Recovery of decreased metabotropic glutamate receptor 5 availability in abstinent alcohol-dependent subjects

Objectives: Animal models of alcohol dependence have demonstrated a central role of cerebral metabotropic glutamate receptor 5 (mGluR5) in relapse behaviors. Using [¹⁸F]FPEB positron emission tomography, it was found that chronic alcohol use lead to decreased limbic mGluR5 availability compared to healthy controls, where lower mGluR5 was associated with less craving. Here, we tested whether the state of decreased mGluR5 availability in the same alcohol-dependent subjects normalizes during longer-term (6 months) abstinence and whether initial mGluR5 imaging parameters can predict relapse.

Methods: Dynamic 90 minute [¹⁸F]FPEB scans combined with arterial blood sampling were performed in healthy controls (n = 32) and in alcohol-dependent patients (n = 16) within the 2 first weeks of medically supervised abstinence (i.e., the baseline condition), and after 2 months (n = 10) and 6 months (n = 8) following a alcohol detoxification program after baseline. Craving at these follow-up moments was assessed using the Desire for Alcohol Questionnaire (DAQ), a validated tool measuring three facets of craving. Alcohol consumption was assessed subjectively by a Time-Line Follow Back for the entire follow-up period and serial quantitative hair ethyl glucuronide analysis. Regional mGluR5 availability was quantified in controls and at each time point in patients by the [¹⁸F]FPEB total distribution volume [Leurquin-Sterk et al. Synapse 2016], corrected for partial volume effect, and analyzed using both a voxel-by-voxel and a volume-of-interest analysis.

Results: During abstinence, alcohol-dependent subjects showed gradual increases in mGluR5 availability in cortical and subcortical brain areas (p_height < 0.001, t statistic > 5.7) compared to baseline, up to the levels observed in healthy controls after 6 months (see Figure A), except in the hippocampus, nucleus accumbens and thalamus that had not recovered fully. A higher striatal mGluR5 availability at baseline was observed in patients who relapsed during the 6-month follow-up period compared to abstainers (+25.1%, p_height = 0.003 at x=-22; y=-10; z=-2) (see Figure B). Also, better recovery of mGluR5 in the striatum was associated with higher reduction in two different aspects of craving (i.e., Desire and intention to drink and Negative reinforcement; r > 0.72, p range = 0.001 - 0.045).

Conclusion: This study provides the first evidence that reduced cerebral mGluR5 availability in alcohol-dependent subjects recovers during abstinence, linked to reduction in craving behaviors. Higher striatal mGluR5 availability at the start of detoxification may be a predictive marker for long-term relapse. Research Support: Jenny Ceccarini is a postdoctoral fellow of the Research Foundation - Flanders (FWO). Koen Van Laere is senior clinical research fellow for the FWO and has received an FWO research grant for this work (FWO/G.0548.06).

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