**12. Effects on the serotonergic system**

Serotonin is a neurotransmitter and modulator that favors the excitability of cortical neurons; a decrease in serotonergic tonus potentiates the effects of increased GABAergic tone [31]. Serotonergic neurons have both ascending and descending projections (**Figure 7**). The ascending projections originate in the raphe nuclei in the brainstem and extend to the cerebellum, hypothalamus, thalamus, amygdala, hippocampus, striatum, accumbens nucleus, basal forebrain, and prefrontal cortex [37]. They are related to the regulation of mood, hunger, impulsivity, and circadian rhythm [35]. The descending projections extend to the lower portions of the brainstem and spinal cord, being important for pain regulation [37].

The dysfunction of the serotonergic system has been widely documented in both minimal hepatic encephalopathy and overt hepatic encephalopathy: it underlies several early neuropsychiatric disorders in the disease, such as mood and sleep disorders. Serotonin levels correlate with the severity of cirrhosis and the degree of portosystemic shunt [35]. There is an increase in the circulation of l-tryptophan, the precursor amino acid of this neurotransmitter, in blood and cerebrospinal fluid. It is hypothesized that hyperammonemia not only stimulates serotonin synthesis, but also its degradation by the enzyme monoamine oxidase A (MAO-A), which is shown by the concomitant increase of the main product of its metabolism, 5-hydroxyindoleacetic acid [31, 33, 35].

#### **Figure 7.**

*The ascending serotonergic pathway originates in the raphe nucleus (RN) and extends to the medial portion of the temporal cortex and prefrontal cortex, while the descending pathway modulates the activity of the spinal cord. AN: accumbens nucleus, GP: globus pallidus, S: striatum, and T: thalamus.*
