Effect of ammonia on GABA uptake and release in cultured astrocytes

While the pathogenesis of hepatic encephalopathy (HE) is unclear, there is evidence of enhanced GABAergic neurotransmission in this condition. Ammonia is believed to play a major pathogenetic role in HE. To determine whether ammonia might contribute to abnormalities in GABAergic neurotransmission, i ts effects on GABA uptake and release were studied in cultured astrocytes, cells that appear to be targets of ammonia neurotoxicity. Acutely, ammonium chloride (5 mM) inhibited GABA uptake by 30%, and by 50-60% after 4-day tr eatment. GABA uptake inhibition was associated with a predominant decrease in V-max; the K-m was also decreased. Ammonia also enhanced GABA release af ter 4-day treatment, although such release was initially inhibited. These e ffects of ammonia (inhibition of GABA uptake and enhanced GABA release) may elevate extracellular levels of GABA and contribute to a dysfunction of GA BAergic neurotransmission in HE and other hyperammonemic states. (C) 2000 P ublished by Elsevier Science Ltd. All rights reserved.