Substantia nigra
Encyclopedia
The substantia nigra is a brain structure located in the mesencephalon
(midbrain) that plays an important role in reward, addiction
, and movement
. Substantia nigra is Latin
for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin
in dopamine
rgic neuron
s. Parkinson's disease
is characterized by the death of dopaminergic neurons in the substantia nigra pars compacta
.
Although the substantia nigra appears as a continuous band in brain sections, anatomical studies have found that it actually consists of two parts with very different connections and functions, the pars compacta and pars reticulata. The pars compacta serves mainly as an input to the basal ganglia circuit, supplying the striatum with dopamine. The pars reticulata, on the other hand, serves mainly as an output, conveying signals from the basal ganglia to numerous other brain structures.
The substantia nigra, along with four other nuclei, is part of the basal ganglia
. The substantia nigra lies in the midbrain, dorsal to the cerebral peduncles. Humans have two substantiae nigrae, one on each side of the midline. The substantia nigra is the largest nucleus
in the midbrain. The substantia nigra is divided into two parts: the pars reticulata (SNr) and pars compacta (SNc), which lies medial to the pars reticulata. Sometimes a third region, the pars lateralis, is mentioned; however, this is usually classified as part of the pars reticulata. The pars reticulata and the internal globus pallidus
are separated by the internal capsule
.
.
. It comes by two routes, known as the direct and indirect pathways. The direct pathway consists of axons from medium spiny cells in the striatum that project directly to SNr. The indirect pathway consists of three links, first a projection from striatal medium spiny cells to the external part of the globus pallidus
(GPe); second a GABAergic projection from GPe to the subthalamic nucleus
(STN); third a glutamatergic projection from STN to SNr. Thus, striatal activity exerts an excitatory (or rather disinhibitory) effect on SNr neurons via the direct pathway, but an inhibitory effect via the indirect pathway. The direct and indirect pathways originate from different subsets of striatal medium spiny cells: they are tightly intermingled but express different types of dopamine receptors, as well as showing other neurochemical differences.
, and addiction. Many of the substantia nigra's effects are mediated through the striatum
. The nigral dopaminergic
input to the striatum via the nigrostriatal pathway
is intimately linked with the striatum's function. The co-dependence between the striatum and substantia nigra can be seen in this way: when the substantia nigra is electrically stimulated, no movement occurs; however, the symptoms of nigral degeneration due to Parkinson's is a poignant example of the substantia nigra's influence on movement. In addition to striatum-mediated functions, the substantia nigra also serves as a major source of GABAergic inhibition to various brain targets.
of the substantia nigra is an important processing center in the basal ganglia
. The GABAergic neurons in the pars reticulata convey the final processed signals of the basal ganglia
to the thalamus
and superior colliculus
. In addition, the pars reticulata also inhibits dopaminergic activity in the pars compacta
via axon collaterals, although the functional organization of these connections remains unclear.
The GABAergic neurons of the pars reticulata spontaneously fire action potential
s. In rats, the frequency of action potentials is roughly 25 Hz. The purpose of these spontaneous action potentials is to inhibit targets of the basal ganglia, and decreases in inhibition are associated with movement. The subthalamic nucleus gives excitatory input that modulates the rate of firing of these spontaneous action potentials. However, lesion of the subthalamic nucleus leads to only a 20% decrease in pars reticulata firing rate, suggesting that the generation of action potentials in the pars reticulata is largely autonomous. An example of this inhibitory output is the important role of the pars reticulata in saccadic eye movement
. A group of GABAergic neurons from the pars reticulata projects to the superior colliculus
. This connection exhibits a high level of sustained, inhibitory activity. Projections from the caudate nucleus
to the superior colliculus also modulate saccadic eye movement.
Altered patterns of pars reticulata firing such as single-spike or burst firing are found in Parkinson's disease
and epilepsy
.
