BENZODIAZEPINE RECEPTOR ANTAGONISTS FLUMAZENIL AND CGS-8216 AND INVERSE-AGONIST BETA-CCM ENHANCE SPATIAL-LEARNING IN THE RAT - DISSOCIATIONFROM ANXIOGENIC ACTIONS

The effects of the benzodiazepine receptor antagonists flumazenil (10, 20, and 30 mg/kg) and CGS 8216 (10, 20, and 30 mg/kg), the benzodiaze pine receptor inverse-agonist methyl beta-carboline-3-carboxylate (bet a-CCM; 0.3, 0.6, and 1.0 mg/kg), and the benzodiazepine receptor agoni st diazepam (3 mg/kg) were investigated on spatial learning in the Mor ris water maze and thigmotaxia in an open field. Flumazenil, CGS 8216, and beta-CCM dose-dependently enhanced spatial learning, whereas diaz epam impaired it. Flumazenil (10 mg/kg) antagonized both the enhanceme nt produced by beta-CCM (0.3 mg/kg) and the impairment produced by dia zepam. The impairment produced by diazepam was not blocked by beta-CCM (0.3 mg/kg). In the open field, flumazenil, CGS 8216, and beta-CCM do se-dependently increased thigmotaxia (anxiogenesis), whereas diazepam had no effect. Flumazenil (10 mg/kg) blocked the anxiogenic effect of beta-CCM (0.6 mg/kg) and increased anxiety when combined with diazepam ; the anxiogenic effect of beta-CCM (0.6 mg/kg) was not antagonized by diazepam. Since the dose-response profiles of flumazenil, CGS 8216, a nd beta-CCM on spatial learning and thigmotaxia were highly dissimilar , it is unlikely that the mnemonic-enhancing actions of these drugs ar e due to their anxiogenic actions.