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Bidirectional effects of benzodiazepine binding site ligands in the passive avoidance task: differential antagonism by flumazenil and beta-CCt.
Behav Brain Res. 2005 Mar 30; 158(2):293-300.BB

Abstract

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).

Authors+Show Affiliations

Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia and Montenegro. miroslav@pharmacy.bg.ac.yuNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15698896

Citation

Savić, Miroslav M., et al. "Bidirectional Effects of Benzodiazepine Binding Site Ligands in the Passive Avoidance Task: Differential Antagonism By Flumazenil and Beta-CCt." Behavioural Brain Research, vol. 158, no. 2, 2005, pp. 293-300.
Savić MM, Obradović DI, Ugresić ND, et al. Bidirectional effects of benzodiazepine binding site ligands in the passive avoidance task: differential antagonism by flumazenil and beta-CCt. Behav Brain Res. 2005;158(2):293-300.
Savić, M. M., Obradović, D. I., Ugresić, N. D., Cook, J. M., Yin, W., & Bokonjić, D. R. (2005). Bidirectional effects of benzodiazepine binding site ligands in the passive avoidance task: differential antagonism by flumazenil and beta-CCt. Behavioural Brain Research, 158(2), 293-300.
Savić MM, et al. Bidirectional Effects of Benzodiazepine Binding Site Ligands in the Passive Avoidance Task: Differential Antagonism By Flumazenil and Beta-CCt. Behav Brain Res. 2005 Mar 30;158(2):293-300. PubMed PMID: 15698896.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Bidirectional effects of benzodiazepine binding site ligands in the passive avoidance task: differential antagonism by flumazenil and beta-CCt. AU - Savić,Miroslav M, AU - Obradović,Dragan I, AU - Ugresić,Nenad D, AU - Cook,James M, AU - Yin,Wenyuan, AU - Bokonjić,Dubravko R, PY - 2004/08/19/received PY - 2004/09/08/accepted PY - 2005/2/9/pubmed PY - 2005/4/20/medline PY - 2005/2/9/entrez SP - 293 EP - 300 JF - Behavioural brain research JO - Behav Brain Res VL - 158 IS - 2 N2 - 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). SN - 0166-4328 UR - https://www.unboundmedicine.com/medline/citation/15698896/Bidirectional_effects_of_benzodiazepine_binding_site_ligands_in_the_passive_avoidance_task:_differential_antagonism_by_flumazenil_and_beta_CCt_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0166-4328(04)00370-5 DB - PRIME DP - Unbound Medicine ER -