Neocortical synapses display several forms of short-term plasticity including paired-pulse facilitation and depression. The mechanisms underlying this diversity are unclear. Synaptic currents in response to paired stimulation were recorded from layer II/III pyramidal neurons in rat frontal neocortical slices using the whole-cell patch-clamp method. Both paired-pulse facilitation (PPF) and paired-pulse depression (PPD) were observed in control saline. In the presence of 10 μM bicuculline (BIC), prominent PPD was consistently elicited. The maximal depression of the second EPSC occurred around 100 ms although PPD was still observed at intervals up to 1500 ms. Manipulations that reduced the probability of transmitter release significantly affected PPD. Both conditioning (C)- and test (T)-EPSCs were reduced when the extracellular Ca2+ concentration was lowered from 3 to 1 mM. The decrease was greater in the C-EPSC resulting in a decrease in PPD. The γ-aminobutyric acid (GABA)B receptor agonist baclofen (10 μM) reduced the amplitude of both evoked EPSCs and changed PPD to PPF. In the presence of the GABAB antagonists 2(OH)-saclofen (200-400 μM) or SCH50911 (10 μM), PPF was commonly observed. The metabotropic glutamate receptor antagonist MCPG (500 μM) had no effect on neocortical PPD. Brief stimulus trains induced a progressive depression that was insensitive to GABAB antagonists. Paired-pulse depression of excitatory synaptic transmission is a prominent phenomenon in frontal neocortex. At least two components of depression were observed. They may play an important role in regulating the balance between excitation and inhibition, therefore maintaining stability in cortical circuits. © 2002 Elsevier Science B.V. All rights reserved.