We have used an in vitro trauma model to examine the effects of modulation of group III metabotropic glutamate receptors (mGluR) on post-traumatic neuronal cell death. Rat cortical neuronal/glial cultures were subjected to standardized mechanical injury using a punch that delivers 28 parallel cuts to 96-well culture plates, resulting in approximately 50% neuronal cell loss in untreated cultures. RT-PCR demonstrated expression of mRNA for mGluR4, mGluR6, mGluR7, and mGluR8 in uninjured cultures as well as in adult rat brain. Treatment with the group III agonists L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) or L-serine-O-phosphate (L-SOP) resulted in dose-dependent neuroprotection. In contrast, treatment with the group III antagonists alpha-methyl-AP4 (MAP4) or (RS)-alpha-methylserine-O-phosphate (MSOP) caused dose-dependent exacerbation of injury, which was significantly attenuated by L-AP4 or L-SOP. The neuroprotective actions of L-AP4 or L-SOP were markedly reduced by the cyclic AMP analog 8-CPT-cAMP (500 microm), which by itself had no effects at this concentration. Moreover, treatment with L-AP4 or L-SOP reduced basal cyclic AMP levels. Treatment with the NMDA antagonist MK 801 decreased post-traumatic cell death by 45% at optimal concentrations; combined treatment with MK 801 and group III agonists showed a significant enhancement of neuroprotection as compared to treatment with the NMDA antagonist alone. Our findings indicate a clear neuroprotective action for group III agonists in this model and suggest that group III mGluR are endogenously activated in response to trauma. The neuroprotective effects of group III agonists appear to result in part from modulation of adenylyl cyclase activity and are additive to those of an NMDA receptor antagonist.