An in vitro mammalian model neuronal system to evaluate the intrinsic toxicity of soman and other neurotoxicants as well as the efficacy of potential countermeasures was investigated. The link between soman toxicity, glutamate hyperactivity and neuronal death in the central nervous system was investigated in primary dissociated cell cultures from rat hippocampus and cerebral neocortex. Exposure of cortical or hippocampal neurons to glutamate for 30 min produced neuronal death in almost 80% of the cells examined at 24 h. Hippocampal neurons exposed to soman for 15-120 min at 0.1 microM concentration caused almost complete inhibition (> or = 90%) of acetylcholinesterase but failed to show any evidence of effects on cell viability, indicating a lack of direct cytotoxicity by this agent. Acetylcholine (ACh, 0.1 mM), alone or in combination with soman, did not potentiate glutamate toxicity in hippocampal neurons. Memantine, a drug used for the therapy of Parkinson's disease, spasticity and other brain disorders, significantly protected hippocampal and cortical neurons in culture against glutamate and N-methyl-D-aspartate (NMDA) excitotoxicity. In rats a single dose of memantine (18 mg/kg) administered 1 h prior to a s.c. injection of a 0.9 LD50 dose of soman reduced the severity of convulsions and increased survival. Survival, however, was accompanied by neuronal loss in the frontal cortex, piriform cortex and hippocampus.