Supersensitivity of Benzodiazepine Receptors in Hepatic Encephalopathy Due to Fulminant Hepatic Failure in the Rat: Reversal by a Benzodiazepine Antagonist

Abstract

1. Benzodiazepine receptors were studied in rats with hepatic encephalopathy due to fulminant hepatic failure induced by galactosamine. [3H]-Diazepam binding studies on brain synaptic membranes of rats with mild and severe encephalopathy show a significant increase in the number of receptors in both stages of coma. 2. [3H]Diazepam binding to synaptic membrane preparations from rats in the mild or severe stage of encephalopathy hyper-responded to the stimulatory effect of γ-aminobutyric acid (GABA) applied in vitro at doses which for control rat preparations were in a subthreshold range. The effect of GABA was shown to be specific, since it was blocked by bicuculline methiodide. The sensitivity of benzodiazepine receptors in hepatic encephalopathy to nanomolar concentrations of GABA, which induced a significant increase in their affinity, seems to indicate a functional supersensitivity of benzodiazepine receptors in vivo in both mild and severe stages of encephalopathy. 3. The phenomena described may be attributed to a partial degeneration of nerve terminals in hepatic encephalopathy, leading to a supersensitivity of benzodiazepine receptors, which parallels the previously described denervation supersensitivity of GABA receptors present in this animal model of fulminant hepatic failure. These findings may account for the brain hypersensitivity to sedatives administered to patients with liver diseases. 4. The administration in vivo of a benzodiazepine antagonist, 2-phenylpyrazolo [4,3-c]-quinolin-3(5H)-one, counteracted the hypersensitivity of benzodiazepine receptors in the mild stage of encephalopathy. In fact, electrophysiological studies with visually evoked potential recordings in rats in the mild stage of encephalopathy 30-60 min after the administration of the drug showed a recovery of the wave pattern, and this electrophysiological finding was substantiated by the demonstration that both the number and the affinity of benzodiazepine receptors were strongly reduced.