{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,5]],"date-time":"2026-04-05T07:28:17Z","timestamp":1775374097467,"version":"3.50.1"},"reference-count":49,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2017,12,18]],"date-time":"2017-12-18T00:00:00Z","timestamp":1513555200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008373","name":"Takeda Pharmaceutical Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008373","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2018,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Activation of indirect pathway medium spiny neurons (<jats:styled-content style=\"fixed-case\">MSN<\/jats:styled-content>s) via promotion of <jats:styled-content style=\"fixed-case\">cAMP<\/jats:styled-content> production is the principal mechanism of action of current antipsychotics with dopamine D<jats:sub>2<\/jats:sub> receptor antagonism. <jats:styled-content style=\"fixed-case\">TAK<\/jats:styled-content>\u2010063 [1\u2010[2\u2010fluoro\u20104\u2010(1H\u2010pyrazol\u20101\u2010yl)phenyl]\u20105\u2010methoxy\u20103\u2010(1\u2010phenyl\u20101H\u2010pyrazol\u20105\u2010yl)pyridazin\u20104(1H)\u2010one] is a novel phosphodiesterase 10A inhibitor that activates both direct and indirect pathway <jats:styled-content style=\"fixed-case\">MSN<\/jats:styled-content>s through increasing both <jats:styled-content style=\"fixed-case\">cAMP<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">cGMP<\/jats:styled-content> levels by inhibition of their degradation. The activation of indirect pathway <jats:styled-content style=\"fixed-case\">MSN<\/jats:styled-content>s through the distinct mechanism of action of these drugs raises the possibility of augmented pharmacological effects by combination therapy. In this study, we evaluated the potential of combination therapy with <jats:styled-content style=\"fixed-case\">TAK<\/jats:styled-content>\u2010063 and current antipsychotics, such as haloperidol or olanzapine after oral administration. Combined treatment with <jats:styled-content style=\"fixed-case\">TAK<\/jats:styled-content>\u2010063 and either haloperidol or olanzapine produced a significant increase in phosphorylation of glutamate receptor subunit 1 in the rat striatum. An electrophysiological study using rat corticostriatal slices showed that <jats:styled-content style=\"fixed-case\">TAK<\/jats:styled-content>\u2010063 enhanced <jats:italic>N<\/jats:italic>\u2010methyl\u2010<jats:sub>D<\/jats:sub>\u2010aspartic acid receptor\u2010mediated synaptic responses in both direct and indirect pathway <jats:styled-content style=\"fixed-case\">MSN<\/jats:styled-content>s to a similar extent. Further evaluation using pathway\u2010specific markers revealed that coadministration of <jats:styled-content style=\"fixed-case\">TAK<\/jats:styled-content>\u2010063 with haloperidol or olanzapine additively activated the indirect pathway, but not the direct pathway. Combined treatment with <jats:styled-content style=\"fixed-case\">TAK<\/jats:styled-content>\u2010063 and either haloperidol or olanzapine at subeffective doses produced significant effects on methamphetamine\u2010 or <jats:styled-content style=\"fixed-case\">MK<\/jats:styled-content>\u2010801\u2010induced hyperactivity in rats and <jats:styled-content style=\"fixed-case\">MK<\/jats:styled-content>\u2010801\u2010induced deficits in prepulse inhibition in mice. <jats:styled-content style=\"fixed-case\">TAK<\/jats:styled-content>\u2010063 at 0.1\u00a0mg\/kg did not affect plasma prolactin levels and cataleptic response from antipsychotics in rats. Thus, <jats:styled-content style=\"fixed-case\">TAK<\/jats:styled-content>\u2010063 may produce augmented antipsychotic\u2010like activities in combination with antipsychotics without effects on plasma prolactin levels and cataleptic responses in rodents.<\/jats:p>","DOI":"10.1002\/prp2.372","type":"journal-article","created":{"date-parts":[[2017,12,23]],"date-time":"2017-12-23T01:59:03Z","timestamp":1513994343000},"source":"Crossref","is-referenced-by-count":10,"title":["Combined treatment with a selective PDE10A inhibitor TAK\u2010063 and either haloperidol or olanzapine at subeffective doses produces potent antipsychotic\u2010like effects without affecting plasma prolactin levels and cataleptic responses in rodents"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9584-1974","authenticated-orcid":false,"given":"Kazunori","family":"Suzuki","sequence":"first","affiliation":[{"name":"CNS Drug Discovery Unit, Research Takeda Pharmaceutical Company Limited Fujisawa Kanagawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akina","family":"Harada","sequence":"additional","affiliation":[{"name":"CNS Drug Discovery Unit, Research Takeda Pharmaceutical Company Limited Fujisawa Kanagawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirobumi","family":"Suzuki","sequence":"additional","affiliation":[{"name":"CNS Drug Discovery Unit, Research Takeda Pharmaceutical Company Limited Fujisawa Kanagawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clizia","family":"Capuani","sequence":"additional","affiliation":[{"name":"Center for Drug Design &amp; Discovery Aptuit Inc. 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