. However, the substantia nigra's role in motor control is indirect; electrical stimulation of the substantia nigra does not result in movement. This is due to the mediation of the striatum in the nigral influence of movement. However, lack of pars compacta neurons clearly has a large influence on movement, as evidenced by the symptoms of Parkinson's. The motor role of the pars compacta may involve fine motor control; this has been confirmed in animal models with lesions in the pars compacta.
The pars compacta is heavily involved in learned responses to stimuli. In primates, dopaminergic neuron activity increases in the nigrostriatal pathway when a new stimulus is presented. Dopaminergic activity decreases with repeated stimulus presentation. However, behaviorally significant stimulus presentation (such as classical conditioning
where a reward is presented) continues to activate the dopaminergic neurons. This phenomenon helps explain the role of the dopamine system in the addictiveness of drugs. In addition, the pars compacta is important in "spatial learning," the observations about one's environment and location in space. Lesions in the pars compacta lead to learning deficits in repeating identical movements, and some studies point to its involvement in a dorsal striatal-dependent, response-based memory system that functions relatively independent of the hippocampus
, which is traditionally believed to subserve spatial or episodic-like memory functions.
Temporal processing is also an important function of the pars compacta. The pars compacta is activated during time reproduction and lesion
s in the pars compacta leads to temporal deficits. As of late, the pars compacta has been suspected of regulating the sleep-wake cycle. This is consistent with symptoms such as insomnia
and REM sleep disturbances that are reported by patients with Parkinson's disease
. Even so, partial dopamine deficits that do not affect motor control can lead to disturbances in the sleep-wake cycle, especially REM-like patterns of neural activity while awake, especially in the hippocampus
.
.
, akinesia, bradykinesia, and stiffness. Other symptoms include disturbances to posture, fatigue, sleep abnormalities, and depression
.
The cause of death of dopaminergic neurons in the pars compacta is unknown. However, some contributions to the unique susceptibility of dopaminergic neurons in the pars compacta have been identified. For one, dopaminergic neurons show abnormalities in mitochondrial complex 1, causing aggregation of alpha-synuclein
. This could result in abnormal protein handling and neuron death. Secondly, dopaminergic neurons in the pars compacta contain less calbindin than other dopaminergic neurons. Calbindin
is a protein involved in calcium
ion transport within cells, and excess calcium in cells is toxic. The calbindin theory would explain the high cytotoxicity of Parkinson's in the substantia nigra compared to the ventral tegmental area. Regardless of the cause of neuronal death, the plasticity of the pars compacta is very robust; Parkinsonian symptoms do not appear until up to 50-80% of pars compacta dopaminergic neurons have died. Most of this plasticity occurs at the neurochemical level; dopamine transport systems are slowed, allowing dopamine to linger for longer periods of time in the chemical synapses in the striatum.
. However, much debate continues to this day surrounding this theory, commonly known as the dopamine hypothesis of schizophrenia
. Despite the controversy, dopamine antagonists remain a standard and successful treatment for schizophrenia. These antagonists include first generation (typical) antipsychotics
such as butyrophenones, phenothiazines, and thioxanthenes. These drugs have largely been replaced by second generation (atypical) antipsychotics
such as clozapine
and paliperidone
. It should be noted that these drugs generally do not act on dopamine-producing neurons themselves, but on the receptors on the post-synaptic neuron.
Other, non-pharmacological evidence in support of the dopamine hypothesis relating to the substantia nigra include structural changes in the pars compacta, such as reduction in synaptic terminal size. Other changes in the substantia nigra include increased expression of NMDA receptor
s in the substantia nigra, and reduced dysbindin
expression. Increased NMDA receptors may point to the involvement of glutamate-dopamine
interactions in schizophrenia. Dysbindin, which has been (controversially) linked to schizophrenia, may regulate dopamine release, and low expression of dysbindin in the substantia nigra may be important in schizophrenia etiology. Due to the changes to the substantia nigra in the schizophrenic brain, it may eventually be possible to use specific imaging techniques (such as melanin-specific imaging) to detect physiological signs of schizophrenia in the substantia nigra.
and toxicology
. Various compounds such as levodopa and MPTP are used in the treatment and study of Parkinson's disease, and many other drugs have effects on the substantia nigra.
