PET imaging of the metabotropic glutamate receptor 5 (mGluR5) in healthy and alcohol-dependent subjects

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Leurquin-Sterk G1, Ceccarini J1, Van den Stock J2, Postnov A1, Crunelle CL4, de Laat B1,2, Weerasekera A5, Himmelreich U4, Peuskens H6, Bormans G7, Van Laere K1,2

1Department of Nuclear Medicine & Molecular Imaging, University Hospitals Leuven & Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
2Laboratory for Translational Neuropsychiatry, Department of Neurosciences, KU Leuven & Department of Old Age Psychiatry, University Hospitals Leuven, Leuven, Belgium
3MoSAIC, Molecular Small Animal Imaging Center, KU Leuven, Leuven, Belgium
4Toxicological Center, University of Antwerp, Antwerp, Belgium & Department of Psychiatry, University Hospital Brussels, Brussels, Belgium
5Biomedical MRI/MoSAIC, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
6University Psychiatric Centrum (UPC), KU Leuven, Leuven, Belgium
7Laboratory for Radiopharmacy, KU Leuven, Leuven, Belgium

Preclinical studies demonstrated involvement of mGluR5 in the physiopathology of alcohol addiction, but direct human evidence is lacking. The goal of this study was to investigate cerebral mGluR5 availability in healthy and alcohol-dependent subjects using dynamic [18F]FPEB PET imaging.
First, in 44 healthy subjects (non-smokers; 22F/22M; age range, 22-65 years), we evaluated age/gender-dependency of mGluR5 availability and its relationship to personality traits associated with alcohol-use disorders. Out of this sample, 11 male subjects also underwent an intravenous alcohol administration protocol to assess the relationship between baseline mGluR5 availability and alcohol-induced subjective responses. Moreover, in another subsample (n=9), we evaluated the long-term (6-month) test-retest reproducibility of [18F]FPEB binding to validate its use for longitudinal mGluR5 monitoring in patients. Second, regional mGluR5 availability was measured in 16 recently abstinent alcohol-dependent subjects (11 smokers; 3F/13M; age 45±8 years) and compared to 32 age-matched controls (14F/18M; age 45±13 years). Finally, to assess the impact of mGluR5 on relapse risk, follow-up scans at 2-month (n=10) and 6-month (n=8) after abstinence have been performed.
In healthy subjects, we found that 1) cerebral mGluR5 availability decreased with age (p<0.001) but was gender-independent, and was positively associated with the novelty-seeking temperament in several para(limbic) areas (Figure 1; all p<0.05, FEW-corrected), that 2) mGluR5 availability positively correlated with the ‘high’ effect of alcohol in the prefrontal and temporal cortices, thalamus and caudate nucleus (p<0.05), and that 3) quantitative [18F]FPEB PET has good long-term test-retest reproducibility (variability≤13%). Compared to healthy subjects, alcohol-dependent individuals showed decreased mGluR5 availability in the caudate (-27±4%), cingulate (-19±5%) and insula (-26±4%) (Figure 2; p<0.05, FEW-corrected).These findings persisted after correction for partial volume effects and were independent of smoking status. Moreover, mGluR5 binding in alcohol-dependent subjects correlated positively with instant alcohol-craving (e.g. r insula=0.64; p=0.007) and negatively with ethyl glucuronide hair levels (e.g., r insula=-0.77; p=0.004). Currently, the 2- and 6-month follow-up data are still being analyzed.

In conclusion, these novel in vivo human findings strongly support the functional role of limbic mGluR5-signaling at various stages of alcohol use and abuse and posit this receptor as an appealing biomarker candidate for relapse prediction.

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Figure 1. Statistical parametric mapping showing the positive correlation between mGluR5 availability (VT) in limbic areas and the temperament trait novelty-seeking (NS).

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Figure 2. Statistical parametric mapping showing the regional decrease of mGluR5 availability in alcohol-dependent subjects.