**11. Effects on the cholinergic system**

Acetylcholine is a neurotransmitter and modulator that, when bound to nicotinic receptors, favors neuronal excitability, and when bound to muscarinic receptors (mainly of the M2 subtype), inhibits the inhibitory activity triggered by the activation of GABAA receptors, i.e., disinhibits the postsynaptic terminal [31]. Two cholinergic pathways are particularly important in the pathophysiology of hepatic encephalopathy (**Figure 6**): (1) those originating from the ascending activating reticular system in the brainstem (particularly the laterodorsal tegmental nuclei and pedunculopontine nuclei) and (2) those originating from the basal forebrain, an area that includes the nucleus basalis of Meynert, the medial septal nucleus, and the diagonal band of Broca [37].

The projections of acetylcholine that originate in the ascending reticular activating system extend to the prefrontal cortex, basal forebrain, thalamus, hypothalamus, amygdala, and hippocampus; they are considered to be involved in vigilance (sustained attention) [39]. Cholinergic neurons that originate in the basal forebrain extend to the prefrontal cortex, hippocampus, and amygdala; they are involved with the formation of episodic memory [37].

The effects of acetylcholine are terminated by two enzymes, acetylcholinesterase and butyrylcholinesterase. Both convert acetylcholine to choline, which is then transported back to the presynaptic terminal for further synthesis of this neurotransmitter [37]. Cirrhosis is associated with an increase of approximately 30% in acetylcholinesterase activity in humans, which contributes to a decrease in acetylcholine levels and a consequent potentiation of the effects of GABAergic tonus [34]. Little is known about how chronic hyperammonemia and neuroinflammation induce changes in the cholinergic system [31]. There is no correlation, for example, between serum ammonia levels and acetylcholinesterase activity [34]. However, experimental studies have shown that the increased availability of acetylcholine in

#### **Figure 6.**

*The cholinergic pathways originate in the basal forebrain (BF) and reticular formation (RF). They extend to the prefrontal cortex and medial portion of the temporal cortex. AN: accumbens nucleus, GP: globus pallidus, S: striatum, and T: thalamus.*

**51**

**Figure 7.**

*The Neurobiology of Hepatic Encephalopathy DOI: http://dx.doi.org/10.5772/intechopen.86320*

severity of hepatic encephalopathy [31].

**12. Effects on the serotonergic system**

**13. Effects on the histaminergic system**

*cord. AN: accumbens nucleus, GP: globus pallidus, S: striatum, and T: thalamus.*

the synaptic cleft, either by direct administration or by inhibition of its degradation, is related to the reduction in glutamate neurotoxicity and improvement in the

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

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].

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

*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* 

brainstem and spinal cord, being important for pain regulation [37].

*Liver Disease and Surgery*

**11. Effects on the cholinergic system**

with the formation of episodic memory [37].

**50**

**Figure 6.**

*S: striatum, and T: thalamus.*

*The cholinergic pathways originate in the basal forebrain (BF) and reticular formation (RF). They extend to the prefrontal cortex and medial portion of the temporal cortex. AN: accumbens nucleus, GP: globus pallidus,* 

that the activation of glutamatergic metabotropic receptors in the substantia nigra can also cause a decrease in the locomotion of rodents, since the substantia nigra has a second pathway of GABAergic neurons that extends into the thalamus, where a group

Acetylcholine is a neurotransmitter and modulator that, when bound to nicotinic

The projections of acetylcholine that originate in the ascending reticular activating system extend to the prefrontal cortex, basal forebrain, thalamus, hypothalamus, amygdala, and hippocampus; they are considered to be involved in vigilance (sustained attention) [39]. Cholinergic neurons that originate in the basal forebrain extend to the prefrontal cortex, hippocampus, and amygdala; they are involved

The effects of acetylcholine are terminated by two enzymes, acetylcholinesterase

and butyrylcholinesterase. Both convert acetylcholine to choline, which is then transported back to the presynaptic terminal for further synthesis of this neurotransmitter [37]. Cirrhosis is associated with an increase of approximately 30% in acetylcholinesterase activity in humans, which contributes to a decrease in acetylcholine levels and a consequent potentiation of the effects of GABAergic tonus [34]. Little is known about how chronic hyperammonemia and neuroinflammation induce changes in the cholinergic system [31]. There is no correlation, for example, between serum ammonia levels and acetylcholinesterase activity [34]. However, experimental studies have shown that the increased availability of acetylcholine in

of GABAergic interneurons inhibit motor cells, resulting in hypokinesia [26].

receptors, favors neuronal excitability, and when bound to muscarinic receptors (mainly of the M2 subtype), inhibits the inhibitory activity triggered by the activation of GABAA receptors, i.e., disinhibits the postsynaptic terminal [31]. Two cholinergic pathways are particularly important in the pathophysiology of hepatic encephalopathy (**Figure 6**): (1) those originating from the ascending activating reticular system in the brainstem (particularly the laterodorsal tegmental nuclei and pedunculopontine nuclei) and (2) those originating from the basal forebrain, an area that includes the nucleus basalis of Meynert, the medial septal nucleus, and the diagonal band of Broca [37].

the synaptic cleft, either by direct administration or by inhibition of its degradation, is related to the reduction in glutamate neurotoxicity and improvement in the severity of hepatic encephalopathy [31].
