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.
Highlights
Alcoholism is an important risk factor for many disease conditions, including neuropsychiatric disorders, and a major contributor to years of life lost to disability and premature death.[1]
To compare metabotropic glutamate receptor subtype 5 (mGluR5) distribution volume ratio (DVR) between both groups, we carried out a multivariate analysis of covariance with mGluR5 DVR in 36 brain regions as dependent variables, group as a fixed factor and Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) as covariates
We found increased mGluR5 DVR in various brain regions located in the temporal lobe in alcohol use disorder
Summary
Alcoholism is an important risk factor for many disease conditions, including neuropsychiatric disorders, and a major contributor to years of life lost to disability and premature death.[1] Alcohol use disorder is characterized by intense craving and compulsive intake of alcohol despite its adverse consequences.[2] Glutamate signaling in the brain plays a major role in the pathogenesis of addiction disorders.[3,4,5] Glutamate acts on ionotropic receptors and G-protein-coupled metabotropic receptors, of which, currently, eight subtypes with distinct molecular and pharmacological properties have been described (metabotropic glutamate receptor subtypes 1–8 (mGluR1–8), correspondingly).[6] Preclinical studies implicate mGluR5 in binge alcohol intake.[7,8,9] Prolonged alcohol intake can increase mGluR5 protein levels in the nucleus accumbens and the amygdala, depending on the experimental protocol.[10,11,12,13] Reversely, systemic administration of mGluR5 negative allosteric modulators (NAMs) can inhibit alcohol self-administration.[7] intracranial injections of mGluR5 NAMs directly into the nucleus accumbens and the amygdala reduce alcohol intake and reinstatement of alcohol seeking.[11,12,13,14,15,16]
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