The substantia nigra (SN) is a

basal ganglia The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an extern ...

structure located in the

midbrain The midbrain or mesencephalon is the forward-most portion of the brainstem and is associated with vision, hearing, motor control, sleep and wakefulness, arousal (alertness), and temperature regulation. The name comes from the Greek ''mesos'', " ...

that plays an important role in

reward Reward may refer to: Places * Reward (Shelltown, Maryland), a historic home in Shelltown Maryland * Reward, California (disambiguation) * Reward-Tilden's Farm, a historic home in Chestertown Maryland Arts, entertainment, and media * "Rewa ...

and

movement Movement may refer to: Common uses * Movement (clockwork), the internal mechanism of a timepiece * Motion, commonly referred to as movement Arts, entertainment, and media Literature * "Movement" (short story), a short story by Nancy Fu ...

. ''Substantia nigra'' is

Latin Latin (, or , ) is a classical language belonging to the Italic branch of the Indo-European languages. Latin was originally a dialect spoken in the lower Tiber area (then known as Latium) around present-day Rome, but through the power of the ...

for "black substance", reflecting the fact that parts of the substantia nigra appear darker than neighboring areas due to high levels of

neuromelanin Neuromelanin (NM) is a dark pigment found in the brain which is structurally related to melanin. It is a polymer of Melanin#Eumelanin, 5,6-dihydroxyindole monomers. Neuromelanin is found in large quantities in catecholaminergic cell groups, catecho ...

dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate d ...

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

is characterized by the loss of dopaminergic neurons in the substantia nigra

pars compacta The pars compacta (SNpc) is a portion of the ''substantia nigra'', located in the midbrain. It is formed by dopaminergic neurons and located medial to the pars reticulata. Parkinson's disease is characterized by the death of dopaminergic 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

(SNpc) and the

pars reticulata The pars reticulata (SNpr) is a portion of the substantia nigra and is located lateral to the pars compacta. Most of the neurons that project out of the pars reticulata are inhibitory GABAergic neurons (i.e., these neurons release GABA, which is ...

(SNpr). The pars compacta serves mainly as a projection to the basal ganglia circuit, supplying the

striatum The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamate ...

with dopamine. The pars reticulata conveys signals from the

to numerous other brain structures.

Structure

The substantia nigra, along with four other nuclei, is part of the

. It is the largest

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucle ...

in the midbrain, lying dorsal to the

cerebral peduncles The cerebral peduncles are the two stalks that attach the cerebrum to the brainstem. They are structures at the front of the midbrain which arise from the ventral pons and contain the large ascending (sensory) and descending (motor) nerve tract ...

. Humans have two substantiae nigrae, one on each side of the midline. The SN is divided into two parts: the

(SNpr) and the

(SNpc), which lies medial to the pars reticulata. Sometimes, a third region, the pars lateralis, is mentioned, though it is usually classified as part of the pars reticulata. The (SNpr) and the internal

globus pallidus The globus pallidus (GP), also known as paleostriatum or dorsal pallidum, is a subcortical structure of the brain. It consists of two adjacent segments, one external, known in rodents simply as the globus pallidus, and one internal, known in rod ...

(GPi) are separated by the

internal capsule The internal capsule is a white matter structure situated in the inferomedial part of each cerebral hemisphere of the brain. It carries information past the basal ganglia, separating the caudate nucleus and the thalamus from the putamen and the g ...

Pars reticulata

The pars reticulata bears a strong structural and functional resemblance to the internal part of the globus pallidus. 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 pars reticulata are mainly

GABAergic In molecular biology and physiology, something is GABAergic or GABAnergic if it pertains to or affects the neurotransmitter GABA. For example, a synapse is GABAergic if it uses GABA as its neurotransmitter, and a GABAergic neuron produces GABA. A ...

