Hepatic encephalopathy, GABA-ergic neurotransmission and benzodiazepine receptor ligands

Evidence compatible with increased GABAergic tone contributing to the manifestations of hepatic encephalopathy (HE) in animal models of fulminant hepatic failure (FHF) includes: (i) increased resistance to drugs which induce seizures by reducing GABAergic tone; (ii) abnormalities of visual evoked responses (VERs) which resemble those induced by drugs which augment GABAergic tone; (iii) increased sensitivity of CNS neurons to a GABA agonist; and (iv) ameliorations of the encephalopathy induced by a GABA receptor antagonist. Evidence compatible with a benzodiazepine (BZ) receptor ligand with agonist properties contributing to increased GABAergic tone in animal models of FHF includes: (i) abnormalities of VERs which resemble those in BZ agonist-induced coma; (ii) increased sensitivity of CNS neurons to a BZ receptor agonist; (iii) excitation of CNS neurons induced by BZ receptor antagonists; (iv) reversal of the increased sensitivity of CNS neurons to a GABA agonist by a BZ receptor antagonist; (v) presence of a ligand(s) in brain which displaces a radiolabeled ligand from BZ receptors; and (vi) increased affinity of this ligand(s) for BZ receptors in the presence of GABA ("positive GABA shift").