Dual intracellular recordings in slices of adult rat neocortex and hippocampus investigated slow, putative GABA(B) receptor-mediated inhibitory postsynaptic potentials. In most pairs tested in which the interneuron elicited a fast inhibitory postsynaptic potential in the pyramid, this GABA(A) receptor mediated inhibitory postsynaptic potential was entirely blocked by bicuculline or picrotoxin (3:3 in neocortex, 6:8 in CA1, all CA1 basket cells), even when high-frequency presynaptic spike trains were elicited. However, in three of 85 neocortical paired recordings involving an interneuron, although no discernible response was elicited by single presynaptic interneuronal spikes, a long latency (> or =20 ms) inhibitory postsynaptic potential was elicited by a train of > or =3 spikes at frequencies > or =50-100 Hz. This slow inhibitory postsynaptic potential was insensitive to bicuculline (one pair tested). In neocortex, slow inhibitory postsynaptic potential duration reached a maximum of 200 ms even with prolonged presynaptic spike trains. In contrast, summing fast, GABA(A) inhibitory postsynaptic potentials, elicited by spike trains, lasted as long as the train. Between four and 10 presynaptic spikes, mean peak slow inhibitory postsynaptic potential amplitude increased sharply to 0.38, 2.6 and 2.9 mV, respectively, in the three neocortical pairs (membrane potential -60 to -65 mV). Thereafter increases in spike number had little additional effect on amplitude. In two of eight pairs in CA1, one involving a presynaptic basket cell and the other a putative bistratified interneuron, the fast inhibitory postsynaptic potential was blocked by bicuculline revealing a slow inhibitory postsynaptic potential that was greatly reduced by 100 microM CGP 35348 (basket cell pair). The sensitivity of this slow inhibitory postsynaptic potential to spike number was similar to that of neocortical 'pure' slow inhibitory postsynaptic potentials, but was of longer duration, its plateau phase outlasting 200 ms spike trains and its maximum duration exceeding 400 ms. Computational models of GABA release, diffusion and uptake suggested that extracellular accumulation of GABA cannot alone account for the non-linear relationship between spike number and inhibitory postsynaptic potential amplitude. However, cooperativity in the kinetics of GABA(B) transduction mechanisms provided non-linear relations similar to experimental data. Different kinetic models were considered for how G-proteins activate K+ channels, including allosteric models. For all models, the best fit to experimental data was obtained with four G-protein binding sites on the K+ channels, consistent with a tetrameric structure for the K+ channels associated with GABA(B) receptors. Thus some inhibitory connections in neocortex and hippocampus appear mediated solely by fast GABA(A) receptors, while others appear mediated solely by slow, non-ionotropic, possibly GABA(B) receptors. In addition, some inhibitory postsynaptic potentials arising in proximal portions of CA1 pyramidal cells are mediated by both GABA(A) and GABA(B) receptors. Our data indicate that the GABA released by a single interneuron can saturate the GABA(B) receptor mechanism(s) accessible to it and that 'spillover' to extrasynaptic sites need not necessarily be proposed to explain these slow inhibitory postsynaptic potential properties.