PURPOSE: This study was aimed to investigate the modulatory effect of ammonium carbonate on the GABAA receptor. METHODS: The effects of ammonium carbonate on the binding of radioligands to components of the GABAA receptor complex were observed. RESULTS: [3H]Flunitrazepam binding to the benzodiazepine receptor was enhanced by ammonium (<800 micrometer). Further increasing ammonium carbonate concentrations decreased [3H]flunitrazepam binding to control levels. Furthermore, GABA and muscimol increased the potency of ammonium carbonate in enhancing [3H]flunitrazepam binding. Ammonium carbonate also increased, then decreased the binding of 10nM [3H]muscimol binding to the GABAA receptor in a concentration-dependent manner. More importantly, the presence of ammonia along with a benzodiazepine receptor agonist synergistically enhanced [3H]muscimol binding to the GABA receptor. CONCLUSION: These suggest that ammonia may enhance GABAergic neurotransmission at concentrations commonly encountered in hepatic failure, then suppress the inhibitory neuronal function observed at higher (>1mM) ammonia concentrations. This increase in GABAergic neurotransmission is consistent with the clinical picture of lethargy, ataxia and cognitive deficits associated with liver failure and congenital hyperammonemia.