The role of group I and group II metabotropic glutamate receptors in modulation of striatal NMDA and quinolinic acid toxicity.

Excitotoxic lesions of the striatum are mediated by the combined activity of N-methyl-d-aspartate (NMDA) receptors and metabotropic glutamate receptors (mGluRs). Intrastriatal injection of the NMDA receptor agonists NMDA or quinolinic acid creates large lesions, but in rats that have been decorticated to remove endogenous glutamatergic input, NMDA and quinolinic acid are no longer toxic. We report that NMDA toxicity can be restored in decorticated animals by coinjection of the group I mGluR agonists t-ACPD, t-ADA, or CHPG. In addition, injections of two group I mGluR antagonists, AIDA and (S)-4C3HPG, can protect against striatal lesions produced by quinolinic acid or NMDA injections in normal rats by blocking activation of group I mGluRs. The group II mGluR agonist APDC fails to protect against quinolinic acid or NMDA toxicity in intact animals or to restore NMDA toxicity in decorticated animals, suggesting that the role of group II receptors in this excitotoxic model is minimal. These observations confirm the important role of group I mGluRs in excitotoxicity and identify these receptors as promising targets for therapeutic intervention in neurodegenerative disease processes.