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

1 GABA(A) receptor agonists have previously been characterized at human GABA(A) 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 alpha(1)beta(3)gamma(2s), containing receptors expressed in Xenopus oocytes, whereas the antagonist was equipotent under these two conditions. 4 Partial agonists with responses above 6% at alpha(1)beta(3)gamma(2s) 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 GABA(A) receptors in the rat cortical wedge needs to be activated by GABA(A) agonists in order to obtain a maximum response. Results therefore indicate a significant contribution of extrasynaptic receptors to pharmacological activity of exogenous applied GABA(A) agonists in this system.