These is increasing evidence to suggest that central noradrenergic mechanisms may contribute to the central nervous system manifestations of acute liver failure. To further elucidate this possibility, extracellular brain concentrations of the monoamines, noradrenaline (NA), dopamine (DA), and serotonin, were measured by high-performance liquid chromatography with electrochemical detection in microdialysates from the extracellular compartment of frontal cortex in rats with acute (ischemic) liver failure at various times during the progression of encephalopathy and brain edema, as well as in obligate control groups of animals. In addition, binding sites for the noradrenergic receptor subtype ligands, [ 3 H]-prazosin (โฃ 1 sites), [ 3 H]-RX821002 (โฃ 2 sites), and [ 125 ]I-iodopindolol (โค sites), were assessed using quantitative receptor autoradiography in regions of the brains of rats at coma stage of acute liver failure and of control groups of animals. Coma stages of encephalopathy in acute liver failure were associated with selectively increased noradrenaline concentrations (P F .05) and a concomitant selective loss of โฃ 1 and โค 1 sites in frontal cortex and thalamus. These findings add to a growing body of evidence that central noradrenergic function is modified in acute liver failure and suggest that โฃ 1 /โค 1 receptor-mediated noradrenergic mechanisms may play a role in the pathogenesis of brain edema and encephalopathy in this condition. (HEPATOLOGY 1998;27:362-368.) The pathophysiological mechanisms responsible for cerebral edema and hepatic encephalopathy (HE), two major central nervous system complications of acute liver failure, have not been fully elucidated. The current consensus of opinion is that neurotransmitter-related mechanisms, 1-3 rather than a primary deficit of cerebral energy metabolism, 4,5 are responsible. Alterations of both glutamatergic 2 and serotoninergic 1 systems have been described in HE resulting from experimental acute liver failure, and there is a growing body