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


Address correspondence and reprint requests to Vicente Felipo, Laboratory of Neurobiology, Centro de Investigacion Principe Felipe, Calle Eduardo Primo Yufera, 3, 46012 Valencia, Spain.

E-mail: vfelipo@cipf.es


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. Hyperammonemia potentiates the actions of tetrahydrodeoxy-corticosterone (THDOC) as a GABAA receptor agonist, allopregnanolone as an NMDA receptor antagonist, and pregnenolone sulfate as an NMDA receptor activation enhancer. Neurosteroids that reduce the pathway (pregnanolone, THDOC, allopregnanolone, DHEAS) may contribute to cognitive impairment in hyperammonemia and hepatic encephalopathy. Pregnenolone would impair cognitive function in hyperammonemia. Neurosteroids that restore the pathway in hyperammonemia (pregnenolone sulfate) could restore cognitive function in hyperammonemia and encephalopathy.