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

Selective antagonists of mGlu1 (LY367385 and CPCCOEt) and mGlu5 (MPEP) meta botropic glutamate receptors were neuroprotective against NMDA toxicity whe n either applied to mixed cortical cultures or locally infused into the cau date nucleus. Neuroprotection produced by LY367385 or CPCCOEt was occluded by GABA and was abolished by a cocktail of GABA(A) and GABA(B) receptor ant agonists. In contrast, GABAergic drugs did not influence the action of MPEP . In microdialysis studies, LY367385 and CPCCOEt substantially enhanced GAB A release in the corpus striatum of freely moving animals, whereas MPEP had no effect on GABA but abolished the stimulation of glutamate release induc ed by NMDA. A role for mGlu1 receptors in modulating GABAergic transmission was supported by electrophysiological studies carried out in cortico-stria tal slices. In this particular model, the mixed mGlu1/5 receptor agonist, D HPG, reduced bicuculline-sensitive Inhibitory postsynaptic currents presuma bly via a presynaptic mechanism. The action of DHPG was antagonized by LY36 7385, but not by MPEP. Taken together, these results indicate that selectiv e blockade of mGlu1 receptors produces neuroprotection by enhancing GABAerg ic transmission.