Amoxapine inhibition of GABA-stimulated chloride conductance: investigations of potential sites of activity.
Amoxapine inhibits GABA-stimulated chloride conductance by acting on the GABAA-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 pA2 value of 5.52 with a slope of 0.79. Amoxapine inhibits the binding of the GABAA receptor selective antagonist [3H]SR 95531 with an IC50 value of 3.45 microM and a pseudo Hill coefficient of 0.83. In contrast, 10 microM 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 GABAA 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.
Ikeda
M
M
Department of Pharmacology, University of Arizona, Tucson 85724.
Knapp
R J
RJ
Malatynska
E
E
Yamamura
H I
HI
D000657:Amoxapine / Q000494:pharmacology*; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism*; D003989:Dibenzoxazepines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil / Q000494:pharmacology; D005445:Flunitrazepam / Q000378:metabolism; D018756:GABA Antagonists; D008024:Ligands; D008297:Male; D011724:Pyridazines / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism
D002712:Chlorides; D003989:Dibenzoxazepines; D018756:GABA Antagonists; D008024:Ligands; D011724:Pyridazines; D011963:Receptors, GABA-A; D005442:Flumazenil; D005445:Flunitrazepam; C049853:gabazine; D000657:Amoxapine