{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T10:53:10Z","timestamp":1791975190120,"version":"4.4.0"},"reference-count":25,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:00:00Z","timestamp":1791936000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:00:00Z","timestamp":1791936000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004330","name":"Smoking Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004330","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Neuropsychopharm Rep"],"published-print":{"date-parts":[[2026,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The therapeutic effects of antipsychotic drugs are primarily achieved through dopamine D2 receptor antagonism. However, excessive striatal D2 receptor blockade is associated with extrapyramidal side effects (EPS) in schizophrenic patients. Clinical studies indicate a therapeutic window of approximately 60%\u201380% striatal D2 receptor occupancy, with higher occupancy increasing the risk of EPS. However, conventional rodent dosing paradigms rarely maintain clinically comparable receptor occupancy, limiting their translational relevance. Here, we investigated whether continuous antipsychotic administration designed to achieve clinically relevant striatal D2 receptor occupancy can be used to evaluate extrapyramidal motor liability in mice. Using an occupancy\u2010guided dosing paradigm, we continuously administered haloperidol or olanzapine and assessed catalepsy as an index of EPS. To validate catalepsy as an EPS\u2010like phenotype, we examined whether it could be attenuated by an anticholinergic agent, consistent with the clinical management of EPS. Catalepsy was observed only under high\u2010occupancy haloperidol condition. A significant increase in catalepsy time was observed only in mice receiving haloperidol at a dose producing approximately 90% D2 receptor occupancy on day 3, whereas no catalepsy was detected under lower occupancy conditions with either haloperidol or olanzapine. Importantly, haloperidol\u2010induced catalepsy was significantly attenuated by scopolamine. Together, these findings demonstrate that an occupancy\u2010guided continuous antipsychotic dosing paradigm enables evaluation of EPS\u2010like behavior under clinically relevant D2 receptor occupancy conditions in mice, providing a translational framework linking clinical PET studies with preclinical research.<\/jats:p>","DOI":"10.1002\/npr2.70176","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T10:32:52Z","timestamp":1791973972000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Occupancy\u2010Guided Continuous Antipsychotic Dosing Provides a Translational Model for Evaluating Extrapyramidal Motor Liability in Mice"],"prefix":"10.1002","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5801-4550","authenticated-orcid":false,"given":"Yosefu","family":"Arime","sequence":"first","affiliation":[{"name":"Laboratory for Memory and Cognitive Function, Research Center for Advanced Medical Science Dokkyo Medical University  Tochigi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaoru","family":"Irahara","sequence":"additional","affiliation":[{"name":"Laboratory for Memory and Cognitive Function, Research Center for Advanced Medical Science Dokkyo Medical University  Tochigi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6754-9933","authenticated-orcid":false,"given":"Noriaki","family":"Ohkawa","sequence":"additional","affiliation":[{"name":"Laboratory for Memory and Cognitive Function, Research Center for Advanced Medical Science Dokkyo Medical University  Tochigi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,14]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1517\/14728222.10.4.515","article-title":"Targeting the Dopamine D2 Receptor in Schizophrenia","volume":"10","author":"Seeman P.","year":"2006","journal-title":"Expert Opinion on Therapeutic Targets"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapsychiatry.2019.3360"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"3267","DOI":"10.1038\/s41380-023-02203-y","article-title":"Antipsychotic Dose, Dopamine D2 Receptor Occupancy and Extrapyramidal Side\u2010Effects: A Systematic Review and Dose\u2010Response Meta\u2010Analysis","volume":"28","author":"Siafis S.","year":"2023","journal-title":"Molecular Psychiatry"},{"key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1176\/appi.ajp.157.4.514","article-title":"Relationship Between Dopamine D(2) Occupancy, Clinical Response, and Side Effects: A Double\u2010Blind PET Study of First\u2010Episode Schizophrenia","volume":"157","author":"Kapur S.","year":"2000","journal-title":"American Journal of Psychiatry"},{"key":"e_1_2_10_6_1","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1001\/archpsyc.1992.01820070032005","article-title":"Positron Emission Tomographic Analysis of Central D1 and D2 Dopamine Receptor Occupancy in Patients Treated With Classical Neuroleptics and Clozapine: Relation to Extrapyramidal Side Effects","volume":"49","author":"Farde L.","year":"1992","journal-title":"Archives of General Psychiatry"},{"key":"e_1_2_10_7_1","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1176\/appi.ajp.2020.20081212","article-title":"Anticholinergic Medication Burden\u2013Associated Cognitive Impairment in Schizophrenia","volume":"178","author":"Joshi Y. B.","year":"2021","journal-title":"American Journal of Psychiatry"},{"key":"e_1_2_10_8_1","doi-asserted-by":"crossref","first-page":"2571","DOI":"10.1038\/s41380-024-02503-x","article-title":"Advancing Understanding of the Mechanisms of Antipsychotic\u2010Associated Cognitive Impairment to Minimise Harm: A Call to Action","volume":"29","author":"Allott K.","year":"2024","journal-title":"Molecular Psychiatry"},{"key":"e_1_2_10_9_1","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1124\/jpet.102.046987","article-title":"Antipsychotic Dosing in Preclinical Models Is Often Unrepresentative of the Clinical Condition: A Suggested Solution Based on In\u00a0Vivo Occupancy","volume":"305","author":"Kapur S.","year":"2003","journal-title":"Journal of Pharmacology and Experimental Therapeutics"},{"key":"e_1_2_10_10_1","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1002\/bdd.2510130106","article-title":"Linear Pharmacokinetics of Haloperidol in the Rat","volume":"13","author":"Cheng Y. 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J.","year":"2016","journal-title":"Nature Reviews Drug Discovery"},{"key":"e_1_2_10_14_1","doi-asserted-by":"crossref","first-page":"S132","DOI":"10.1590\/1516-4446-2013-1164","article-title":"Animal Models for Predicting the Efficacy and Side Effects of Antipsychotic Drugs","volume":"35","author":"Gobira P. H.","year":"2013","journal-title":"Revista Brasileira de Psiquiatria"},{"key":"e_1_2_10_15_1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4103\/0976-0105.177703","article-title":"A Simple Practice Guide for Dose Conversion Between Animals and Human","volume":"7","author":"Nair A. 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G.","year":"2023","journal-title":"Biomedicine"},{"key":"e_1_2_10_18_1","doi-asserted-by":"crossref","DOI":"10.3389\/fnmol.2024.1451010","article-title":"A Sex\u2010Specific Effect of M4 Muscarinic Cholinergic Autoreceptor Deletion on Locomotor Stimulation by Cocaine and Scopolamine","volume":"17","author":"Berezovskaia A.","year":"2024","journal-title":"Frontiers in Molecular Neuroscience"},{"key":"e_1_2_10_19_1","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1002\/wps.20567","article-title":"Management of Common Adverse Effects of Antipsychotic Medications","volume":"17","author":"Stroup T. S.","year":"2018","journal-title":"World Psychiatry"},{"key":"e_1_2_10_20_1","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/s002130000590","article-title":"Distinct Contributions of Glutamate and Dopamine Receptors to Temporal Aspects of Rodent Working Memory Using a Clinically Relevant Task","volume":"153","author":"Aultman J. 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