Many studies on long-term potentiation (LTP) in hippocampal region CA1 focus on receptor-mediated events that are often presumed to be linked to postsynaptic processes. Whereas it is now well-known that LTP consists of multiple components involving increases in postsynaptic responsiveness as well as enhanced presynaptic release of transmitter, little specific information has accrued on the nature of the presynaptic receptor-linked events. In the course of a series of experiments examining the actions of several antagonists of N-methyl-D-aspartate (NMDA) receptors on LTP, we made certain observations that suggested the role of a novel type of amino acid receptor which possibly was located presynaptically and that seemed to contribute to the induction of LTP. LTP evoked in region CA1 following high frequency stimulation (HFS) of the Schaffer collateral-commissural pathway measured 20-30 min after HFS always was attenuated incompletely when induced during administration of DalphaAA at doses ranging from 50 mu M to as high as 1000 mu M, whereas 2-amino-5-phosphonopropionate (AP5), at a concentration of 30 mu M, always abolished the process completely. 6,7-Dinitroquinoxaline-2,3-dione (DNQX) (10 mu M) administered alone also did not block LTP completely unless delivered in combination with DalphaAA. These non-AP5-like effects of DalphaAA could not be attributed to incomplete antagonism of postsynaptic NMDA receptors, since DalphaAA (200 mu M) completely and reversibly blocked the membrane depolarising effects of NMDA, as assessed through intracellular recording. Furthermore, the pharmacologically isolated NMDA-receptor-mediated component of the low-frequency, stimulus-evoked synaptic response was always abolished reversibly by DalphaAA (200 mu M). The most parsimonious explanation of these data is that a receptor which is only activated during HFS, is sensitive to the antagonising actions of AP5 and possibly also to DNQX but not to DalphaAA, and which could conceivably exist on terminals of the Schaffer collateral-commissural fibres, makes a significant contribution to LTP.