Abstract Metabotropic glutamate receptors of the mGlu 1 and mGlu 5 subtypes exhibit a high degree of sequence homology and are both coupled to phospholipase C and intracellular Ca 2+ mobilization. However, functional differences have been detected for these receptor subtypes when they are coexpressed in the same neuronal populations. Experimental evidence indicates that mGlu 1 and mGlu 5 receptors play a differential role in models of cerebral ischemia and that only mGlu 1 receptors are implicated in the pathways leading to post-ischemic neuronal injury. The localization of mGlu 1 receptors in GABA-containing interneurons rather than in hippocampal CA1 pyramidal cells that are vulnerable to ischemia has prompted studies that have provided a new viewpoint on the neuroprotective mechanism of mGlu 1 receptor antagonists. The hypothesis predicts that these pharmacological agents attenuate post-ischemic injury by enhancing GABA-mediated neurotransmission.