3.4.6 Major neurochemical pathways

The Anatomical Course of Major Neurochemical Pathways

Neurochemical pathway:	Summary:
Nigrostriatal dopamine pathway	The nigrostriatal pathway connects the substantia nigra (a region of the midbrain) to the basal ganglia and plays a role in movement control.
Mesolimbic dopamine pathway	The mesolimbic pathway projects from the ventral tegmental area of the midbrain to the nucleus accumbens and is involved in reward and pleasure.
Mesocortical dopamine pathway	The mesocortical pathway projects from the ventral tegmental area to the prefrontal cortex and is involved in emotional and cognitive processes.
Tuberoinfundibular dopamine pathway	The tuberoinfundibular pathway projects from the hypothalamus to the pituitary gland and regulates the secretion of hormones.
Ascending noradrenergic pathway from locus coeruleus	The ascending noradrenergic pathway from the locus coeruleus projects from the locus coeruleus to various brain regions and is involved in the regulation of attention, arousal, and emotional responses.
Basal forebrain cholinergic pathway	The basal forebrain cholinergic pathway originates in the basal forebrain and projects to various brain regions, including the prefrontal cortex and hippocampus, and plays a role in learning, memory, and attention.
Brain stem cholinergic pathway	The brain stem cholinergic pathway is located in the brain stem and projects to various brain regions, including the thalamus, hippocampus, and cortex, and is involved in arousal, attention, and cognitive function.
Corticofugal glutamate system	The corticofugal glutamate system projects from the cerebral cortex to various brain regions, including the hippocampus and amygdala, and is involved in the integration of sensory information and the modulation of cognitive and emotional processes.
Serotonin pathway	The serotonin pathway involves the neurotransmitter serotonin and is involved in the regulation of mood, anxiety, appetite, sleep, and other functions in various brain regions, including the raphe nuclei, hippocampus, and prefrontal cortex.

Nigrostriatal dopamine pathway:

The nigrostriatal dopamine pathway is a neural pathway that plays a critical role in the control of movement. It is made up of a group of nerve cells that produce and release the neurotransmitter dopamine and extend from an area of the brain called the substantia nigra to an area called the striatum.

Dopamine released by these nerve cells helps to regulate the activity of neurons in the striatum, which are involved in the planning, initiation, and execution of voluntary movement. Dysfunction of the nigrostriatal dopamine pathway, such as a loss of dopamine-producing cells or a deficiency in dopamine release, can lead to movement disorders such as Parkinson’s disease.

Studies have shown that people with schizophrenia often have abnormalities in the activity of dopamine neurons in the substantia nigra and the striatum. These abnormalities may be due to a deficiency in dopamine production or a failure of dopamine signalling in these brain regions.

One of the ways in which antipsychotics work is by modulating the activity of the nigrostriatal dopamine pathway. Many antipsychotics, particularly those known as “typical” or “first-generation” antipsychotics, act by blocking dopamine receptors in the brain, including those in the nigrostriatal pathway. This can help to reduce abnormal dopamine signalling in the brain, which may be involved in the symptoms of schizophrenia and other psychotic disorders.

Mesolimbic dopamine pathway:

The mesolimbic pathway is a dopamine-rich neural pathway that plays a central role in reward and motivation. It is a major part of the brain’s reward system, which is responsible for reinforcing behaviours that are necessary for the survival and reproduction of an organism. The mesolimbic pathway begins in the ventral tegmental area (VTA) of the midbrain and projects to the nucleus accumbens in the forebrain. It is thought to be involved in the pleasurable effects of drugs of abuse, including stimulants such as cocaine and amphetamines, as well as other pleasurable experiences such as eating and sex (Hyman et al., 2006). Dysfunction of the mesolimbic pathway has been linked to several psychiatric disorders, including addiction, schizophrenia, and depression (Koo et al., 2010).

It is thought that the overactivity of dopamine in the mesolimbic pathway may contribute to the positive symptoms of schizophrenia, such as hallucinations and delusions (Kapur, 2003). By blocking dopamine receptors, antipsychotic medications can reduce the activity of the mesolimbic pathway and alleviate these symptoms.

However, the relationship between the mesolimbic pathway and antipsychotics in schizophrenia is complex and not fully understood. While dopamine receptor blockade is thought to be the primary mechanism of action of antipsychotics, these medications may also have effects on other neurotransmitter systems in the brain, such as serotonin and glutamate (Meltzer, 2015). Additionally, the long-term use of antipsychotics may lead to changes in the mesolimbic pathway and other brain regions, which may contribute to their therapeutic effects as well as side effects (Seeman, 2010).

