title: Negative Association Between MR-Spectroscopic Glutamate Markers and Gray Matter Volume After Alcohol Withdrawal in the Hippocampus: A Translational Study in Humans and Rats.
abstract: Both chronic alcohol consumption and alcohol withdrawal lead to neural tissue damage which partly recovers during abstinence. This study investigated withdrawal-associated changes in glutamatergic compounds, markers of neuronal integrity, and gray matter volumes during acute alcohol withdrawal in the hippocampus, a key region in development and maintenance of alcohol dependence in humans and rats.
  
  
  
  Alcohol-dependent patients (N = 39) underwent magnetic resonance imaging (MRI) and MR spectroscopy (MRS) measurements within 24 hours after the last drink and after 2 weeks of abstinence. MRI and MRS data of healthy controls (N = 34) were acquired once. Our thorough quality criteria resulted in N = 15 available spectra from the first and of N = 21 from the second measurement in patients, and of N = 19 from healthy controls. In a translational approach, chronic intermittent ethanol-exposed rats and respective controls (8/group) underwent 5 MRS measurements covering baseline, intoxication, 12 and 60 hours of withdrawal, and 3 weeks of abstinence.
  
  
  
  In both species, higher levels of markers of glutamatergic metabolism were associated with lower gray matter volumes in the hippocampus in early abstinence. Trends of reduced N-acetylaspartate levels during intoxication persisted in patients with severe alcohol withdrawal symptoms over 2 weeks of abstinence. We observed a higher ratio of glutamate to glutamine during alcohol withdrawal in our animal model.
  
  
  
  Due to limited statistical power, we regard the results as preliminary and discuss them in the framework of the hypothesis of withdrawal-induced hyperglutamatergic neurotoxicity, alcohol-induced neural changes, and training-associated effects of abstinence on hippocampal tissue integrity.
authors.affiliation: Department of Addictive Behavior and Addiction Medicine , Central Institute for Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Frischknecht
authors.affiliation: Department of Addictive Behavior and Addiction Medicine , Central Institute for Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Derik
authors.initials: D
authors.lastname: Hermann
authors.affiliation: Department of Neuroimaging , Central Institute for Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Nuran
authors.initials: N
authors.lastname: Tunc-Skarka
authors.affiliation: Department of Neuroimaging , Central Institute for Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Guo-Ying
authors.initials: GY
authors.lastname: Wang
authors.affiliation: Department of Neuroimaging , Central Institute for Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Sack
authors.affiliation: Department of Neuroimaging , Central Institute for Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: van Eijk
authors.affiliation: Department of Neuroimaging , Central Institute for Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Traute
authors.initials: T
authors.lastname: Demirakca
authors.affiliation: Research Group for Translational Imaging , Central Institute for Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Falfan-Melgoza
authors.affiliation: Department of Biostatistics , Central Institute for Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Bertram
authors.initials: B
authors.lastname: Krumm
authors.affiliation: Institute of Psychopharmacology , Central Institute for Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Dieter
authors.affiliation: Institute of Psychopharmacology , Central Institute for Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Spanagel
authors.affiliation: Department of Addictive Behavior and Addiction Medicine , Central Institute for Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Kiefer
authors.affiliation: Department of Addictive Behavior and Addiction Medicine , Central Institute for Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Karl F
authors.initials: KF
authors.lastname: Mann
authors.affiliation: Department of Addictive Behavior and Addiction Medicine , Central Institute for Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.|Institute of Psychopharmacology , Central Institute for Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Sommer
authors.affiliation: Department of Neuroimaging , Central Institute for Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Ende
authors.affiliation: Research Group for Translational Imaging , Central Institute for Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Weber-Fahr
mesh_terms: D000328:Adult; D064829:Alcohol Abstinence; D000437:Alcoholism / Q000378:metabolism / Q000523:psychology; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000097:blood; D015415:Biomarkers / Q000378:metabolism*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D066128:Gray Matter / Q000473:pathology*; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000473:pathology* / Q000523:psychology; D057170:Translational Research, Biomedical
chemical_list: D015415:Biomarkers; D001224:Aspartic Acid; D018698:Glutamic Acid; C000179:N-acetylaspartate
keywords: Alcohol Withdrawal; Glutamate; Gray Matter; Hippocampus; Magnetic Resonance Spectroscopy