title: Quantitative evaluation of the potencies of GABA-receptor agonists and antagonists using the rat hippocampal slice preparation.
abstract: 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. Apart from GABA itself, GABA A-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. 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 X 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. 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. 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 GABAAreceptor antagonists and were presumed to be mediated by actions at GABA5-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 CAI 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.
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007539:Isonicotinic Acids / Q000494:pharmacology; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D007539:Isonicotinic Acids; D011963:Receptors, GABA-A; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; C015300:isoguvacine