Mesocortical dopamine pathway:

The mesocortical pathway is a neural pathway that projects from the ventral tegmental area (VTA) of the midbrain to the prefrontal cortex, a region of the brain involved in higher cognitive functions such as planning, decision-making, and behaviour regulation. The mesocortical pathway is rich in dopamine and is thought to play a role in the regulation of emotional and cognitive processes (Goldman-Rakic, 1994). Dysfunction of the mesocortical pathway has been implicated in several psychiatric disorders, including schizophrenia, depression, and Parkinson’s disease (Nestler & Carlezon, 2006).

Studies have shown that activation of the mesocortical pathway can enhance cognitive performance and that deficits in dopamine signalling in this pathway may contribute to the cognitive impairments observed in schizophrenia (Goldman-Rakic, 1994; Arnsten, 2009). Antipsychotic medications, which are commonly used to treat schizophrenia, are thought to improve cognitive function by normalizing dopamine signalling in the mesocortical pathway (Meltzer, 2015).

Tuburoinfundibular dopamine pathway:

The tuberoinfundibular pathway is a neural pathway that regulates the secretion of hormones from the hypothalamus, a region of the brain located below the thalamus. The pathway begins in the hypothalamus and projects to the pituitary gland, a gland located at the base of the brain that produces and releases hormones into the bloodstream. The tuberoinfundibular pathway is rich in dopamine and is thought to play a role in the regulation of prolactin, a hormone involved in milk production and other processes (Lopez & Mehler, 2011).

Dysfunction of the tuberoinfundibular pathway has been linked to several endocrine disorders, including hyperprolactinemia, a condition characterized by high levels of prolactin in the blood. Hyperprolactinemia can cause a range of symptoms, including irregular menstrual cycles and reduced libido in women, and breast milk production and impotence in men (Lopez & Mehler, 2011). Antipsychotic medications, which are commonly used to treat psychiatric disorders, can also disrupt the normal functioning of the tuberoinfundibular pathway and cause hyperprolactinemia as a side effect (Meltzer, 2015).

Ascending noradrenergic pathway from the locus coeruleus:

The ascending noradrenergic pathway from the locus coeruleus is a neural pathway that originates in the locus coeruleus, a small nucleus located in the brainstem, and projects to various brain regions including the prefrontal cortex, hippocampus, and amygdala. The locus coeruleus is the primary source of noradrenaline, a neurotransmitter that plays a role in the regulation of attention, arousal, and emotional responses. The ascending noradrenergic pathway is thought to play a role in the integration of sensory information and the modulation of cognitive and emotional processes (Aston-Jones & Cohen, 2005).

Dysfunction of the ascending noradrenergic pathway has been implicated in several psychiatric disorders, including depression, anxiety, and post-traumatic stress disorder (PTSD) (Herman et al., 2003). Antidepressant medications, such as selective serotonin reuptake inhibitors (SSRIs), are thought to work by increasing the availability of noradrenaline in the brain, including in the ascending noradrenergic pathway (Meltzer, 2015).

Basal forebrain cholinergic pathway:

The basal forebrain cholinergic pathway is a neural pathway that originates in the basal forebrain and projects to various brain regions including the prefrontal cortex, hippocampus, and amygdala. The basal forebrain is a region of the brain that contains a group of neurons that produce and release acetylcholine, a neurotransmitter that plays a role in learning, memory, and attention. The basal forebrain cholinergic pathway is thought to play a crucial role in the regulation of cognitive function and the consolidation of memories (Hasselmo & Sarter, 2011).

Dysfunction of the basal forebrain cholinergic pathway has been linked to several neurodegenerative disorders, including Alzheimer’s disease, which is characterized by a decline in cognitive function and memory impairment (Olabarria et al., 2013). Cholinesterase inhibitors, a class of medications used to treat Alzheimer’s disease, are thought to work by increasing the availability of acetylcholine in the basal forebrain cholinergic pathway (Olabarria et al., 2013).

Brain stem cholinergic pathway:

The brain stem cholinergic system is a group of neurons that produce and release acetylcholine, a neurotransmitter that plays a role in learning, memory, and attention. The brain stem cholinergic system is located in the brain stem, which is the lower part of the brain that controls essential functions such as heart rate, blood pressure, and respiration. The brain stems cholinergic system projects to various brain regions including the thalamus, hippocampus, and cortex and is thought to play a role in the regulation of arousal, attention, and cognitive function (Hasselmo & Sarter, 2011).

