Behavioral and biochemical characterization of rats treated chronically with thioacetamide: proposal of an animal model for hepatic encephalopathy associated with cirrhosis

Hepatic encephalopathy (HE) is a syndrome observed in patients with liver dysfunction such as hepatitis and cirrhosis, and is characterized by cognitive impairment, personality changes, and a depressed level of consciousness. The detailed mechanism underlying the pathogenesis of HE remains unclear. In the present study, our aim was to establish an animal model for HE with cirrhosis. Therefore, we carried out behavioral and biochemical analysis of cirrhotic rats after treatment with thioacetamide (TAA) for 20 weeks. The rats subjected to chronic TAA treatment (TAA rats) showed reduction of cognitive scores in the novel object recognition test (NOR), and a decrease in immobility and an increase in swimming in the forced swim test (FST). In biochemical analyses, the TAA rats exhibited elevated blood levels of ammonia, and increased metabolic activities of serotonergic and noradrenergic neurons in the brain, while the levels of Glu and GABA were not affected. Post-oral treatment of lactulose, a clinically utilized drug for HE, effectively reduced the elevated blood ammonia levels, and restored the reduced cognitive scores and the decreased immobility, without any effects on neurotransmitter contents in the brain, compared with the control. These results indicated lactulose-restorable memory disturbance and irritated mood in the TAA rats. In other words, rats treated chronically with TAA are a potential model for cirrhosis-HE, and the combination of NOR and FST in TAA rats may be useful as a simple assay system for the screening and development of anti-HE agents.