Metabotropic Glutamate Receptor 5 and Glutamate Involvement in Major Depressive Disorder: A Multimodal Imaging Study

Abstract

Background Preclinical and postmortem studies have implicated the metabotropic glutamate receptor 5 (mGluR5) in the pathophysiology of major depressive disorder (MDD). The goal of the present study was to determine the role of mGluR5 in a large group of individuals with MDD compared to healthy controls (HC) in vivo with [18F]FPEB and positron emission tomography (PET). Furthermore, we sought to determine the role glutamate plays on mGluR5 availability in MDD. Methods Sixty-five participants (30 MDD and 35 HC) completed [18F]FPEB PET to estimate the primary outcome measure - mGluR5 volume of distribution (VT), and the secondary outcome measure - mGluR5 distribution volume ratio (DVR). A subgroup of 39 participants (16 MDD and 23 HC) completed proton magnetic resonance spectroscopy (1H MRS) to estimate anterior cingulate (ACC) glutamate, glutamine, and Glx (glutamate + glutamine) levels relative to creatine (Cr). Results No significant between-group differences were observed in mGluR5 VT or DVR. Compared to HC, individuals with MDD had higher ACC glutamate, glutamine, and Glx levels. Importantly, the ACC mGluR5 DVR negatively correlated with glutamate/Cr and Glx/Cr levels. Conclusions In this novel in vivo examination, we show an inverse relationship between mGluR5 availability and glutamate levels. These data highlight the need to further investigate the role of glutamatergic system in depression.

Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence

“…Previously, mGluR5 availability was reported to be lower in MDD (63,64). However, more recent studies have shown no differences between MDD and HC groups (65,66). Sample size limited examination of the additive effects of MDD in this study; however, future work should examine the potential effects.…”

In vivo evidence for dysregulation of mGluR5 as a biomarker of suicidal ideation

“…The metabotropic glutamate receptor type 5 (mGluR5) has emerged as a target of interest for PTSD and suicide research. mGluR5 is implicated in mood and anxiety symptoms in both human (3,4) and animal studies (5,6). We recently reported significantly higher mGluR5 availability in individuals with PTSD relative to matched controls across many brain regions (4).…”

Metabotropic glutamate receptor 5 in bulimia nervosa

“…Differences between the effects of substances of abuse on mGlu5 might reflect their different pharmacodynamic profiles. Heterogeneous findings for the same substance of abuse may reflect differences in imaging methods, clinical heterogeneity of study samples 36 . Importantly, both human PET studies and animal models with different mGlu5 PET tracers and protocols showed normalization in mGlu5 after prolonged abstinence from alcohol abuse 18,22,[37][38][39] .…”