title: Reciprocal alterations in cortical cannabinoid receptor 1 binding relative to protein immunoreactivity and transcript levels in schizophrenia.
abstract: The deleterious effects of cannabis use in schizophrenia have been linked, in part, to underlying disturbances in endogenous cannabinoid signaling in the prefrontal cortex. However, while receptor autoradiography studies of the primary cannabinoid receptor (CB1R) have consistently found higher CB1R binding in the prefrontal cortex in schizophrenia, deficits in CB1R mRNA levels and protein immunoreactivity have also been reported in the illness. To investigate this apparent discrepancy, we quantified CB1R binding using receptor autoradiography with the selective CB1R ligand [(3)H]-OMAR in the prefrontal cortex of 21 subjects with schizophrenia who were previously found to have lower levels of both CB1R mRNA using in situ hybridization and CB1R protein using radioimmunocytochemistry relative to matched healthy comparison subjects. We observed higher levels of [(3)H]-OMAR binding in the prefrontal cortex of schizophrenia subjects that did not appear to be attributable to psychotropic medications or substance abuse. The combination of lower levels of CB1R mRNA and immunoreactivity with higher CB1R receptor binding may reflect 1) altered trafficking of the receptor resulting in higher levels of membrane-bound CB1R or 2) higher CB1R affinity. In either case, greater CB1R receptor availability may contribute to the increased susceptibility of schizophrenia subjects to the deleterious effects of cannabis use.
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, United States. Electronic address: volkdw@upmc.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Volk
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, United States.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Eggan
authors.affiliation: Department of Radiology, Johns Hopkins University, Baltimore, MD 21287, United States.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Horti
authors.affiliation: Department of Radiology, Johns Hopkins University, Baltimore, MD 21287, United States; Department of Psychiatry, Johns Hopkins University, Baltimore, MD 21287, United States; Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21287, United States.
authors.forename: Dean F
authors.initials: DF
authors.lastname: Wong
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, United States; Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15213, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Lewis
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001345:Autoradiography; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011720:Pyrazoles / Q000493:pharmacokinetics; D012333:RNA, Messenger / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics* / Q000378:metabolism*; D012559:Schizophrenia / Q000473:pathology*; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: C515663:4-cyano-1-(2,4-dichlorophenyl)-5-(4-methoxyphenyl)-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide; C571130:CNR1 protein, human; D010880:Piperidines; D011720:Pyrazoles; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D014316:Tritium
keywords: CB1R; Cannabinoid; Cannabis; Marijuana; PET; Prefrontal cortex; Radioligand; Rimonabant; Schizophrenia
references.citation: Mol Pharmacol. 2005 Nov;68(5):1484-95
references.pmid: 16113085
references.citation: Schizophr Res. 2013 Jun;147(1):53-57
references.pmid: 23561296
references.citation: Biol Psychiatry. 2005 Mar 15;57(6):594-608
references.pmid: 15780846
references.citation: Cereb Cortex. 2012 May;22(5):1215-23
references.pmid: 21810780
references.citation: Schizophr Res. 2012 Nov;141(2-3):185-8
references.pmid: 22910406
references.citation: Neuroscience. 2010 Sep 15;169(4):1651-61
references.pmid: 20542094
references.citation: J Nucl Med. 2006 Oct;47(10):1689-96
references.pmid: 17015906
references.citation: Arch Gen Psychiatry. 2000 Mar;57(3):237-45
references.pmid: 10711910
references.citation: Neurosci Biobehav Rev. 2011 Aug;35(8):1779-87
references.pmid: 21530584
references.citation: Psychopharmacology (Berl). 2009 Oct;206(2):313-24
references.pmid: 19652957
references.citation: Nat Neurosci. 2010 Aug;13(8):951-7
references.pmid: 20657592
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2004 Mar;28(2):355-60
references.pmid: 14751433
references.citation: Schizophr Res. 2012 Aug;139(1-3):157-60
references.pmid: 22727454
references.citation: Neuroscience. 2001;103(1):9-15
references.pmid: 11311783
references.citation: Neuropsychopharmacology. 2010 Sep;35(10):2060-71
references.pmid: 20555313
references.citation: Cereb Cortex. 2007 Jan;17(1):175-91
references.pmid: 16467563
references.citation: Arch Gen Psychiatry. 2008 Jul;65(7):772-84
references.pmid: 18606950
references.citation: Cereb Cortex. 1995 Jul-Aug;5(4):307-22
references.pmid: 7580124
references.citation: Neuroimage. 2010 Oct 1;52(4):1505-13
references.pmid: 20406692
references.citation: Am J Psychiatry. 2010 Dec;167(12):1489-98
references.pmid: 20889653
references.citation: Am J Psychiatry. 2012 Oct;169(10):1082-91
references.pmid: 22983435
references.citation: Exp Brain Res. 2006 Jul;172(4):556-60
references.pmid: 16710682
references.citation: Am J Psychiatry. 2009 Nov;166(11):1251-7
references.pmid: 19797432
references.citation: Am J Psychiatry. 2010 Aug;167(8):987-93
references.pmid: 20478874
references.citation: J Neural Transm (Vienna). 2007;114(8):1055-63
references.pmid: 17370106
references.citation: Am J Psychiatry. 1999 Nov;156(11):1709-19
references.pmid: 10553733
references.citation: Neuropsychopharmacology. 2011 Jul;36(8):1620-30
references.pmid: 21471953