Étifoxine : pharmacologie comportementale

Abstract

Etifoxine, a benzodiazepine anxiolytic, exerts an autonomic regulatory activity. Two clinical studies have shown that etifoxine is effective in the treatment of adjustment disorder with anxiety. In view of the diversity of disorders associated with anxiety, with or without various autonomic manifestations, we were interested in the behavioural effects of etifoxine in animal models, particularly when animals exposed to stressful stimuli exhibit exaggerated autonomic signs other than those of cardiovascular origin. The effects of etifoxine were first evaluated in a stress-induced hyperthermia model in the rat. Manipulation of this animal causes an elevation of rectal temperature corresponding to a state of anticipatory anxiety. Again in the rat, etifoxine was evaluated in a conditioned fear test during which a more stressful stimulus constituted by the presentation of unavoidable, unpleasant electric shocks was applied. Behavioural blockade or freezing in response to this stress and the amplitude of colonic motor activity quantified by recording myoelectrical activity were measured. Subsequently, given the importance of the role played by corticoliberin or CRF, a hypothalamic neurohormone and/or neurotransmitter, in the co-ordination and mediation of autonomic responses to stress, we used a mouse model in which intracerebral administration of CRF mimics a major stress state, evidenced by a reduction in gastric emptying of a solid meal. The effects of etifoxine were evaluated in this model. A benzodiazepine (bromazepam or diazepam) was chosen as a positive control in each experiment. The elevation of rectal temperature following manipulation is significantly reduced in the presence of etifoxine (50 mg/kg). Likewise, etifoxine significantly and dose-dependently (12.5-50 mg/kg) reduces the duration of behavioural blockade or freezing following the application of unavoidable electric shocks. At the same time, the same stimulus causes an increase in the number of myoelectrical signals in the colon, which are significantly reduced by etifoxine. In the mouse, centrally administered CRF (0.35 μg/animal) reduces gastric emptying of a solid meal. This effect of CRF is dose-dependently antagonised by etifoxine. This series of results shows that etifoxine reduces the amplitude of autonomic manifestations in response to a stressful stimulus of variable intensity, such as hyperthermia, increased colonic motor activity or reduced gastric emptying. The anxiolytic properties of etifoxine are therefore exerted on both the behavioural and the autonomic aspects. These results provide a basis for evaluating this drug in anxious patients in whom autonomic nervous system manifestations constitute pathological symptoms.