Comparison of antagonist potencies at pre- and post-synaptic GABA(B) receptors at inhibitory synapses in the CA1 region of the rat hippocampus

1 Synaptic activation of gamma-aminobutyric acid (GABA), receptors at GABA synapses causes (a) postsynaptic hyperpolarization mediating a slow inhibit ory 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 effec ts are mediated by pharmacologically identical receptors the effects of six GABA(B) receptor antagonists of widely ranging potencies were tested again st each response. 2 Monosynaptic IPSP(B)s were recorded in the presence of GABA(A), AMPA/kain ate and NMDA receptor antagonists. All GABA(B) receptor antagonists tested depressed the IPSPB with an IC50 based rank order of potency of CGP55679 gr eater than or equal to CGP56433 = CGP55845A = CGP52432 > CGPS1176 > CGP3674 2. 3 Paired-pulse EPSP widening was recorded as an index of paired-pulse depre ssion of GABA-mediated IPSP/Cs. A similar rank order of potency of antagoni sm of paired-pulse widening was observed to that for IPSPB inhibition. 4 Comparison of the IC50 values for IPSPB inhibition and paired-pulse EPSP widening revealed a close correlation between the two effects in that their IC(50)s lay within the 95% confidence limits of a correlation line that de scribed IC50 values for inhibition of paired-pulse EPSP widening that were 7.3 times higher than those for IPSPB inhibition. 5 Using the compounds tested here it is not possible to assign different su btypes of GABA(B) receptor to pre- and post-synaptic loci at GABAergic syna pses. However, 5-10 fold higher concentrations of antagonist are required t o block presynaptic as opposed to postsynaptic receptors when these are act ivated by synaptically released GABA.