{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T17:40:53Z","timestamp":1791394853576,"version":"4.3.3"},"reference-count":96,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2014,12,8]],"date-time":"2014-12-08T00:00:00Z","timestamp":1417996800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2015,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Four individuals stand out as pioneers of the early work that led to levodopa becoming a revolutionary new treatment for Parkinson's disease: Arvid Carlsson, Oleh Hornykiewicz, George C. Cotzias, and Melvin D. Yahr. All four were MDs. The first three had extra training in pharmacology, and in fact did their research in pharmacology. The fourth was a clinical neurologist, the only one in this group with those credentials. The story starts with Carlsson, who became interested in studying the mechanism of reserpine's sedative effect, now recognized as a drug\u2010induced parkinsonian state. A key experiment in 1957 showed that levodopa (<jats:sc>l<\/jats:sc>\u2010dopa) could alleviate the immobility induced by reserpine in animals. Carlsson then showed that reserpine depleted brain dopamine, and that <jats:sc>l<\/jats:sc>\u2010dopa restored it. Carlsson developed a sensitive fluorescent technique to measure dopamine levels, and his laboratory also showed the distribution of dopamine in animal brain to be highest in the striatum. Within a year, Carlsson postulated that dopamine appears to play a role in motor function. His proposal that dopamine serves as a neurotransmitter in brain was met with much skepticism, but he persisted and continued to study brain dopamine, eventually leading to being awarded the Nobel Prize in Medicine in 2000. Hornykiewicz also went into pharmacology research after graduating from medical school. Fortuitously, his assigned first project was on the blood pressure effects of dopamine, recognized as a precursor of norepinephrine. When he completed his postdoctoral studies, Carlsson's work on the reserpinized animal and on the regional distribution of brain dopamine was published. This inspired Hornykiewicz to determine dopamine levels in patients with Parkinson's disease. He obtained postmortem material, and his 1960 paper showed a marked depletion of dopamine in the striatum in this disorder. He went on in subsequent papers to correlate severity of parkinsonian features with the amount of striatal dopamine depletion. In the meantime, after his discovery of low dopamine in brains of patients with Parkinson's disease, Hornykiewicz persuaded Walther Birkmayer to inject <jats:sc>l<\/jats:sc>\u2010dopa into patients. They reported success and continued this treatment, usually combining it with the use of a monoamine oxidase inhibitor. However, the response was limited in duration, and subsequent trials by others were not achieving similar success, and many failed to find any benefit. The fulfilment of the <jats:sc>l<\/jats:sc>\u2010dopa story stemmed from the hypothesis held by Cotzias that Parkinson's disease was caused by loss of brain neuromelanin in the substantia nigra. Although Cotzias's research had been in pharmacology, he also headed a clinical pharmacology research group at a federal laboratory on Long Island, New York, USA. He decided to try to restore this pigment in patients, not animals, and one of the three drugs he tried was <jats:sc>d,l<\/jats:sc>\u2010dopa. As reported in his 1967 article, <jats:sc>d,l<\/jats:sc>\u2010dopa proved to be dramatically successful in reversing the symptoms, but at extremely high dosages and with considerable hematologic adverse effects. Cotzias immediately tested <jats:sc>l<\/jats:sc>\u2010dopa and found the same benefit with half the dosage and without the hematologic problems. Yahr was a clinical neurologist who had been treating patients with PD with available therapy and also headed a federally financed research group investigating the disorder. Always on the lookout for potential new treatments, he was initially skeptical about <jats:sc>l<\/jats:sc>\u2010dopa when studies with low doses were being reported. Seeing videos of patients presented by Cotzias, however, he realized that the results needed confirmation through a double\u2010blind controlled clinical trial. He proceeded to develop and execute such a trial with <jats:sc>l<\/jats:sc>\u2010dopa, duplicating Cotzias's success. Both Cotzias and Yahr had encountered motor fluctuations and dyskinesias, but the amelioration of bradykinesia, rigidity, and tremor was so pronounced that these adverse effects did not prevent regulatory approval of <jats:sc>l<\/jats:sc>\u2010dopa, and almost 50 years later <jats:sc>l<\/jats:sc>\u2010dopa remains the most effective