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Wolfang SOMMER"Translational predictors of treatment efficacy in alcoholism: Prefrontal glutamate responses in humans and rodents"

Abstract :


Alcoholism is a common psychiatric disorder with largely unmet treatment needs.
This is at least partly due to the very limited arsenal of pharmacotherapeutics. The development of new medications critically depends on animal models. Although a number of promising molecular targets for medication development have been put forward by the use of such models, several clinical trials aimed to exploit this potential fell short to expectations. To increase consilience between basic and clinical alcoholism research and thus to positively impact on medication development we focus on obtaining convergent lines of evidence from humans and experimental animals as will be illustrated by several examples:
A key deficit in alcohol dependence is disrupted prefrontal function leading to excessive alcohol seeking, but the molecular events underlying the emergence of addictive responses remain unknown. We found by convergent transcriptome analysis that the pyramidal neurons of the infralimbic cortex are particularly vulnerable for the long-term effects of chronic intermittent ethanol intoxication. These neurons exhibit a pronounced deficit in mGluR2 and thereby a loss of autoreceptor feedback control. Alcohol dependent rats show escalation of ethanol seeking, which was abolished by restoring mGluR2 expression in the infralimbic cortex via viral-mediated gene transfer. Human anterior cingulate cortex from alcoholic patients shows a significant reduction in mGluR2 transcripts compared to control subjects suggesting that mGluR2 loss in the rodent and human cortico-accumbal neurocircuitry may be a major consequence of alcohol dependence and a key pathophysiological mechanism mediating increased propensity to relapse. Normalization of mGluR2 function within this brain circuit may be of therapeutic value.
To validate putative disease mechanism suggested by preclinical models in vivo neuroimaging can serve as a translational tool. Using high-resolution magnetic resonance spectroscopy, we found increased glutamate levels during acute alcohol withdrawal in corresponding prefrontal brain regions of both humans and rats. Such metabolic alterations related to glutamatergic neurotransmission may provide an easy accessible biomarker for monitoring disease progression or treatment response in alcoholism. This approach will now be further developed for functional MRI.

Selected publications

1.    MW Meinhardt, AC Hansson, S Perreau-Lenz, C Bauder, C Harper, M Heilig, KU Drescher, R Spanagel, WH Sommer. Rescue of infralimbic mGluR2 deficit restores control over drug-seeking behavior in alcohol dependence. submitted
2.    Tapocik J, Solomon M, Flanigan M, Meinhardt M, Barbier E, Schank J, Schwandt M, Sommer MH, Heilig M. Coordinated dysregulation of mRNAs and microRNAs in the rat medial prefrontal cortex following a history of alcohol dependence. Pharmacogenomics J, 2012.
3.    Hermann D, Weber-Fahr W, Sartorius A, Hoerst M, Frischknecht U, Tunc-Skarka N, Perreau-Lenz S, Hansson AC, Krumm B, Kiefer F, Spanagel R, Mann K, Ende G, Sommer WH. Translational magnetic resonance spectroscopy reveals excessive central glutamate levels during alcohol withdrawal in humans and rats. Biological Psychiatry, 71(11):1015-21, 2012
4.    Sommer WH and Spanagel R. Eds. Neurobiology of Alcoholism, in Current Topics in Behavioral Neurobiology, Vol 13. Springer, 2012
5.    Sommer WH, Rimondini R, Hansson AC, Hipskind PA, Gehlert DR, Barr CS, Heilig MA. Up-regulation of voluntary alcohol intake, behavioral sensitivity to stress, and amygdala Crhr1 expression following a history of dependence. Biological Psychiatry 63(2):139-45,2008

Scientific focus :

One of the goals of our group is to unravel neurobiological mechanisms underlying addictive behaviours, in particular those that could be relevant for the treatment of alcohol addiction. An equally important task is to translate this knowledge into clinical applications. To address these issues we focuses on highly comparable responses between humans and experimental animals. We use a broad spectrum of methods including molecular biology and genetics, behavioural pharmacology and neuroimaging applications. Currently, within the framework of an ERA-Net Neuron funded project (www.transalc.eu) we develop MRI techniques to identify altered brain connectivity in animal models of alcohol addiction, and to monitor how these networks respond to medications.

Véronique Deroche Gamonet du Neurocentre Magendie