Abstract

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Objectives Animal studies have demonstrated a critical role of metabotropic glutamate receptor subtype 5 (mGluR5) signaling in the physiopathology of alcohol addiction (1-3), but direct human evidence is lacking. The goal of this study was to investigate cerebral mGluR5 availability in alcohol-dependent subjects in comparison to healthy controls using 18F-FPEB PET imaging.

Methods Dynamic 18F-FPEB PET scans (90min) combined with arterial blood sampling were acquired in 16 recently abstinent alcohol-dependent patients (11 smokers; 3F/13M; age 45±8 y, range 32-57 y) and 32 age-matched healthy controls (non-smokers; 14F/18M; age 45±13 y, range 27-65 y). Regional mGluR5 availability was quantified as the 18F-FPEB total distribution volume (VT), using both voxel- and VOI-based analyses in PMOD v3.6, with and without partial volume effect correction (PVC). Alcohol use patterns were determined by self-report questionnaires, and recent alcohol consumption was quantitatively assessed using ethyl glucuronide hair analysis.

Results Compared to controls, voxel-wise analysis showed regional decreased mGluR5 availability in alcoholics in the bilateral cingulate, caudate, and insular cortex (Figure; P<0.05, FWE corrected), independently of gender and smoking status. These findings persisted after PVC and were confirmed by the VOI analysis, showing a mean decrease in VT in dependent subjects versus controls of -27±4% in the caudate, -26±4% in the insula, and -23±5% and -19±5% in the anterior and posterior cingulate, respectively (all P<0.001). Moreover, mGluR5 binding in dependent subjects was negatively correlated with ethyl glucuronide hair levels (rcaudate=-0.70, rinsula=-0.74, ranterior cingulate=-0.66; all P<0.02).