Recent data indicate that the neurotoxic effects of organophosphate compounds, including those of the nerve agents VX and sarin, are not solely due to irreversible cholinesterase inhibition. In this study we applied the patch clamp technique to hippocampal neurons in culture and slices to investigate the effects of VX, sarin and huperzine A on transmitter release and the mechanisms related with such effects. The nerve agents VX and sarin at very low concentrations significantly reduced the evoked release of GABA and glutamate. This effect was dependent of the activation of muscarinic receptors. In the presence or absence of the Na(+)-channel blocker tetrodotoxin (TTX), VX increased the frequency of spontaneous glutamate and GABA-induced postsynaptic currents. The effect of VX on TTX-insensitive spontaneous currents appears to be unrelated to cholinesterase inhibition, because it could be detected even after cholinesterase was blocked by high concentrations of the nerve agent soman. The ability of the nerve gases to decrease evoked release of GABA and increase spontaneous transmitter release may underlie some of the neurotoxic effects of the compounds. Huperzine A did not affect spontaneous or evoked release of GABA and glutamate, suggesting that this compound may be a pure cholinesterase inhibitor and had no effect on postsynaptic GABAA or AMPA receptors.