Interactions between metabotropic glutamate and N-methyl-D-aspartate (NMDA) receptor-mediated responses were investigated in hippocampal CA3 cells using the single electrode voltage-clamp method. Bath application (2.5-10 microM, 30 s) or iontophoresis of 1-amino-cyclopentyl-trans-1S,3R-dicarboxylate (ACPD), a selective agonist for metabotropic glutamate receptors, resulted in an inward current associated with a decrease in membrane conductance. Following transient bath application of NMDA (5-10 microM, 30-60 s), the ACPD-induced inward current was potentiated for a period of up to 25 min (by 61 +/- 8% with bath application, by 32 +/- 15% with iontophoresis). Transient application of NMDA did not result in a potentiation of ionotropic RS-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or metabotropic muscarinic responses. ACPD responses were not potentiated following transient AMPA application. Intracellular buffering of calcium with tetrapotassium bis(O-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid (BAPTA) prevented potentiation by NMDA in all cells. Bath application of arachidonic acid did not mimic the NMDA-induced potentiation. These results demonstrate that activation of NMDA receptors can specifically induce a long-lasting potentiation of a metabotropic glutamatergic response in hippocampal CA3 pyramidal cells. The characterization of this interaction may contribute to the elucidation of the physiological significance of metabotropic glutamate receptors.