Modulation of hepatic encephalopathy in rats with thioacetamide-induced acute liver failure by serotonin antagonists

Objective : Accumulated neurochemical data in different animal models of fulminant hepatic failure and in humans with hepatic encephalopathy suggest that serotoninergic tone is increased in the brain in hepatic encephalopathy. Since neurochemical alterations may not have behavioural or electrophysiological consequences the contribution of the serotoninergic system to the pathogenesis of hepatic encephalopathy was explored. Methods : The effects of drugs modulating serotoninergic neurotransmission, the non-selective serotonin receptor antagonist methysergide and the serotonin 2 receptor antagonist seganserin were tested neuropharmacologically in thioacetamide-induced acute liver failure in rats. Results : Methysergide had no effect in control rats, but dose dependently increased motor activity in stage II-III hepatic encephalopathy by 232% (5 mg/kg methysergide), 531% (10 mg/kg) and 507% (20mg/kg). In contrast, seganserin had no effect in encephalopathic rats. Conclusion : It is suggested that the beneficial effects of methysergide are serotonin 1 receptor mediated. Overall the results suggest that serotoninergic mechanisms contribute to some of the behavioural manifestations of hepatic encephalopathy in this animal model.