Functional Analysis of Brain Imaging Suggests Changes in the Availability of mGluR5 and Altered Connectivity in the Cerebral Cortex of Long-Term Abstaining Males with Alcohol Dependence: A Preliminary Study.

Yo-Han Joo,Jeong-Hee Kim,Hang-Keun Kim,Young-Don Son,Jong-Hoon Kim,Paul Cumming

doi:10.3390/life11060506

Abstract

Direct in vivo evidence of altered metabotropic glutamate receptor-5 (mGluR5) availability in alcohol-related disorders is lacking. We performed [11C]ABP688 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in prolonged abstinent subjects with alcohol dependence to examine alterations of mGluR5 availability, and to investigate their functional significance relating to neural systems-level changes. Twelve prolonged abstinent male subjects with alcohol dependence (median abstinence duration: six months) and ten healthy male controls underwent [11C]ABP688 PET imaging and 3-Tesla MRI. For mGluR5 availability, binding potential (BPND) was calculated using the simplified reference tissue model with cerebellar gray matter as the reference region. The initial region-of-interest (ROI)-based analysis yielded no significant group differences in mGluR5 availability. The voxel-based analysis revealed significantly lower [11C]ABP688 BPND in the middle temporal and inferior parietal cortices, and higher BPND in the superior temporal cortex in the alcohol dependence group compared with controls. Functional connectivity analysis of the rs-fMRI data employed seed regions identified from the quantitative [11C]ABP688 PET analysis, which revealed significantly altered functional connectivity from the inferior parietal cortex seed to the occipital pole and dorsal visual cortex in the alcohol dependence group compared with the control group. To our knowledge, this is the first report on the combined analysis of mGluR5 PET imaging and rs-fMRI in subjects with alcohol dependence. These preliminary results suggest the possibility of region-specific alterations of mGluR5 availability in vivo and related functional connectivity perturbations in prolonged abstinent subjects.

Highlights

Recent years have seen the emergence of a greater understanding of the contribution of glutamatergic neurotransmission to the pathophysiology of the symptoms and signs related to alcohol dependence [1,2,3], a chronic disorder characterized by compulsive alcohol-seeking behaviors and progressive psychosocial dysfunction
The ROI-based analysis using the two-tailed t-test showed no significant group differences in regional metabotropic glutamate receptor-5 (mGluR5) availability in any individual ROI, we do note that, with the single exception of globus pallidus, the mean binding potential with respect to nondisplaceable compartment (BPND) was numerically lower in the alcohol group that in the control group (Table 2)
Age and the number of cigarettes smoked per day were both significantly negatively correlated with [11 C]ABP688 BPND values in widespread regions in the voxel-based analysis for whole subjects (n = 22) at p < 0.005 (Supplementary Table S1; Supplementary Figure S2)

Summary

Introduction

Recent years have seen the emergence of a greater understanding of the contribution of glutamatergic neurotransmission to the pathophysiology of the symptoms and signs related to alcohol dependence [1,2,3], a chronic disorder characterized by compulsive alcohol-seeking behaviors and progressive psychosocial dysfunction. The development of alcohol dependence occurs through multiple stages such as reward seeking/binge drinking, withdrawal, and cue-induced craving [4]. Glutamatergic signaling is mainly involved in incentive salience/binge drinking and alcohol craving [5]. Other rat studies showed that the glutamatergic signaling in the infralimbic subregion of the PFC facilitated extinction of alcohol-seeking behaviors [7], while activity-dependent ablation of neurons in parts of the PFC induced excessive alcohol seeking in rats [8]. Pharmacological blockade of glutamate receptors in the basolateral amygdala and nucleus accumbens reduced cue-induced reinstatement of alcohol in rats [9]. A range of preclinical studies emphasize the role of glutamatergic signaling in the prelimbic and infralimbic subregions of the PFC and subcortical limbic circuits in the components of incentive salience and cue-induced reinstatement of alcohol. MGluRs are being actively explored as useful markers for alcohol dependence, and as therapeutic targets for treatment of alcohol-related disorders [11]

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