The functional roles played by metabotropic glutamate receptors in the neostriatum is just beginning to be examined. One possibility, raised by previous studies, is that metabotropic glutamate receptors act to modulate responses mediated by ionotropic glutamate receptors. In the present study, we examined this possibility in a neostriatal brain slice preparation using intracellular recording and iontophoretic techniques. We found that the iontophoretic application of the metabotropic glutamate receptor agonist 1-amino-cyclopentane-1,3-dicarboxylic acid markedly attenuated both the amplitude and duration of excitatory responses induced by the iontophoretic application of N-methyl-D-aspartate. These inhibitory effects were stereo-selective and relatively long-lasting. The metabotropic glutamate receptor antagonist 2-amino-3-phosphonopropionic acid applied either iontophoretically or in the bath prevented the inhibitory effects of 1-amino-cyclopentane-1,3-dicarboxylic acid. The inhibitory action of 1-amino-cyclopentane-1,3-dicarboxylic acid was specific to N-methyl-D-aspartate, as 1-amino-cyclopentane-1,3-dicarboxylic acid had no consistent action on the responses evoked by the iontophoretic application of glutamate, amino-3-hydroxy-5-methyl-4-isoazolepropionic acid or quisqualate. Bath application of 1-amino-cyclopentane-1,3-dicarboxylic acid inhibited the evoked depolarizing postsynaptic potentials recorded in neostriatal cells. Thus, activation of metabotropic glutamate receptors may play an important role in modulating N-methyl-D-aspartate receptor function in neostriatal neurons.