(L-DOPA), the dopamine precursor, is the most commonly prescribed medication for Parkinson's disease. Despite controversy concerning the neurotoxicity of dopamine and L-DOPA, it remains the most common treatment for Parkinson's disease. The drug is especially effective in treating patients in the early stages of Parkinson's, although the drug does lose its efficacy over time. Levodopa can cross the blood-brain barrier
and increases dopamine levels in the substantia nigra, thus alleviating the symptoms of Parkinson's disease. The drawback of levodopa treatment is that it treats the symptoms of Parkinson's (low dopamine levels), rather than the cause (the death of dopaminergic neurons in the substantia nigra).
(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), is a neurotoxin specific to dopaminergic cells in the brain, specifically in the substantia nigra. MPTP was brought to the spotlight in 1982 when heroin users in California displayed Parkinson's-like symptoms after using MPPP
contaminated with MPTP. The patients, who were rigid and almost completely immobile, responded to levodopa treatment. No remission of the Parkinson's-like symptoms was reported, suggesting irreversible death of the dopaminergic neurons. The proposed mechanism of MPTP involves disruption of mitochondrial function, including disruption of metabolism
and creation of free radicals.
Soon after, MPTP was tested in animal models for its efficacy in inducing Parkinson's disease (with success). MPTP induced akinesia, rigidity, and tremor in primates, and its neurotoxicity was found to be very specific to the substantia nigra pars compacta. In other animals, such as rodents, the induction of Parkinson's by MPTP is incomplete or requires much higher and frequent doses than in primates. Today, MPTP remains the most favored model for studying Parkinson's.
's mechanism of action in the human brain includes the inhibition of dopamine reuptake. This blockage of dopamine reuptake explains cocaine's addictive properties, as dopamine is the critical neurotransmitter for reward. However, cocaine is more active in the dopaminergic neurons of the ventral tegmental area than the substantia nigra. Cocaine administration increases metabolism in the substantia nigra, which can explain the altered motor function seen in cocaine-using subjects. The inhibition of dopamine reuptake by cocaine also inhibits the firing of spontaneous action potentials by the pars compacta. The mechanism by which cocaine inhibits dopamine reuptake involves its binding to the dopamine transporter
protein, or DAT. However, recent studies show that cocaine can also cause a decrease in DAT mRNA levels. This is probably caused by cocaine's blockade of DAT rather than direct interference with transcriptional or translational pathways.
Inactivation of the substantia nigra could prove to be a possible treatment for cocaine addiction. In a study of cocaine-dependent rats, inactivation of the substantia nigra via implanted cannulae greatly reduced cocaine addiction relapse.
increases the concentrations of dopamine
in the synaptic cleft, thereby heightening the response of the post-synaptic neuron. Also like cocaine, the altered dopamine function contributes to the addictiveness of amphetamines.
The mechanism by which amphetamines increase synaptic levels of dopamine is to release dopamine from pre-synaptic vesicles
, increasing concentrations of dopamine
in the cytosol
of the pre-synaptic neuron. The high concentration of dopamine in the pre-synaptic terminal causes the reverse transport of dopamine through the dopamine transporter
(DAT) and into the synaptic cleft.
Mesencephalon
The midbrain or mesencephalon is a portion of the central nervous system associated with vision, hearing, motor control, sleep/wake, arousal , and temperature regulation....
(midbrain) that plays an important role in reward, addiction
Substance use disorder
Substance use disorders include substance abuse and substance dependence. In DSM-IV, the conditions are formally diagnosed as one or the other, but it has been proposed that DSM-5 combine the two into a single condition called "Substance-use disorder"....
, and movement
Motor system
The motor system is the part of the central nervous system that is involved with movement. It consists of the pyramidal and extrapyramidal system....
