Benzodiazepine receptor ligand influences on acquisition: suggestion of an endogenous modulatory mechanism mediated by benzodiazepine receptors.

In rats, pretraining ip administration of the central benzodiazepine receptor antagonist, flumazenil (5.0 mg/kg), or of the inverse agonist, n-butyl-beta-carboline-3-carboxylate (BCCB) (0.2 or 0.5 mg/kg), facilitated retention of a step-down inhibitory avoidance task; the central agonists, clonazepam and diazepam (0.4 or 1.0 mg/kg), had an opposite effect, and the peripheral agonist, 4'-chlordiazepam (1.25 or 6.25 mg/kg), was without effect. Pre- but not post-training flumazenil (2.0 mg/kg) blocked the effect of BCCB (0.5 mg/kg), clonazepam (1.0 mg/kg), or diazepam (1.0 mg/kg) given also pretraining. The post-training administration of all of these drugs had no effect on retention of the avoidance task. Flumazenil (5.0 mg/kg) and BCCB (0.5 mg/kg), given before training, enhanced retention test performance of habituation to a buzzer but not of habituation to an open field. In the three tasks studied, none of the drugs used had any appreciable effect on training session parameters. These results suggest that there is an endogenous mechanism mediated by benzodiazepine agonists, sensitive to inverse agonists, that normally down-regulates acquisition of certain behaviors; this mechanism becomes activated only when the tasks involve or occur with a certain degree of stress or anxiety (i.e., inhibitory avoidance or habituation to the buzzer) and not in less stressful or anxiogenic tasks (i.e., habituation to an open field).