Group I mGluR-dependent LTD has previously shown to be induced by low-frequency stimulation in the CA1 and dentate gyrus of the hippocampus. In the present study, we demonstrate that group I mGluR-dependent LTD evoked by synaptic stimulation is inhibited by prior physiological activation of mGluR. Rat hippocampal slices were prepared humanely according to local guidelines using standard methods. A stimulation protocol consisting of pairing of a brief high-frequency stimulation (HFS) with mild depolarisation under conditions of NMDAR blockade with AP5 induced a group I mGluR-dependent LTD of 38 ± 15 % (S.E.M., n = 9) of excitatory postsynaptic currents (EPSCs) in the medial perforant path of the dentate gyrus. However, following HFS-induced LTP, group I mGluR-dependent depotentiation (DP) was not induced by the pairing stimulation protocol. Thus following LTP induction of field EPSPs (152 ± 15 %, n = 6), the pairing protocol given in the presence of AP5 failed to induce DP of patch-clamp recorded EPSCs, which measured 102 ± 5 % (n = 6) at 25 min post-pairing. The involvement of activation of NMDAR and mGluR in the preconditioning HFS block of the pairing-induced DP were investigated by applying the antagonists AP5 or MCPG, respectively, during the preconditioning HFS. D-AP5, applied during the preconditioning HFS, inhibited the induction of LTP but did not reverse the block of the pairing-induced LTD (98 ± 9 %, n = 5), i.e. no pairing-induced LTD was observed from the baseline level following preconditioning HFS in AP5. In contrast, the mGluR antagonist MCPG reversed the preconditioning HFS block of HFS-induced DP. Thus mGluR-dependent DP of 21 ± 7 % (n = 5) was induced by the pairing protocol following the prior preconditioning HFS given in the presence of MCPG (which did not inhibit induction of HFS-induced LTP, 149 ± 15 %, n = 5). The induction of the group I mGluR-dependent LTD was also inhibited (107 ± 6 %, n = 5) by a series of depolarising steps from -70 to 0 mV preceding the pairing stimulation protocol, implying a role for Ca²⁺ influx in the block of the LTD induction by the preconditioning stimulation. We suggest that activation of group I mGluR during the preconditioning HFS results in desensitisation of the group I mGluR and thereby prevents their activation by the subsequent pairing stimulation protocol.