Functional interactions between presynaptic NMDA receptors and metabotropic glutamate receptors co-expressed on rat and human noradrenergic terminals

Background and purpose: Electrophysiological studies described potentiation of NMDA receptor function by metabotropic glutamate receptors (mGluRs) of group I occurring postsynaptically. Since release-enhancing NMDA receptors exist on noradrenergic terminals and group I mGluRs have recently been identified on these nerve endings, we have investigated if NMDA receptor-mGluR interactions also can occur at the presynaptic level. Experimental approach: Rat hippocampus and human neocortex synaptosomes were labelled with [H-3] noradrenaline and superfused with mGluR agonists and antagonists. NMDA-evoked [H-3] noradrenaline release was produced by removal of external Mg2+ or by simultaneous application of NMDA and AMPA in Mg2+ -containing solutions. Key results: The mGluR1/5 agonist 3,5-DHPG, inactive on its own, potentiated both the release of [H-3] noradrenaline elicited by AMPA/NMDA/glycine and that evoked by NMDA/glycine following Mg2+ removal. The effect of 3,5-DHPG on the AMPA/ NMDA/glycine-induced release was insensitive to the mGluR1 antagonist CPCCOEt, but it was abolished by the mGluR5 antagonist MPEP; moreover, it was potentiated by the mGluR5 positive allosteric modulator DFB. When NMDA receptors were activated by Mg2+ removal, both mGluR5 and mGluR1 contributed to the evoked release, the mGluR-mediated release being blocked only by CPCCOEt and MPEP in combination. Experiments with human neocortex synaptosomes show NMDA receptor-mGluR interactions qualitatively similar to those observed in rodents. Conclusions and implications: Group I mGluRs, both of the mGluR1 and mGluR5 subtypes, co-localize with NMDA receptors on noradrenergic terminals of rat hippocampus and human neocortex. Depending on the mode of activation, NMDA receptors exert differential permissive roles on the activation of presynaptic mGluR1 and mGluR5.