BENZODIAZEPINE RECEPTOR LIGANDS ARE ELEVATED IN AN ANIMAL-MODEL OF HEPATIC-ENCEPHALOPATHY - RELATIONSHIP BETWEEN BRAIN CONCENTRATION AND SEVERITY OF ENCEPHALOPATHY

Elevated levels of benzodiazepine receptor agonists are found in both animal models of hepatic encephalopathy and in humans with this syndro me. The present study investigated the relationship between agonist le vels and the severity of the encephalopathy, as well as the potential reversibility of the syndrome by benzodiazepine receptor antagonists. The concentrations of benzodiazepine receptor ligands in rat brains we re measured at several intervals during the induction of liver failure with thioacetamide. Six hours after the first dose of thioacetamide, brain concentrations of benzodiazepine receptor ligands were increased and open field activity decreased compared to control rats. However, the brain concentrations of benzodiazepine receptor ligands correlated better with the stage of hepatic encephalopathy than time after initi ation of thioacetamide treatment. The benzodiazepine receptor ligands Ro 15-3505, Ro 15-4513 and CGS-8216 ameliorated motor abnormalities in rats with stage 3 hepatic encephalopathy. Only Ro 15-3505 improved mo tor activity in rats in stage 2 encephalopathy to levels observed in r ats with stage 1 encephalopathy. Furthermore, although Ro 15-4513 and CGS 8216 significantly increased motor activity in stage 4 hepatic enc ephalopathy, this may reflect their partial inverse agonist properties . These findings support the hypothesis that increased brain levels of benzodiazepine receptor agonists contribute to the severity of hepati c encephalopathy and suggest that high-affinity benzodiazepine recepto r antagonists are efficacious in reversing this syndrome.