NEUROACTIVE AMINO-ACIDS AND GLUTAMATE (NMDA) RECEPTORS IN FRONTAL-CORTEX OF RATS WITH EXPERIMENTAL ACUTE LIVER-FAILURE

It has been proposed that alterations of excitatory and inhibitory ami no acids play a role in the pathogenesis of hepatic encephalopathy in acute liver failure. To evaluate this possibility, in vivo cerebral mi crodialysis was used to sample extracellular concentrations of amino a cids in the frontal cortex of unanesthetized rats at various times dur ing the progression of encephalopathy resulting from acute liver failu re. Liver failure was induced by portacaval anastomosis followed 24 ho urs later by hepatic artery ligation. Dialysate concentrations of amin o acids were measured by high-performance liquid chromatography (HPLC) with fluorescence detection. Deterioration of neurological status was accompanied by two- to four-fold increases in extracellular glutamate , glutamine, and glycine; concentrations of gamma-aminobutyric acid (G ABA) and taurine were unchanged. Densities of binding sites for the gl utamate (N-methyl-D-aspartate [MMDA]) receptor ligand H-3-MK801, asses sed using quantitative receptor autoradiography, however, were unchang ed in the frontal cortex of rats at coma stages of ischemic liver fail ure. Increased extracellular glutamate concentrations were positively correlated with the severity of encephalopathy and with arterial ammon ia concentrations. Such changes may result horn an ammonia-induced red uction in the capacity for astrocytes to uptake glutamate. Increased e xtracellular glutamate in brain, together with increases in concentrat ions of glycine, a positive allosteric modulator of glutamate (NMDA) r eceptors, are consistent with increased NMDA-related glutamatergic neu rotransmission in this model of acute liver failure. Increased extrace llular glutamate, therefore, could contribute to the pathogenesis of h epatic encephalopathy and brain edema in acute liver failure.