Serotonin brain circuits with a focus on hepatic encephalopathy

Despite enormous strides in our understanding of human disease, the precise mechanisms of hepatic encephalopathy (HE), a potential long-term complication of liver failure, are still unclear. Brain serotonin, a neurotransmitter with widespread distribution in the CNS, plays a role in the regulation of a wide range of physiological behaviors and functions. In addition, it has been implicated in the pathogenesis of several pathological processes, including HE. This work reviews the relationship between brain serotonergic dysfunction and hepatic encephalopathy in cirrhotic patients and experimental animals. The existing changes in the synthesis, metabolism, storage, and release of neuronal serotonin in HE point to a serotonergic synaptic deficit in this condition. Given the established role of the brain serotonergic system in the regulation of sleep, circadian rhythmicity, and locomotion, selective alterations of this system could be an important part of the neurophysiological background responsible for the behavioral changes in rats with portacaval anastomosis and may contribute to the pathogenesis of HE in cirrhotic patients. The findings that serotoninergic turnover is exquisitely and selectively sensitive to the degree of porto-systemic shunting and hyperammonemia suggest a role for serotonin in early neuropsychiatric symptoms of HE. Pharmacological manipulation of the brain serotonergic system may be beneficial in the prevention and treatment of HE in cirrhotic patients.