Decreased anxiety, voluntary ethanol intake and ethanol-induced CPP acquisition following activation of the metabotropic glutamate receptor 8 mGluR8

Metabotropic glutamate receptors (mGluRs) are important modulators of excitatory neurotransmission, and have been implicated in addiction to alcohol and anxiety-related behaviors. However, the behavioral consequence and contribution of individual subtypes are not known yet. This study determined the effects of mGluR8 activation on anxiety-like behavior, voluntary ethanol intake and ethanol-induced conditioned reward. To this aim, anxiety and spontaneous behavior were measured in C57BL/6J mice using the elevated plus maze (EPM), open field (OF) and light-dark box (LDB) tests after systemic injection of the selective mGluR8 agonist (S)-3,4-dicarboxyphenylglycine ((S)-3,4-DCPG). In addition, the anti-alcohol properties of mGluR8 were studied using a two-bottle choice continuous access drinking paradigm and ethanol-conditioned place preference (CPP). Results have shown that, compared to vehicle, DCPG produced an anxiolytic-like effect in the LDB, and OF tests. Furthermore, DCPG-injected mice displayed significantly lower intake and preference for ethanol [2.5-20% (v/v) escalating over 2 weeks] in a two-bottle choice paradigm, with no significant difference observed with saccharin [0.04 & 0.08% (w/v)] nor on quinine [20 8240 mu M (w/v)]. Interestingly, DCPG administration attenuated ethanol- induced acquisition, but not expression, of CPP. More importantly, these effects were significantly attenuated when mice were pre-injected with the group III mGluR-specific antagonist (S)-2-amino-2-methyl-4-phosphonobutyric (MAP4). These data demonstrate that activation of the mGluR8 reduces voluntary ethanol in-take in male mice and eliminates place preference acquisition suggesting that mGluR8 signaling may contribute to the rewarding properties of ethanol. Taken together; these findings demonstrate that mGluR8-targeted pharmacotherapies may be beneficial for the treatment of anxiety and alcoholism. (C) 2017 Elsevier Inc. All rights reserved.