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Dr. Markus Sack

Mann KF, Ende G, Sommer WH. DFG - Deutsche Forschungsgemeinschaft SFB 636: TP D07: Neuroplasticity of brain glutamate and glutamine and treatment. 01/2012-12/2015.

The glutamate hypothesis of alcoholism posits that chronic alcohol intake leads to an enhanced activity of the glutamate system. As soon as alcohol is discontinued, withdrawal develops with marked brain hyperexcitability. Under abstinent conditions this hyperglutamatergic state could be reinstated by stress or alcohol cues and precipitate relapse. Anti-glutamatergic compounds are effective in preventing relapse and potentially also in alleviation of withdrawal. Effect sizes of this pharmacotherapy are moderate, a fact which may be accounted for by individual differences in the extent of neuroplastic changes of the glutamate system. Thus, we predict that antiglutamatergic medications work primarily in individuals who develop a pronounced hyperglutamatergic state, a condition that can be identified and monitored by magnetic resonance spectroscopy (MRS). We previously found that alcohol withdrawal is reflected by increased central glutamate levels. A new measure to be studied in the coming funding period is the glutamate/glutamine ratio which we now can also measure reliably in humans. This ratio will be tested as a potential biomarker for monitoring alcoholism, which may lay the grounds for a personalized treatment approach of this condition. We believe that a translational approach involving human patients and “alcohol dependent rats” serves the purpose of our research best. In both species prefrontal cortex changes in metabolite concentrations during acute withdrawal and into several weeks of abstinence are measured with and without pharmacological interference targeting the glutamatergic system. In the last funding period we developed methods for absolute quantification of metabolites in the human and rat brain. Under control conditions glutamate concentrations in the human anterior cingulate cortex (ACC) and the rat medial prefrontal cortex (mPFC) were highly similar. Thus, for the first time direct evidence for increased central glutamate levels during acute alcohol withdrawal in both species was provided. In the animal experiments, we will induce alcohol dependence through chronic, intermittent, ethanol-vapor exposure. Rats will be assessed repeatedly, over the course of acute alcohol withdrawal into abstinence, for neurometabolic changes in the medial-prefrontal cortex, using MRS at 9.4T. In the new funding period we shall concentrate on the effects of experimental pharmacotherapies for alcohol detoxification (glutamate modulators, such as acamprosate, memantine and lamotrigine) on neurometabolic profiles and on alcohol-related behaviors, comparing these therapies to standard treatments (GABAergic: diazepam). We will also compare neurometabolic profiles to in vivo, microdialysis measurements of extracellular glutamate release from parallel groups of rats. In the human study, we will continue to assess the effects of alcohol withdrawal. As a new element, alcohol cues and pharmacological intervention on levels of glutamate, glutamine and GABA in the prefrontal cortices of treatment-seeking alcoholics will be studied. Alcohol dependent inpatients (n=60) will undergo three combined measurements of MRS and fMRI cue reactivity. The first MR session will take place during acute withdrawal (without medication). The second group of measurements will be taken after five days of abstinence, in order to monitor the glutamate/glutamine ratio over time, and to what extent this ratio is affected by the diazepam that will at this point have been administered for withdrawal-symptom relief. The third MR session will take place on day 14 to monitor the effects of abstinence, both for patients under treatment with acamprosate (which will have been initiated as an open-label treatment following the second MR session) and for patients not being treated with medication. Relapse behavior will be monitored in follow-up assessments, and correlated to MRS metabolites. A control group of n=20 healthy subjects will undergo combined MRS and fMRI twice, two weeks apart.

Zentralinstitut für Seelische Gesundheit (ZI) - https://www.zi-mannheim.de