**10. Effects on the dopaminergic system**

The main dopaminergic projections originate predominantly in the neurotransmission centers of the brainstem, especially the ventral tegmental area and substantia nigra. They are modulated by glutamatergic and GABAergic neurons and, among other functions, regulate movements, reward, and cognition [37]. Three dopaminergic circuits are particularly important in the pathophysiology of chronic hepatic encephalopathy: (1) the mesocortical pathway, (2) the striatal-thalamic-cortical pathway, and (3) the nigrostriatal pathway.

The mesocortical pathway (**Figure 3**) originates in the cellular bodies of the ventral tegmental area and extends to the prefrontal cortex, where it regulates executive functions [37]. The latter correspond to a set of abilities that, in an integrated way, allow the individual to direct behaviors to goals, to evaluate the efficiency and

#### **Figure 3.**

*The mesocortical pathway originates in the dopaminergic neurons in the ventral tegmental area and extends to the prefrontal cortex, where it regulates the executive functions. It is influenced by the activity of the frontal glutamatergic cells through GABAergic inhibitory interneurons. AN: accumbens nucleus, GP: globus pallidus, S: striatum, SN: substantia nigra, and T: thalamus.*

#### **Figure 4.**

*The striatal-thalamic-cortical pathway originates in the dopaminergic neurons in the accumbens nucleus (AN) and extends to the globus pallidus (GP), where it regulates GABAergic interneurons that inhibit the activity of GABAergic interneurons in the thalamus (T), disinhibiting frontal glutamatergic activity. S: striatum.*

adequacy of these behaviors; to abandon ineffective strategies in favor of others more efficient; and, thus, solve immediate, medium, and long-term problems [3]. It is hypothesized that the dopaminergic neurons of the ventral tegmental area are influenced by the glutamatergic neurons of the frontal descending pathway [37]. Moreover, in chronic hepatic encephalopathy, there is an increase in the activity of the enzyme monoamine oxidase B (MAO-B), with increased dopamine degradation, contributing to the development of a dysexecutive syndrome [33].

Experimental research demonstrates that the striatal-thalamic-cortical pathway (**Figure 4**) originates in the nucleus accumbens and projects to the internal globus pallidus, having an important role in the regulation of motor activity. It is believed that it is also influenced by the glutamatergic neurons from the frontal lobes, which

**49**

**Figure 5.**

*T: thalamus.*

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

would excite inhibitory GABAergic interneurons. This would lead, in physiological circumstances, to a decrease in dopaminergic activity that extends from the accumbens nucleus to the internal globus pallidus, disinhibiting GABAergic interneurons that extend from the internal globus pallidus to the thalamus, where another group of GABAergic interneurons is located, with inhibitory projections to cortical glutamatergic cells. If the circuit is normofunctioning, very little dopamine is released from the accumbens nucleus, increasing the inhibitory activity that the internal globus pallidus exerts on the thalamus and preventing the latter from restricting the release of glutamate by the cortical neurons. The result is an increase in frontal glutamatergic activity, responsible for motor function. In rats submitted to a portosystemic shunt, it is observed that hyperammonemia causes greater activation of glutamatergic metabotropic receptors in the accumbens nucleus, from which results a greater release of glutamate in the frontal region, a mechanism involved in the appearance of mini-asterixis [26]. It is also hypothesized that the portosystemic shunt can promote a cerebral deposition of manganese, which characteristically generates a hypersignal in the globus pallidus in T1-weighted sequence on MRI [9]. Moreover, manganese also has a predilection for deposition in substantia nigra, with a profound toxic action on the dopaminergic neurons, which could induce or aggravate the parkinsonian symptoms of hepatic encephalopathy [10]. Human studies, however, do not demonstrate a correlation between the hyperintensity of

the globus pallidus and the severity of motor symptoms [27].

The nigrostriatal pathway (**Figure 5**) extends from the dopaminergic cell bodies of the substantia nigra to the striatum, forming part of the extrapyramidal system. It is modulated by the glutamatergic pathway and the accumbens nucleus, both being connected to it through inhibitory GABAergic interneurons. In rats submitted to a portosystemic shunt, hyperammonemia causes activation of glutamatergic ionotropic AMPA receptors in the accumbens nucleus [26], and neuroinflammation decreases the expression of glutamatergic transporters EEAT1 and VGLUT1, increasing the availability of glutamate in substantia nigra [11]. The result of this glutamatergic hyperactivity is an increase in inhibition of the nigrostriatal pathway [26], whose deficiency in dopaminergic release leads to the onset of parkinsonian symptoms such as stiffness, bradykinesia, and tremor [37]. Interestingly, experimental studies show

