The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement.

[9] The substantia nigra is an important player in brain function, in particular, in eye movement, motor planning, reward-seeking, learning, and addiction.

In addition to striatum-mediated functions, the substantia nigra also serves as a major source of GABAergic inhibition to various brain targets.

The GABAergic neurons in the pars reticulata convey the final processed signals of the basal ganglia to the thalamus and superior colliculus.

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

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.

[19] 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 (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 ventral tegmental area) are implicated in reward, pleasure, and addictive behavior.

[22] As of late, the pars compacta has been suspected of regulating the sleep-wake cycle,[23] which 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.

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

The calbindin theory would explain the high cytotoxicity of Parkinson's in the substantia nigra compared to the ventral tegmental area.

[31] 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.

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.

[34] Alpha synuclein is expressed in the substantia nigra, but its DNA repair function appears to be compromised in Lewy body inclusion bearing neurons.

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.

Studies have shown that, in certain brain regions, amphetamine and trace amines increase the concentrations of dopamine in the synaptic cleft, thereby heightening the response of the post-synaptic neuron.

[45][46][47] Amphetamine is similar in structure to dopamine and trace amines; as a consequence, it can enter the presynaptic neuron via DAT as well as by diffusing through the neural membrane directly.

[45] Upon entering the presynaptic neuron, amphetamine and trace amines activate TAAR1, which, through protein kinase signaling, induces dopamine efflux, phosphorylation-dependent DAT internalization, and non-competitive reuptake inhibition.

Cocaine administration increases metabolism in the substantia nigra, which can explain the altered motor function seen in cocaine-using subjects.

In a study of cocaine-dependent rats, inactivation of the substantia nigra via implanted cannulae greatly reduced cocaine addiction relapse.

[55] 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 induced akinesia, rigidity, and tremor in primates, and its neurotoxicity was found to be very specific to the substantia nigra pars compacta.

[62] In 1963, Oleh Hornykiewicz 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.