Editing Substantia nigra (section)

==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===
{{See also|Amphetamine|Trace amine}}
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.<ref name="Miller" /> The various mechanisms by which amphetamine and trace amines affect dopamine concentrations have been studied extensively, and are known to involve both [[dopamine transporter|DAT]] and [[vesicular monoamine transporter 2|VMAT2]].<ref name="Miller">{{cite journal | vauthors = Miller GM | title = The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity | journal = Journal of Neurochemistry | volume = 116 | issue = 2 | pages = 164–76 | date = January 2011 | pmid = 21073468 | pmc = 3005101 | doi = 10.1111/j.1471-4159.2010.07109.x }}</ref><ref name="DrugBank 2">{{cite web | title=Amphetamine | url=http://www.drugbank.ca/drugs/DB00182#targets | work=DrugBank | publisher= University of Alberta | access-date=13 October 2013 | date=8 February 2013 }}</ref><ref name="E Weihe">{{cite journal | vauthors = Eiden LE, Weihe E | title = VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse | journal = Annals of the New York Academy of Sciences | volume = 1216 | issue = 1 | pages = 86–98 | date = January 2011 | pmid = 21272013 | pmc = 4183197 | doi = 10.1111/j.1749-6632.2010.05906.x | bibcode = 2011NYASA1216...86E }}</ref>  Amphetamine is similar in structure to dopamine and trace amines; as a consequence, it can enter the presynaptic neuron via {{abbr|DAT|dopamine transporter}} as well as by diffusing through the neural membrane directly.<ref name="Miller" /> Upon entering the presynaptic neuron, amphetamine and trace amines activate [[TAAR1]], which, through [[protein kinase]] signaling, induces dopamine efflux, [[phosphorylation|phosphorylation-dependent]] {{abbr|DAT|dopamine transporter}} [[endocytosis|internalization]], and non-competitive reuptake inhibition.<ref name="Miller" /><ref name="TAAR1 Review">{{cite journal | vauthors = Maguire JJ, Parker WA, Foord SM, Bonner TI, Neubig RR, Davenport AP | title = International Union of Pharmacology. LXXII. Recommendations for trace amine receptor nomenclature | journal = Pharmacological Reviews | volume = 61 | issue = 1 | pages = 1–8 | date = March 2009 | pmid = 19325074 | pmc = 2830119 | doi = 10.1124/pr.109.001107 }}</ref> 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.<ref name="Miller" />

In addition, amphetamine and trace amines are substrates for the neuronal vesicular monoamine transporter, [[vesicular monoamine transporter 2]] (VMAT2).<ref name="E Weihe" /> When amphetamine is taken up by {{abbr|VMAT2|vesicular monoamine transporter 2}}, the vesicle releases (effluxes) dopamine molecules into the cytosol in exchange.<ref name="E Weihe" />

===Cocaine===
{{See also|Cocaine}}
[[Cocaine]]'s mechanism of action in the human brain includes the inhibition of dopamine reuptake,<ref>{{cite journal | vauthors = Heikkila RE, Cabbat FS, Duvoisin RC | title = Motor activity and rotational behavior after analogs of cocaine: correlation with dopamine uptake blockade | journal = Communications in Psychopharmacology | volume = 3 | issue = 5 | pages = 285–90 | year = 1979 | pmid = 575770 }}</ref> 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.<ref>{{cite book |title=Cocaine | first1 = Joan M. | last1 = Lakoski | first2 = Matthew P. | last2 = Galloway | first3 = Francis J. | last3 = White | name-list-style = vanc |publisher=Telford Press |year=1991 |isbn=978-0-8493-8813-2}}</ref> The inhibition of dopamine reuptake by cocaine also inhibits the firing of spontaneous action potentials by the pars compacta.<ref>{{cite journal | vauthors = Lacey MG, Mercuri NB, North RA | title = Actions of cocaine on rat dopaminergic neurones in vitro | journal = British Journal of Pharmacology | volume = 99 | issue = 4 | pages = 731–5 | date = April 1990 | pmid = 2361170 | pmc = 1917549 | doi = 10.1111/j.1476-5381.1990.tb12998.x }}</ref> The mechanism by which cocaine inhibits dopamine reuptake involves its binding to the [[dopamine transporter]] protein. However, studies show that cocaine can also cause a decrease in DAT [[mRNA]] levels,<ref name="coke">{{cite journal | vauthors = Xia Y, Goebel DJ, Kapatos G, Bannon MJ | title = Quantitation of rat dopamine transporter mRNA: effects of cocaine treatment and withdrawal | journal = Journal of Neurochemistry | volume = 59 | issue = 3 | pages = 1179–82 | date = September 1992 | pmid = 1494906 | doi = 10.1111/j.1471-4159.1992.tb08365.x | s2cid = 34068876 }}</ref> most likely due to cocaine blocking dopamine receptors rather than direct interference with transcriptional or translational pathways.<ref name = coke/>

