Effects of etifoxine on stress-induced hyperthermia, freezing behavior and colonic motor activation in rats

Anxiety disorders are often associated with autonomic symptoms, including heart palpitations, sweating, elevation of body temperature and alterations of gastrointestinal motility. Some of the alterations observed in animals exposed to stress are analogous to changes in a number of physiological and endocrine parameters observed in anxious patients. With the purpose to guide further clinical studies in subtypes of anxious patients, etifoxine, a nonbenzodiazepine anxiolytic compound, was evaluated in two rat models of anxiety with measures of physiological manifestations: stress-induced hyperthermia (SIH) and conditioned-fear-stress-induced freezing behavior and activation of colonic motility. The sequential handling of animals induced a rise in body temperature attenuated by etifoxine (50 mg/kg IP). The emotional stress induced by fear to receive electric foot shocks is accompanied by freezing behavior and an increase of the frequency of ceco-colonic spike bursts: both parameters were reduced by etifoxine (25-50 mg/kg IP), independently of changes in pain perception and memory-related processes. In response to a stressful event, the stimulation of the corticotropin-releasing hormone (CRH) system is probably involved in the observed modifications of body temperature and colonic motility. It is hypothesized that stress-induced CRH activation is attenuated by the enhancement of the inhibitory GABAergic system activity associated with etifoxine. These findings will guide future evaluation of etifoxine in the treatment of selected anxious patients with altered autonomic symptomatology.