The GABAergic agonist, muscimol, and antagonists, picrotoxin and bicuculline, have been studied in rats with chronic portacaval shunts and in rats developing hepatic encephalopathy after massive ischemic necrosis due to hepatic artery ligation within 48 hr of a portacaval shunt. After the chronic portacaval shunt and to a lesser extent in normal rats intraventricular muscimol resulted in chewing and eating behavior, ataxia and loss of balance that lasted 2 to 3 hr. Lethargy, stupor and coma did not occur. Intraventricular saline had no effect. Bicuculline i.p. lessened the effects of the muscimol. In rats developing hepatic encephalopathy, intraventricular muscimol shortened the time to precoma and coma by approximately 40%. Bicuculline i.p. counteracted this effect of muscimol significantly. However, neither bicuculline nor picrotoxin given alone altered the times to precoma (Stage 111), coma (Stage IV) or death. While hepatic encephalopathy in this experimental model is susceptible to GABAergic effects, its natural progression does not appear to be due to GABA.
A GABAergic effect has been suggested as the basis for hepatic coma because in uitro studies in rabbits and rats have found an increased density of GABA receptors on brain synaptosomes after severe liver damage with galactosamine (1, 2). Increased amounts of GABA were thought to pass through an abnormally permeable bloodbrain barrier into the brain where it was bound to receptors for GABA on postsynaptic neural membranes. This resulted in increased chloride ion conductance across the membrane, hyperpolarization and generation of inhibitory postsynaptic potentials (1). Since GABA is a prominent inhibitory neurotransmitter normally, it was assumed that increased amounts of GABA on synaptosomes during hepatic failure resulted in hepatic encephalopathy (HE). Jones and coworkers (1) attributed the encephalopathy entirely t o GABA, finding no role for ammonia and other toxins of hepatic failure. Baraldi and Zeneroli (3) suggested that the depressant effect of GABA was on neurons already damaged by the toxinsammonia, mercaptans and fatty acids-that accumulate with hepatic failure and were thus sensitized to the effects of GABA.