Modulation of [3H]Diazepam Binding in Rat Cortical Membranes by GABAA Agonists

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Abstract
GABAA receptor agonists modulate [3H]diazepam binding in rat cortical membranes with different efficacies. At 23.degree. C, the relative potencies for enhancement of [3H]diazepam binding by agonists parallel their potencies in inhibiting [3H]GABA binding. The agonist concentrations needed for enhancement of [3H]diazepam binding are up to 35 times higher than for [3H]GABA binding and correspond closely to the concentrations required for displacement of [3H] bicucullin methochloride (BMC) binding. The maximum enhancement of [3H]diazepam varied among agonists: muscimol = GABA > isoguvacine > 3-aminopropane sulfonic acid (3APS) = imidazoleacetic acid (IAA) > 4,5,6,7-tetrahydroisoxazolo[5-4-c]-pyridin-3-ol (THIP) = taurine > piperidine-4-sulfonic acid (P4S). At 37.degree. C, the potencies of agonists remained unchanged, but isoguvacine, 3 APS and THIP acquired efficacies similar to GABA, whereas IAA, taurine and P4S maintained their partial agonist profiles. At both temperatures the agonist-induced enhancement of [3H]diazepam binding was reversible by bicuculline methobromide and by the steroid GABA antagonist RU 5135 [3.alpha.-hydroxy-16-imino-5.beta.-17-azaandrostan-11-one]. The importance of studying receptor-receptor interaction under near-physiological conditions is stressed and an in vitro assay that may predict the agonist status of putative GABAA receptor ligands is described.