Characterization of GABA(A) 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.
Department of Molecular Pharmacology, H. Lundbeck A/S, Ottiliavej 9, DK 2500 Valby, Denmark. Bjeb@lundbeck.com
B
B
Ebert
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S
i Storustovu
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M
Mortensen
B
B
Frølund
D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D018755:GABA Agonists / Q000737:chemistry / Q000494:pharmacology*; D018756:GABA Antagonists / Q000737:chemistry / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D021122:Protein Subunits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D013329:Structure-Activity Relationship; D013569:Synapses / Q000378:metabolism*
D018755:GABA Agonists; D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D007555:Isoxazoles; D021122:Protein Subunits; D011963:Receptors, GABA-A; C015542:gaboxadol