Does ammonia contribute to increased GABA-ergic neurotransmission in liverfailure?

The ammonia and GABAergic neurotransmission hypotheses of the pathogenesis of hepatic encephalopathy (HE) have appeared to be unrelated and perhaps mu tually exclusive. Observations in animal models of fulminant hepatic failur e, that are consistent with increased GABAergic inhibitory neurotransmissio n contributing to the manifestations of HE, include: (i) abnormal visual ev oked potential waveforms that resemble those induced by GABA(A)/benzodiazep ine (BZ) receptor complex agonists; (ii) GABA(A)/BZ receptor complex antago nist-induced ameliorations of encephalopathy; (iii) increased resistance to drugs which decrease GABAergic tone; and (iv) hypersensitivity of CNS neur ons to depression by GABA(A)/BZ receptor complex agonists. Mechanisms of in creased GABAergic tone in HE may include the following: (i) increased brain concentrations of natural BZs; and (ii) increased GABA concentrations in s ynaptic clefts, possibly due to increased blood-brain-barrier permeability to GABA and a decrease in GABA(B) receptor density. Both neuroelectrophysio logical and behavioral data indicate that ammonia concentrations in the ran ge 0.75-2 mM induce increased excitatory neurotransmission. In contrast, re cently, ammonia concentrations in the range 0.15-0.75 mM, i.e. concentratio ns that commonly occur in plasma in precoma HE, have been shown: (i) to inc rease GABA-induced chloride current in cultured neurons; and (ii) to enhanc e synergistically the binding of GABA(A)/BZ receptor agonists. In addition, increased ammonia concentrations enhance synthesis of neurosteroids in ast rocytes, and some neurosteroids potently augment GABAergic neurotransmissio n. Thus, the modestly elevated concentrations of ammonia, that commonly occ ur in liver failure, may contribute to the manifestations of HE by enhancin g GABAergic inhibitory neurotransmission. This concept appears to unify the ammonia and GABAergic neurotransmission hypotheses.