. Substantia nigra is Latin
Latin
Latin is an Italic language originally spoken in Latium and Ancient Rome. It, along with most European languages, is a descendant of the ancient Proto-Indo-European language. Although it is considered a dead language, a number of scholars and members of the Christian clergy speak it fluently, and...
for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin
Melanin
Melanin is a pigment that is ubiquitous in nature, being found in most organisms . In animals melanin pigments are derivatives of the amino acid tyrosine. The most common form of biological melanin is eumelanin, a brown-black polymer of dihydroxyindole carboxylic acids, and their reduced forms...
in dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
rgic neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s. Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
is characterized by the death of dopaminergic neurons in the substantia nigra pars compacta
Pars compacta
-Anatomy:In humans, the nerve cell bodies of the pars compacta are coloured black by the pigment neuromelanin. The degree of pigmentation increases with age. This pigmentation is visible as a distinctive black stripe in brain sections and is the origin of the name given to this area. The neurons...
.
Although the substantia nigra appears as a continuous band in brain sections, anatomical studies have found that it actually consists of two parts with very different connections and functions, the pars compacta and pars reticulata. The pars compacta serves mainly as an input to the basal ganglia circuit, supplying the striatum with dopamine. The pars reticulata, on the other hand, serves mainly as an output, conveying signals from the basal ganglia to numerous other brain structures.
Anatomy
The substantia nigra, along with four other nuclei, is part of the basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
. The substantia nigra lies in the midbrain, dorsal to the cerebral peduncles. Humans have two substantiae nigrae, one on each side of the midline. The substantia nigra is the largest nucleus
Nucleus (neuroanatomy)
In neuroanatomy, a nucleus is a brain structure consisting of a relatively compact cluster of neurons. It is one of the two most common forms of nerve cell organization, the other being layered structures such as the cerebral cortex or cerebellar cortex. In anatomical sections, a nucleus shows up...
in the midbrain. The substantia nigra is divided into two parts: the pars reticulata (SNr) and pars compacta (SNc), which lies medial to the pars reticulata. Sometimes a third region, the pars lateralis, is mentioned; however, this is usually classified as part of the pars reticulata. The pars reticulata and the internal globus pallidus
Globus pallidus
The globus pallidus also known as paleostriatum, is a sub-cortical structure of the brain. Topographically, it is part of the telencephalon, but retains close functional ties with the subthalamus - both of which are part of the extrapyramidal motor system...
are separated by the internal capsule
Internal capsule
The internal capsule is an area of white matter in the brain that separates the caudate nucleus and the thalamus from the lenticular nucleus. The internal capsule contains both ascending and descending axons....
.
Pars reticulata
The SNr bears a strong resemblance, both structurally and functionally, to the internal part of the globus pallidus (GPi). The two are sometimes considered parts of the same structure, separated by the white matter of the internal capsule. Like those of the globus pallidus, the neurons in SNr are mainly GABAergicGamma-aminobutyric acid
γ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...
.
Afferent connections
The main input to the SNr derives from the striatumStriatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
. It comes by two routes, known as the direct and indirect pathways. The direct pathway consists of axons from medium spiny cells in the striatum that project directly to SNr. The indirect pathway consists of three links, first a projection from striatal medium spiny cells to the external part of the globus pallidus
Globus pallidus
The globus pallidus also known as paleostriatum, is a sub-cortical structure of the brain. Topographically, it is part of the telencephalon, but retains close functional ties with the subthalamus - both of which are part of the extrapyramidal motor system...
(GPe); second a GABAergic projection from GPe to the subthalamic nucleus
Subthalamic nucleus
The subthalamic nucleus is a small lens-shaped nucleus in the brain where it is, from a functional point of view, part of the basal ganglia system. Anatomically, it is the major part of subthalamus. As suggested by its name, the subthalamic nucleus is located ventral to the thalamus. It is also...
(STN); third a glutamatergic projection from STN to SNr. Thus, striatal activity exerts an excitatory (or rather disinhibitory) effect on SNr neurons via the direct pathway, but an inhibitory effect via the indirect pathway. The direct and indirect pathways originate from different subsets of striatal medium spiny cells: they are tightly intermingled but express different types of dopamine receptors, as well as showing other neurochemical differences.
