Extracellular recording was used to study the effects of high-frequency (tetanic) stimulation on excitatory synaptic transmission in the CA1 region of rat hippocampal slices in the presence of the γ-aminobutyric acid (GABA) type A antagonist, picrotoxin (50 γM). Under these conditions tetanic stimulation (100 Hz, 1 s) at the test intensity resulted in homosynaptic long-term potentiation (LTP). In contrast, tetanic stimulation of higher intensity (100 Hz, 1 s, double test intensity) resulted in homo- and heterosynaptic depression which recovered within 45 min. A transient (1–3 min) negative shift in DC potential and a transient (5–10 min) depression of the homosynaptic fibre volley occurred immediately following the higher intensity tetanus. The DC shift, induction of homo- and heterosynaptic depression and depression of the fibre volley were reversibly prevented by the N-methyl-d-aspartate (NMDA) receptor antagonist, d-2-amino-5-phosphonopentanoate (AP5; 20 γM) but were not prevented by a variety of L-type calcium channel antagonists. Transient (30 - 45 min) synaptic depression of pharmacologically isolated NMDA receptor-mediated field excitatory postsynaptic potentials also occurred following tetanic stimulation (100 Hz, 1 s) at double test intensity. These results demonstrate an NMDA receptor-dependent form of reversible synaptic depression in the CA1 region of the hippocampus.