Afferent connections

The main input to the SNpr derives from the

. It comes by two routes, known as the

direct Direct may refer to: Mathematics * Directed set, in order theory * Direct limit of (pre), sheaves * Direct sum of modules, a construction in abstract algebra which combines several vector spaces Computing * Direct access (disambiguation), a ...

and

indirect pathway The indirect pathway, sometimes known as the indirect pathway of movement, is a neuronal circuit through the basal ganglia and several associated nuclei within the central nervous system (CNS) which helps to prevent unwanted muscle contractions f ...

s. The direct pathway consists of axons from medium spiny cells in the striatum that project directly to pars reticulata. The indirect pathway consists of three links: a projection from striatal medium spiny cells to the external part of the

; a

projection from the globus pallidus to the

subthalamic nucleus The subthalamic nucleus (STN) is a small lens-shaped nucleus in the brain where it is, from a functional point of view, part of the basal ganglia system. In terms of anatomy, it is the major part of the subthalamus. As suggested by its name, the ...

, and a

glutamatergic Glutamatergic means "related to glutamate". A glutamatergic agent (or drug) is a chemical that directly modulates the excitatory amino acid (glutamate/ aspartate) system in the body or brain. Examples include excitatory amino acid receptor agonist ...

projection from the subthalamic nucleus to the pars reticulata. Thus, striatal activity via the direct pathway exerts an inhibitory effect on neurons in the (SNpr) but an excitatory 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

Significant projections occur to the thalamus (ventral lateral and ventral anterior nuclei),

superior colliculus In neuroanatomy, the superior colliculus () is a structure lying on the roof of the mammalian midbrain. In non-mammalian vertebrates, the homologous structure is known as the optic tectum, or optic lobe. The adjective form ''tectal'' is commonly ...

, and other caudal nuclei from the pars reticulata (the nigrothalamic pathway), which 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 Eye movement includes the voluntary or involuntary movement of the eyes. Eye movements are used by a number of organisms (e.g. primates, rodents, flies, birds, fish, cats, crabs, octopus) to fixate, inspect and track visual objects of interests. ...

motor planning In psychology and neuroscience, motor planning is a set of processes related to the preparation of a movement that occurs during the reaction time (the time between the presentation of a stimulus to a person and that person's initiation of a motor r ...

, reward-seeking,

learning Learning is the process of acquiring new understanding, knowledge, behaviors, skills, value (personal and cultural), values, attitudes, and preferences. The ability to learn is possessed by humans, animals, and some machine learning, machines ...

, and

addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use o ...

. Many of the substantia nigra's effects are mediated through the

. The nigral

input to the striatum via the

nigrostriatal pathway The nigrostriatal pathway is a bilateral dopaminergic pathway in the brain that connects the substantia nigra pars compacta (SNc) in the midbrain with the dorsal striatum (i.e., the caudate nucleus and putamen) in the forebrain. It is one of the fou ...

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

inhibition to various brain targets.

Pars reticulata

The

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

to the

thalamus The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all directions, ...

and

. In addition, the pars reticulata also inhibits dopaminergic activity in the

via axon collaterals, although the functional organization of these connections remains unclear. The GABAergic neurons of the pars reticulata spontaneously fire

action potential An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...

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, as exemplified by the pars reticulata's role in

saccadic eye movement A saccade ( , French for ''jerk'') is a quick, simultaneous movement of both eyes between two or more phases of fixation in the same direction.Cassin, B. and Solomon, S. ''Dictionary of Eye Terminology''. Gainesville, Florida: Triad Publishin ...

. A group of GABAergic neurons from the pars reticulata projects to the superior colliculus, exhibiting a high level of sustained inhibitory activity. Projections from the

caudate nucleus The caudate nucleus is one of the structures that make up the corpus striatum, which is a component of the basal ganglia in the human brain. While the caudate nucleus has long been associated with motor processes due to its role in Parkinson's di ...

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

and

epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...

Pars compacta

The most prominent function of the pars compacta is

motor control Motor control is the regulation of movement in organisms that possess a nervous system. Motor control includes reflexes as well as directed movement. To control movement, the nervous system must integrate multimodal sensory information (both f ...