pharmacologic agent for treating Parkinson's disease. This article relates the personal stories of these four pioneers and how they achieved their success. \u00a9 2014 International Parkinson and Movement Disorder Society<\/jats:p>","DOI":"10.1002\/mds.26120","type":"journal-article","created":{"date-parts":[[2014,12,9]],"date-time":"2014-12-09T03:13:39Z","timestamp":1418094819000},"page":"19-36","source":"Crossref","is-referenced-by-count":108,"title":["Four pioneers of L\u2010dopa treatment: Arvid Carlsson, Oleh Hornykiewicz, George Cotzias, and Melvin Yahr"],"prefix":"10.1002","volume":"30","author":[{"given":"Andrew J.","family":"Lees","sequence":"first","affiliation":[{"name":"The National Hospital Queen Square and University College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Tolosa","sequence":"additional","affiliation":[{"name":"Neurology Service, Hospital Cl\u00ednic de Barcelona Universitat de Barcelona, IDIBAPS, Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas Barcelona Catalonia Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. Warren","family":"Olanow","sequence":"additional","affiliation":[{"name":"Departments of Neurology and Neuroscience Mount Sinai School of Medicine, New York  New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,12,8]]},"reference":[{"key":"e_1_2_8_2_1","first-page":"421","article-title":"Alkaloids of Rauwolfia serpentina benth","volume":"16","author":"Siddiqui S","year":"1939","journal-title":"J Indian Chem Soc"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/hrt.11.4.350"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1954.tb45922.x"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1955.tb42463.x"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.122.3177.968"},{"key":"e_1_2_8_7_1","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/S0022-3565(25)23281-5","article-title":"Release of serotonin from blood platelets by reserpine in vitro","volume":"120","author":"Carlsson A","year":"1957","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1177\/3.1.1"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1748-1716.1956.tb01359.x"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02157069"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/1801200a0"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.127.3296.471.a"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1748-1716.1958.tb01618.x"},{"key":"e_1_2_8_14_1","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/S0031-6997(25)07428-9","article-title":"The occurrence, distribution and physiological role of catecholamines in the nervous system","volume":"11","author":"Carlsson A","year":"1959","journal-title":"Pharmacol Rev"},{"key":"e_1_2_8_15_1","first-page":"123","article-title":"A new histochemical method for visualization of tissue catechol amines","volume":"4","author":"Carlsson A","year":"1961","journal-title":"Med Exp Int J Exp Med"},{"key":"e_1_2_8_16_1","first-page":"1","article-title":"Cellular localization of brain monoamines","volume":"56","author":"Carlsson A","year":"1962","journal-title":"Acta Physiol Scand Suppl"},{"key":"e_1_2_8_17_1","volume-title":"Synaptic Transmission","author":"McLellan H","year":"1963"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s007020200064"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02156938"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/180244a0"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-3002(59)90652-3"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.10115"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1748-1716.1958.tb01627.x"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01485901"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1353-8020(98)00012-1"},{"key":"e_1_2_8_26_1","first-page":"309","article-title":"[The topical localization and content of noradrenalin and dopamine (3\u2010hydroxytyramine) in the substantia nigra of normal persons and patients with Parkinson's disease]","volume":"75","author":"Hornykiewicz O","year":"1963","journal-title":"Wien Klin Wochenschr"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0028-1114024"},{"key":"e_1_2_8_28_1","first-page":"787","article-title":"[The L\u20103,4\u2010dioxyphenylalanine (DOPA)\u2010effect in Parkinson\u2010akinesia.]","volume":"73","author":"Birkmayer W","year":"1961","journal-title":"Wien Klin Wochenschr"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1159\/000131242"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02189076"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.133.3465.1706-a"},{"key":"e_1_2_8_32_1","volume-title":"Biochemistry and Pharmacology of the Basal Ganglia. 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