**13. Effects on the histaminergic system**

Histamine acts in conjunction with serotonin to regulate the circadian rhythm [31]. Histaminergic neurons originate in the tuberomammillary nucleus of the hypothalamus and make extensive projection throughout the central nervous system, including the spinal cord (**Figure 8**) [37]. Significant increase in histamine

#### **Figure 8.**

*The ascending histaminergic pathway originates in the hypothalamus 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.*

levels have been documented in patients with hepatic encephalopathy [31]. Histamine is produced from the amino acid histidine [37]; hyperammonemia increases both the concentration of histidine and the activity of its membrane transporter into the histaminergic neurons, stimulating the synthesis of histamine [31].
