A modified medium containing an AMPA receptor antagonist and low concentrations of magnesium was used to investigate the factors governing the potentiation of synaptic responses mediated by NMDA receptors. When long-term potentiation (LTP) was induced in standard medium and NMDA responses were analyzed by changing to the modified medium, no statistically significant differences were observed between potentiated and control pathways. Returning the slices to the standard medium showed that LTP was still present, indicating that the potentiation effect was not reversed by the modified medium. High-frequency stimulation applied in the modified medium produced an enhancement of synaptic responses, but this was not occluded by prior potentiation in standard medium. The degree of potentiation induced in the modified medium and expressed by NMDA responses was larger in the presence than in the absence of inhibition and, unlike LTP, was proportionately larger when recorded in the stratum pyramidale than in the stratum radiatum. These results indicate that the potentiation of NMDA receptor-mediated responses triggered by high-frequency stimulation applied in modified medium differs in several respects from the LTP induced in standard conditions. They confirm that LTP is expressed to a markedly different degree by NMDA and non-NMDA receptors and suggest that events that do not necessarily accompany LTP affect the potentiation of NMDA receptor-dependent synaptic responses.