Quantitative evaluation of the potencies of GABA‐receptor agonists and antagonists using the rat hippocampal slice preparation

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Abstract
1 CA1 population spikes recorded in the rat hippocampal slice were used to assess quantitatively the potencies of GABA-receptor agonists and antagonists on mammalian CNS neurones. 2 Apart from GABA itself, GABAA-receptor agonists inhibited the CA1 population spikes with potencies that correlated closely (r = 0.96) with their ability to displace [3H]-GABA from GABAA-binding sites. 3 The low potency of GABA in this preparation was attributed to the action of uptake processes as the GABA uptake inhibitor, cis-4-hydroxynipecotic acid (2 × 10−4 m.), produced an approximate 6 fold increase in the potency of GABA whilst having no effect on the potency of 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridin-3-ol (THIP), a GABAA-receptor agonist which is not a substrate for the GABA uptake system. 4 The inhibitory effects of the selective GABAA-receptor agonists isoguvacine and muscimol were antagonized by bicuculline methochloride, which shifted the dose-response curves to the right in a parallel manner. The Schild plots for bicuculline methochloride against isoguvacine and muscimol had slopes of 1 and gave pA2 values of 6.24 and 6.10, respectively. Picrotoxin also antagonized the inhibitory effects of isoguvacine and produced parallel shifts to the right of the dose-response curve. However, the Schild plot for picrotoxin had a slope significantly less than unity (0.82) and gave a pA2 value of 6.89. 5 The novel GABAA-receptor antagonist, pitrazepin, antagonized the inhibitory effects of isoguvacine in an apparently competitive manner. The Schild plot had a slope of 1 and gave a pA2 of 6.69. 6 The inhibitory effects of baclofen, GABA and kojic amine were not antagonized by GABAA-receptor antagonists and were presumed to be mediated by actions at GABAB-receptors. 7 The inhibitory effects of THIP and isoguvacine were antagonized with the same potency by bicuculline methobromide. These results do not support the suggestion that THIP acts preferentially at a ‘synaptic’ bicuculline-sensitive, GABA receptor. 8 It is concluded that the CA1 population spike in the rat hippocampal slice is a useful test system for the quantitative analysis of both GABAA- and GABAB-receptor agonists and antagonists.