Bidirectional effects of benzodiazepine binding site ligands in the passive avoidance task: differential antagonism by flumazenil and beta-CCt.
Recent research on genetically modified mice has attributed the amnesic effect of benzodiazepines mainly to the alpha1-containing GABA(A) receptor subtypes. The pharmacological approach, using subtype selective ligands, is needed to complement genetic studies. We tested the effects of the non-selective antagonist flumazenil (0-20.0 mg/kg), the preferential alpha1-subunit selective antagonist beta-carboline-3-carboxylate-t-butyl ester (beta-CCt) (0-30.0 mg/kg), the non-selective agonist midazolam (0-2.0 mg/kg), the preferential alpha1-subunit selective agonist zolpidem (0-3.0 mg/kg), and the non-selective inverse agonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) (0-2.0 mg/kg) in the one-trial step-through passive avoidance task in rats. The compounds were administered intraperitoneally, before the acquisition test. Flumazenil and beta-CCt did not affect retention performance. Midazolam and zolpidem induced amnesia in a dose-dependent manner. The complete reversal of amnesia was unattainable. The effects of zolpidem were significantly attenuated by the both, flumazenil (10.0 mg/kg) and beta-CCt (30.0 mg/kg); by contrast, only flumazenil was considerably effective when combined with midazolam. DMCM exerted promnesic effects at 0.2mg/kg, in an inverted U-shape manner. Both antagonists tended to abolish this action. The results indicate that some other alpha-subunit(s), in addition to the alpha1-subunit, contribute to the amnesic actions of non-selective benzodiazepine site agonists in the passive avoidance task. On the other hand, a significant part of the DMCM-induced promnesic effect could involve the alpha1-subunit and/or other putative beta-CCt-sensitive binding site(s).
Savić
Miroslav M
MM
Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia and Montenegro. miroslav@pharmacy.bg.ac.yu
Obradović
Dragan I
DI
Ugresić
Nenad D
ND
Cook
James M
JM
Yin
Wenyuan
W
Bokonjić
Dubravko R
DR
D000818:Animals; D001362:Avoidance Learning / Q000502:physiology*; D001665:Binding Sites / Q000187:drug effects; D002243:Carbolines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D005442:Flumazenil / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D008024:Ligands; D008297:Male; D008568:Memory / Q000187:drug effects; D008874:Midazolam / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects; D011963:Receptors, GABA-A / Q000187:drug effects
D002243:Carbolines; D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; D008024:Ligands; D018340:Receptors, Adrenergic, alpha-1; D011963:Receptors, GABA-A; D005442:Flumazenil; C043232:tert-butyl beta-carboline-3-carboxylate; D008874:Midazolam