Perturbation of the Glutamate–Glutamine System in Alcohol Dependence and Remission

Abstract

As acute ethanol exposure inhibits N-methyl-D-aspartate glutamate (Glu) receptors, sudden withdrawal from chronic alcohol use may lead to an increased activation of these receptors with excitotoxic effects. In the longer term, brain levels of Glu and its metabolites, such as glutamine (Gln), are likely to be chronically altered by alcohol, possibly providing a measure of overall abnormal Glu-Gln cycling. However, few studies have assessed concentrations of these metabolites in clinical populations of individuals with alcohol use disorders. Glu and Gln levels were compared in groups of 17 healthy controls and in 13 participants with alcohol dependence. Within the alcohol-dependent group, seven participants had current alcohol use disorder (AUD), and six had AUD in remission for at least 1 year (AUD-R). Neurometabolite concentrations were measured with proton magnetic resonance spectroscopy ((1)H-MRS) in a predominantly gray matter voxel that included the bilateral anterior cingulate gyri. Tissue segmentation provided an assessment of the proportion of gray matter in the (1)H-MRS voxel. The Drinker Inventory of Consequences (DrInC) and Form-90 were administered to all participants to quantify alcohol consequences and use. Glu level was lower and Gln level was higher in the AUD and AUD-R groups relative to the control group; creatine, choline, myo-inositol, and total N-acetyl groups, primarily N-acetylaspartate did not differ across groups. These results were not confounded by age, sex, or proportion of gray matter in the (1)H-MRS voxel. Neurometabolite concentrations did not differ between AUD and AUD-R groups. Subsequent regressions in the combined clinical group, treating voxel gray matter proportion as a covariate, revealed that total score on the DrInC was positively correlated with Gln but negatively correlated with both Glu and gray matter proportion. Regression analyses, including DrInC scores and smoking variables, identified a marginal independent effect of smoking on Gln. The current findings of higher Gln and lower Glu in the combined AUD and AUD-R groups might indicate a perturbation of the Glu-Gln cycle in alcohol use disorders. The absence of differences in mean Glu and Gln between the AUD and AUD-R groups suggests that altered Glu-Gln metabolism may either predate the onset of abuse or persist during prolonged abstinence.

Binge ethanol withdrawal: Effects on post-withdrawal ethanol intake, glutamate–glutamine cycle and monoamine tissue content in P rat model

“…The unchanged tissue concentration of glutamine in NAc suggests differential adaptations in mPFC and NAc following severe withdrawal. However, our current finding of decreased glutamate and increased glutamine content is consistent with a previous study conducted on human volunteers, through proton magnetic resonance spectroscopy, with alcohol dependence (Thoma et al, 2011). …”

“…The effects of imported glutamate within astrocytes include: formation of glutamine by glutamine synthetase (GS) enzyme, exchanging for cystine to the extracellular space through xCT, and subsequent formation of glutathione. The formed glutamine within astrocytes is further used up by neurons, and this recycle process is termed the glutamate-glutamine cycle (Thoma et al, 2011). Thus, GLT-1, xCT and GLAST play key roles in regulating extracellular glutamate concentration in the brain.…”

Glutamate Signaling in Alcohol Abuse and Dependence

“…This suggests enhanced glutamatergic signaling in these areas that might drive continued excessive drinking or relapse (e.g., Gass & Olive, 2008). It is possible that these increases in glutamate may reflect withdrawal-induced excitability or time in remission, as other studies using magnetic resonance spectroscopy revealed reduced levels of glutamate in anterior cingulate of alcohol-dependent subjects (Mon, Durazzo, & Meyerhoff, 2012;Thoma et al, 2011), a finding consistent with the data from animal studies suggesting that alcohol-induced alterations in extracellular glutamate may vary as a function of alcohol withdrawal (Ding et al, 2012b).…”

Chronic and acute alcohol administration induced neurochemical changes in the brain: comparison of distinct zebrafish populations

“…Acute alcohol exposure inhibits glutamate receptors, e.g. the NMDA-R, while chronic alcohol exposure reduces brain levels of glutamate (Thoma et al, 2011). GABA has been implicated in alcohol induced functional changes in the brain both in rodents (Feller et al, 1988) and in humans (Maccioni & Colombo, 2009).…”