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 [ 11 C]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.

mGluR5 receptor availability is associated with lower levels of negative symptoms and better cognition in male patients with chronic schizophrenia

“…The BP ND did not correlate with the medication intake (chlorpromazine equivalents) and illness duration in any region. However, we observed, as others (Akkus et al, ; Akkus et al, ; Akkus et al, ), a significant difference between smokers and nonsmokers F (27,1) = 15.500; p = .001; effect η p 2 = 0.365, and a reduction of up to 50% in BP ND values in smokers , according to the observed brain region (Figure a,b). Figure shows the BP ND comparison between groups, but this was not found to be significant.…”

“…The maximum probability operation was applied to generate the VOIs related to the gray matter cortex (GM) in all brain temporofrontal regions except in basal ganglia regions. The cerebellum GM has been chosen as the most appropriate reference region for human brain studies on mGluR5 (Akkus et al, ; Akkus et al, ; Smart et al, ). In all cases, the nondisplaceable binding potential (BP ND ) of [ 11 C]ABP688 was estimated as: where C region is the specifically bound radioligand concentration and C ref is the nondisplaceable ligand concentration in the cerebellar GM reference tissue.…”

“…Only a small number of studies investigated the role of mGluR5 receptors in schizophrenia. Akkus et al () did not find differences in mGluR5 distribution volume ratio (DVR) between controls and patients but found a correlation between DVR in the medial orbitofrontal cortex and the use of antipsychotics. A highly significant global reduction in mGluR5 density has been reported in smokers and also in ex‐smokers and is thought to be a possible result of an adaptation to a chronic increase in glutamate, induced by chronic nicotine administration (Akkus et al, ; Akkus et al, ; Hulka et al, ).…”

Dopamine and glutamate in schizophrenia: biology, symptoms and treatment

“…One study found reduced NMDA receptor binding in the left hippocampus of patients with schizophrenia, but no further studies have been attempted, in part due to concerns regarding a lack of specificity of the tracer. A recent study using a tracer for the metabotropic glutamate receptor 5 found no patient‐control differences. New tracers are under development, but lack of specificity remains an ongoing problem when attempting to image glutamate receptors.…”

Excitatory-Inhibitory Balance within EEG Microstates and Resting-state fMRI Networks: Assessed via Simultaneous PET-MR-EEG Imaging

“…The cerebellum (Akkus et al, 2017) and pons (Odano et al, 2009) were chosen as CREF regions for ABP and FMZ, respectively. The CREF regions were defined using a threedimensional maximum probability atlas (Hammers et al, 2003) on the MNI space coregistered anatomical images (MP-RAGE).…”