Effects of thioacetamide-induced hepatic failure on the N-methyl-D-aspartate receptor complex in the rat cerebral cortex, striatum, and hippocampus. Binding of different ligands and expression of receptor subunit mRNAs.
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 the N-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 and N-(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, Bmax 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, Bmax 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. Bmax 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.
Saransaari
P
P
Tampere Brain Research Center, University of Tampere Medical School, Finland.
Oja
S S
SS
Borkowska
H D
HD
Koistinaho
J
J
Hilgier
W
W
Albrecht
J
J
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D017403:In Situ Hybridization; D007700:Kinetics; D008024:Ligands; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D013853:Thioacetamide / Q000633:toxicity*
D008024:Ligands; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D013853:Thioacetamide