title: Bidirectional effects of benzodiazepine binding site ligands on active avoidance acquisition and retention: differential antagonism by flumazenil and beta-CCt.
abstract: BACKGROUND
  The pharmacological approach, using subtype selective ligands, complements genetic studies on the specific contribution of individual receptor subtypes to the various effects of benzodiazepines.
  
  
  OBJECTIVE
  The aim of this study was to examine the relative significance of alpha1-containing GABA(A) receptors in the effects of modulators at the benzodiazepine site on anxiety and memory processes.
  
  
  METHODS
  We tested the effects of the nonselective antagonist flumazenil, the preferential alpha1-subunit selective antagonist beta-carboline-3-carboxylate-t-butyl ester (beta-CCt), the nonselective agonist midazolam, the preferential alpha1-subunit selective agonist zolpidem, and the nonselective inverse agonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) in a two-way active avoidance task in rats. The influence of flumazenil (10.0 mg/kg) and beta-CCt (30.0 mg/kg) on the effects of the two agonists were also examined. In the schedule 2 x 30 trials, drugs were administered i.p. 20 min before the training session. Avoidance responses in the training session are an anxiety-mediated behavior, whereas performance in the retention session relates to the effects on memory.
  
  
  RESULTS
  Flumazenil and beta-CCt did not affect behavior. Midazolam (2.0 mg/kg) facilitated acquisition performance, while DMCM (1.0 and 2.0 mg/kg) induced the opposite effect. Flumazenil antagonized both effects. Beta-CCt potentiated the effect of midazolam, and partly antagonized the effect of DMCM. Midazolam (0.5 and 1.0 mg/kg) and zolpidem (1.0-3.0 mg/kg) impaired, while DMCM (0.1 mg/kg) facilitated the subjects' performance in the retention test. The amnesic effects were attenuated but not fully reversed, while the effect of DMCM was counteracted by both antagonists.
  
  
  CONCLUSIONS
  The results indicate the alpha1-subunit interferes with the anxiolytic effect of a benzodiazepine site agonist and may contribute to the DMCM-induced anxiogenic effect. It is also substantially involved in the bidirectional memory processing in the active avoidance paradigm.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221, Belgrade, Serbia and Montenegro. miroslav@pharmacy.bg.ac.yu
authors.forename: Miroslav M
authors.initials: MM
authors.lastname: Savić
authors.forename: Dragan I
authors.initials: DI
authors.lastname: Obradović
authors.forename: Nenad D
authors.initials: ND
authors.lastname: Ugresić
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
authors.forename: P V V S
authors.initials: PV
authors.lastname: Sarma
authors.forename: Dubravko R
authors.initials: DR
authors.lastname: Bokonjić
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects* / Q000502:physiology; D001569:Benzodiazepines / Q000008:administration & dosage / Q000494:pharmacology*; D001665:Binding Sites; D002243:Carbolines / Q000008:administration & dosage / Q000494:pharmacology*; D003292:Convulsants / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil / Q000008:administration & dosage / Q000494:pharmacology*; D018755:GABA Agonists / Q000008:administration & dosage / Q000494:pharmacology; D018757:GABA Modulators / Q000008:administration & dosage / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D006185:Habituation, Psychophysiologic / Q000187:drug effects / Q000502:physiology; D007274:Injections, Intraperitoneal; D008024:Ligands; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000502:physiology; D012153:Retention, Psychology / Q000187:drug effects* / Q000502:physiology; D000077334:Zolpidem
chemical_list: D014151:Anti-Anxiety Agents; D002243:Carbolines; D003292:Convulsants; D018755:GABA Agonists; D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; D008024:Ligands; D011725:Pyridines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D005442:Flumazenil; D000077334:Zolpidem; C043232:tert-butyl beta-carboline-3-carboxylate; D008874:Midazolam
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