Excitatory postsynaptic currents (EPSCs) were induced in layer II-V pyramidal cells in the frontal cortex of the young rat (postnatal day 14–21) by stimulation of layers II/III in the presence of bicuculline using the whole-cell patch-clamp technique. EPSCs usually consisted of fast and slow components that were sensitive to CNQX and APV, respectively. In response to paired stimuli of identical strength, paired pulse depression (PPD) was seen for these EPSCs. The PPD of fast EPSCs was most pronounced at an interstimulus interval (ISI) of 200–300 msec and ceased to occur at ISIs greater than 3–5 sec, while the PPD of slow EPSCs became most pronounced at an ISI of 500–1000 msec and ceased to occur at ISIs greater than 10 sec. The PPD of fast EPSCs was attenuated by (-)-baclofen (1–5 microM) and removed by 2-hydroxy- saclofen (0.2–0.4 mM). By contrast, the PPD of slow EPSCs consisted of early and late components that were attenuated by (-)-baclofen and muscarine (1–5 microM), respectively. The late PPD of slow EPSCs induced in the presence of baclofen was removed by pirenzepine (1–3 microM). Thus, fast and slow components of glutamatergic EPSCs displayed two distinct PPDs. These results suggest that a part of the glutamatergic afferents likely arising from layer II/III pyramidal cells may terminate predominantly on NMDA receptors in pyramidal cells of the frontal cortex and receive distinct presynaptic inhibition through at least the muscarinic receptors.