Translational Magnetic Resonance Spectroscopy Reveals Excessive Central Glutamate Levels During Alcohol Withdrawal in Humans and Rats

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• 作者：Derik Hermann^a ; Wolfgang Weber-Fahr^f ; Alexander Sartorius^d ; ^f ; Mareen Hoerst^b ; Ulrich Frischknecht^a ; Nuran Tunc-Skarka^b ; Stephanie Perreau-Lenz^c ; Anita C. Hansson^c ; Bertram Krumm^e ; Falk Kiefer^a ; Rainer Spanagel^c ; Karl Mann^a ; Gabriele Ende^b ; Wolfgang H. Sommer^c ; ^{wolfgang.sommer@zi-mannheim.de}
• 关键词：Alcoholism ; chronic intermittent alcohol vapor exposure ; glutamate-glutamine cycle ; human ; neuroimaging ; rat model
• 刊名：Biological Psychiatry
• 出版年：2012
• 出版时间：1 June, 2012
• 年：2012
• 卷：71
• 期：11
• 页码：1015-1021
• 全文大小：874 K

文摘

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Background

In alcoholism, excessive glutamatergic neurotransmission has long been implicated in the acute withdrawal syndrome and as a key signal for dependence-related neuroplasticity. Our understanding of this pathophysiological mechanism originates largely from animal studies, but human data are needed for translation into successful medication development.

Methods

We measured brain glutamate levels during detoxification in alcohol-dependent patients (n = 47) and in healthy control subjects (n = 57) as well as in a rat model of alcoholism by state-of-the-art ¹H-magnetic magnetic resonance spectroscopy at 3 and 9.4 T, respectively.

Results

We found significantly increased glutamate levels during acute alcohol withdrawal in corresponding prefrontocortical regions of treatment-seeking alcoholic patients and alcohol-dependent rats versus respective control subjects. The augmented spectroscopic glutamate signal is likely related to increased glutamatergic neurotransmission because, enabled by the high field strength of the animal scanner, we detected a profoundly elevated glutamate/glutamine ratio in alcohol-dependent rats during acute withdrawal. All dependence-induced metabolic alterations normalize within a few weeks of abstinence in both humans and rats.

Conclusions

Our data provide first-time direct support from humans for the glutamate hypothesis of alcoholism, demonstrate the comparability of human and animal magnetic resonance spectroscopy responses, and identify the glutamate/glutamine ratio as potential biomarker for monitoring disease progression.