Binding of a tritiated inverse agonist to cannabinoid CB1 receptors is increased in patients with schizophrenia

Abstract

This study sought to determine whether cannabinoid-1 (CB1) receptor binding was altered in the postmortem dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia (schizophrenia; n=47) compared to controls (n=43). The CB1 receptor inverse agonist radioligand [3H]MePPEP was used to measure specific binding to CB1 receptors. The specific binding of [3H]MePPEP to CB1 receptors was 20% higher in patients with schizophrenia than in controls. Power analyses suggested that 53 subjects per group would be needed to detect a similar difference in vivo with positron emission tomography (PET) and the structurally related inverse agonist radioligand [18F]FMPEP-d2 (80% statistical power, p<0.05).

Reciprocal alterations in cortical cannabinoid receptor 1 binding relative to protein immunoreactivity and transcript levels in schizophrenia

“…However, our findings of higher CB1R binding, even in the presence of deficits in CB1R mRNA and protein immunoreactivity levels, may have important relevance for cannabis use in schizophrenia. The consistent finding of higher CB1R binding in the present study and many others (Dean et al 2001; Zavitsanou et al 2004; Newell et al 2006; Dalton et al 2011; Jenko et al 2012) suggests that schizophrenia subjects may be more susceptible and have a amplified response to the effects of cannabis, even in the face of lower numbers of receptors. Furthermore, if the number of CB1R-containing axon terminals is indeed reduced and higher CB1R receptor binding is a compensatory response in individuals with schizophrenia, then cannabis use may interfere with the functioning of an already disturbed signaling pathway.…”

“…Using the novel CB1R selective ligand [ 3 H]-OMAR, we report that schizophrenia subjects with lower CB1R mRNA and protein immunoreactivity levels also have higher levels of [ 3 H]-OMAR binding to CB1R. The magnitude of higher [ 3 H]-OMAR binding in the prefrontal cortex in schizophrenia that we report (+8%) is consistent with, though slightly smaller, than the reported increases in binding previously reported using other CB1R ligands in the same brain region (+19-25% using [ 3 H]-MePPeP and [ 3 H]-CP55940) (Dean et al 2001; Dalton et al 2011; Jenko et al 2012). Furthermore, we report for the first time that [ 3 H]-OMAR receptor binding was increased across all cortical layers in schizophrenia subjects and achieved statistical significance in layers 1, deep 3, and 5.…”

“…However, prior studies of CB1R in the prefrontal cortex of subjects with schizophrenia have reported apparently conflicting findings of higher CB1R receptor binding (Dean et al 2001; Zavitsanou et al 2004; Newell et al 2006; Dalton et al 2011; Jenko et al 2012) and lower or unchanged CB1R mRNA and protein immunoreactivity levels (Koethe et al 2007; Eggan et al 2008; Uriguen et al 2009; Eggan et al 2010b). We sought to explore this apparent discrepancy by conducting CB1R receptor binding studies with a new ligand and comparing the results to measures of CB1R mRNA and protein (assessed by radioimmunocytochemistry) in nearby prefrontal cortex tissue sections from the same cohort of schizophrenia and comparison subjects.…”

“…Therefore, the ANCOVA model we report includes [ 3 H]-OMAR binding as the dependent variable, diagnostic group as the main effect, and subject pair as a blocking factor. The reported p values for comparisons of [ 3 H]-OMAR binding are one-tailed because CB1R receptor binding has been repeatedly shown to be higher in the prefrontal cortex in schizophrenia (Dean et al 2001; Zavitsanou et al 2004; Newell et al 2006; Dalton et al 2011; Jenko et al 2012). …”

“…However, at the present time, studies of the primary endogenous cannabinoid receptor (CB1R) in the brains of individuals with schizophrenia have yielded apparently conflicting results. Receptor autoradiography studies using a CB1R agonist ([ 3 H]-CP55940) or antagonists/inverse agonists ([ 3 H]-SR141716 and [ 3 H]-MePPEP) have consistently found higher CB1R binding to receptor protein across multiple brain regions, including the prefrontal cortex, in schizophrenia subjects (Dean et al 2001; Zavitsanou et al 2004; Newell et al 2006; Dalton et al 2011; Jenko et al 2012). In contrast, we previously reported lower CB1R mRNA levels by in situ hybridization and CB1R protein levels using radioimmunocytochemistry in the prefrontal cortex of subjects with schizophrenia (Eggan et al 2008; Eggan et al 2010b).…”