinoid CB1 receptor. Mol Pharmacol, 68, 1484–1495.Google Scholar
Ryberg, E., Vu, H. K., Larsson, N., et al. (2005). Identification and characterisation of a novel splice variant of the human CB1 receptor. FEBS Lett, 579, 259–264.Google Scholar
Schlicker, E., and Kathmann, M. (2001). Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci, 22, 565–572.Google Scholar
Shire, D., Carillon, C., Kaghad, M., et al. (1995). An amino-terminal variant of the central cannabinoid receptor resulting from alternative splicing. J Biol Chem, 270, 3726–3731.CrossRefGoogle ScholarPubMed
Stella, N. (2010). Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and astrocytomas. Glia, 58, 1017–1030.Google Scholar
Straiker, A., Wager-Miller, J., Hutchens, J., et al. (2012). Differential signalling in human cannabinoid CB1 receptors and their splice variants in autaptic hippocampal neurones. Br J Pharmacol, 165, 2660–2671.Google Scholar
Sundram, S., Copolov, D., and Dean, B. (2005). Clozapine decreases [3H] CP 55940 binding to the cannabinoid 1 receptor in the rat nucleus accumbens. Naunyn Schmiedebergs Arch Pharmacol, 371, 428–433.Google Scholar
Tao, R., Li, C., Jaffe, A. E., et al. (2020). Cannabinoid receptor CNR1 expression and DNA methylation in human prefrontal cortex, hippocampus and caudate in brain development and schizophrenia. Transl Psychiatry, 10, 158.CrossRefGoogle ScholarPubMed
Thune, J. J., Uylings, H. B. M., and Pakkenberg, B. (2001). No deficit in total number of neurons in the prefrontal cortex in schizophrenics. J Psychiatr Res, 35, 15–21.Google Scholar
Uriguen, L., Garcia-Fuster, M. J., Callado, L. F., et al. (2009). Immunodensity and mRNA expression of A2A adenosine, D2 dopamine, and CB1 cannabinoid receptors in postmortem frontal cortex of subjects with schizophrenia: Effect of antipsychotic treatment. Psychopharmacology (Berl), 206, 313–324.CrossRefGoogle ScholarPubMed
Van Sickle, M. D., Duncan, M., Kingsley, P. J., et al. (2005). Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science, 310, 329–332.Google Scholar
Vogt, B. A., Pandya, D. N., and Rosene, D. L. (1987). Cingulate cortex of the rhesus monkey: I. Cytoarchitecture and thalamic afferents. J Comp Neurol, 262, 256–270.Google Scholar
Volk, D. W., Eggan, S. M., Horti, A. G., et al. (2014). Reciprocal alterations in cortical cannabinoid receptor 1 binding relative to protein immunoreactivity and transcript levels in schizophrenia. Schizophr Res, 159, 124–129.Google Scholar
Volk, D. W., Eggan, S. M., and Lewis, D. A. (2010). Alterations in metabotropic glutamate receptor 1α and regulator of G protein signaling 4 in the prefrontal cortex in schizophrenia. Am J Psychiatry, 167, 1489–1498.Google Scholar
Volk, D. W., and Lewis, D. A. (2016). The role of endocannabinoid signaling in cortical inhibitory neuron dysfunction in schizophrenia. Biol Psychiatry, 79, 595–603.Google Scholar
Volk, D. W., Siegel, B. I., Verrico, C. D., et al. (2013). Endocannabinoid metabolism in the prefrontal cortex in schizophrenia. Schizophr Res, 147, 53–57.CrossRefGoogle ScholarPubMed
Westlake, T. M., Howlett, A. C., Bonner, T. I., et al. (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.Google Scholar
Wiley, J. L., Kendler, S. H., Burston, J. J., et al. (2008). Antipsychotic-induced alterations in CB1 receptor-mediated G-protein signaling and in vivo pharmacology in rats. Neuropharmacology, 55, 1183–1190.Google Scholar
Zavitsanou, K., Garrick, T., and Huang, X. F. (2004). Selective antagonist [3H]SR141716A binding to cannabinoid CB1 receptors is increased in the anterior cingulate cortex in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry, 28, 355–360.Google Scholar

Save book to Kindle

To save this book to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×