Selective blockade of type-1 metabotropic glutamate receptors induces neuroprotection by enhancing gabaergic transmission

Selective antagonists of mGlu1 (LY367385 and CPCCOEt) and mGlu5 (MPEP) metabotropic glutamate receptors were neuroprotective against NMDA toxicity when either applied to mixed cortical cultures or locally infused into the caudate nucleus. Neuroprotection produced by LY367385 or CPCCOEt was occluded by GABA and was abolished by a cocktail of GABA(A) and GABA(B) receptor antagonists. In contrast, GABAergic drugs did not influence the action of MPEP. In microdialysis studies, LY367385 and CPCCOEt substantially enhanced GABA release in the corpus striatum of freely moving animals, whereas MPEP had no effect on GABA but abolished the stimulation of glutamate release induced by NMDA. A role for mGlu1 receptors in modulating GABAergic transmission was supported by electrophysiological studies carried out in cortico-striatal slices. In this particular model, the mixed mGlu1/5 receptor agonist, DHPG, reduced bicuculline-sensitive Inhibitory postsynaptic currents presumably via a presynaptic mechanism. The action of DHPG was antagonized by LY367385, but not by MPEP. Taken together, these results indicate that selective blockade of mGlu1 receptors produces neuroprotection by enhancing GABAergic transmission.