Mechanisms of action of midazolam on expression of contextual fear in rats.

BACKGROUND Midazolam may suppress conditioned fear after an aversive event by disrupting the memory trace formed during conditioning, by altering the emotional part of the aversive event, or by the combination of both effects. The purpose of the present study was to determine whether affective-related processes contribute to the amnesic-like effects of midazolam on aversive events. METHODS The effects of acute administration of low doses of midazolam (0.37-3 mg kg(-1)) on fear conditioning (association between a neutral context and an aversive stimulus) and on innate anxiety in fearful surroundings were examined in rats. The effect of midazolam on the deleterious consequences of pre-exposure to the context (a non-aversive event) for subsequent fear conditioning was then compared with its effect on fear conditioning. The role of midazolam as an affective context was assessed by performing the testing phase under midazolam. Possible locomotor impairment or long-term effects of midazolam were controlled in additional experiments. RESULTS Midazolam reduced both contextual fear conditioning and spontaneous fear. The deleterious effect of midazolam on pre-exposure to the context was of the same magnitude as its effect on the acquisition phase of fear conditioning. The effects of midazolam on both pre-exposure to the context and fear conditioning were unchanged when rats received a second injection of midazolam before the retention phase. CONCLUSIONS Low doses of midazolam that do not impair locomotion suppress conditioned fear to the context by acting on memory processes rather than on affective or anxiolytic processes.