Increased ventral striatal CB1 receptor binding is related to negative symptoms in drug-free patients with schizophrenia
Introduction
Schizophrenia (SCZ) is one of the most common severe psychiatric disorders with a lifetime prevalence of about 1% (Van Os and Kapur, 2009). Existing antipsychotics reduce psychotic symptoms but are generally not very effective in treating negative symptoms, and a significant portion of patients are refractory to all current treatments. Despite the availability of treatments that reduce psychotic symptoms, a clear biochemical basis of SCZ has not been identified yet.
Several neurobiological, pharmacological and epidemiological studies support an association between SCZ and the endogenous endocannabinoid system (ECS) (Leweke and Koethe, 2008). The ECS mediates the psychotomimetic effects of Δ9-tetrahydrocannabinol (Δ9-THC), the major psychoactive ingredient of Cannabis sativa, by activation of the type 1 cannabinoid (CB1) receptor. CB1 receptor activation modulates synaptic release of other transmitters such as glutamate, dopamine, and γ-aminobutyric acid (GABA) (Wilson and Nicoll, 2002).
High rates of cannabis consumption in normal volunteers induce cognitive impairment resembling of SCZ patients (Henquet et al., 2005). In SCZ patients, cannabis use is associated with a reduction in age at onset (De Hert et al., 2011). Moreover, several studies have suggested that frequent cannabis use is associated with increased risk for psychotic disorder and symptoms (Moore et al., 2007, Van Winkel and GROUP investigators, 2011). Postmortem binding studies in SCZ patients showed an increase of CB1 receptor binding in the posterior and anterior cingulate cortex (ACC) (Newell et al., 2006, Zavitsanou et al., 2004). [3H]CP-55940 binding was also increased in the dorsolateral prefrontal cortex (DLPFC) in SCZ patients, whereas no changes in CB1 receptor binding were found in the striatum or temporal lobe (Dean et al., 2001). This was confirmed in two recent postmortem human tissue studies that reported a 22% increase in [3H]CP-55940 binding and a 20% increase in [3H]MePPEP binding in the DLPFC in schizophrenic patients (Dalton et al., 2011, Jenko et al., 2012). From postmortem immunochemistry and in situ hybridization experiments, conflicting results have been found. Reduced CB1 receptor messenger RNA and protein expression were detected in the postmortem DLPFC of SCZ patients (Eggan et al., 2008), and reduced immunodensity of CB1 receptor was in the PFC of antipsychotic-treated schizophrenics but not in drug-free patients (Uriguen et al., 2009). Additional arguments for involvement of the ECS in SCZ include endogenous ligand studies where elevated anandamide levels were demonstrated in the cerebrospinal fluid of SCZ patients (Giuffrida et al., 2004, Koethe et al., 2009, Leweke et al., 1999). These were inversely correlated with psychotic symptoms and negative symptoms in particular and suggest that the ECS system, acting through one of its major endogenous ligands, represents a protective and counterbalancing system toward psychosis (Leweke, 2012).
Several radioligands for in vivo imaging of the CB1 receptor have been developed recently that can be used for quantitative positron emission tomography (PET). Berding et al. (2006) showed the feasibility of CB1 receptor imaging with [124I]AM281 PET in a SCZ patient; however, the poor signal-to-noise ratio and the high radiation burden of the ligand constituted a major difficulty to extend the investigation to a larger number of subjects. Using [11C]OMAR in 9 treated SCZ patients, Wong et al. (2010) demonstrated elevated CB1 receptor binding across all the brain regions studied. Furthermore significant correlations between the ratio of positive versus negative symptoms and CB1 receptor binding were found.
Since SCZ is a heterogeneous disorder and antipsychotic treatment can lead to bias in observed findings, we have investigated cerebral CB1 receptor binding of 67 SCZ patients using the selective CB1 receptor radioligand [18F]MK-9470 (Burns et al., 2007) and PET. As most of the post-mortem and in vivo studies showed an increase in CB1 receptor binding as outlined above, the primary outcome was to test the hypothesis that in vivo CB1 receptor binding is increased in antipsychotic-free and/or SCZ patients on antipsychotic monotherapy in comparison to healthy controls. As a second objective, we tested the hypothesis that regional CB1 receptor binding was related to the severity of SCZ symptoms.
Section snippets
Participants
A total of 67 patients with schizophrenia (SCZ) (age: 36.7 ± 9.2 years) were recruited in a prospective study: an antipsychotic-free group (SCZ-F, n = 16), consisting of first-episode antipsychotic-naïve patients (n = 10) and patients after treatment washout (n = 6; duration of the washout period = 9.4 ± 4.0 months), as well as five groups of patients treated (SCZ-T, n = 51) under stable treatment with one among the five different second generation antipsychotics (SGAs): amisulpride (n = 11), risperidone (n = 10),
Clinical characteristics and treatment effects
Table 1 presents clinical characteristics and neurocognitive performances of SCZ patients and controls. Significant differences were present between SCZ-T and SCZ-F antipsychotic-naïve on all psychopathological symptoms (p from .01 to 10− 7). Globally, SCZ-F antipsychotic-naïve had the highest PANSS total score (PANSS-T) among all SCZ subgroups. Within the SCZ-T group, ANOVA revealed no differential effect of antipsychotic treatment on symptom domains. Moreover, no difference in clinical
Discussion
Several lines of experimental evidence point to a dysregulation of the functions of the CB1 receptor in SCZ. The majority of the studies investigating CB1 receptor in SCZ examined CB1 receptor changes using radioligand binding and quantitative autoradiography in postmortem tissue (Dean et al., 2001, Eggan et al., 2008, Newell et al., 2006, Uriguen et al., 2009, Zavitsanou et al., 2004). Concerning in vivo investigations, few quantitative CB1 receptor PET studies in the brain of SCZ patients
Conclusions
In conclusion, both medicated and antipsychotic-free patients show increased CB1 receptor binding compared to controls, particularly pronounced in the NuAc, cingulate and insular cortex. Moreover the increased CB1 receptor binding is negatively associated with negative symptoms and depression in antipsychotic-free patients. The current in vivo data strengthens the hypothesis that the endogenous cannabinoid system of the brain is involved in the pathology of SCZ.
Acknowledgments
The authors gratefully acknowledge Ms. Kim Sweers and Ms. Leen Gielen for collecting demographic, clinical and neurocognitive data, and all study patients. Merck Research Laboratories (West Point, Pennsylvania) is acknowledged for the availability of the tracer precursor of [18F]MK-9470.
Financial disclosures
This study was supported by the Research Council of the Katholieke Universiteit Leuven (OT/05/58) and a partial site-initiated study sponsor was granted by Merck Research Laboratories (West
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