The involvement of group I metabotropic glutamate receptors (mGluRs) and ryanodine receptors was investigated in the induction of LTP induced either by application of one standard high frequency stimulation (HFS) or by strong multiple HFS in the medial perforant path to granule cell synapse of the rat dentate gyrus. Whilst a standard brief HFS induced LTP close to 50%, strong stimulation consisting of multiple HFS induced a much larger LTP. mGluR5 was found to be partially involved in the induction of the enhanced LTP induced by the strong HFS but not in the standard LTP induced by the brief HFS. Thus the mGluR5 antagonists LY341495 and MPEP partially inhibited the induction of LTP induced by strong HFS but did not inhibit LTP induced by a standard HFS. Ryanodine was found to partially inhibit LTP induced by the strong HFS but not to inhibit the standard LTP induced by the brief HFS, demonstrating the involvement of Ca-induced Ca release from ryanodine-sensitive Ca stores in the former. These studies demonstrate that the large amplitude LTP induced by strong stimulation involves additional mechanisms to the LTP induced by brief HFS, in particular involving activation of mGluR5 and RyR-sensitive Ca stores.