Efferent connections
There are significant projections to the thalamus (ventral lateral and ventral anterior nuclei), superior colliculus, and other caudal nuclei from the pars reticulata (the nigrothalamic pathway). These neurons use GABA as their neurotransmitter. In addition, these neurons form up to five collaterals that branch within both the pars compacta and pars reticulata, likely modulating dopaminergic activity in the pars compacta.Function
The substantia nigra is an important player in brain function, in particular, in eye movement, motor planning, reward seeking, learningLearning
Learning is acquiring new or modifying existing knowledge, behaviors, skills, values, or preferences and may involve synthesizing different types of information. The ability to learn is possessed by humans, animals and some machines. Progress over time tends to follow learning curves.Human learning...
, and addiction. Many of the substantia nigra's effects are mediated through the striatum
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
. The nigral dopaminergic
Dopaminergic
Dopaminergic means related to the neurotransmitter dopamine. For example, certain proteins such as the dopamine transporter , vesicular monoamine transporter 2 , and dopamine receptors can be classified as dopaminergic, and neurons which synthesize or contain dopamine and synapses with dopamine...
input to the striatum via the nigrostriatal pathway
Nigrostriatal pathway
The nigrostriatal pathway is a neural pathway that connects the substantia nigra with the striatum. It is one of the four major dopamine pathways in the brain, and is particularly involved in the production of movement, as part of a system called the basal ganglia motor loop.Loss of dopamine...
is intimately linked with the striatum's function. The co-dependence between the striatum and substantia nigra can be seen in this way: when the substantia nigra is electrically stimulated, no movement occurs; however, the symptoms of nigral degeneration due to Parkinson's is a poignant example of the substantia nigra's influence on movement. In addition to striatum-mediated functions, the substantia nigra also serves as a major source of GABAergic inhibition to various brain targets.
Pars Reticulata
The pars reticulataPars reticulata
-Anatomy:Neurons in the pars reticulata are much less densely packed than those in the pars compacta . They are smaller and thinner than the dopaminergic neurons and conversely identical and morphologically similar to the pallidal neurons...
of the substantia nigra is an important processing center in the basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
. The GABAergic neurons in the pars reticulata convey the final processed signals of the basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
to the thalamus
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
and superior colliculus
Superior colliculus
The optic tectum or simply tectum is a paired structure that forms a major component of the vertebrate midbrain. In mammals this structure is more commonly called the superior colliculus , but, even in mammals, the adjective tectal is commonly used. The tectum is a layered structure, with a...
. In addition, the pars reticulata also inhibits dopaminergic activity in the pars compacta
Pars compacta
-Anatomy:In humans, the nerve cell bodies of the pars compacta are coloured black by the pigment neuromelanin. The degree of pigmentation increases with age. This pigmentation is visible as a distinctive black stripe in brain sections and is the origin of the name given to this area. The neurons...
via axon collaterals, although the functional organization of these connections remains unclear.
The GABAergic neurons of the pars reticulata spontaneously fire action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
s. In rats, the frequency of action potentials is roughly 25 Hz. The purpose of these spontaneous action potentials is to inhibit targets of the basal ganglia, and decreases in inhibition are associated with movement. The subthalamic nucleus gives excitatory input that modulates the rate of firing of these spontaneous action potentials. However, lesion of the subthalamic nucleus leads to only a 20% decrease in pars reticulata firing rate, suggesting that the generation of action potentials in the pars reticulata is largely autonomous. An example of this inhibitory output is the important role of the pars reticulata in saccadic eye movement
Saccade
A saccade is a fast movement of an eye, head or other part of an animal's body or device. It can also be a fast shift in frequency of an emitted signal or other quick change. Saccades are quick, simultaneous movements of both eyes in the same direction...
