|Brain: Substantia nigra|
Section through superior colliculus showing Substantia nigra.
|Gray's||subject #188 802|
|Part of||Midbrain, Basal ganglia|
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", reflecting the fact that parts of the substantia nigra appear darker than neighboring areas due to high levels of neuromelanin in dopaminergic neurons. 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.
- 1 Anatomy
- 2 Function
- 3 Pathophysiology
- 4 Chemical modification of the substantia nigra
- 5 Additional images
- 6 References
- 7 External links
The substantia nigra, along with four other nuclei, is part of the basal ganglia. It is the largest nucleus in the midbrain, lying dorsal to the cerebral peduncles. Humans have two substantiae nigrae, one on each side of the midline.
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, though its is usually classified as part of the pars reticulata. The pars reticulata and the internal globus pallidus are separated by the internal capsule.
The pars reticulata bears a strong resemblance, both structurally and functionally, 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.
The main input to the pars reticulata derives from the striatum. 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 pars reticulata. The indirect pathway consists of three links: a projection from striatal medium spiny cells to the external part of the globus pallidus; a GABAergic projection from the globus pallidus to the subthalamic nucleus, and a glutamatergic projection from the subthalamic nucleus to the pars reticulata.[better source needed] Thus, striatal activity via the direct pathway exerts an inhibitory effect on neurons in the pars reticulata, 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.
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)., 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.
The substantia nigra is an important player in brain function, in particular, 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 source of GABAergic inhibition to various brain targets.
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 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 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 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.
The most prominent function of the pars compacta is motor control, 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. 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 (such as classical conditioning, where a reward is presented) continues to activate the dopaminergic neurons, which has been used to explain the addictiveness of drugs. 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, 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. Lesions 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 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.
The substantia nigra is critical in the development of many diseases, including 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 tremor, akinesia, bradykinesia, and stiffness. Other symptoms include disturbances to posture, fatigue, sleep abnormalities, and depressed mood.
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 can 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.
Increased levels of dopamine have long been implicated in the development of schizophrenia. However, much debate continues to this day surrounding this 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 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.
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, 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. Amphetamine is similar in structure to dopamine and trace amines; consequently, it can enter the presynaptic neuron via DAT as well as by diffusing through the neural membrane directly. 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. Because of the similarity between amphetamine and trace amines, it is also a substrate for monoamine transporters; consequently, 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 (VMAT2). When amphetamine is taken up by VMAT2, the vesicle releases (effluxes) dopamine molecules into the cytosol in exchange.
Cocaine'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 protein. However, recent studies show that cocaine can also cause a decrease in DAT mRNA 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 greatly reduced cocaine addiction relapse.
The substantia nigra is the target of chemical therapeutics for the treatment of Parkinson's disease. Levodopa (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, 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, 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.
- Kim, Se Jung; J.Y. Sung, J.W. UM, N. Hattori, Y. Mizuno, K. Tanaka, S.R. Paik, J. Kim, K.C. Chung (24.). "Parkin Cleaves Intracellular alpha-Synuclein Inclusions via the Activation of Calpain". The Journal of Biological Chemistry. 43 278: 41890–41899.
- Nauta, H J; Cole, M (1978). "Efferent projections of the subthalamic nucleus: an autoradiographic study in monkey and cat.". J Comp Neurol 180 (1): 1–16. doi:10.1002/cne.901800102. PMID 418083.
- Carpenter, M B; Nakano, K; Kim, R (1976). "Nigrothalamic projections in the monkey demonstrated by autoradiographic technics". J Comp Neurol 165 (4): 401–15. doi:10.1002/cne.901650402. PMID 57125.
- Deniau, J M; Kitai, S T; Donoghue, J P; Grofova, I (1992). "Neuronal interactions in the substantia nigra pars reticulata through axon collaterals of the projection neurons. An electrophysiological and morphological study.". Exp Brain Res 47 (1): 105–13. PMID 6288427.
- Nicola, S M; Surmeier, J; Malenka, R C (2000). "Dopaminergic modulation of neuronal excitability in the striatum and nucleus accumbens". Annu Rev Neurosci 23: 185–215. doi:10.1146/annurev.neuro.23.1.185. PMID 10845063.
- Gernert, Manuela; Fedrowitz, Maren; Wlaz, Piotr; Loscher, Wolfgang (2004). "Subregional changes in discharge rate, pattern, and drug sensitivity of putative GABAergic nigral neurons in the kindling model of epilepsy.". Eur J Neurosci 20 (9): 2377–86. doi:10.1111/j.1460-9568.2004.03699.x. PMID 15525279.
- Sato, Makoto; Hikosaka, Okihide (March 15, 2002). "Role of primate substantia nigra pars reticulata in reward-oriented saccadic eye movement.". J Neurosci 22 (6): 2363–73. PMID 11896175.
- Zahr, Natalie May; Martin, Lynn Pauline; Waszczak, Barbara Lee (2004). "Subthalamic nucleus lesions alter basal and dopamine agonist stimulated electrophysiological output from the rat basal ganglia.". Synapse 53 (2): 119–28. doi:10.1002/syn.20064. PMID 15352137.
