Hyperammonemia alters the modulation by different neurosteroids of the glutamate-nitric oxide-cyclic GMP pathway through NMDA-GABAA- or sigma receptors in cerebellum in vivo

摘要

Several neurosteroids modulate the glutamate-nitric oxide (NO)-cGMP pathway in cerebellum through modulation of NMDA- GABAA- or sigma receptors. Hyperammonemia alters the concentration of several neurosteroids and impairs the glutamate-NO-cGMP pathway, leading to impaired learning ability. This work aimed to assess whether chronic hyperammonemia alters the modulation by different neurosteroids of GABAA, NMDA, and/or sigma receptors and of the glutamate-NO-cGMP pathway in cerebellum. Neurosteroids were administered through microdialysis probes, and extracellular cGMP and citrulline were measured. Then NMDA was administered to assess the effects on the glutamate-NO-cGMP pathway activation. Hyperammonemia completely modifies the effects of pregnanolone and pregnenolone. Pregnanolone acts as a GABAA receptor agonist in controls, but as an NMDA receptor antagonist in hyperammonemic rats. Pregnenolone does not induce any effect in controls, but acts as a sigma receptor agonist in hyperammonemic rats