We have analyzed the effects of agonists acting at different classes of metabotropic glutamate receptors (mGluRs) on paired pulse depression (PPD) at the medial perforant path/granule cell synapse. Drugs were bath applied and paired pulses delivered at 3-min intervals during control and during drug application. Both 1S,3R-1-aminocyclopentane- 1,3-dicarboxylic acid (1S,3R-ACPD, 100 microM), which acts at class I (mGluR1, 5) and class II (mGluR2, 3) mGluRs and L-2-amino-4-phosphobutyric acid (L-AP4, 100 microM) which is specific for class III (mGluR4, 6-8) mGluRs, strongly reduced PPD with an interstimulus interval (ISI) of 40 ms (P < 0.001). The class I specific agonists trans-azetidine-2,4,dicarboxylic acid (t-ADA, 100 microM) and 3,5,dihydroxyphenylglycine (DHPG, 100 microM) did not affect PPD. The relatively specific class II agonists S-3-carboxy-4-hydroxyphenylglycine (3C4HPG) and 2S,3S,4S-alpha- carboxycyclopropyl-glycine (L-CCG-I) did reduce PPD, but only at very high concentrations (500 and 40 microM respectively) with respect to their EC50 values. These results suggest that two types of mGluRs control PPD at this synapse--a class III mGluR and a class II-like mGluR, which may not correspond to one of the currently cloned receptors.