Benzodiazepine receptor antagonists flumazenil and CGS 8216 and inverse-agonist β-CCM nhance spatial learning in the rat: Dissociation from 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 benzodiazepine receptor inverse-agonist methyl β-carboline-3-carboxylate (β-CCM; 0.3, 0.6, and 1.0 mg/kg), and the benzodiazepine receptor agonist diazepam (3 mg/kg) were investigated on spatial learning in the Morris water maze and thigmotaxia in an open field. Flumazenil, CGS 8216, and β-CCM dose-dependently enhanced spatial learning, whereas diazepam impaired it. Flumazenil (10 mg/kg) antagonized both the enhancement produced by β-CCM (0.3 mg/kg) and the impairment produced by diazepam. The impairment produced by diazepam was not blocked by β-CCM (0.3 mg/kg). In the open field, flumazenil, CGS 8216, and β-CCM dose-dependently increased thigmotaxia (anxiogenesis), whereas diazepam had no effect. Flumazenil (10 mg/kg) blocked the anxiogenic effect of β-CCM (0.6 mg/kg) and increased anxiety when combined with diazepam; the anxiogenic effect of β-CCM (0.6 mg/kg) was not antagonized by diazepam. Since the dose-response profiles of flumazenil, CGS 8216, and β-CCM on spatial learning and thigmotaxia were highly dissimilar, it is unlikely that the mnemonic-enhancing actions of these drugs are due to their anxiogenic actions.