Functional interaction of metabotropic glutamate receptor 5 and NMDA-receptor by a metabotropic glutamate receptor 5 positive allosteric modulator

The NMDA (N-methyl-D-aspartate)-receptor is fundamentally involved in cognitive functions. Recent studies demonstrated a functional interaction between the metabotropic glutamate receptor 5 (mGlu5 receptor) and the NMDA-receptor in neurons. In rat hippocampal slices, it was shown that activation of mGlu5 receptor by a positive modulator in the presence of a subthreshold agonist concentration potentiated NMDA-receptor mediated currents and phosphorylation of intracellular signalling proteins. In the present study, we investigated the functional interaction of mGlu5 receptor and NMDA-receptor by the selective mGlu5 receptor positive modulator ADX-47273 in-vitro and in-vivo. In rat primary neurons, this compound potentiated Ca2+ mobilization in the presence of a subthreshold concentration of the mGluR1/5 agonist DHPG (0.3 µM) with an EC50 of 0.28 ± 0.05 µM. NMDA-induced Ca2+-mobilization in primary neurons could be potentiated when neurons were pre-stimulated with 1 µM ADX-47273 in the presence of 0.3 µM DHPG. The specific mGlu5 receptor antagonist MPEP and the Src-family kinase inhibitor PP2 blocked this potentiation demonstrating the functional interaction of the NMDA-receptor and mGlu5 receptor in neurons. Furthermore, ADX-47273 elicited an enhancement of NMDA-receptor dependent long-term potentiation in rat hippocampal slices that could be reversed by MPEP. After intraperitoneal administration to rats, ADX-47273 showed a dose-dependent reduction of NMDA-receptor antagonist (ketamine) induced hyperlocomotion, supporting the mechanistic interaction of the NMDA-receptor and mGlu5 receptor in-vivo. In conclusion, these findings further support the idea of a functional interaction between the mGlu5 receptor and NMDA-receptor, which may provide a pharmacological strategy for addressing CNS diseases with cognitive impairments linked to NMDA-receptor hypofunction.