Functional changes of various neurotransmitter systems have been implicated in the pathogenesis of hepatic encephalopathy. In this study the role of brain monoaminergic neurotransmitter systems in hepatic encephalopathy was investigated in rats with thioacetamide-induced acute liver failure. Concentrations of serotonin, dopamine, noradrenaline and of their metabolites 5-hydroxyindoleacetic acid, dihydroxyphenylalanine (following inhibition of dihydroxyphenylalanine-decarboxylase), dihydroxyphenylacetic acid, homovanillic acid and 3-methoxy-4-hydroxyphenyl-glycol, were measured in the cerebral cortex, striatum and hippocampus by high performance liquid chromatography with electrochemical detection. In hepatic encephalopathy concentrations of 5-hydroxyindoleacetic acid were increased in all three brain areas (196%, 204% and 264% of saline-treated controls, p less than 0.01), and concentrations of serotonin were increased in the frontal cortex (121%, p less than 0.01). In the frontal cortex and hippocampus of encephalopathic rats dopamine levels were increased (157% and 289%, p less than 0.05), and levels of noradrenaline (53% and 46%, p less than 0.05) were decreased associated with increased 3-methoxy-4-hydroxyphenylglycol levels (173% and 206%, p less than 0.05). The extent of these changes correlated with the stage of hepatic encephalopathy. In hepatic encephalopathy dihydroxyphenylalanine accumulation was increased in the hippocampus and unchanged in the cerebral cortex. Dopamine, noradrenaline, dihydroxyphenylacetic acid and homovanillic acid concentrations were unchanged in the striatum. The results of this study indicate that hepatic encephalopathy in thioacetamide-induced acute liver failure in rats is associated with neurochemical changes, suggesting an increased activity of the noradrenergic and serotoninergic neurotransmitter systems.