Paranoid Schizophrenia is Characterized by Increased CB1 Receptor Binding in the Dorsolateral Prefrontal Cortex

Abstract

A number of studies suggest a dysregulation of the endogenous cannabinoid system in schizophrenia (SCZ). In the present study, we examined cannabinoid CB 1 receptor (CB 1 R) binding and mRNA expression in the dorsolateral prefrontal cortex (DLPFC) (Brodmann's area 46) of SCZ patients and controls, post-mortem. Receptor density was investigated using autoradiography with the CB 1 R ligand [ 3 H] CP 55 940 and CB 1 R mRNA expression was measured using quantitative RT-PCR in a cohort of 16 patients with paranoid SCZ, 21 patients with non-paranoid SCZ and 37 controls matched for age, post-mortem interval and pH. All cases were obtained from the University of Sydney Tissue Resource Centre. Results were analyzed using one-way analysis of variance (ANOVA) and post hoc Bonferroni tests and with analysis of covariance (ANCOVA) to control for demographic factors that would potentially influence CB 1 R expression. There was a main effect of diagnosis on [ 3 H] CP 55 940 binding quantified across all layers of the DLPFC (F(2,71) ¼ 3.740, p ¼ 0.029). Post hoc tests indicated that this main effect was due to patients with paranoid SCZ having 22% higher levels of CB 1 R binding compared with the control group. When ANCOVA was employed, this effect was strengthened (F(2,67) ¼ 6.048, p ¼ 0.004) with paranoid SCZ patients differing significantly from the control (p ¼ 0.004) and from the non-paranoid group (p ¼ 0.016). In contrast, no significant differences were observed in mRNA expression between the different disease subtypes and the control group. Our findings confirm the existence of a CB 1 R dysregulation in SCZ and underline the need for further investigation of the role of this receptor particularly in those diagnosed with paranoid SCZ.

Phencyclidine-Induced Social Withdrawal Results from Deficient Stimulation of Cannabinoid CB1 Receptors: Implications for Schizophrenia

“…The possibility that overactive CB 1 receptors might account for the emergence of schizophrenic symptoms has also been challenged. Indeed, although initial postmortem studies showed increased CB 1 binding in cortical areas of schizophrenic patients (Dean et al, 2001;Zavitsanou et al, 2004), more recent measurements of CB 1 mRNA or protein have not confirmed this putative upregulation (Dalton et al, 2011;Koethe et al, 2007;Uriguen et al, 2009), and found instead decreased CB 1 density in the dorsolateral prefrontal cortex (Eggan et al, 2008). Moreover, CB 1 abnormalities have been related to specific schizophrenia subtypes, as suggested by the association of some polymorphisms of the CB 1 receptor Deficient CB 1 activation in social withdrawal A Seillier et al gene CNR1 with the hebephrenic type of schizophrenia (Chavarria-Siles et al, 2008;Ujike et al, 2002).…”

“…Moreover, CB 1 abnormalities have been related to specific schizophrenia subtypes, as suggested by the association of some polymorphisms of the CB 1 receptor Deficient CB 1 activation in social withdrawal A Seillier et al gene CNR1 with the hebephrenic type of schizophrenia (Chavarria-Siles et al, 2008;Ujike et al, 2002). On the same line, Dalton et al (2011) showed that only paranoid schizophrenics had higher CB 1 levels in the dorsolateral prefrontal cortex, whereas the disorganized and residual subgroups had lower CB 1 densities, as reported by Eggan et al (2008). Finally, a recent imaging study has shown that CB 1 receptor binding is positively correlated with the severity of positive symptoms, whereas patients with reduced CB 1 binding had more pronounced negative symptomatology (Wong et al, 2010).…”

Functional Genetic Variation of the Cannabinoid Receptor 1 and Cannabis Use Interact on Prefrontal Connectivity and Related Working Memory Behavior

“…Furthermore, convergent findings suggest that CNR1 signaling may be abnormal in patients with this brain disorder, even if the functional specificity of these anomalies is unclear (Dalton et al, 2011). Moreover, CNR1 has been inconsistently associated with diagnoses of schizophrenia (Chavarría-Siles et al, 2008;Seifert et al, 2007), and genetic variability and cannabis use appear to interact in conferring risk for psychosis (Caspi et al, 2005;van Winkel et al, 2011b, Di Forti et al, 2012.…”

Transmembrane domain Nrg1 mutant mice show altered susceptibility to the neurobehavioural actions of repeated THC exposure in adolescence

“…We expected that these behavioural changes would be accompanied by alterations in CB 1 , 5-HT 2A and NMDA receptors (NMDARs). These receptors are relevant to the pharmacological effects of cannabis and the pathophysiology of schizophrenia (Dalton et al 2011 ;Kang et al 2009 ;Matsumoto et al 2005 ;Zavitsanou et al 2002Zavitsanou et al , 2004) and levels and/or activation of which are altered in adult Nrg1 TM HET mice (Bjarnadottir et al 2007 ;Dean et al 2008 ;van den Buuse et al 2009). …”