. A group of GABAergic neurons from the pars reticulata projects to the superior colliculus
Superior colliculus
The optic tectum or simply tectum is a paired structure that forms a major component of the vertebrate midbrain. In mammals this structure is more commonly called the superior colliculus , but, even in mammals, the adjective tectal is commonly used. The tectum is a layered structure, with a...
. This connection exhibits a high level of sustained, inhibitory activity. Projections from the caudate nucleus
Caudate nucleus
The caudate nucleus is a nucleus located within the basal ganglia of the brains of many animal species. The caudate nucleus is an important part of the brain's learning and memory system.-Anatomy:...
to the superior colliculus also modulate saccadic eye movement.
Altered patterns of pars reticulata firing such as single-spike or burst firing are found in Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
and epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
.
Pars Compacta
The most prominent function of the pars compacta is motor controlMotor control
Motor control are information processing related activities carried out by the central nervous system that organize the musculoskeletal system to create coordinated movements and skilled actions...
. However, the substantia nigra's role in motor control is indirect; electrical stimulation of the substantia nigra does not result in movement. This is due to the mediation of the striatum in the nigral influence of movement. However, lack of pars compacta neurons clearly has a large influence on movement, as evidenced by the symptoms of Parkinson's. The motor role of the pars compacta may involve fine motor control; this has been confirmed in animal models with lesions in the pars compacta.
The pars compacta is heavily involved in learned responses to stimuli. In primates, dopaminergic neuron activity increases in the nigrostriatal pathway when a new stimulus is presented. Dopaminergic activity decreases with repeated stimulus presentation. However, behaviorally significant stimulus presentation (such as classical conditioning
Classical conditioning
Classical conditioning is a form of conditioning that was first demonstrated by Ivan Pavlov...
where a reward is presented) continues to activate the dopaminergic neurons. This phenomenon helps explain the role of the dopamine system in the addictiveness of drugs. In addition, the pars compacta is important in "spatial learning," the observations about one's environment and location in space. Lesions in the pars compacta lead to learning deficits in repeating identical movements, and some studies point to its involvement in a dorsal striatal-dependent, response-based memory system that functions relatively independent of the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
, which is traditionally believed to subserve spatial or episodic-like memory functions.
Temporal processing is also an important function of the pars compacta. The pars compacta is activated during time reproduction and lesion
Lesion
A lesion is any abnormality in the tissue of an organism , usually caused by disease or trauma. Lesion is derived from the Latin word laesio which means injury.- Types :...
s in the pars compacta leads to temporal deficits. As of late, the pars compacta has been suspected of regulating the sleep-wake cycle. This is consistent with symptoms such as insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
and REM sleep disturbances that are reported by patients with Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
. Even so, partial dopamine deficits that do not affect motor control can lead to disturbances in the sleep-wake cycle, especially REM-like patterns of neural activity while awake, especially in the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
.
Pathophysiology
The substantia nigra is critical in the development of many diseases, including Parkinson's diseaseParkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
.
Parkinson's Disease
Parkinson's disease is a neurodegenerative disease characterized, in part, by the death of dopaminergic neurons in the pars compacta of the substantia nigra. The major symptoms of Parkinson's disease include tremorTremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
, akinesia, bradykinesia, and stiffness. Other symptoms include disturbances to posture, fatigue, sleep abnormalities, and depression
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
.
The cause of death of dopaminergic neurons in the pars compacta is unknown. However, some contributions to the unique susceptibility of dopaminergic neurons in the pars compacta have been identified. For one, dopaminergic neurons show abnormalities in mitochondrial complex 1, causing aggregation of alpha-synuclein
Alpha-synuclein
Alpha-synuclein is a protein that, in humans, is encoded by the SNCA gene. An alpha-synuclein fragment, known as the non-Abeta component of Alzheimer's disease amyloid, originally found in an amyloid-enriched fraction, is shown to be a fragment of its precursor protein, NACP, by cloning of the...
