Effects of thioacetamide-induced hepatic failure on theN-methyl-d-aspartate receptor complex in the rat cerebral cortex, striatum, and hippocampus

Hepatic encephalopathy (HE) is characterized by symptoms pointing at disturbances in glutamatergic neurotransmission in the brain, particularly in the striatum. The binding parameters of ligands specific for different recognition sites in theN-methyl-d-aspartate (NMDA) receptor complex and the distribution of the receptor subunit mRNAs (NR1, NR2A-D) were assessed in rats with acute HE induced with a hepatotoxin, thioacetamide (TAA). The binding of:

1. l-³H]glutamate (NMDA-displaceable);
2. ³H]dizocilpine andN-(1-2-thienyl]-cyclohexyl) ³H]piperidine (³H]TCP); and
3. The coactivator site agonist ³H]glycine was assayed in purified membranes of the cerebral cortex, hippocampus, and striatum.

In HE rats,B _max of NMDA-displaceable glutamate binding was increased in the cerebral cortex and hippocampus, but slightly decreased in the striatum. In this region, the binding affinity was also slightly increased. In HE,B _max of ³H]dizocilpine binding was unchanged in the striatum and cerebral cortex, but substantially decreased in the hippocampus. Pretreatment with phorbol ester enhanced the binding of dizocilpine more in HE than in control rats.B _max of ³H]TCP binding was decreased in the cerebral cortex and striatum, but increased in the hippocampus. The different responses of these two phencyclidine site antagonists to HE may be indicative of a conformational change within the ion channel and/or the presence of microdomains reacting differently to extrinsic factors. HE did not affect glycine binding, but potentiated the maximal stimulation of ³H]dizocilpine binding by glycine in the cerebral cortex. The results emphasize the brain region and domain specificity of the responses of the NMDA receptor complex to HE.