Translational addiction research

                                                                                                         Rainer SPANAGEL - Mannheim - Allemagne

Since many years we focus on the identification of brain responses and genomic profiles that can be
objectively compared between humans and animal models. Linking preclinical and clinical research on
such a level is a major challenge, and so far has been implemented only at a few sites worldwide. At our
institute we benefit from the collaborative attitude among researchers and the close proximity of preclinical
and clinical research facilities. We have already successfully proven that such direct human-animal
comparisons can be obtained by (i) comparative post-mortem brain analysis, (i) by in vivo mutimodal neuroimaging
or (iii) convergent genomic analyses. By post-mortem brain analysis we identified a common
central glutamatergic mechanism (down-regulation of metabotropic glutamate receptor 2 and enhanced
glutamate levels) in humans and animals during protracted alcohol withdrawal (Hermann et al., 2012;
Meinhardt et al., 2013). We also showed in alcohol dependent rats and humans that a hyper-dopaminergic
system (down-regulation of the dopamine transporter and enhanced dopamine levels) can drive
craving responses during protracted withdrawal (Hirth et al., 2016). In another study we detected the first
genome-wide association for excessive alcohol consumption by combining gene expression profiles from
animals, human association studies and reverse genetics in animals (Stacey et al., 2012). By means of humanized
mouse models we were able to show that the A118G variant is essential for alcohol and nicotine
reinforcement processes and can predict pharmaco-response to naltrexone and nalmefene (Bilbao et al.,
2015). These studies are by now recognized as prototypical examples for translational work in psychiatry.

Bilbao A. et al. (2015) A pharmacogenetic determinant of mu-opioid receptor antagonist effects on alcohol reward and consumption: evidence from humanized mice. Biol Psychiatry 77:850-8.

Hermann D. et al. (2012) Translational magnetic resonance spectroscopy reveals excessive central glutamate levels during alcohol withdrawal in humans and rats. Biol Psychiatry 71:1015-21

Hirth N. et al. (2016) Convergent evidence from alcohol dependent humans and rats for a hyperdopaminergic state in protracted abstinence. Proc Natl Acad Sci USA

Meinhardt M. et al. (2013) Rescue of infralimbic mGluR2 deficit restores control over drug-seeking behavior in alcohol dependence. J Neurosci 33:2794-806.

Stacey D. et al. (2012) RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release. Proc Natl Acad Sci USA 109:21128-33.