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 alterations in hepatic encephalopathy. It was suggested that ammonia toxicity is mediated by activation of N-methyl-D-aspartate (NMDA) receptors. The aim of this work was to assess, by in vivo brain microdialysis in freely moving rats, whether acute ammonia intoxication leads to activation of NMDA receptors in the cerebellum of the rat in vivo. We measured the effects of ammonia intoxication on the neuronal glutamate-nitric oxide-cyclic guanosine monophosphate (cGMP) pathway, by measuring the ammonia-induced increase of extracellular cGMP. Ammonia intoxication increases extracellular cGMP, and this increase is prevented by (5R,10S)-5-methyl-10,11-dihydro-5H-dibenzo[a, d]cyclohepten-5,10-imine hydrogen maleate (MK-801). There is a good correlation between the increase in cGMP and the seriousness of the neurological symptoms 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 ammonia, cGMP, and glutamate indicate that NMDA receptor activation occurs before the increase in extracellular glutamate. Ammonia-induced increase in glutamate is prevented by MK-801. These results indicate that ammonia intoxication leads to activation of NMDA receptors in the animal in vivo, and that this activation is not caused by increased extracellular glutamate. The possible underlying mechanism is discussed.
Hermenegildo
C
C
Instituto de Investigaciones Citologicas, Fundación Valenciana de Investigaciones Biomédicas, Valencia, Spain.
Monfort
P
P
Felipo
V
V
D000641:Ammonia / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000032:analysis; D008297:Male; D017551:Microdialysis / Q000379:methods; D009460:Neurologic Examination; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013997:Time Factors
D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D000641:Ammonia; D006152:Cyclic GMP