title: RO15-4513 but not FG-7142 reverses anticonvulsant effects of ethanol against bicuculline- and picrotoxin-induced convulsions in rats.
abstract: The reversal of anticonvulsant effect of ethanol against chemoconvulsions by RO15-4513 was investigated in rats as this novel imidazobenzodiazepine (ethyl-8 azido-5, 6-dihydro-5-methyl-6-Oxo-4H-imidazo [1,5a] [1,4] benzodiazepine-3-carboxylate) is reported to antagonize the acute behavioral and biochemical effects of ethanol in animals. Reversal of ethanol effects on onset of myoclonic jerks, tonic extensor phase, mortality time and percent protection against mortality were compared with not only other anticonvulsant pentobarbital but also with another inverse agonist FG-7142. Pretreatment with RO15-4513 (4 mg/kg) reversed the protective effect of ethanol against bicuculline-induced tonic extensor phase and mortality (87%). This response was sensitive to reversal by RO15-1788 (10 mg/kg). However, onset of myoclonic jerks and duration of clonus were not significantly altered. It also reversed the effect against picrotoxin but the reversal against mortality was up to 50%. As compared to ethanol, RO15-4513 reversed partially the protective effect of pentobarbital against bicuculline- and picrotoxin-induced convulsions. FG-7142 failed to reverse the protective effect of ethanol and pentobarbital against bicuculline-induced tonic extensor phase although it reversed the effect against onset and mortality. It had no effect on the protective effect against picrotoxin-induced convulsions. Both RO15-4513 and FG-7142 possessed proconvulsant effects against bicuculline but not against picrotoxin. These observations suggest that RO15-4513 has a more preferential action against ethanol effects as compared to the other inverse agonist.
authors.affiliation: University of Texas Health Science Center, Department of Pharmacology, San Antonio 78284-7764.
authors.forename: S K
authors.initials: SK
authors.lastname: Kulkarni
authors.forename: M K
authors.initials: MK
authors.lastname: Ticku
mesh_terms: D000345:Affinity Labels / Q000494:pharmacology*; D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D001386:Azides / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D001640:Bicuculline / Q000633:toxicity; D002243:Carbolines / Q000494:pharmacology*; D000431:Ethanol / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D008297:Male; D010424:Pentobarbital / Q000627:therapeutic use; D010852:Picrotoxin / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced
chemical_list: D000345:Affinity Labels; D001067:Appetite Depressants; D001386:Azides; D001569:Benzodiazepines; D001640:Bicuculline; D002243:Carbolines; D000431:Ethanol; D010424:Pentobarbital; D010852:Picrotoxin; C035874:FG 7142; C042957:Ro 15-4513