The effect of metabotropic glutamate receptor (mGluR) activation on inhibitory synaptic transmission was examined by using whole cell patch- clamp recordings. Spontaneous (s) and miniature (m) inhibitory postsynaptic currents (IPSCs) were recorded from visually identified layer II/III pyramidal neurons in rat neocortex in vitro. Excitatory postsynaptic currents (EPSCs) were blocked by using bath application of 20 μM D(-) 2-amino-5- phosphonovaleric acid and 10 μM 6-cyano-7-nitroquinoxaline-2,3-dione. In the presence of 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (30-100 μM), L- quisqualate (5 μM), and the group I selective mGluR agonist (S)-3,5- dihydroxyphenylglycine (100 μM), the frequency of sIPSCs was increased. Decay kinetics of sIPSCs were unaffected. No enhancement of mIPSCs was observed. Bath application of group II (2S,3S,4S-α-carboxycyclopropyl- glycine; 5 μM) and group III selective mGluR agonists (L-2-amino-4- phosphonobutyric acid; 100 μM) had no detectable effects on the frequency or amplitude of sIPSCs. These findings indicate that activation of group I mGluRs (mGluR1 and/or mGluR5) enhances γ-aminobutyric acid-mediated synaptic inhibition in layer II/III pyramidal neurons in neocortex. The lack of effect on mIPSCs suggests a presynaptic action via excitation of inhibitory interneurons.