- Hikosaka, O; Wurtz, R H (1983). "Visual and oculomotor functions of monkey substantia nigra pars reticulata. III. Memory-contingent visual and saccade responses.". J Neurophysiol 49 (5): 1268–84. PMID 6864250.
- Tseng, K Y; Riquelme, L A; Belforte, J E; Pazo, J H; Murer, M G (2000). "Substantia nigra pars reticulata units in 6-hydroxydopamine-lesioned rats: responses to striatal D2 dopamine receptor stimulation and subthalamic lesions.". Eur J Neurosci 12 (1): 247–56. doi:10.1046/j.1460-9568.2000.00910.x. PMID 10651879.
- Deransart, Colin; Hellwig, Bernhard; Heupel-Reuter, Miriam; Leger, Jean-Francois; Heck, Detlef; Lucking, Carl Hermann (2003). "Single-unit analysis of substantia nigra pars reticulata neurons in freely behaving rats with genetic absence epilepsy.". Epilepsia 44 (12): 1513–20. doi:10.1111/j.0013-9580.2003.26603.x. PMID 14636321.
- Hodge, G K; Butcher, L L (1980). "Pars compacta of the substantia nigra modulates motor activity but is not involved importantly in regulating food and water intake.". Naunyn Schmiedebergs Arch Pharmacol 313 (1): 51–67. doi:10.1007/BF00505805. PMID 7207636.
- Pioli, E Y; Meissner, W; Sohr, R; Gross, C E; Bezard, E; Bioulac, B H (2008). "Differential behavioral effects of partial bilateral lesions of ventral tegmental area or substantia nigra pars compacta in rats.". Neuroscience 153 (4): 1213–24. doi:10.1016/j.neuroscience.2008.01.084. PMID 18455318.
- Ljungberg, T; Apicella, P; Schultz, W (January 1, 1992). "Responses of monkey dopamine neurons during learning of behavioral reactions.". J Neurophysio 67 (1): 145–63. PMID 1552316.
- Da Cunha, Claudio; Silva, Marcio H C; Wietzikoski, Samantha; Wietzikoski, Evellyn C; Ferro, Marcelo M; Kouzmine, Ivana; Canteras, Newton S (2006). "Place learning strategy of substantia nigra pars compacta-lesioned rats.". Behav Neurosci 120 (6): 1279–84. doi:10.1037/0735-7044.120.6.1279. PMID 17201473.
- Da Cunha, Claudio; Wietzikoski, Samantha; Wietzikoski, Evellyn C; Miyoshi, Edmar; Ferro, Marcelo M; Anselmo-Franci, Janete A; Canteras, Newton S (2003). "Evidence for the substantia nigra pars compacta as an essential component of a memory system independent of the hippocampal memory system.". Neurobiol Learn Mem 79 (3): 236–42. doi:10.1016/S1074-7427(03)00008-X. PMID 12676522.
- Matell, M S; Meck, W H (2000). "Neuropsychological mechanisms of interval timing behavior.". BioEssays 22 (1): 94–103. doi:10.1002/(SICI)1521-1878(200001)22:1<94::AID-BIES14>3.0.CO;2-E. PMID 10649295.
- Lima, Marcelo M S; Andersen, Monica L; Reksidler, Angela B; Vital, Maria A B F; Tufik, Sergio (2007). "The Role of the Substantia Nigra Pars Compacta in Regulating Sleep Patterns in Rats". In Brosnan, Sarah. PLoS ONE 2 (6): e513. Bibcode:2007PLoSO...2..513L. doi:10.1371/journal.pone.0000513. PMC 1876809. PMID 17551593.
- Dzirasa, Kafui; Ribeiro, Sidarta; Costa, Rui; Santos, Lucas M; Lin, Shih-Chieh; Grosmark, Andres; Sotnikova, Tatyana D; Gainetdinov, Raul R; Caron, Marc G; Nicolelis, Miguel A L (2006). "Dopaminergic control of sleep-wake states". J Neurosci 26 (41): 10577–89. doi:10.1523/JNEUROSCI.1767-06.2006. PMID 17035544.
- Jankovic J (April 2008). "Parkinson's disease: clinical features and diagnosis". J. Neurol. Neurosurg. Psychiatr. 79 (4): 368–76. doi:10.1136/jnnp.2007.131045. PMID 18344392.
- Adler, CH (2005). "Nonmotor complications in Parkinson's disease". Movement Disorders 20: S23–9. doi:10.1002/mds.20460. PMID 15822106.
- Dawson, T; Dawson, V (2003). "Molecular Pathways of Neurodegeneration in Parkinson's Disease". Science 302 (5646): 819–22. Bibcode:2003Sci...302..819D. doi:10.1126/science.1087753. PMID 14593166.
- Liang CL, Sinton CM, Sonsalla PK, German DC (1996). "Midbrain dopaminergic neurons in the mouse that contain calbindin-D28k exhibit reduced vulnerability to MPTP-induced neurodegeneration". Neurodegeneration 5 (4): 313–8. doi:10.1006/neur.1996.0042. PMID 9117542.
