In rat cortical neuronal cultures, metabotropic glutamate (mGlu) receptor agonists: LY354740 (+)-2-aminobicyclo[3.1.0]hexane-2,6dicarboxylate); LY379268 (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate, and LY389795 (-)-2-thia-4-aminobicyclo[3.1.0]-hexane-4,6-dicarboxylate, were neuroprotective against toxicity induced by N-methyl-D-aspartic acid (NMDA), kainic acid and staurosporine as measured by release of lactate dehydrogenase (LDH) activity into culture supernatants and DNA fragmentation by oligonucleosome formation. The potencies of the agonists were at least 100 times greater in reducing nucleosome formation than LDH release indicating a differential effect on neurons dying by apoptosis than by necrosis. In vivo studies showed that LY354740 was able to mediate a partial protection against apoptosis in CA1 hippocampal cells under ischaemic conditions where substantial CA1 cell loss occurred. The effects of the agonists in vitro were: (a) reversed by mGlu receptor antagonist LY341495, (b) enhanced by the presence of glial cells, (c) abrogated by RNA and protein synthesis inhibitors, and (d) unaltered by inhibition of endogenous adenosine activity. These results suggest that group II mGlu receptor agonists may represent a novel therapeutic strategy for the treatment of neurodegenerative diseases.