Synaptic activation of gamma-aminobutyric acid (GABA)B receptors at GABA synapses causes (a) postsynaptic hyperpolarization mediating a slow inhibitory postsynaptic potential/current (IPSP/C) and (b) presynaptic inhibition of GABA release which depresses IPSPs and leads to paired-pulse widening of excitatory postsynaptic potentials (EPSPs). To address whether these effects are mediated by pharmacologically identical receptors the effects of six GABA(B) receptor antagonists of widely ranging potencies were tested against each response. Monosynaptic IPSP(B)s were recorded in the presence of GABA(A), AMPA/kainate and NMDA receptor antagonists. All GABA(B) receptor antagonists tested depressed the IPSP(B) with an IC50 based rank order of potency of CGP55679> or =CGP56433 = CGP55845A = CGP52432>CGP51176>CGP36742. Paired-pulse EPSP widening was recorded as an index of paired-pulse depression of GABA-mediated IPSP/Cs. A similar rank order of potency of antagonism of paired-pulse widening was observed to that for IPSP(B) inhibition. Comparison of the IC50 values for IPSP(B) inhibition and paired-pulse EPSP widening revealed a close correlation between the two effects in that their IC50s lay within the 95% confidence limits of a correlation line that described IC50 values for inhibition of paired-pulse EPSP widening that were 7.3 times higher than those for IPSP(B) inhibition. Using the compounds tested here it is not possible to assign different subtypes of GABA(B) receptor to pre- and post-synaptic loci at GABAergic synapses. However, 5-10 fold higher concentrations of antagonist are required to block presynaptic as opposed to postsynaptic receptors when these are activated by synaptically released GABA.