Similar effects of a beta-carboline and of flumazenil in negatively and positively reinforced learning tasks in mice.

Methyl beta-carboline-3-carboxylate (beta-CCM) and flumazenil (Ro15-1788) are known to be respectively an inverse agonist and an antagonist of the central benzodiazepine-receptor. Surprisingly, these two drugs have shown a similar enhancing effect in a negatively reinforced multiple-trial brightness discrimination task in mice. Thus, to evaluate the role of anxiety in this task, the action of these two drugs were compared in the same learning task with a positive or a negative reinforcement. Mice were trained for sessions of ten trials per day for six consecutive days. The sessions during the first three days took place after administration of beta-CCM (0.3 mg/kg), flumazenil (15 mg/kg) or vehicles of these drugs. A negative reinforcement (electric foot-shock) was used in a first experiment, and a positive one (food reward) in a second experiment. Results showed that, whatever the reinforcement, the two drugs enhance learning in a brightness discrimination task. The hypothesis is that flumazenil could have an inverse agonist profile in learning tasks. The question remains as to whether the flumazenil enhancing learning process results from increased arousal and/or anxiogenic factors, or from a negative modulatory influence of endogenous diazepam-like ligands for benzodiazepine receptors.