*The nigrostriatal dopaminergic pathway originates from the substantia nigra (SN) and extends to the striatum (S), where it regulates the extrapyramidal system. It is inhibited by GABAergic interneurons in the accumbens nucleus (AN) or brainstem, the latter being modulated by frontal glutamatergic cells. GP: globus pallidus and* 

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

*Liver Disease and Surgery*

**48**

**Figure 4.**

**Figure 3.**

*S: striatum, SN: substantia nigra, and T: thalamus.*

*striatum.*

*The striatal-thalamic-cortical pathway originates in the dopaminergic neurons in the accumbens nucleus (AN) and extends to the globus pallidus (GP), where it regulates GABAergic interneurons that inhibit the activity of GABAergic interneurons in the thalamus (T), disinhibiting frontal glutamatergic activity. S:* 

*The mesocortical pathway originates in the dopaminergic neurons in the ventral tegmental area and extends to the prefrontal cortex, where it regulates the executive functions. It is influenced by the activity of the frontal glutamatergic cells through GABAergic inhibitory interneurons. AN: accumbens nucleus, GP: globus pallidus,* 

adequacy of these behaviors; to abandon ineffective strategies in favor of others more efficient; and, thus, solve immediate, medium, and long-term problems [3]. It is hypothesized that the dopaminergic neurons of the ventral tegmental area are influenced by the glutamatergic neurons of the frontal descending pathway [37]. Moreover, in chronic hepatic encephalopathy, there is an increase in the activity of the enzyme monoamine oxidase B (MAO-B), with increased dopamine degrada-

Experimental research demonstrates that the striatal-thalamic-cortical pathway (**Figure 4**) originates in the nucleus accumbens and projects to the internal globus pallidus, having an important role in the regulation of motor activity. It is believed that it is also influenced by the glutamatergic neurons from the frontal lobes, which

tion, contributing to the development of a dysexecutive syndrome [33].

would excite inhibitory GABAergic interneurons. This would lead, in physiological circumstances, to a decrease in dopaminergic activity that extends from the accumbens nucleus to the internal globus pallidus, disinhibiting GABAergic interneurons that extend from the internal globus pallidus to the thalamus, where another group of GABAergic interneurons is located, with inhibitory projections to cortical glutamatergic cells. If the circuit is normofunctioning, very little dopamine is released from the accumbens nucleus, increasing the inhibitory activity that the internal globus pallidus exerts on the thalamus and preventing the latter from restricting the release of glutamate by the cortical neurons. The result is an increase in frontal glutamatergic activity, responsible for motor function. In rats submitted to a portosystemic shunt, it is observed that hyperammonemia causes greater activation of glutamatergic metabotropic receptors in the accumbens nucleus, from which results a greater release of glutamate in the frontal region, a mechanism involved in the appearance of mini-asterixis [26]. It is also hypothesized that the portosystemic shunt can promote a cerebral deposition of manganese, which characteristically generates a hypersignal in the globus pallidus in T1-weighted sequence on MRI [9]. Moreover, manganese also has a predilection for deposition in substantia nigra, with a profound toxic action on the dopaminergic neurons, which could induce or aggravate the parkinsonian symptoms of hepatic encephalopathy [10]. Human studies, however, do not demonstrate a correlation between the hyperintensity of the globus pallidus and the severity of motor symptoms [27].

The nigrostriatal pathway (**Figure 5**) extends from the dopaminergic cell bodies of the substantia nigra to the striatum, forming part of the extrapyramidal system. It is modulated by the glutamatergic pathway and the accumbens nucleus, both being connected to it through inhibitory GABAergic interneurons. In rats submitted to a portosystemic shunt, hyperammonemia causes activation of glutamatergic ionotropic AMPA receptors in the accumbens nucleus [26], and neuroinflammation decreases the expression of glutamatergic transporters EEAT1 and VGLUT1, increasing the availability of glutamate in substantia nigra [11]. The result of this glutamatergic hyperactivity is an increase in inhibition of the nigrostriatal pathway [26], whose deficiency in dopaminergic release leads to the onset of parkinsonian symptoms such as stiffness, bradykinesia, and tremor [37]. Interestingly, experimental studies show

#### **Figure 5.**

*The nigrostriatal dopaminergic pathway originates from the substantia nigra (SN) and extends to the striatum (S), where it regulates the extrapyramidal system. It is inhibited by GABAergic interneurons in the accumbens nucleus (AN) or brainstem, the latter being modulated by frontal glutamatergic cells. GP: globus pallidus and T: thalamus.*

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