In rat hippocampal slices bathed in Mg2(+)-free medium tetanic stimulation generally failed to elicit long-term potentiation (LTP) in the Schaffer collateral-commissural pathway. However, LTP could be induced in the same slices following the re-introduction of 1 mM Mg2+. In Mg2(+)-free medium, LTP could be induced in the presence of 20 microM D-2-amino-5-phosphonovalerate (APV) but was blocked by increasing the APV concentration to 200 microM. The lower concentration of APV is sufficient to prevent N-methyl-D-aspartate (NMDA) receptor activation during low-frequency transmission but not during the tetanus. We suggest therefore, that certain types of activation of the NMDA receptor system can disable the LTP induction mechanism.