Benzodiazepine receptor antagonists flumazenil and CGS 8216 and inverse-agonist {3-CCM enhance spatial learning in the rat: Dissociation from anxiogenic actions

The effects of the benzodiazepine receptor antagonists flumazenil (10, 20, and 30 mglkg) and CGS 8216 (10, 20, and 30 mglkg), the benzodiazepine receptor inverse-agonist methyl {3-carboline3-carboxylate ({3-CCM; 0.3, 0.6, and 1.0 mglkg), and the benzodiazepine receptor agonist diazepam (3 mglkg) were investigated on spatial learning in the Morris water maze and thigmotaxia in an open field. Flumazenil, CGS 8216, and {3-CCM dose-dependently enhanced spatial learning, whereas diazepam impaired it. Flumazenil (10 mglkg) antagonized both the enhancement produced by {3-CCM (0.3 mglkg) and the impairment produced by diazepam. The impairment produced by diazepam was not blocked by {3-CCM (0.3 mglkg). In the open field, flumazenil, CGS 8216, and {3-CCM dose-dependently increased thigmotaxia (anxiogenesis), whereas diazepam had no effect. Flumazenil (10 mglkg) blocked the anxiogenic effect of {3-CCM (0.6 mglkg) and increased anxiety when combined with diazepam; the anxiogenic effect of {3-CCM (0.6 mglkg) was not antagonized by diazepam. Since the dose-response profiles of flumazenil, CGS 8216, and {3-CCM on spatial learning and thigmotaxia were highly dissimilar, it is unlikely that the mnemonicenhancing actions of these drugs are due to their anxiogenic actions.