Metabotropic glutamate receptor 5 neuroimaging in schizophrenia

Abstract

The metabotropic glutamate receptor 5 (mGluR5) is a promising drug target for the treatment of schizophrenia. In this study, we compared mGluR5 distribution volume ration (DVR) in subjects with schizophrenia and healthy controls. Given our previous findings, we matched samples for gender, age, and smoking status. Binding to mGluR5 was determined using positron emission tomography and [¹¹C]ABP688, which binds to an allosteric site with high selectivity. DVR in the 15 individuals with schizophrenia did not differ from that of the 15 controls. In both groups, smoking was associated with marked global reductions in mGluR5 availability (on average 23.8%). In nonsmoking subjects with schizophrenia, there was a positive correlation between mGluR5 DVR in the medial orbitofrontal cortex and the use of antipsychotic drugs (r = 0.9, p = 0.019). Because antipsychotic drugs such as clozapine appeared to have indirect effects on mGluR5 signaling, our findings may be clinically relevant. They also provide promising leads for elucidating the high comorbidity between schizophrenia and tobacco addiction. Low mGluR5 DVR in smokers my represent a risk factor for schizophrenia. Alternatively, smoking may counteract the potential upregulation of mGluR5 by antipsychotic drugs.

Introduction

Current pathogenic models of schizophrenia emphasize hypofunction of the N-methyl-d-aspartate (NMDA) receptor (Iwata et al., 2015, Kantrowitz and Javitt, 2010). There is growing evidence from genetic and animal studies that the metabotropic glutamate receptors 5 (mGluR5) critically modulates the NMDA receptor (Matosin et al., 2015a). Both receptors co-localize and share the same scaffolding proteins and show strong functional associations. Consequently, mGluR5 has been proposed as an important target for the development of antipsychotic drugs (Goff, 2015). In addition, mGluR5 may be directly involved in abnormal glutamate signaling in schizophrenia. Genetic deletion of mGluR5 in mice has been shown to trigger a schizophrenia-like phenotype with decreased sensorimotor gating and short-term spatial memory deficits (Brody et al., 2004, Gray et al., 2009). In rats, treatment with specific negative allosteric modulators of mGluR5 leads to similar behavioral deficits, including impairments in sensory processing, working memory, and executive function (Vales et al., 2010, Zou et al., 2007). In humans, the allele frequency distribution of an intragenic microsatellite of the mGluR5 gene, GRM5, has been associated with schizophrenia (Devon et al., 2001). Several recent genome-wide association studies confirmed the involvement putative SNPs in GRM5 (Matosin et al., 2015b). In animal models, administration of cannabinoids during adolescence was shown to a reduction in hippocampal mGluR5, which was associated with learning deficits (Gleason et al., 2012). In contrast, postmortem studies have found only minimal changes in mGluR5 mRNA and mGluR5 protein in schizophrenia (Corti et al., 2011, Gupta et al., 2005, Matosin et al., 2013, Volk et al., 2010).

There is limited evidence for the involvement of mGluR5 in the effects of currently available antipsychotic drugs. In mGluR5 knockout mice, chronic administration of clozapine reversed sensorimotor gating deficits and abnormal locomotion (Gray et al., 2009). In rats, typical and atypical antipsychotics increased mGluR5 mRNA expression (Iasevoli et al., 2010), while other studies did not show changes in mGluR5 binding following treatment with antipsychotic drugs, in either animals or human postmortem tissue (Matosin and Newell, 2013). In previous studies, we have demonstrated that smoking is associated with a marked global reduction in mGluR5 DVR (Akkus et al., 2013, Akkus et al., 2015). This is a potentially relevant finding because 60%–90% of individuals with schizophrenia smoke (Chapman et al., 2009), and they usually smoke more heavily and experience more difficulty quitting smoking than do smokers without schizophrenia (Tidey et al., 2005, Wing et al., 2012).

This is the first study to assess mGluR5 DVR in subjects with schizophrenia and test for a hypothetical difference in DVR between patients and healthy controls. We applied positron emission tomography (PET) with the radiolabeled mGluR5 antagonist 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-11C-methyl-oxime ([¹¹C]ABP688) (Ametamey et al., 2007). This radiotracer binds to an allosteric site on mGluR5 with high selectivity. Given that age, gender, and smoking have been associated with mGluR5 DVR (Akkus et al., 2013, Akkus et al., 2015), we matched cases and controls for age, gender, and smoking. Based on preclinical and postmortem findings, we hypothesized that lower mGluR5 binding would be present in schizophrenia. Based on our previous findings in smokers, we also hypothesized that there would be marked global reductions in mGluR5 binding in smokers from both diagnostic groups.