An important characteristic of long-term potentiation (LTP) in the hippocampal CA1 region is that it is specific for those synapses which are active during the induction event. This input specificity is commonly attributed to the location and properties of the N-methyl-D-aspartate (NMDA) receptor channel. Experiments using strong high-frequency orthodromic activation have suggested that input-specific LTP can occur also in the absence of NMDA receptor activation. The present experiments have re-examined this question. They were performed in the CA1 region of hippocampal slices, and the synaptic strength was evaluated from the initial slope of the dendritically recorded field potential. In agreement with previous reports, 0.5 s, 200 Hz, orthodromic trains were found to lead to a substantial input-specific LTP (averaging 62%) in the presence of the competitive NMDA receptor antagonist D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5) (20 microM). Under conditions of higher NMDA receptor blockade considerably less LTP was evoked. In 50 microM D-AP5 and 20 microM chloro-kynurenate LTP averaged 13.4%, and after addition of 20 microM (+)-dizicilpine maleate (MK-801) LTP averaged 5.9%. On the other hand, in 20 microM D-AP5 and 20 microM of the calcium channel antagonist nifedipine LTP averaged 49.9%. The present results suggest that NMDA receptor activity remaining in high concentrations of AP5 is sufficient to underly LTP induction under strong induction conditions.