, though the substantia nigra's role in motor control is indirect; electrical stimulation of the substantia nigra does not result in movement, due to mediation of the striatum in the nigral influence of movement. The pars compacta sends excitatory input to the striatum via D1 pathway that excites and activates the striatum, resulting in the release of GABA onto the globus pallidus to inhibit its inhibitory effects on the thalamic nucleus. This causes the thalamocortical pathways to become excited and transmits motor neuron signals to the cerebral cortex to allow the initiation of movement, which is absent in Parkinson's disease. However, lack of pars compacta neurons 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, as has been confirmed in animal models with lesions in that region. 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 (i.e. rewards) continues to activate dopaminergic neurons in the substantia nigra pars compacta. Dopaminergic projections from the

ventral tegmental area The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is the ...

(bottom part of the "midbrain" or mesencephalon) to the prefrontal cortex (mesocortical pathway) and to the nucleus accumbens (mesolimbic pathway – "meso" referring to "from the mesencephalon"... specifically the

) are implicated in reward, pleasure, and addictive behavior. The pars compacta is also 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 The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, a ...

, which is traditionally believed to subserve spatial or episodic-like memory functions. The pars compacta also plays a role in temporal processing and is activated during time reproduction.

Lesion A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals. Types There is no designated classifi ...

s in the pars compacta leads to temporal deficits. As of late, the pars compacta has been suspected of regulating the sleep-wake cycle, which is consistent with symptoms such as

insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

and

REM sleep Rapid eye movement sleep (REM sleep or REMS) is a unique phase of sleep in mammals and birds, characterized by random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the sleeper to dream viv ...

disturbances that are reported by patients with

. 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

Clinical significance

The substantia nigra is critical in the development of many diseases and syndromes, including

parkinsonism Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), rigidity, and postural instability. These are the four motor symptoms found in Parkinson's disease (PD), after which it is named, dementia with Lewy bo ...

and

. There exist a study showing that high-frequency stimulation delivery to the left substantia nigra can induce transient acute depression symptoms.

Parkinson's disease

Substantia nigra with Lewy body pathology

Parkinson's disease is a

neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...

characterized, in part, by the death of dopaminergic neurons in the SNpc. The major symptoms of Parkinson's disease include

tremor A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, fa ...

akinesia Hypokinesia is one of the classifications of movement disorders, and refers to decreased bodily movement. Hypokinesia is characterized by a partial or complete loss of muscle movement due to a disruption in the basal ganglia. Hypokinesia is a sym ...

bradykinesia Hypokinesia is one of the classifications of movement disorders, and refers to decreased bodily movement. Hypokinesia is characterized by a partial or complete loss of muscle movement due to a disruption in the basal ganglia. Hypokinesia is a sym ...

, and stiffness. Other symptoms include disturbances to posture,

fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...

, sleep abnormalities, and

depressed mood Depression is a mental state of low mood and aversion to activity, which affects more than 280 million people of all ages (about 3.5% of the global population). Classified medically as a mental and behavioral disorder, the experience of ...

. The cause of death of dopaminergic neurons in the SNpc 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 is a protein that, in humans, is encoded by the ''SNCA'' gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release. It is abundant in the brain, while smaller a ...

; this can result in abnormal protein handling and neuron death. Secondly, dopaminergic neurons in the pars compacta contain less

calbindin Calbindins are three different calcium-binding proteins: calbindin, calretinin and S100G. They were originally described as vitamin D-dependent calcium-binding proteins in the intestine and kidney in the chick and mammals. They are now classified ...

than other dopaminergic neurons.

