Abstract
Conditioned avoidance response (CAR) behavior and catalepsy (CAT) are the standard preclinical tests used to predict antipsychotic activity and motor side-effect liability, respectively. Recent data in patients show that striatal dopamine D2 occupancy predicts antipsychotic response (at 65% D2 occupancy) and motor side-effects (at greater than 80%). To relate preclinical and clinical findings, this study examined the relationship between striatal D2 occupancy, CAT and CAR in rats receiving typical and atypical antipsychotics. CAT was observed in animals receiving haloperidol, risperidone and olanzapine, but only at doses that produced a D2 receptor occupancy ⩾85%. The D2 occupancy of quetiapine did not cross the 85% threshold (up to 100 mg/kg) and it did not show catalepsy. All drugs were effective in the CAR model at a lower level of D2 occupancy than was required for catalepsy. We suggest that the CAR and CAT models may have displayed high predictive accuracy because they share with the clinical condition a common underlying mechanism: dopamine D2 occupancy. The implications of this finding for understanding antipsychotic action as well as the continued use of these models in drug discovery is discussed.
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Acknowledgements
We thank Corey Jones, Alex Kecojevic, Doug Hussey, Kevin Cheung, and Judy Sinyard for their expert technical assistance. This study was partially funded by support from the Theodore and Vada Stanley Foundation (USA) and by the Canada Research Chair to SK. Partial financial support from Eli Lilly Canada and AstraZeneca Canada is acknowledged.
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Wadenberg, ML., Soliman, A., VanderSpek, S. et al. Dopamine D2 Receptor Occupancy Is a Common Mechanism Underlying Animal Models of Antipsychotics and Their Clinical Effects. Neuropsychopharmacol 25, 633–641 (2001). https://doi.org/10.1016/S0893-133X(01)00261-5
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DOI: https://doi.org/10.1016/S0893-133X(01)00261-5
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