Functional modulation of gamma-aminobutyric acid(A) receptors by etifoxine and allopregnanolone in rodents.
We looked for an interaction between etifoxine and the neurosteroid allopregnanolone at central gamma-aminobutyric acid (GABA(A)) receptors. Etifoxine (2 microM) did not affect the affinity of allopregnanolone (IC(50)=108 nM) for its site in preparations of Sprague-Dawley rat cerebral cortex membranes, as determined by the inhibition of [(35)S] t-butylbicyclophosphorothionate binding, a specific ligand of the GABA(A) receptor chloride channel site. Etifoxine and allopregnanolone were anticonvulsants, blocking the clonic convulsions induced by bicuculline (an antagonist of the GABA(A) receptor) in CD1 mice. A combination of subactive doses of the two compounds showed additive anticonvulsant effects. These results suggest that etifoxine and allopregnanolone bind to distinct putative recognition sites at or near the chloride channel site. Functionally, their binding may have an additive effect by enhancing GABA(A) inhibitory transmission.
Verleye
M
M
Département de Pharmacologie, Laboratoires Biocodex, Zac de Mercières, Chemin d'Armancourt, 60200, Compiègne, France. m.verleye@biocodex.fr
Schlichter
R
R
Neliat
G
G
Pansart
Y
Y
Gillardin
J M
JM
D000495:Allosteric Site / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001640:Bicuculline / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism / Q000494:pharmacology; D018118:Chloride Channels / Q000737:chemistry / Q000378:metabolism; D003292:Convulsants / Q000378:metabolism / Q000494:pharmacology; D004347:Drug Interactions; D018756:GABA Antagonists / Q000494:pharmacology; D008297:Male; D010078:Oxazines / Q000494:pharmacology*; D011280:Pregnanolone / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000737:chemistry / Q000378:metabolism*; D013462:Sulfur Radioisotopes
D000927:Anticonvulsants; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018118:Chloride Channels; D003292:Convulsants; D018756:GABA Antagonists; D010078:Oxazines; D011963:Receptors, GABA-A; D013462:Sulfur Radioisotopes; C037476:tert-butylbicyclophosphorothionate; D011280:Pregnanolone; C002125:etifoxine; D001640:Bicuculline