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Glutamate concentration in the anterior cingulate cortex in alcohol dependence

association with alcohol withdrawal and exploration of contribution from glutamatergic candidate genes

Streit, Fabiana,*; Treutlein, Jensa,*; Frischknecht, Ulrichb; Hermann, Derikb; Mann, Karlb; Kiefer, Falkb; Sack, Markusd; Hall, Alisha S.M.a; Frank, Josefa; Witt, Stephanie H.a; Foo, Jerome C.a; Degenhardt, Franziskae,f; Heilmann-Heimbach, Stefaniee,f; Nöthen, Markus M.e,f; Sommer, Wolfgang H.b,c; Spanagel, Rainerc; Rietschel, Marcellaa,*; Ende, Gabrieled,*

doi: 10.1097/YPG.0000000000000202

Departments of aGenetic Epidemiology in Psychiatry

bAddictive Behaviour and Addiction Medicine


dNeuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

eInstitute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn

fDepartment of Genomics, Life&Brain Research Center, University of Bonn, Bonn, Germany

*Fabian Streit, Jens Treutlein, Marcella Rietschel, and Gabriele Ende contributed equally to the writing of this article.

Correspondence to Fabian Streit, PhD, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Zentralinstitut fur Seelische Gesundheit, J5, Mannheim 68159, Germany Tel: +49 621 1703 6054; fax: +49 621 1703 6055; e-mail:

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Received May 17, 2018

Accepted May 24, 2018

Glutamate-mediated neuronal excitability is found to be increased during alcohol withdrawal in animal studies. The present study aimed to corroborate whether, in humans, the level of glutamate measured by magnetic resonance spectroscopy is increased during withdrawal in the anterior cingulate cortex (ACC), a brain region important for the reward circuitry. It furthermore aimed to test whether glutamatergic candidate genes play a role in this pathophysiological state.

Two previous magnetic resonance spectroscopy studies suggest that the glutamate-to-creatine ratio (Glu/Cr) is increased during early abstinence in the ACC. These two studies included only a few individuals: (i) n=33 alcohol-dependent patients (n=15 with acamprosate treatment, and n=18 with placebo) measured at days 4 and 25 of abstinence (Umhau et al., 2010), and (ii) n=13 at least 2-week-abstinent alcohol-dependent patients and n=18 controls (Lee et al., 2007). Umhau et al. (2010) found a significant decrease in Glu/Cr over time in the acamprosate group and a nonsignificant trend of an increase in Glu/Cr in the placebo group. Lee et al. (2007) reported increased Glu/Cr in patients compared with controls. We previously showed an increase in Glu, referenced to unsuppressed water signal (Hermann et al., 2012; see Supplementary Text, Supplemental digital content 1,, for further information).

The present study comprised 62 cases and 57 controls (see Supplementary Information, Supplemental digital content 1,, for details). Glutamate concentrations were assessed using Glu/Cr, as a comparatively large region of interest was analyzed, and Glu/Cr better corrects for the large proportion of cerebrospinal fluid in large measurement areas than the reference to a water signal.

In cases, Glu/Cr in the ACC was significantly increased compared with controls [t(116.74)=−2.27; P=0.025]. This association was based on the absolute Glucorrected level [t(101.13)=2.81; P=0.006], but not on the Crcorrected level [t(117.00)=1.11; P=0.27] (both: ratio to water, corrected for cerebrospinal fluid content in the voxel), indicating that in our study, Glu is the main neurometabolite driving the Glu/Cr association signal.

In the genetic analysis, 216 genes related to the glutamate system (rat ‘glutamate chip’, Supplementary Information, Supplemental digital content 1, were tested for association with glutamate levels. No association was significant after correction for multiple testing. The most significant glutamatergic candidate gene in the 62 cases was GATA-binding protein 4 (GATA4) (gene-based test, Puncorrected=0.0029; Supplementary Tables S2–S4, Supplemental digital content 1, GATA4 influences the neuroendocrine regulation of stress by the atrial natriuretic peptide and in a recently published large genome-wide association study of neuroticism in over 329 000 individuals (Luciano et al., 2018), GATA4 was found to be located in a genome-wide significant region (P=2.18×10–24). Neuroticism, a personality trait characterized by negative emotionality, is considered a risk factor for psychiatric disorders including alcohol dependence. Furthermore, GATA4 was among the top findings in two independent GWAS on alcohol dependence (see Supplementary text, Supplemental digital content 1,, for further information), as well as in a genetic study on relapse risk (Kiefer et al., 2011).

In conclusion, in the largest sample to date, we corroborated that alcohol withdrawal is associated with increased Glu/Cr in the ACC. Although our top finding GATA4 is plausible, it should be considered that it was not significant after correction for multiple testing.

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The study was supported by the German Federal Ministry of Education and Research (BMBF) within the context of the following research consortia of the BMBF e:Med Systems Medicine Programme: (1) SysMedAlcoholism (Alcohol Addiction: A Systems-Oriented Approach, grant 01ZX1311A to M.M.N. and M.R.); (2) IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders; grant 01ZX1314A to M.M.N. and F.D., grant 01ZX1314G to M.R.); M.M.N. is a member of the DFG-funded Excellence-Cluster ImmunoSensation. The study was also supported by the German Research Foundation (DFG) (SFB636, project D07; grant FOR2107, RI908/11-1 to M.R., NO246/10-1 to M.M.N.).

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Conflicts of interest

There are no conflicts of interest.

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Hermann D, Weber-Fahr W, Sartorius A, Hoerst M, Frischknecht U, Tunc-Skarka N, et al (2012). Translational magnetic resonance spectroscopy reveals excessive central glutamate levels during alcohol withdrawal in humans and rats. Biol Psychiatry 71:1015–1021.
Kiefer F, Witt SH, Frank J, Richter A, Treutlein J, Lemenager T, et al (2011). Involvement of the atrial natriuretic peptide transcription factor GATA4 in alcohol dependence, relapse risk and treatment response to acamprosate. Pharmacogenomics J 11:368–374.
Lee E, Jang DP, Kim JJ, An SK, Park S, Kim IY, et al (2007). Alteration of brain metabolites in young alcoholics without structural changes. Neuroreport 18:1511–1514.
Luciano M, Hagenaars SP, Davies G, Hill WD, Clarke TK, Shirali M, et al (2018). Association analysis in over 329 000 individuals identifies 116 independent variants influencing neuroticism. Nat Genet 50:6–11.
Umhau JC, Momenan R, Schwandt ML, Singley E, Lifshitz M, Doty L, et al (2010). Effect of acamprosate on magnetic resonance spectroscopy measures of central glutamate in detoxified alcohol-dependent individuals: a randomized controlled experimental medicine study. Arch Gen Psychiatry 67:1069–1077.

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