Occupancy‐Guided Continuous Antipsychotic Dosing Provides a Translational Model for Evaluating Extrapyramidal Motor Liability in Mice

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%–80% 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‐guided dosing paradigm, we continuously administered haloperidol or olanzapine and assessed catalepsy as an index of EPS. To validate catalepsy as an EPS‐like 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‐occupancy 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‐induced catalepsy was significantly attenuated by scopolamine. Together, these findings demonstrate that an occupancy‐guided continuous antipsychotic dosing paradigm enables evaluation of EPS‐like behavior under clinically relevant D2 receptor occupancy conditions in mice, providing a translational framework linking clinical PET studies with preclinical research.