Dysfunction of the brain stem cholinergic system has been implicated in several neurodegenerative disorders, including Alzheimer’s disease, which is characterized by a decline in cognitive function and memory impairment (Olabarria et al., 2013). Cholinesterase inhibitors, a class of medications used to treat Alzheimer’s disease, are thought to work by increasing the availability of acetylcholine in the brain stem cholinergic system (Olabarria et al., 2013).

Corticofugal glutamate system:

The corticofugal glutamate system is a neural pathway that projects from the cerebral cortex, the outer layer of the brain responsible for higher cognitive functions, to various brain regions, including the hippocampus and amygdala. The corticofugal glutamate system is rich in glutamate, a neurotransmitter that plays a role in learning, memory, and other cognitive processes. The corticofugal glutamate system is thought to play a role in the integration of sensory information and the modulation of cognitive and emotional processes (Aston-Jones & Cohen, 2005).

Dysfunction of the corticofugal glutamate system has been linked to several neurological and psychiatric disorders, including schizophrenia, addiction, and depression. Glutamate receptor antagonists, a class of medications that block the effects of glutamate, are sometimes used to treat these disorders. However, the use of these medications can also have undesirable side effects, including memory impairment and movement disorders (Kumar et al., 2016).

Serotonin pathway:

The serotonin pathway is a neural pathway that involves the neurotransmitter serotonin. Serotonin is synthesized in the brain and is involved in the regulation of mood, anxiety, appetite, sleep, and other functions. The serotonin pathway includes several brain regions, including the raphe nuclei in the brainstem, the hippocampus, and the prefrontal cortex, as well as various neurotransmitter receptors.

Dysfunction of the serotonin pathway has been linked to several psychiatric disorders, including depression, anxiety, and obsessive-compulsive disorder (OCD) (Cryan et al., 2002). Selective serotonin reuptake inhibitors (SSRIs), a class of antidepressant medications, are thought to work by increasing the availability of serotonin in the brain, including in the serotonin pathway (Cryan et al., 2002). SSRIs are commonly used to treat depression and anxiety disorders and have been found to be effective in reducing symptoms in many people (Blier & Ward, 2003).

References:

(1) Arnsten, A. F. (2009). Stress signaling pathways that impair prefrontal cortex structure and function. Nature Reviews Neuroscience, 10(6), 410-422.

(2) Aston-Jones, G., & Cohen, J. D. (2005). An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annual Review of Neuroscience, 28, 403-450.

(3) Blier, P., & Ward, H. E. (2003). The role of serotonin in the mechanism of action of antidepressant treatment. Journal of Clinical Psychiatry, 64(Suppl 4), 14-19.

(4) Cryan, J. F., Markou, A., & Lucki, I. (2002). Assessing antidepressant activity in rodents: recent developments and future needs. Trends in Pharmacological Sciences, 23(2), 67-73.

(4) Goldman-Rakic, P. S. (1994). Working memory dysfunction in schizophrenia. Journal of Neuropsychiatry and Clinical Neurosciences, 6(3), 348-357.

(5) Herman, J. P., Ostrander, M. M., Mueller, N. K., & Figueiredo, H. (2003). Limbic system mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 27(2), 181-197.

(6) Hyman, S. E., Malenka, R. C., & Nestler, E. J. (2006). Neural mechanisms of addiction: the role of reward-related learning and memory. Annual Review of Neuroscience, 29, 565-598.

(7) Kapur, S. (2003). Psychosis as a state of aberrant salience: a framework linking biology, phenomenology

(8) Kumar, A., Jones, A. K., & Wykes, T. (2016). Glutamate receptor antagonists as treatments for psychiatric disorders: a review. Current Opinion in Psychiatry, 29(6), 423-428.

(9) Lopez, F., & Mehler, M. F. (2011). Hyperprolactinemia: a review. Pituitary, 14(2), 123-136.

(10) Meltzer, H. Y. (2015). Serotonin-dopamine interaction and its relevance to schizophrenia. Dialogues in Clinical Neuroscience, 17(3), 345-359.

(11) Nestler, E. J., & Carlezon, W. A. (2006). The mesolimbic dopamine reward circuit in depression. Biological Psychiatry, 59(12), 1151-1159.

(12) Olabarria, M., Korten, A., & van der Meer, A. D. (2013). The basal forebrain cholinergic system in Alzheimer’s disease. Frontiers in Aging Neuroscience, 5, 6.

(13) Seeman, P. (2010). Antipsychotic drugs and their effects on neurotransmitter receptors. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 34(8), 1523-1534.