Cannabinoid CB1 Receptor Immunoreactivity in the Prefrontal Cortex: Comparison of Schizophrenia and Major Depressive Disorder

Abstract

We recently demonstrated that measures of CB1R mRNA and protein were significantly reduced in DLPFC area 9 in schizophrenia subjects relative to matched normal comparison subjects. However, other studies have reported unaltered or higher measures of CB1R levels in schizophrenia. To determine whether these discrepancies reflect differences across brain regions or across subject groups (e.g., presence of depression, cannabis exposure, etc), we used immunocytochemical techniques to determine whether lower levels of CB1R immunoreactivity are 1) present in another DLPFC region, area 46, in the same subjects with schizophrenia, 2) present in area 46 in a new cohort of schizophrenia subjects, 3) present in major depressive disorder (MDD) subjects, or 4) attributable to factors other than a diagnosis of schizophrenia, including prior cannabis use. CB1R immunoreactivity levels in area 46 were significantly 19% lower in schizophrenia subjects relative to matched normal comparison subjects, a deficit similar to that observed in area 9 in the same subjects. In a new cohort of subjects, CB1R immunoreactivity levels were significantly 20% and 23% lower in schizophrenia subjects relative to matched comparison and MDD subjects, respectively. Lower levels of CB1R immunoreactivity in schizophrenia subjects were not explained by other factors such as cannabis use, suicide, or pharmacological treatment. In addition, CB1R immunoreactivity levels were not altered in monkeys chronically exposed to haloperidol. Thus, lower levels of CB1R immunoreactivity may be common in schizophrenia, conserved across DLPFC regions, not present in MDD, and not attributable to other factors, and thus a reflection of the underlying disease process.

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

“…In the current study, however, we observed no effect of cannabis exposure on CB 1 R density or mRNA in the DLPFC, in agreement with other studies in the DLPFC (Dean et al, 2001;Eggan et al, 2010) and superior temporal gyrus (Deng et al, 2007).…”

“…In contrast to the receptor binding studies, reduced cortical CB 1 R mRNA and protein expression have been found in the post-mortem DLPFC (Brodmann's areas 9 and 46) in SCZ (Eggan et al, 2008;Eggan et al, 2010), whereas another study (Koethe et al, 2007) found no change in the density of CB 1 R immunopositive cells in the anterior cingulate cortex in SCZ. Importantly, a recent imaging study using the novel positron emission tomography (PET) CB 1 R tracer […”

Exogenous and Endogenous Cannabinoids Suppress Inhibitory Neurotransmission in the Human Neocortex

“…Neuroanatomical and positron emission tomography studies have demonstrated that CB 1 receptor mRNA and protein occur in most layers of the human neocortex (Westlake et al, 1994;Lopez de Jesus et al, 2006;van Laere et al, 2008;Eggan et al, 2010). We studied synaptic transmission using patch-clamp electrophysiological methods in cortical tissue removed during neurosurgery to eliminate epileptogenic foci.…”

Endocannabinoids and Mental Disorders

“…Indeed, in women diagnosed with depression, serum content of AEA and 2-AG was decreased, suggesting that hypoactivity of the EC system may also be present in patients (Hill et al 2009). Unfortunately, data regarding CB1r density in the frontal cortex of patients with major depression appear to be inconsistent: there have been reports of decreased CB1 density (Koethe et al 2007), no alterations (Eggan et al 2010), or even upregulation (Hungund et al 2004;Vinod et al 2010;Choi et al 2012). Possible reasons for this complexity include ante-and postmortem factors such as medication, substance use, brain pH, and different methodological approaches for evaluating receptor levels.…”