Calbindin Calbindins are three different calcium-binding proteins: calbindin, calretinin and S100G. They were originally described as vitamin D-dependent calcium-binding proteins in the intestine and kidney in the chick and mammals. They are now classified ...

is a protein involved in

calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...

ion transport within cells, and excess calcium in cells is toxic. The

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.Interview. Yoland Smith, PhD 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. Menke, Jbabdi, Miller, Matthews and Zari (2010) used diffusion tensor imaging, as well as T1 mapping to assess volumetric differences in the SNpc and SNpr, in participants with Parkinson's compared to healthy individuals. These researchers found that participants with Parkinson's consistently had a smaller substantia nigra, specifically in the SNpr. Because the SNpr is connected to the posterior thalamus, ventral thalamus and specifically, the motor cortex, and because participants with Parkinson's disease report having a smaller SNprs (Menke, Jbabdi, Miller, Matthews and Zari, 2010), the small volume of this region may be responsible for motor impairments found in Parkinson's disease patients. This small volume may be responsible for weaker and/or less controlled motor movements, which may result in the tremors often experienced by those with Parkinson's.

Oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...

and oxidative damage in the SNpc are likely key drivers in the etiology of

Parkinson’s disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

as individuals age. DNA damages caused by oxidative stress can be repaired by processes modulated by

.Schaser AJ, Osterberg VR, Dent SE, Stackhouse TL, Wakeham CM, Boutros SW, Weston LJ, Owen N, Weissman TA, Luna E, Raber J, Luk KC, McCullough AK, Woltjer RL, Unni VK. Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders. Sci Rep. 2019 Jul 29;9(1):10919. doi: 10.1038/s41598-019-47227-z. Alpha synuclein is expressed in the substantia nigra, but its

DNA repair DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...

function appears to be compromised in

Lewy body Lewy bodies are the inclusion bodies – abnormal aggregations of protein – that develop inside nerve cells affected by Parkinson's disease (PD), the Lewy body dementias (Parkinson's disease dementia and dementia with Lewy bodies (DLB)), and ...

inclusion bearing

s. This loss may trigger cell death.

Schizophrenia

Increased levels of dopamine have long been implicated in the development of

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...

. However, much debate continues to this day surrounding this

dopamine hypothesis of schizophrenia The dopamine hypothesis of schizophrenia or the dopamine hypothesis of psychosis is a model that attributes the positive symptoms of schizophrenia to a disturbed and hyperactive dopaminergic signal transduction. The model draws evidence from the ...

. Despite the controversy, dopamine antagonists remain a standard and successful treatment for schizophrenia. These antagonists include first generation (typical) antipsychotics such as

butyrophenones Butyrophenone is an organic compound with the formula C6H5C(O)C3H7. It is a colorless liquid. The butyrophenone structure—a ketone flanked by a phenyl ring and a butyl chain—forms the basis for many other chemicals containing various sub ...

phenothiazines Phenothiazine, abbreviated PTZ, is an organic compound that has the formula S(C6H4)2NH and is related to the thiazine-class of heterocyclic compounds. Derivatives of phenothiazine are highly bioactive and have widespread use and rich history. Th ...

, and thioxanthenes. These drugs have largely been replaced by second-generation (atypical) antipsychotics such as

clozapine Clozapine is a psychiatric medication and is the first atypical antipsychotic (also called second-generation antipsychotic). It is primarily used to treat people with schizophrenia and schizoaffective disorders who have had an inadequate respo ...

and

paliperidone Paliperidone, sold under the trade name Invega among others, is an atypical antipsychotic. It is mainly used to treat schizophrenia and schizoaffective disorder. It is marketed by Janssen Pharmaceuticals. An extended release formulation is a ...

. In general, these drugs 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 The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA rece ...

s in the substantia nigra, and reduced

dysbindin Dysbindin, short for dystrobrevin-binding protein 1, is a protein constituent of the dystrophin-associated protein complex (DPC) of skeletal muscle cells. It is also a part of BLOC-1, or biogenesis of lysosome-related organelles complex 1. Dysbind ...

expression. Increased NMDA receptors may point to the involvement of

glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...

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 neuromelanin-specific imaging) to detect physiological signs of schizophrenia in the substantia nigra.

Wooden Chest Syndrome

Wooden chest, also called fentanyl chest wall rigidity syndrome, is a rare side effect of synthetic

opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid us ...

s such as

Fentanyl Fentanyl, also spelled fentanil, is a very potent synthetic opioid used as a pain medication. Together with other drugs, fentanyl is used for anesthesia. It is also used illicitly as a recreational drug, sometimes mixed with heroin, cocaine ...

