Metabotropic glutamate receptor 5 binding in male patients with alcohol use disorder

Abstract

Glutamate signaling plays a major role in addiction. Preclinical research strongly suggests an implication of G-protein-coupled metabotropic glutamate receptor subtype 5 (mGluR5) in nicotine addiction and alcohol use disorder. In humans, smoking is related to a global reduction in mGluR5 availability. In the present study, we investigated mGluR5 in vivo in patients with alcohol use disorder without the confounding effects of smoking. A total of 14 male subjects with alcohol use disorder and at least a 25-day abstinence and 14 matched male non-smoking healthy controls were included in the study. We employed positron emission tomography (PET) with the mGluR5-specific radiotracer [11C]ABP688, using a bolus/infusion protocol. We found increased mGluR5 DVR in several regions within the temporal lobe in patients, as compared to controls. The largest between-group difference was in the amygdala. There was a marked positive relation between mGluR5 DVR in the anterior cingulate and mGluR5 DVR in the orbitofrontal cortex in patients, but not in controls. In patients, lower temptation to drink was related to higher amygdala mGluR5 DVR. We did not find altered mGluR5 DVR in the basal ganglia of subjects recovering from alcohol use disorder. In conclusion, our study provides clinical evidence for altered mGluR5 signaling in the amygdala in alcohol use disorder. This alteration was associated with the temptation to drink. In addition, this study suggests abnormal mGluR5 signaling in a network underlying reward-related behavioral flexibility. These findings strengthen the case for pharmacological agents acting on mGluR5 as promising candidates for the treatment of alcohol use disorder.

Fig. 1

a Amygdala mGluR5 DVR in patients (red) and controls (blue). b The relation between mGluR5 DVR in the amygdala and the total craving score of the AASE in the patient group. c Amygdala mGluR5 DVR in patients who reported a relapse after 3–6 months and those who reported they remained abstinent. d The mean imipramine equivalent dose of antidepressants at the timepoint of scanning in patients who reported a relapse, as compared to those who remained abstinent

Fig. 2. Inter-regional mGluR5 DVR correlations across various brain structures differ between healthy controls and patients with alcohol use disorder.

a For each inter-regional correlation the numeric difference between healthy controls and patients is shown, calculated as r_controls−r_patients. Color heat represents the direction and magnitude of this difference, as indicated in the color bar. Thus, red squares indicate higher correlation in controls than in patients, whereas blue indicates higher correlation in patients than in controls. Black circles highlight the most pronounced differences in ACC–OFC and ACC–straight gyrus mGluR5 DVR correlations between patients and controls (p < 0.001, one-tailed, uncorrected for multiple comparisons). b Shown are the highlighted correlations in each group separately. The red line represents a linear regression estimate