Lactulose is a nonabsorbable disaccharide commonly used in clinical practice to treat hepatic encephalopathy. However, its effects on neuropsychiatric disorders and motor behavior have not been fully elucidated. Male Wistar rats were bile-duct ligated, and 3 weeks after surgery, treated with lactulose administrated by gavage (1.43 or 3.57 g/kg), once a day for seven days. Plasma levels of ammonia, aspartate aminotransferase, total bilirubin, and creatinine were quantified and histopathological analysis of the livers was performed. Locomotor activity measurements were performed in an open field. The expression of water channel aquaporin-4 was investigated and the analysis of Fos protein immunoreactivity was used to evaluate the pattern of neural activation in brain areas related to motor behavior. Bile-duct ligated rats showed hyperammonemia, loss of liver integrity and function, impaired locomotor activity, reduced aquaporin-4 protein expression, and neuronal hyperactivity. Lactulose treatment was able to reduce ammonia plasma levels, despite not having an effect on biochemical parameters of liver function, such as aspartate aminotransferase activity and total bilirubin levels, or on the cirrhotic hepatic architecture. Lactulose was also able to reduce the locomotor activity impairments and to mitigate or reverse most changes in neuronal activation. Lactulose had no effect on reduced aquaporin-4 protein expression. Our findings confirm the effectiveness of lactulose in reducing hyperammonemia and neuronal hyperactivity in brain areas related to motor behavior, reinforcing the importance of its clinical use in the treatment of the symptoms of cirrhosis-associated encephalopathy.

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