1 Synaptic activation of g-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 e ects are mediated by pharmacologically identical receptors the e ects of six GABA B receptor antagonists of widely ranging potencies were tested against each response. 2 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 IC 50 based rank order of potency of CGP556795CGP56433=CGP55845A=CGP524324CGP511764 CGP36742. 3 Paired-pulse EPSP widening was recorded as an index of paired-pulse depression of GABAmediated IPSP/Cs. A similar rank order of potency of antagonism of paired-pulse widening was observed to that for IPSP B inhibition. 4 Comparison of the IC 50 values for IPSP B inhibition and paired-pulse EPSP widening revealed a close correlation between the two e ects in that their IC 50 s lay within the 95% con®dence limits of a correlation line that described IC 50 values for inhibition of paired-pulse EPSP widening that were 7.3 times higher than those for IPSP B inhibition. 5 Using the compounds tested here it is not possible to assign di erent 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.

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1 It is unclear whether GABA A receptor-mediated hyperpolarizing and depolarizing synaptic potentials (IPSP A s and DPSP A s, respectively) are evoked by (a) the same populations of GABAergic interneurones and (b) exhibit similar regulation by allosteric modulators of GABA A receptor function. We have attempted to address these questions by investigating the eects of (a) known agonists for presynaptic receptors on GABAergic terminals, and (b) a range of GABA A receptor ligands, on each response. 2 The GABA uptake inhibitor NNC 05-711 (10 mM) enhanced whereas bicuculline (10 mM) inhibited both IPSP A s and DPSP A s.-ol]-enkephalin (DAGO; 0.5 mM), and carbachol (10 mM) caused substantial depressions (up to 99%) of DPSP A s that were reversed by CGP 55845A (1 mM), naloxone (10 mM) and atropine (5 mM), respectively. In contrast, 2-chloroadenosine (CADO; 10 mM) only slightly depressed DPSP A s. Quantitatively, the eect of each agonist was similar to that reported for IPSP A s. 4 The neurosteroid ORG 21465 (1 ± 10 mM), the anaesthetic propofol (50 ± 500 mM), the barbiturate pentobarbitone (100 ± 300 mM) and zinc (50 mM) all enhanced DPSP A s and IPSP A s. 5 The benzodiazepine (BZ) agonist¯unitrazepam (10 ± 50 mM) and inverse agonist DMCM (1 mM) caused a respective enhancement and inhibition of both IPSP A s and DPSP A s. The BZo 1 site agonist zolpidem (10 ± 30 mM) produced similar eects to¯unitrazepam. 6 The anticonvulsant loreclezole (1 ± 100 mM) did not aect either response. 7 These data demonstrate that similar populations of inhibitory interneurones can generate both IPSP A s and DPSP A s by activating GABA A receptors that are subject to similar allosteric modulation.

1 The monosynaptic reflex (MSR), recorded in vitro from the neonatal rat spinal cord, was depressed by 5-hydroxytryptamine (5-HT), 5-carboxamidotryptamine (5-CT), methysergide and R( + )-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), and also by the selective 5-HTlD agonists, sumatriptan and N-methyl-3-(1-methyl-1-piperidinyl)-1H-indole-5-ethane sulphonamide (GR 85548).2 Ketanserin (1 gM) and methiothepin (1 gM) reduced the duration of depressions elicited by 5-CT, but not those produced by 5-HT, sumatriptan, GR 85548, methysergide or 8-OH-DPAT.3 The IC50 for MSR depression by 5-CT was 3.6, 2.1 -6.2nM (n=4), by sumatriptan was 15.2, 12.9-18.0nM (n=32), by GR 85548 was 18.4, 11.7-29.1 nM (n =12), by methysergide was 29.8, 10.2-87.1nM (n=4) and by 8-OH-DPAT was 0.21, 0.11-0.43 MM (n=3) (geometric means and 95% confidence limits). 4 Ketanserin (0.1 or 1 UM) antagonized competitively responses to sumatriptan (apparent pA2 7.8 ± 0.1, n = 5), GR 85548 (apparent pA2 7.6, unpaired data, n = 5), methysergide (apparent pA2 7.9 ± 0.12, n=4) and 8-OH-DPAT (apparent pA2 8.3 ± 0.1, n= 3). Concentration-response curves to 5-CT showed a smaller, parallel shift to the right (apparent pA2 6.8 ± 0.1, n = 4), but responses to 5-HT were unaffected by ketanserin (1 gM) (n = 4). Neither with these concentrations nor with concentrations in the range 1-3 nm was there any unequivocal blockade of responses to sumatriptan. 9 It is concluded that sumatriptan, GR 85548, methysergide and 8-OH-DPAT depress the MSR in the neonate rat spinal cord via ketanserin-sensitive receptors, which have some similarities to 5-HTLIT1 receptors but which are not blocked by GR 127935. 5-HT released by tryptaminergic pathways may act via the same receptors to depress the MSR. 5-HT applied to the cord probably acts via a different, possibly novel 5-HT receptor to depress the MSR.