{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T05:14:02Z","timestamp":1790399642199,"version":"4.1.0"},"reference-count":53,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2018,3,6]],"date-time":"2018-03-06T00:00:00Z","timestamp":1520294400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["NS45962"],"award-info":[{"award-number":["NS45962"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["NS073994"],"award-info":[{"award-number":["NS073994"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["NCRRRR000165"],"award-info":[{"award-number":["NCRRRR000165"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2018,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Phosphodiesterase 10A is a member of the phosphodiesterase family whose brain expression is restricted to the striatum. Phosphodiesterase 10A regulates cyclic adenosine monophosphate and cyclic guanosine monophosphate, which mediate responses to dopamine receptor activation, and the levels of these cyclic nucleotides are decreased in experimental models of <jats:sc>l<\/jats:sc>\u2010dopa\u2010induced dyskinesia. The elevation of cyclic adenosine monophosphate\/cyclic guanosine monophosphate levels by phosphodiesterase 10A inhibition may thus be targeted to reduce <jats:sc>l<\/jats:sc>\u2010dopa\u2010induced dyskinesia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>The present study was aimed at determining the potential antidyskinetic effects of phosphodiesterase 10A inhibitors in a primate model of Parkinson's disease (PD). The experiments performed in this model were also intended to provide translational data for the design of future clinical trials.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Five MPTP\u2010treated macaques with advanced parkinsonism and reproducible <jats:sc>l<\/jats:sc>\u2010dopa\u2010induced dyskinesia were used. MR1916, a selective phosphodiesterase 10A inhibitor, at doses 0.0015 to 0.05 mg\/kg, subcutaneously, or its vehicle (control test) was coadministered with <jats:sc>l<\/jats:sc>\u2010dopa methyl ester acutely (predetermined optimal and suboptimal subcutaneous doses) and oral <jats:sc>l<\/jats:sc>\u2010dopa chronically as daily treatment for 5 weeks. Standardized scales were used to assess motor disability and <jats:sc>l<\/jats:sc>\u2010dopa\u2010induced dyskinesia by blinded examiners. Pharmacokinetics was also examined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>MR1916 consistently reduced <jats:sc>l<\/jats:sc>\u2010dopa\u2010induced dyskinesia in acute tests of <jats:sc>l<\/jats:sc>\u2010dopa optimal and suboptimal doses. Significant effects were present with every MR1916 dose tested, but the most effective was 0.015 mg\/kg. None of the MR1916 doses tested affected the antiparkinsonian action of <jats:sc>l<\/jats:sc>\u2010dopa at the optimal dose. The anti\u2010<jats:sc>l<\/jats:sc>\u2010dopa\u2010induced dyskinesia effect of MR1916 (0.015 mg\/kg, subcutaneously) was sustained with chronic administration, indicating that tolerance did not develop over the 5\u2010week treatment. No adverse effects were observed after MR1916 administration acutely or chronically.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Results show that regulation of striatal cyclic nucleotides by phosphodiesterase 10A inhibition could be a useful therapeutic approach for <jats:sc>l<\/jats:sc>\u2010dopa\u2010induced dyskinesia, and therefore data support further studies of selective phosphodiesterase 10A inhibitors for PD therapy. \u00a9 2018 International Parkinson and Movement Disorder Society<\/jats:p><\/jats:sec>","DOI":"10.1002\/mds.27341","type":"journal-article","created":{"date-parts":[[2018,3,6]],"date-time":"2018-03-06T06:36:51Z","timestamp":1520318211000},"page":"805-814","source":"Crossref","is-referenced-by-count":30,"title":["A Selective Phosphodiesterase 10A Inhibitor Reduces <scp>L<\/scp>\u2010Dopa\u2010Induced Dyskinesias in Parkinsonian Monkeys"],"prefix":"10.1002","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8890-2743","authenticated-orcid":false,"given":"Goichi","family":"Beck","sequence":"first","affiliation":[{"name":"Yerkes National Primate Research Center Emory University Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunsuke","family":"Maehara","sequence":"additional","affiliation":[{"name":"Research Center Mochida Pharmaceutical Co., Ltd. Gotemba Shizuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phat Ly","family":"Chang","sequence":"additional","affiliation":[{"name":"Yerkes National Primate Research Center Emory University Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stella M.","family":"Papa","sequence":"additional","affiliation":[{"name":"Yerkes National Primate Research Center Emory University Atlanta Georgia USA"},{"name":"Department of Neurology Emory University School of Medicine Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,3,6]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2471"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.50.5.1323"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/00002826-200003000-00004"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.21387"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-211-45295-0_59"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(10)70218-0"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2013.05.006"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep41432"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6316"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00702-017-1735-6"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1176-08.2008"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00702-017-1744-5"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2014.09.010"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26197"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1369\/jhc.6A6930.2006"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(03)02754-9"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2005.12.042"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.107.132910"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2012.06.013"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2013.10.015"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2518-08.2008"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2007.05152.x"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1254\/jphs.10R01FM"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00910.2014"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2014.10.004"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2008.06387.x"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awq342"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.107.125666"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0052680"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24375"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410390505"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1097\/FBP.0000000000000084"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2013.02.004"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2016.08.012"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0013417"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/0364-7722(79)90008-0"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-58811-7_10"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4306"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(94)90796-X"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awv219"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1006\/nbdi.1999.0259"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0852-07.2007"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2016.10.033"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2017.00112"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2005.05.044"},{"key":"e_1_2_8_47_1","first-page":"435","article-title":"Dopamine D3 Receptor Modulates l\u2010DOPA\u2010Induced Dyskinesia by Targeting D1 Receptor\u2010Mediated Striatal Signaling","volume":"27","author":"Solis O","year":"2017","journal-title":"Cereb Cortex"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep06811"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2840-04.2005"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4223-07.2007"},{"key":"e_1_2_8_51_1","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/S0022-3565(25)39350-X","article-title":"Differential effect of selective D\u20101 and D\u20102 dopamine receptor agonists on levodopa\u2010induced dyskinesia in 1\u2010methyl\u20104\u2010phenyl\u20101,2,3,6\u2010tetrahydropyridine\u2010exposed monkeys","volume":"267","author":"Blanchet P","year":"1993","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.52.4.771"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410310514"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2012.12.008"}],"container-title":["Movement Disorders"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fmds.27341","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/movementdisorders.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mds.27341","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T12:07:18Z","timestamp":1760962038000},"score":1,"resource":{"primary":{"URL":"https:\/\/movementdisorders.onlinelibrary.wiley.com\/doi\/10.1002\/mds.27341"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,6]]},"references-count":53,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2018,5]]}},"alternative-id":["10.1002\/mds.27341"],"URL":"https:\/\/doi.org\/10.1002\/mds.27341","archive":["Portico"],"relation":{},"ISSN":["0885-3185","1531-8257"],"issn-type":[{"value":"0885-3185","type":"print"},{"value":"1531-8257","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,3,6]]}}}