. This could result in abnormal protein handling and neuron death. Secondly, dopaminergic neurons in the pars compacta contain less calbindin than other dopaminergic neurons. Calbindin
Calbindin
Calbindin refers to several calcium-binding proteins. They were originally described as vitamin D-dependent calcium-binding proteins in the intestine and kidney in the chick and mammals...
is a protein involved in calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
ion transport within cells, and excess calcium in cells is toxic. The calbindin theory would explain the high cytotoxicity of Parkinson's in the substantia nigra compared to the ventral tegmental area. Regardless of the cause of neuronal death, the plasticity of the pars compacta is very robust; Parkinsonian symptoms do not appear until up to 50-80% of pars compacta dopaminergic neurons have died. Most of this plasticity occurs at the neurochemical level; dopamine transport systems are slowed, allowing dopamine to linger for longer periods of time in the chemical synapses in the striatum.
Schizophrenia
Increased levels of dopamine have long been implicated in the development of schizophreniaSchizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
. However, much debate continues to this day surrounding this theory, commonly known as the dopamine hypothesis of schizophrenia
Dopamine hypothesis of schizophrenia
The dopamine hypothesis of schizophrenia or the dopamine hypothesis of psychosis is a model attributing symptoms of schizophrenia to a disturbed and hyperactive dopaminergic signal transduction. The model draws evidence from the observation that a large number of antipsychotics have...
. Despite the controversy, dopamine antagonists remain a standard and successful treatment for schizophrenia. These antagonists include first generation (typical) antipsychotics
Typical antipsychotic
Typical antipsychotics are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis...
such as butyrophenones, phenothiazines, and thioxanthenes. These drugs have largely been replaced by second generation (atypical) antipsychotics
Atypical antipsychotic
The atypical antipsychotics are a group of antipsychotic tranquilizing drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...
such as clozapine
Clozapine
Clozapine is an antipsychotic medication used in the treatment of schizophrenia, and is also used off-label in the treatment of bipolar disorder. Wyatt. R and Chew...
and paliperidone
Paliperidone
Paliperidone , also known as 9-hydroxyrisperidone, is an atypical antipsychotic developed by Janssen Pharmaceutica. Invega is an extended release formulation of paliperidone that uses the OROS extended release system to allow for once-daily dosing...
. It should be noted that these drugs generally do not act on dopamine-producing neurons themselves, but on the receptors on the post-synaptic neuron.
Other, non-pharmacological evidence in support of the dopamine hypothesis relating to the substantia nigra include structural changes in the pars compacta, such as reduction in synaptic terminal size. Other changes in the substantia nigra include increased expression of NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
s in the substantia nigra, and reduced dysbindin
Dysbindin
Dysbindin, short for dystrobrevin-binding protein 1, is a protein constituent of the dystrophin-associated protein complex of skeletal muscle cells. It is also a part of BLOC-1, or biogenesis of lysosome-related organelles complex 1. Dysbindin was discovered by the research group of Derek Blake...
expression. Increased NMDA receptors may point to the involvement of glutamate-dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
interactions in schizophrenia. Dysbindin, which has been (controversially) linked to schizophrenia, may regulate dopamine release, and low expression of dysbindin in the substantia nigra may be important in schizophrenia etiology. Due to the changes to the substantia nigra in the schizophrenic brain, it may eventually be possible to use specific imaging techniques (such as melanin-specific imaging) to detect physiological signs of schizophrenia in the substantia nigra.
Chemical Modification of the Substantia Nigra
Chemical manipulation and modification of the substantia nigra is important in the fields of neuropharmacologyNeuropharmacology
Neuropharmacology is the study of how drugs affect cellular function in the nervous system. There are two main branches of neuropharmacology: behavioral and molecular. Behavioral neuropharmacology focuses on the study of how drugs affect human behavior , including the study of how drug dependence...
and toxicology
Toxicology
Toxicology is a branch of biology, chemistry, and medicine concerned with the study of the adverse effects of chemicals on living organisms...
. Various compounds such as levodopa and MPTP are used in the treatment and study of Parkinson's disease, and many other drugs have effects on the substantia nigra.
