Recent work has shown that kynurenic acid and several quinoxaline derivatives act as non-competitive NMDA receptor antagonists by binding to the glycine site associated with this receptor. In this study, we have tested the effect of the most potent and selective of these compounds, 7-chlorokynurenic acid (Cl-Kyn), on the induction of long-term potentiation, an event known to involve activation of NMDA receptors. It was found that 30 pM C1-Kyn reversibly abolished the development of both short-term and long-term potentiation in the CA1 region of hippocampal slices. The effectiveness of C1-Kyn matched its ability to inhibit 3H-glycine binding and the association of 3H-TCP with the NMDA receptor in binding experiments (Ki 0.7-1 pM). Weak interactions of C1-Kyn with AMPA receptor sites were observed and may account for a partial, reversible reduction in the epsp. However, blockade of long-term potentiation by C1-Kyn was completely reversed by simultaneous application of the glycine site agonist D-serine and thus must be attributed to its interaction with the glycine site. These results indicate that the glycine site coupled to the NMDA receptor potently modulates channel function during physiological events related to synaptic activation. Hippocampus, Glycine antagonist, Chlorokynurenic acid