We have investigated long-term synaptic depression in the CA1 region of rat hippocampal slices. Prolonged low-frequency stimulation (LFS; 900 stimuli delivered at 2 Hz) of the Schaffer collateral-commissural pathway in naïve slices did not induce long-term depression (LTD) of synaptic transmission. However, if long-term potentiation (LTP) was firstly induced in the pathway then LFS generated an LTD-like effect (i.e. depotentiation of LTP). Depotentiation could be induced 2 h (the longest time studied) after the induction of LTP and was stable for the duration of the experiment (followed for up to 40 min). The induction of depotentiation was not blocked by the N-methyl-D-aspartate receptor antagonist D-2-amino-5-phosphonopentanoate, the L-type voltage-gated Ca2+ channel blocker nimodipine or the nitric oxide synthase inhibitor N omega-nitro-L-arginine. However, the magnitude of depotentiation was reversibly reduced, in a stereoselective manner, by the specific metabotropic glutamate receptor (mGluR) antagonist (+)-alpha-methyl-4-carboxyphenylglycine. These results show that prolonged low frequency stimulation can result in an mGluR-dependent depotentiation of LTP.