Characterization of GABAA receptor ligands in the rat cortical wedge preparation: Evidence for action at extrasynaptic receptors?

Abstract

1. GABAA receptor agonists have previously been characterized at human GABAA receptors expressed in Xenopus oocytes. The correlation between these data and functional in vivo data of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) has shown that THIP is 100 fold more potent in clinical studies than in oocytes. 2. THIP and a series of agonists (GABA, Isoguvacine), partial agonists (Imidazole acetic acid; P4S, 4-PIOL, thio-4-PIOL) and one antagonist (SR95531) were characterized in the rat cortical wedge preparation using inhibition of spontaneous activity in Mg++ free medium as the measurable parameter. 3. Agonists were in general 40 times more potent in the wedge preparation than at α1β3γ2s containing receptors expressed in Xenopus oocytes, whereas the antagonist was equipotent under these two conditions. 4. Partial agonists with responses above 6% at α1β3γ2s containing receptors were full agonists in the rat cortical wedge preparation, whereas partial agonists with maximum responses below 6% behaved as partial agonists in the rat cortical wedge preparation. 5. These data suggest that only a small fraction of the GABAA receptors in the rat cortical wedge needs to be activated by GABAA agonists in order to obtain a maximum response. Results therefore indicate a significant contribution of extrasynaptic receptors to pharmacological activity of exogenous applied GABAA agonists in this system.