, Sulfentanil,

Alfentanil Alfentanil (R-39209, trade name Alfenta, Rapifen in Australia) is a potent but short-acting synthetic opioid analgesic medication, drug, used for anaesthesia in surgery. It is an analogue of fentanyl with around one-fourth to one-tenth the potency ...

Remifentanil Remifentanil is a potent, short-acting synthetic opioid analgesic drug. It is given to patients during surgery to relieve pain and as an adjunct to an anaesthetic. Remifentanil is used for sedation as well as combined with other medications fo ...

. It results in a generalised increase in skeletal

muscle tone In physiology, medicine, and anatomy, muscle tone (residual muscle tension or tonus) is the continuous and passive partial muscle contraction, contraction of the muscles, or the muscle's resistance to passive stretch during resting state.O’Sull ...

. The mechanism is thought to be via increased dopamine release and decreased GABA release in the nerves of the substantia nigra/striatum. The effect is most pronounced on the chest wall muscles and can lead to impaired ventilation. The condition is most commonly observed in anaesthesia where rapid and high doses of these drugs are given intravenously.

Multiple system atrophy

Multiple system atrophy Multiple system atrophy (MSA) is a rare neurodegenerative disorder characterized by autonomic dysfunction, tremors, slow movement, muscle rigidity, and postural instability (collectively known as parkinsonism) and ataxia. This is caused by progr ...

characterized by neuronal degeneration in the striatum and substantia nigra was previously called ''striatonigral degeneration''.

Chemical modification of the substantia nigra

Chemical manipulation and modification of the substantia nigra is important in the fields of

neuropharmacology Neuropharmacology is the study of how drugs affect function in the nervous system, and the neural mechanisms through which they influence behavior. There are two main branches of neuropharmacology: behavioral and molecular. Behavioral neuropharmac ...

and

toxicology Toxicology is a scientific discipline, overlapping with biology, chemistry, pharmacology, and medicine, that involves the study of the adverse effects of chemical substances on living organisms and the practice of diagnosing and treating expo ...

. 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.

Amphetamine and trace amines

Studies have shown that, in certain brain regions, amphetamine and trace amines increase the concentrations of dopamine in the

synaptic cleft Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...

, thereby heightening the response of the post-synaptic neuron. The various mechanisms by which amphetamine and trace amines affect dopamine concentrations have been studied extensively, and are known to involve both DAT and

VMAT2 The solute carrier family 18 member 2 (SLC18A2) also known as vesicular monoamine transporter 2 (VMAT2) is a protein that in humans is encoded by the ''SLC18A2'' gene. SLC18A2 is an integral membrane protein that transports monoamines—particul ...

. Amphetamine is similar in structure to dopamine and trace amines; as a consequence, it can enter the presynaptic neuron via as well as by diffusing through the neural membrane directly. Upon entering the presynaptic neuron, amphetamine and trace amines activate

TAAR1 Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the ''TAAR1'' gene. TAAR1 is an intracellular amine-activated and G protein-coupled receptor (GPCR) that is primarily exp ...

, which, through

protein kinase A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a fu ...

signaling, induces dopamine efflux, phosphorylation-dependent

internalization Internalization ( or internalisation) is the process of making something internal, with more specific meanings in various fields. It is the opposite of externalization. Psychology and sociology In psychology, internalization is the outcome of ...

, and non-competitive reuptake inhibition. Because of the similarity between amphetamine and trace amines, it is also a substrate for monoamine transporters; as a consequence, it (competitively) inhibits the reuptake of dopamine and other monoamines by competing with them for uptake, as well. In addition, amphetamine and trace amines are substrates for the neuronal vesicular monoamine transporter,

vesicular monoamine transporter 2 The solute carrier family 18 member 2 (SLC18A2) also known as vesicular monoamine transporter 2 (VMAT2) is a protein that in humans is encoded by the ''SLC18A2'' gene. SLC18A2 is an integral membrane protein that transports monoamines—particul ...

