ALTERATIONS IN CORTICAL [H-3] KAINATE AND ALPHA-[H-3]AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLEPROPIONIC ACID BINDING IN A SPONTANEOUS CANINE MODEL OF CHRONIC HEPATIC-ENCEPHALOPATHY

Excitatory amino acid receptor binding parameters were investigated in a spontaneous dog model of chronic hepatic encephalopathy. L-[H-3]Glutamate, (+)-[H-3]-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate ([H-3]MK-801), [H-3]kainate, and alpha-[H-3]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([H-3]AMPA) binding experiments were performed using crude cerebrocortical synaptosomal membrane preparations from dogs with congenital portosystemic encephalopathy (PSE) and control dogs. There was no change in the affinity or density of L-[H-3]-glutamate or [H-3]MK-801 binding sites in dogs with congenital PSE compared with control dogs. However, in the PSE dogs there was a significant reduction in the density of [H-3]kainate binding sites compared with control dogs and abolition of the low-affinity [H-3]AMPA binding site. The relative binding capacity of PSE synaptosomal membranes for [H-3]kainate and [H-3]AMPA was expressed as the ratio B(max)/K(D). There was a significant inverse correlation between the B(max/K(D) ratio for [H-3]AMPA binding and the worst grade of encephalopathy experienced by each dog. These results suggest that there is a significant perturbation of cerebrocortical non-N-methyl-D-aspartate receptor binding in dogs with congenital PSE which may have relevance to the pathogenesis of hepatic encephalopathy.