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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 black due to high levels of melanin in dopaminergic neurons. The substantia nigra is part of the basal ganglia; the other parts of the basal ganglia include the striatum (caudate nucleus and putamen), nucleus accumbens, and the subthalamic nucleus. Parkinson's disease is caused by the death of dopaminergic neurons in the substantia nigra pars compacta.

Anatomy
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 and pars compacta, 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. Segment M1 of the middle cerebral artery supplies blood to all of the basal ganglia, including the substantia nigra. The neurons of the pars compacta are restricted to input from and output to the basal ganglia, while the neurons of the pars reticulata send and receive information from various parts of the brain, not necessarily the basal ganglia.

Neurons in the pars compacta are generally dopaminergic. They are sometimes referred to as the A9 cell group, the A8 and A10 cell groups being the other major dopaminergic groups in the brain, in the retrorubral area and ventral tegmental area, respectively. The dopaminergic neurons in the pars compacta can be distinguished by their blackened appearance due to a buildup of melanin. The neurons in the pars reticulata are generally GABAergic. The neurons in the substantia nigra can be classified into two broad categories: interneurons and projection neurons. Interneurons connect various neurons within the substantia nigra, and projection neurons extend to other parts of the brain (usually the basal ganglia). Many projection neurons in the pars compacta send dendrites into the pars reticulata; this is one mechanism by which GABAergic input can modulate dopamine activity.

Afferent Connections
The chief afferent projection into the substantia nigra is the striatonigral projection. Most striatonigral neurons terminate in the pars reticulata. Additional nigral inputs project from the globus pallidus, amygdala, reticular formation , and the subthalamic nucleus. GABA is the primary neurotransmitter for these connections. The amygdalo-nigrostriatal pathway has recently been implicated in surprised-induced learning. All connections from non-basal ganglia nuclei project into the pars reticulata.

Efferent Projections
The most well-known and important efferent projection of the substantia nigra is the efferent striatonigral projection (sometimes called the nigrostriatal projection), which originates chiefly in the pars compacta, but also includes a smaller number of other dopaminergic cells scattered throughout the pars reticulata. The efferent striatonigral projection uses dopamine as its primary transmitter. Within the striatum, acetylcholine is the primary neurotransmitter, and the striatal dopamine-acetylcholine relationship is very important one: striatal output neurons receive inputs from the entire cerebral cortex and select relevant cortical information, and dopaminergic input from the pars compacta modulates the striatal output. In addition to their chemical synapses, there are also electrical synapses between nigrostriatal dopaminergic neurons and striatal output neurons. Striatal aceytlcholine is elevated in Parkinson's disease, and the interactions between striatal acetylcholine and dopamine are critical in motor response selection, especially stimulus-reaction associations or acquired through positive reinforcement. Nicotine alters this balance, which facilitates addiction.

In addition, 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 which 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, particularly in eye movement, motor planning, reward seeking, learning, 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 sources of GABAergic inhibition to various brain targets.

Pars Reticulata
The pars reticulata 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 potentials. In rats, the frequency of action potentials is roughly 25Hz. 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.

Pars Compacta
The most prominent function of the pars compacta is motor control. 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 a possible spatial memory system independent from the hippocampus, where spatial memory is traditionally thought to be located.

Temporal processing is also an important function of the pars compacta. The pars compacta is activated during time reproduction and lesions 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.

Pathophysiology
The substantia nigra is critical in the development of many diseases, including Parkinson's disease.

Parkinson's Disease
Parkinson's disease's is a neurodegenerative disease caused by the death of dopaminergic neurons in the pars compacta of the substantia nigra. The major symptoms of Parkinson's disease include tremor, 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.

Schizophrenia
Increased levels of dopamine have long been implicated in the development of schizophrenia. 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 dopaminergic receptors on which the dopaminergic neurons synapse.

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 receptors 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.

Chemical Modification of the Substantia Nigra
Chemical manipulation and modification of the substantia nigra is important in the fields of neuropharmacology 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.

Levodopa
The substantia nigra is the target of chemical therapeutics for the treatment of Parkinson's disease. Levodopa (L-DOPA), the dopamine precursor, is the most commonly prescribed medication for Parkinson's disease. Despite controversy concerning the neurotoxicity of dopamine, 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).

MPTP
MPTP (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 heroin contaminated with MPTP. The patients bodies were rigid nearly completely immobile, and they 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 mitochondial 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.

Cocaine
Cocaine'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 cocaine 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.

Amphetamines
Like cocaine, amphetamine 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 specific mechanisms by which amphetamines affect dopamine concentrations is not well understood. Currently, two major hypotheses have been proposed. The first theory emphasizes amphetamine’s actions on the vesicular level, increasing concentrations of dopamine in the cytosol of the pre-synaptic neuron. The other hypothesized mechanism, whichis similar to that of cocaine's, focuses on the role of the dopamine transporter, and proposes that amphetamine may interact with DAT to induce reverse transport of dopamine from the presynaptic neuron into the synaptic cleft.