HYPERAMMONEMIA INCREASES SEROTONIN 1A RECEPTOR EXPRESSION IN BOTH RAT HIPPOCAMPUS AND A TRANSFECTED HIPPOCAMPAL CELL-LINE, HN2-5

Hyperammonemia is an important cause of cerebral dysfunction in liver failure, We used two well-established models to induce hyperammonemia in rats, injection of urease and injection of methionine sulfoximine (MSO), Urease gave a 10-fold increase in blood ammonia while MSO, a glutamine synthetase inhibitor, gave a 4-fold increase in blood ammonia with no increase in brain glutamine levels, We observed a 2-fold increase in 5-HT1A receptor (5-HT1A-R) expression ([H-3] 8-OH-DPAT binding) in hippocampus, and little change elsewhere, including thalamus in both models, thus eliminating a role for increased glutamine in the receptor induction, In contrast, a 4 to 8-fold increase in 5-HT1A-R mRNA was observed both in hippocampus and thalamus, suggesting some post-transcriptional regulation. In the absence of glutamine, ammonium acetate treatment of a hippocampal cell line which had been engineered to stably express the 5-HT1A-R (HN2-5) gave a 1.5-fold increase in [H-3] 8-OH-DPAT binding and a 4-fold increase in the mRNA levels for the 5-HT1A-R. We conclude that the cell line HN2-5 is a good model for studying some of the biochemical sequelae of hyperammonemia and that changes in brain function are not only at the metabolic level, as thought earlier, but can also occur at the transcriptional level. (C) 1995 Wiley-Liss, Inc.