Levodopa
The substantia nigra is the target of chemical therapeutics for the treatment of Parkinson's disease. LevodopaLevodopa
L-DOPA is a chemical that is made and used as part of the normal biology of some animals and plants. Some animals including humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine , and epinephrine collectively...
(L-DOPA), the dopamine precursor, is the most commonly prescribed medication for Parkinson's disease. Despite controversy concerning the neurotoxicity of dopamine and L-DOPA, it remains the most common treatment for Parkinson's disease. The drug is especially effective in treating patients in the early stages of Parkinson's, although the drug does lose its efficacy over time. Levodopa can cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
and increases dopamine levels in the substantia nigra, thus alleviating the symptoms of Parkinson's disease. The drawback of levodopa treatment is that it treats the symptoms of Parkinson's (low dopamine levels), rather than the cause (the death of dopaminergic neurons in the substantia nigra).
MPTP
MPTPMPTP
MPTP is a neurotoxin precursor to MPP+, which causes permanent symptoms of Parkinson's disease by destroying dopaminergic neurons in the substantia nigra of the brain...
(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), is a neurotoxin specific to dopaminergic cells in the brain, specifically in the substantia nigra. MPTP was brought to the spotlight in 1982 when heroin users in California displayed Parkinson's-like symptoms after using MPPP
MPPP
1-Methyl-4-phenyl-4-propionoxypiperidine or Desmethylprodine is an opioid analgesic drug developed in the 1940s by researchers at Hoffmann-La Roche. It is not used in clinical practice, but has been illegally manufactured for recreational drug use...
contaminated with MPTP. The patients, who were rigid and almost completely immobile, responded to levodopa treatment. No remission of the Parkinson's-like symptoms was reported, suggesting irreversible death of the dopaminergic neurons. The proposed mechanism of MPTP involves disruption of mitochondrial function, including disruption of metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
and creation of free radicals.
Soon after, MPTP was tested in animal models for its efficacy in inducing Parkinson's disease (with success). MPTP induced akinesia, rigidity, and tremor in primates, and its neurotoxicity was found to be very specific to the substantia nigra pars compacta. In other animals, such as rodents, the induction of Parkinson's by MPTP is incomplete or requires much higher and frequent doses than in primates. Today, MPTP remains the most favored model for studying Parkinson's.
Cocaine
CocaineCocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
's mechanism of action in the human brain includes the inhibition of dopamine reuptake. This blockage of dopamine reuptake explains cocaine's addictive properties, as dopamine is the critical neurotransmitter for reward. However, cocaine is more active in the dopaminergic neurons of the ventral tegmental area than the substantia nigra. Cocaine administration increases metabolism in the substantia nigra, which can explain the altered motor function seen in cocaine-using subjects. The inhibition of dopamine reuptake by cocaine also inhibits the firing of spontaneous action potentials by the pars compacta. The mechanism by which cocaine inhibits dopamine reuptake involves its binding to the dopamine transporter
Dopamine transporter
The dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...
protein, or DAT. However, recent studies show that cocaine can also cause a decrease in DAT mRNA levels. This is probably caused by cocaine's blockade of DAT rather than direct interference with transcriptional or translational pathways.
Inactivation of the substantia nigra could prove to be a possible treatment for cocaine addiction. In a study of cocaine-dependent rats, inactivation of the substantia nigra via implanted cannulae greatly reduced cocaine addiction relapse.
Amphetamines
Like cocaine, amphetamineAmphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
increases the concentrations of dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
in the synaptic cleft, thereby heightening the response of the post-synaptic neuron. Also like cocaine, the altered dopamine function contributes to the addictiveness of amphetamines.
The mechanism by which amphetamines increase synaptic levels of dopamine is to release dopamine from pre-synaptic vesicles
Synaptic vesicle
In a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell...
, increasing concentrations of dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
in the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
of the pre-synaptic neuron. The high concentration of dopamine in the pre-synaptic terminal causes the reverse transport of dopamine through the dopamine transporter
Dopamine transporter
The dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...
(DAT) and into the synaptic cleft.