Amoxapine inhibition of GABA-stimulated chloride conductance: investigations of potential sites of activity

Amoxapine inhibits GABA-stimulated chloride conductance by acting on the GABA A-receptor chloride-ionophore complex which can be studied using membrane vesicles prepared from rat cerebral cortex. Amoxapine produces a right shift in the GABA concentration-response curve for the stimulation of 36Cl − uptake into these vesicles with no apparent change in the maximum response. Schild analysis of these data gave a pA 2 value of 5.52 with a slope of 0.79. Amoxapine inhibits the binding of the GABA A receptor selective antagonist [ 3H]SR 95531 with an IC 50 value of 3.45 μM and a pseudo Hill coefficient of 0.83. In contrast, 10 μM amoxapine inhibits [ 3H] flunitrazepam binding by less than 25% while the benzodiazepine antagonist Ro 15–1788 reduces the amoxapine inhibition of GABA-stimulated chloride conductance only at high concentrations. These data suggest that amoxapine does not inhibit chloride conductance by acting as a benzodiazepine inverse agonist and either acts directly on the GABA A receptor as an antagonist or blocks GABA activity at a site closely coupled to it. The ability of amoxapine to inhibit GABA-stimulated chloride conductance is a likely explanation for its proconvulsant activity observed at high doses.