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Lowering the L\u2010<jats:styled-content style=\"fixed-case\">DOPA<\/jats:styled-content> dose reduces dyskinesia but also reduces the antiparkinsonian benefit. A therapy that could enhance the antiparkinsonian action of low\u2010dose L\u2010<jats:styled-content style=\"fixed-case\">DOPA<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">LD<\/jats:styled-content>l) without exacerbating dyskinesia would thus be of considerable therapeutic benefit. This study assessed whether catechol\u2010<jats:italic>O<\/jats:italic>\u2010methyltransferase (<jats:styled-content style=\"fixed-case\">COMT<\/jats:styled-content>) inhibition, as an add\u2010on to <jats:styled-content style=\"fixed-case\">LD<\/jats:styled-content>l, might be a means to achieve this goal. Cynomolgus macaques were administered 1\u2010methyl\u20104\u2010phenyl\u20101,2,3,6\u2010tetrahydropyridine. Dyskinesia was established by chronic treatment with L\u2010<jats:styled-content style=\"fixed-case\">DOPA<\/jats:styled-content>. Two doses of L\u2010<jats:styled-content style=\"fixed-case\">DOPA<\/jats:styled-content> were identified \u2013 high\u2010dose L\u2010<jats:styled-content style=\"fixed-case\">DOPA<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">LD<\/jats:styled-content>h), which provided good antiparkinsonian benefit but was compromised by disabling dyskinesia, and <jats:styled-content style=\"fixed-case\">LD<\/jats:styled-content>l, which was sub\u2010threshold for providing significant antiparkinsonian benefit, without dyskinesia. <jats:styled-content style=\"fixed-case\">LD<\/jats:styled-content>h and <jats:styled-content style=\"fixed-case\">LD<\/jats:styled-content>l were administered in acute challenges in combination with vehicle and, for <jats:styled-content style=\"fixed-case\">LD<\/jats:styled-content>l, with the <jats:styled-content style=\"fixed-case\">COMT<\/jats:styled-content> inhibitor entacapone (5, 15 and 45\u00a0mg\/kg). The duration of antiparkinsonian benefit (<jats:styled-content style=\"fixed-case\">ON<\/jats:styled-content>\u2010time), parkinsonism and dyskinesia were determined. The <jats:styled-content style=\"fixed-case\">ON<\/jats:styled-content>\u2010time after <jats:styled-content style=\"fixed-case\">LD<\/jats:styled-content>h was \u223c170\u00a0min and the <jats:styled-content style=\"fixed-case\">ON<\/jats:styled-content>\u2010time after <jats:styled-content style=\"fixed-case\">LD<\/jats:styled-content>l alone (\u223c98\u00a0min) was not significantly different to vehicle (\u223c37\u00a0min). In combination with <jats:styled-content style=\"fixed-case\">LD<\/jats:styled-content>l, entacapone significantly increased the <jats:styled-content style=\"fixed-case\">ON<\/jats:styled-content>\u2010time (5, 15 and 45\u00a0mg\/kg being \u223c123, \u223c148 and \u223c180\u00a0min, respectively). The <jats:styled-content style=\"fixed-case\">ON<\/jats:styled-content>\u2010time after <jats:styled-content style=\"fixed-case\">LD<\/jats:styled-content>l\/entacapone 45\u00a0mg\/kg was not different to that after <jats:styled-content style=\"fixed-case\">LD<\/jats:styled-content>h. However, whereas the percentage <jats:styled-content style=\"fixed-case\">ON<\/jats:styled-content>\u2010time that was compromised by disabling dyskinesia was \u223c56% with <jats:styled-content style=\"fixed-case\">LD<\/jats:styled-content>h, it was only \u223c31% with <jats:styled-content style=\"fixed-case\">LD<\/jats:styled-content>l\/entacapone 45\u00a0mg\/kg. In addition to the well\u2010recognized action of <jats:styled-content style=\"fixed-case\">COMT<\/jats:styled-content> inhibition to reduce wearing\u2010<jats:styled-content style=\"fixed-case\">OFF<\/jats:styled-content>, the data presented suggest that <jats:styled-content style=\"fixed-case\">COMT<\/jats:styled-content> inhibition in combination with low doses of L\u2010<jats:styled-content style=\"fixed-case\">DOPA<\/jats:styled-content> has potential as a strategy to alleviate dyskinesia.<\/jats:p>","DOI":"10.1111\/ejn.12093","type":"journal-article","created":{"date-parts":[[2013,1,3]],"date-time":"2013-01-03T09:00:55Z","timestamp":1357203655000},"page":"831-838","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Use of catechol\u2010<i>O<\/i>\u2010methyltransferase inhibition to minimize L\u20103,4\u2010dihydroxyphenylalanine\u2010induced dyskinesia in the 1\u2010methyl\u20104\u2010phenyl\u20101,2,3,6\u2010tetrahydropyridine\u2010lesioned macaque"],"prefix":"10.1111","volume":"37","author":[{"given":"Philippe","family":"Huot","sequence":"first","affiliation":[{"name":"Baycrest Centre for Geriatric Care Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom H.","family":"Johnston","sequence":"additional","affiliation":[{"name":"Toronto Western Research Institute MCL 11\u2010419 Toronto Western Hospital University Health Network 399 Bathurst Street Toronto ON Canada"},{"name":"Atuka Inc Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tessa","family":"Snoeren","sequence":"additional","affiliation":[{"name":"Faculty of Medicine University of Amsterdam Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James B.","family":"Koprich","sequence":"additional","affiliation":[{"name":"Toronto Western Research Institute MCL 11\u2010419 Toronto Western Hospital University Health Network 399 Bathurst Street Toronto ON Canada"},{"name":"Atuka Inc Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P.","family":"Hill","sequence":"additional","affiliation":[{"name":"Toronto Western Research Institute MCL 11\u2010419 Toronto Western Hospital University Health Network 399 Bathurst Street Toronto ON Canada"},{"name":"Atuka Inc Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan H.","family":"Fox","sequence":"additional","affiliation":[{"name":"Toronto Western Research Institute MCL 11\u2010419 Toronto Western Hospital University Health Network 399 Bathurst Street Toronto ON Canada"},{"name":"Division of Neurology Movement Disorder Clinic Toronto Western Hospital University Health Network Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan M.","family":"Brotchie","sequence":"additional","affiliation":[{"name":"Toronto Western Research Institute MCL 11\u2010419 Toronto Western Hospital University Health Network 399 Bathurst Street Toronto ON Canada"},{"name":"Atuka Inc Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,1,3]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199307153290303"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)61511-5"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.23616"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-4886(03)00250-4"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2004.11.013"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1527-3458.2007.00020.x"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/syn.10034"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2005.12.009"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.21475"},{"key":"e_1_2_8_11_1","first-page":"S2","article-title":"The spectrum of levodopa\u2010induced dyskinesias","volume":"47","author":"Fahn S.","year":"2000","journal-title":"Ann. 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