SYNAPTOSOMAL GLUTAMATE TRANSPORT IN THIOACETAMIDE-INDUCED HEPATIC-ENCEPHALOPATHY IN THE RAT

Dysfunction of excitatory glutamatergic neurotransmission has been imp licated in the cause of hepatic encephalopathy. Brain microdialysis st udies in various animal models of portal systemic encephalopathy (PSE) and encephalopathy associated with acute Liver failure, have establis hed that an increase in extracellular glutamate occurs but the mechani sms of this are unclear. We have measured oxygen consumption, citrate synthase activity (as indices of energy state and mitochondrial conten t, respectively), calcium-dependent glutamate release, and high-affini ty, sodium-dependent glutamate uptake by synaptosomes prepared from ra ts with thioacetamide-induced encephalopathy (2 doses of thioacetamide 200 mg/kg with a 24-hour interval). Synaptosomes were prepared either by a modified P2 method (glutamate release study) or by discontinuous sucrose density gradient centrifugation (all other studies). There wa s no significant difference in synaptosomal oxygen consumption, citrat e synthase activity, glutamate release, total synaptosomal glutamate c ontent, or the Kd for glutamate uptake between the encephalopathy grou p and the controls, However there was a marked decrease in the maximal velocity bf transport (V-max) for glutamate uptake in synaptosomes fr om encephalopathic rats, 2.64 versus 4.40 nmol/min/mg (P < .05). The r esults of this study provide evidence of impaired glutamate uptake in the rat thioacetamide model of hepatic encephalopathy, which could acc ount for the elevated extracellular glutamate seen in the condition.