The synthetic omega-conopeptides SNX-111 (MVIIA), SNX-124 (GVIA), SNX-183 (SVIB), and SNX-185 (TVIA) reduced excitatory postsynaptic potential (EPSP) amplitudes measured in the stratum radiatum of rat hippocampal slices by about 50% at doses at or near 200 nM. These effects were at least partially reversible in most slices. EPSP amplitude was not further reduced at the highest concentrations of SNX-111, SNX-124, and SNX-185 (1.5-10 microM). In contrast, the highest concentrations of SNX-183 (2 and 10 microM) further reduced EPSP amplitude to about 20% of control. SNX-183 reduced EPSP amplitude in slices previously treated with maximally effective doses of SNX-111 or SNX-124. These results suggest that there are at least two classes of omega-conopeptide receptor sites that modulate neurotransmitter release in the rat hippocampus.