SELECTIVE LOSS OF BINDING-SITES FOR THE GLUTAMATE-RECEPTOR LIGANDS [H-3] KAINATE AND (S)-[H-3]5-FLUOROWILLARDIINE IN THE BRAINS OF RATS WITH ACUTE LIVER-FAILURE

There is increasing evidence that alterations of glutamatergic functio n are implicated in the pathogenesis of central nervous system consequ ences of acute liver failure. The aim of the study was to assess the i ntegrity of glutamate receptors in the brain in experimental ischemic liver failure using quantitative receptor autoradiography and the sele ctive ligands [H-3]MK801 (for N-methyl-D-aspartate [NMDA] sites), [H-3 ]5-fluorowillardiine (for non-NMDA, alpha-amino-3-hydroxy-5-methyl-4-i soxazole propionic acid [AMPA] subclass sites), and [H-3]kainate (for non-NMDA, kainate subclass sites). At coma stages of encephalopathy, a selective loss of up to 60% of binding sites for the kainate- and AMP A-receptor ligands was observed in cerebral cortical and hippocampal s tructures as well as in the hypothalamus and cerebellum. The finding o f a selective loss of AMPA sites at coma stages of encephalopathy in t his model of acute liver failure is consistent with previous electroph ysiological reports of inhibition of AMPA-mediated neuronal depolariza tion resulting from exposure of hippocampal neurons to millimolar conc entrations of ammonia. On the other hand, the present study showed tha t binding sites for the NMDA-receptor ligand [H-3]MK801 at coma stages of encephalopathy in acute liver failure were within normal limits in all brain structures examined. NMDA sites are uniquely neuronal, wher eas kainate and AMPA sites are localized on both neurons and astrocyte s. Therefore, the selective loss of non-NMDA sites in acute liver fail ure may also reflect astrocytic changes in this condition. Because ast rocytic glutamate receptors are implicated in K+ and neurotransmitter reuptake, alterations in their density could result in altered neurona l excitability and thus be responsible for the neurological dysfunctio n characteristic of hepatic encephalopathy in acute liver failure.