Bidirectional effects of benzodiazepine binding site ligands on active avoidance acquisition and retention:: differential antagonism by flumazenil and β-CCt

Rationale: 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 alpha 1-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 alpha(1)-subunit selective antagonist beta-carboline-3-carboxylate-t-butyl ester (beta-CCt), the nonselective agonist midazolam, the preferential alpha(1)-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. Conclusion: The results indicate the alpha(1)-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.