Flumazenil-induced improvement of the central dopaminergic system in rats with acute hepatic failure

Several reports have demonstrated the alleviation of hepatic encephalopathy by flumazenil, an antagonist of benzodiazepine receptors. As changes in central monoaminergic activity are involved in the mechanisms for hepatic encephalopathy, the effects of flumazenil on central monoaminergic activity were evaluated in acute hepatic failure produced by ischemia-reperfusion injury in rats. Eighteen male Wistar rats were evenly assigned to three groups: sham-operated group given saline, liver-ischemic group given saline, and liver-ischemic group given flumazenil. Flumazenil (1 mg/kg) or saline (10 mL/kg) was intraperitoneally administered three times, at 1, 6, and 24 hours after 90 minutes of liver ischemia produced by occlusion of the left portal vein. The extracellular concentrations of neurotransmitter amino acids, monoamines, and their metabolites were determined in the striatum using a microdialysis procedure. Another set of 12 rats was subjected to liver ischemia, and the effect of flumazenil on spontaneous motor activity was examined after 24 hours. The extracellular concentration of 3,4-dihydroxyphenylacetic acid, a metabolite of dopamine, decreased to 39% of that in sham-operated animals 24 hours after surgery (P < 0.05), although the dopamine level did not change. The treatment with flumazenil completely abolished the decrease in the metabolite (P < 0.05). Although the glutamate level in the injured animals decreased to 42% of that in sham-operated animals (P < 0.05), no remarkable increase in the glutamate level was observed in animals treated with flumazenil. Spontaneous motor activity decreased 24 hours after surgery in animals subjected to liver ischemia. Flumazenil led to improvement of spontaneous motor activity 5 minutes after administration, but this effect was not observed after 30 minutes. The restoration of the central dopaminergic function may be a contributing factor in the improvement of hepatic encephalopathy.