Bidirectional effects of benzodiazepine binding site ligands in the passive avoidance task: differential antagonism by flumazenil and β-CCt

• Published in: Behavioural brain research Vol. 158; no. 2; pp. 293 - 300
• Main Authors: Savić, Miroslav M., Obradović, Dragan I., Ugrešić, Nenad D., Cook, James M., Yin, Wenyuan, Bokonjić, Dubravko R.
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier B.V 30.03.2005; Elsevier Science
• Subjects: Animal; Animals; Avoidance Learning - physiology; Binding Sites - drug effects; Biological and medical sciences; Carbolines - pharmacology; DMCM; Dose-Response Relationship, Drug; Electroshock; Flumazenil; Flumazenil - pharmacology; Fundamental and applied biological sciences. Psychology; GABA A1 receptor; GABA Modulators - pharmacology; GABA-A Receptor Agonists; Learning. Memory; Ligands; Male; Memory; Memory - drug effects; Midazolam; Midazolam - pharmacology; Passive avoidance; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Rat; Rats; Rats, Wistar; Receptors, Adrenergic, alpha-1 - drug effects; Receptors, GABA-A - drug effects; Zolpidem; β-CCt; β-CCt; Flumazenil; DMCM; Rat; Memory; Passive avoidance; Zolpidem; GABA A1 receptor; Midazolam; Ligand binding; Agonist; Gabaergic agonist; Rodentia; Hypnotic; Benzodiazepine receptor; Binding site; Dose activity relation; Vertebrata; Mammalia; Carboline derivatives; Benzodiazepine antagonist; Animal; Benzodiazepine derivatives; Antagonist; Sedative; Gabaergic receptor A; Avoidance
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2004.09.011

Recent research on genetically modified mice has attributed the amnesic effect of benzodiazepines mainly to the α 1-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 α 1-subunit selective antagonist β-carboline-3-carboxylate- t-butyl ester (β-CCt) (0–30.0 mg/kg), the non-selective agonist midazolam (0–2.0 mg/kg), the preferential α 1-subunit selective agonist zolpidem (0–3.0 mg/kg), and the non-selective inverse agonist methyl 6,7-dimethoxy-4-ethyl-β-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 β-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 β-CCt (30.0 mg/kg); by contrast, only flumazenil was considerably effective when combined with midazolam. DMCM exerted promnesic effects at 0.2 mg/kg, in an inverted U-shape manner. Both antagonists tended to abolish this action. The results indicate that some other α-subunit(s), in addition to the α 1-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 α 1-subunit and/or other putative β-CCt-sensitive binding site(s).