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To assess the possible implication of the allosteric coupling of different modulatory sites at the GABA-A receptor complex in hepatic encephalopathy (HE), we investigated in autopsied frontal cortex of six cirrhotic patients and six appropriately-matched controls, the modulatory effects of the benzodiazepine site agonist flunitrazepam on the binding of [3H]muscimol and the effect of the neurosteroid site agonist allopregnanolone (5α-pregnan-3α-ol-20-one) on the binding of [3H]muscimol and [3H]flunitrazepam. There were no significant differences in either the magnitude Emax: 11.5±1.1% (controls) versus 10.2±2.2% (HE patients) or the efficacy EC50: 20.2±5.5 nM (controls) versus 17.7±6.2 nM (HE patients) of flunitrazepam modulation of [3H]muscimol binding. Allopregnanolone also showed modulation of both sites to a comparable extent in brain tissue from cirrhotic patients and controls Emax: [3H]muscimol, 15.1±2.8% (controls) versus 13.8±1.9% (HE patients); [3H]flunitrazepam, 17.9±2.3% (controls) versus 19.1±2.3% (HE patients), EC50: [3H]muscimol, 386.5±25.8 nM (controls) versus 373.8±13.1 nM (HE patients); [3H]flunitrazepam, 49.8±22.9 nM (controls) versus 55.5±14.0 nM (HE patients). These findings demonstrate unequivocally that the GABA-A sites and their benzodiazepine and neurosteroid modulatory sites manifest normal allosteric coupling in brain in human HE. Therefore, if increased “GABAergic tone” is implicated in the pathophysiology of HE, this must be the consequence of increased brain concentrations of endogenous benzodiazepine and/or neurosteroid ligands for components of the GABA-A receptor complex rather than alterations of the receptor proteins themselves.