ACUTE LIVER-FAILURE AND HYPERAMMONEMIA INCREASE PERIPHERAL-TYPE BENZODIAZEPINE RECEPTOR-BINDING AND PREGNENOLONE SYNTHESIS IN MOUSE-BRAIN

We investigated the role of brain peripheral-type benzodiazepine recep tors (PBRs) and pregnenolone (a product of PBRs activation) in hepatic encephalopathy (HE)/hyperammonemia. Administration of the hepatotoxin , thioacetamide, or ammonium acetate to mice for 3 days significantly increased the number of brain PBRs (138-146% of control) and the affin ity of the ligands for these receptors (2-fold). The total content of pregnenolone and its rate of synthesis in brain of the experimental an imals were significantly increased. Our results suggest a novel integr ated mechanism by which ammonia-induced activation of PBRs leads to el evated levels of pregnenolone-derived neurosteroids which are known to enhance GABA-ergic neurotransmission. This mechanism may play a pivot al role in pathogenesis of HE.