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

Mind Research Network, Albuquerque, NM, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 03/2011; 36(7):1359-65. DOI: 10.1038/npp.2011.20
Source: PubMed


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.

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    • "A similar pattern was observed in studies using alcohol (Roberto et al., 2003; Gomez et al., 2012). However, these are more difficult to interpret because of the pleiotropic effects of alcohol on other neurotransmitter systems, in particular the glutamatergic system (Thoma et al., 2011). "
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    • "These Gln levels were significantly correlated with craving, supporting the alternate hypothesis that the correlation between Glx and craving is mostly driven by Gln. Interestingly, Thoma et al (2011) reported increased levels of Gln in patients with alcohol use disorder, which positively correlated with the long-term severity of alcohol abuse. Still, the limited resolution of both overlapping metabolites with the applied spectroscopy and the complexity of the Glu/Gln cycle as described above allow only cautious interpretations of the differential changes of Glu and Gln. "
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