- Interview. Yoland Smith, PhD
- van Rossum, J (1967). Brill H, Cole J, Deniker P, Hippius H, Bradley P B, ed. Neuropsychopharmacology, Proceedings Fifth Collegium Internationale Neuropsychopharmacologicum: 321–9.
- N. S. Kolomeets and N. A. Uranova (1997). "Synaptic contacts in schizophrenia: Studies using immunocytochemical identification of dopaminergic neurons". Neuroscience and Behavioral Physiology: 217–21.
- Kumamoto, N; Matsuzaki, S; Inoue, K; Hattori, T; Shimizu, S; Hashimoto, R; Yamatodani, A; Katayama, T et al. (2006). "Hyperactivation of midbrain dopaminergic system in schizophrenia could be attributed to the down-regulation of dysbindin". Biochem Biophys Res Commun 345 (2): 904–9. doi:10.1016/j.bbrc.2006.04.163. PMID 16701550.
- Shibata, Eri; Sasaki, Makoto; Tohyama, Koujiro; Otsuka, Kotaro; Endoh, Jin; Terayama, Yasuo; Sakai, Akio (2008). "Use of neuromelanin-sensitive MRI to distinguish schizophrenic and depressive patients and healthy individuals based on signal alterations in the substantia nigra and locus ceruleus". Biol Psychiatry 64 (5): 401–6. doi:10.1016/j. biopsych.2008.03.021. PMID 18452894.
- Miller GM (January 2011). "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". J. Neurochem. 116 (2): 164–176. doi:10.1111/j.1471-4159.2010.07109.x. PMC 3005101. PMID 21073468.
- Targets. "Amphetamine". DrugBank. University of Alberta. 8 February 2013. Retrieved 13 October 2013.
- Eiden LE, Weihe E (January 2011). "VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse". Ann. N. Y. Acad. Sci. 1216: 86–98. doi:10.1111/j.1749-6632.2010.05906.x. PMID 21272013.
- Maguire JJ, Parker WA, Foord SM, Bonner TI, Neubig RR, Davenport AP (March 2009). "International Union of Pharmacology. LXXII. Recommendations for trace amine receptor nomenclature". Pharmacol. Rev. 61 (1): 1–8. doi:10.1124/pr.109.001107. PMC 2830119. PMID 19325074.
- Heikkila, R E; Cabbat, F S; Duvoisin, R C (1979). "Motor activity and rotational behavior after analogs of cocaine: correlation with dopamine uptake blockade". Commun Psychopharmacol 3 (5): 285–90. PMID 575770.
- Joan M. Lakoski, Matthew P. Galloway, Francis J. White (1991). Cocaine. Telford Press. ISBN 0-8493-8813-9.
- M. G. Lacey, N. B. Mercuri, and R. A. North (1990). "Actions of cocaine on rat dopaminergic neurones in vitro". Br J Pharmacol 99 (4): 731–5. PMC 1917549. PMID 2361170.
- Yue Xia, Dennis J. Goebel, Gregory Kapatos Michael J. Banno (2006). "Quantitation of Rat Dopamine Transporter mRNA: Effects of Cocaine Treatment and Withdrawal". J Neurochem 59 (3): 1179–82. doi:10.1111/j.1471-4159.1992.tb08365.x. PMID 1494906.
- See, R E; Elliott, J C; Feltenstein, M W (2007). "The role of dorsal vs ventral striatal pathways in cocaine-seeking behavior after prolonged abstinence in rats". Psychopharmacology (Berl) 194 (3): 321–31. doi:10.1007/s00213-007-0850-8. PMID 17589830.
- Cheng N, Maeda T, Kume T, et al. (December 1996). "Differential neurotoxicity induced by ?-DOPA and dopamine in cultured striatal neurons". Brain Research 743 (1–2): 278–83. doi:10.1016/S0006-8993(96)01056-6. PMID 9017256.
- Rascol O, Payoux P, Ory F, Ferreira JJ, Brefel-Courbon C, Montastruc JL. (2003). "Limitations of current Parkinson's disease therapy". Ann Neurol 53 (S3): S3–S15. doi:10.1002/ana.10513. PMID 12666094.
- JW Langston, P Ballard, JW Tetrud, and I Irwin (1983). "Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis". Science 219 (4587): 979–80. Bibcode:1983Sci...219..979L. doi:10.1126/science.6823561. PMID 6823561.
- Schmidt, N; Ferger, B (2001). "Neurochemical findings in the MPTP model of Parkinson's disease". J Neural Transm 108 (11): 1263–82. doi:10.1007/s007020100004. PMID 11768626.
- Langston, J W; Forno, L S; Rebert, C S; Irwin, I (1984). "Selective nigral toxicity after systemic administration of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyrine (MPTP) in the squirrel monkey". Brain Res 292 (2): 390–4. doi:10.1016/0006-8993(84)90777-7. PMID 6607092.
|Wikimedia Commons has media related to Substantia nigra.|