(VMAT2). When amphetamine is taken up by , the vesicle releases (effluxes) dopamine molecules into the cytosol in exchange.

Cocaine

Cocaine Cocaine (from , from , ultimately from Quechuan languages, Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly recreational drug use, used recreationally for its euphoria, euphoric effects. It is primarily obtained from t ...

's mechanism of action in the human brain includes the inhibition of dopamine reuptake, which accounts for 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 The dopamine transporter (also dopamine active transporter, DAT, SLC6A3) is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopam ...

protein. However, studies show that cocaine can also cause a decrease in DAT

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

levels, most likely due to cocaine blocking dopamine receptors 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 A cannula (; Latin meaning 'little reed'; plural or ) is a tube that can be inserted into the body, often for the delivery or removal of fluid or for the gathering of samples. In simple terms, a cannula can surround the inner or outer surfaces ...

greatly reduced cocaine addiction relapse.

Levodopa

The substantia nigra is the target of chemical therapeutics for the treatment of Parkinson's disease.

Levodopa -DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...

(commonly referred to as 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. The drug is especially effective in treating patients in the early stages of Parkinson's, although it does lose its efficacy over time. Levodopa can cross the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...

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

MPTP MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a prodrug to the neurotoxin MPP+, which causes permanent symptoms of Parkinson's disease by destroying dopaminergic neurons in the substantia nigra of the brain. It has been used to study d ...

, 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 Desmethylprodine or 1-methyl-4-phenyl-4-propionoxypiperidine (MPPP, Ro 2-0718) is an opioid analgesic drug developed in the 1940s by researchers at Hoffmann-La Roche. Desmethylprodine has been labeled by the DEA as a Schedule I drug in the U ...

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

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

l function, including disruption of

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

and creation of

free radical A daughter category of ''Ageing'', this category deals only with the biological aspects of ageing. Ageing Ailments of unknown cause Biogerontology Biological processes Causes of death Cellular processes Gerontology Life extension Metabo ...

s. 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 method to induce Parkinson's disease in

animal models A model organism (often shortened to model) is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workin ...

History

The substantia nigra was discovered in 1784 by

Félix Vicq-d'Azyr Félix Vicq d'Azyr (; 23 April 1748 – 20 June 1794) was a French physician and anatomist, the originator of comparative anatomy and discoverer of the theory of homology in biology. Biography Vicq d'Azyr was born in Valognes, Normandy, the son o ...

, and

Samuel Thomas von Sömmerring Samuel Thomas von Sömmerring (28 January 1755 – 2 March 1830) was a German physician, anatomist, anthropologist, paleontologist and inventor. Sömmerring discovered the macula in the retina of the human eye. His investigations on the brain ...

alluded to this structure in 1791. The differentiation between the substantia nigra pars reticulata and compacta was first proposed by Sano in 1910. In 1963,

Oleh Hornykiewicz Oleh Hornykiewicz (17 November 1926 - 26 May 2020) was an Austrian biochemist. Life Oleh Hornykiewicz was born in 1926 in Sykhiw (a district of Lviv), then in Poland (now Ukraine). In 1951, he received his M.D. degree from the University of Vie ...

concluded from his observation that ‘‘cell loss in the substantia nigra (of Parkinson's disease patients) could well be the cause of the dopamine deficit in the striatum’’.

Additional images

Image:Dopamine_and_serotonin_pathways.png, Dopamine and serotonin File:Blausen 0704 ParkinsonsDisease.png, Degradation of substantia nigra associated with Parkinson's disease. File:Substantia Nigra.jpg, Horizontal MRI (T1 weighted) slice with highlighting indicating location of the substantia nigra. File:Substantia nigra pars compacta.jpg, Enhanced Neuromelanin MRI with Color images (RGB) showing Substantia nigra pars compacta File:SN.tif, Microfilming

References

External links

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Diagram and explanation of cortico-basal pathways
{{Authority control Midbrain Basal ganglia