Activation of N-methyl-D-aspartate receptors in rat brain in vivo following acute ammonia intoxication: Characterization by in vivo brain microdialysis

Ammonia is considered the main agent responsible for the neurological alter ations in hepatic encephalopathy, It was suggested that ammonia toxicity is mediated by activation of N-methyl-D-aspartate (NMDA) receptors. The aim o f this work was to assess, by in vivo brain microdialysis in freely moving rats, whether acute ammonia intoxication leads to activation of NMDA recept ors in the cerebellum of the rat in vivo. We measured the effects of ammoni a intoxication on the neuronal glutamate-nitric oxide-cyclic guanosine mono phosphate (cGMP) pathway, by measuring the ammonia-induced increase of extr acellular cGMF! Ammonia intoxication increases extracellular cGMP, and this increase is prevented by (5R,10S)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cy clohepten-5,10-imine hydrogen maleate (MK-801). There is a good correlation between the increase in cGMP and the seriousness of the neurological sympt oms elicited by different doses of ammonia. Ammonia doses inducing coma did not affect extracellular glutamate, while doses leading to death increased it by 349%. The time courses of ammonia-induced increases in extracellular am monia, cGMP, and glutamate indicate that NMDA receptor activation occur s before the increase in extracellular glutamate. Ammonia-induced increase in glutamate is prevented by MK-801, These results indicate that ammonia in toxication leads to activation of NMDA receptors in the animal in vivo, and that this activation is not caused by increased extracellular glutamate, T he possible underlying mechanism is discussed.