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.<ref>{{cite journal | vauthors = See RE, Elliott JC, Feltenstein MW | title = The role of dorsal vs ventral striatal pathways in cocaine-seeking behavior after prolonged abstinence in rats | journal = Psychopharmacology | volume = 194 | issue = 3 | pages = 321–31 | date = October 2007 | pmid = 17589830 | doi = 10.1007/s00213-007-0850-8 | s2cid = 12652533 }}</ref>

===Levodopa===
{{See also|Levodopa}}
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.<ref name="pmid9017256">{{cite journal | vauthors = Cheng N, Maeda T, Kume T, Kaneko S, Kochiyama H, Akaike A, Goshima Y, Misu Y | title = Differential neurotoxicity induced by L-DOPA and dopamine in cultured striatal neurons | journal = Brain Research | volume = 743 | issue = 1–2 | pages = 278–83 | date = December 1996 | pmid = 9017256 | doi = 10.1016/S0006-8993(96)01056-6 | s2cid = 22529926 }}</ref> The drug is especially effective in treating patients in the early stages of Parkinson's, although it does lose its efficacy over time.<ref>{{cite journal | vauthors = Rascol O, Payoux P, Ory F, Ferreira JJ, Brefel-Courbon C, Montastruc JL | title = Limitations of current Parkinson's disease therapy | journal = Annals of Neurology | volume = 53 | pages = S3–12; discussion S12–5 | year = 2003 | issue = Suppl 3 | pmid = 12666094 | doi = 10.1002/ana.10513 | s2cid = 45078589 }}</ref> 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===
{{See also|MPTP}}
[[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.<ref>{{cite journal | vauthors = Langston JW, Ballard P, Tetrud JW, Irwin I | title = Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis | journal = Science | volume = 219 | issue = 4587 | pages = 979–80 | date = February 1983 | pmid = 6823561 | doi = 10.1126/science.6823561 | bibcode = 1983Sci...219..979L | s2cid = 31966839 }}</ref> The proposed mechanism of MPTP involves disruption of [[mitochondria]]l function, including disruption of [[metabolism]] and creation of [[free radical]]s.<ref name="MPTP">{{cite journal | vauthors = Schmidt N, Ferger B | title = Neurochemical findings in the MPTP model of Parkinson's disease | journal = Journal of Neural Transmission | volume = 108 | issue = 11 | pages = 1263–82 | year = 2001 | pmid = 11768626 | doi = 10.1007/s007020100004 | s2cid = 2834254 }}</ref>

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.<ref>{{cite journal | vauthors = Langston JW, Forno LS, Rebert CS, Irwin I | title = Selective nigral toxicity after systemic administration of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyrine (MPTP) in the squirrel monkey | journal = Brain Research | volume = 292 | issue = 2 | pages = 390–4 | date = February 1984 | pmid = 6607092 | doi = 10.1016/0006-8993(84)90777-7 | s2cid = 34183578 }}</ref> 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]].<ref name="MPTP" /><ref>{{cite journal | vauthors = Blanchet PJ, Calon F, Morissette M, Hadj Tahar A, Bélanger N, Samadi P, Grondin R, Grégoire L, Meltzer L, Di Paolo T, Bédard PJ | title = Relevance of the MPTP primate model in the study of dyskinesia priming mechanisms | journal = Parkinsonism & Related Disorders | volume = 10 | issue = 5 | pages = 297–304 | date = July 2004 | pmid = 15196509 | doi = 10.1016/j.parkreldis.2004.02.011 }}</ref>