Do antiepileptics phenytoin, carbamazepine, and loreclezole show GABA(A) receptor subtype selectivity in rat brain sections?
[35S]t-Butylbicyclophosphorothionate ([35S]TBPS), a convulsant site ligand of GABA(A) receptors, was used in autoradiography with rat brain sections to test suggested receptor subtype-selective actions of antiepileptics phenytoin, carbamazepine and loreclezole on native GABA(A) receptors. At maximal 100 microM concentration, both phenytoin and carbamazepine decreased [35S]TBPS binding only by 20%, indicating that their low potency and efficacy prevents their use as alpha1 subunit-identifying compounds. Ten microM loreclezole did not affect the binding, but a further increase in loreclezole concentration strongly decreased it. The action of loreclezole, assumed to reflect beta2/3 subunit-containing receptors, varied from brain region to region, but the effects were unrelated to the regional expression profiles of beta subunit variants. We conclude that in autoradiographic [35S]TBPS binding assay neither carbamazepine, phenytoin nor loreclezole are useful tools in characterizing brain regional heterogeneity of GABA(A) receptors in rats and that only loreclezole exhibits high, pharmacologically relevant efficacy.
Holopainen
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IE
Department of Pharmacology and Clinical Pharmacology, University of Turku, Finland. irma.holopainen@utu.fi
Kivelä
R
R
Korpi
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ER
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001345:Autoradiography; D001921:Brain / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000037:antagonists & inhibitors / Q000378:metabolism; D002220:Carbamazepine / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D010672:Phenytoin / Q000494:pharmacology*; D020033:Protein Isoforms / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*
D000927:Anticonvulsants; D019086:Bridged Bicyclo Compounds, Heterocyclic; D020033:Protein Isoforms; D011963:Receptors, GABA-A; D014230:Triazoles; D002220:Carbamazepine; D010672:Phenytoin; C066440:loreclezole; C037476:tert-butylbicyclophosphorothionate