Quantitative prediction of catalepsy induced by amoxapine, cinnarizine and cyclophosphamide in mice

Parkinsonism can be a side effect of antipsychotic drugs, and has recently been reported with peripherally acting drugs such as calcium channel blockers, antiarrhythmic agents and so on. In this study, we examined the quantitative prediction of drug-induced catalepsy by amoxapine, cinnarizine and cyclophosphamide, which have been reported to induce parkinsonism. Dose-dependent catalepsy was induced by these drugs in mice. In vivo dopamine D₁, D₂ and muscarinic acetylcholine (mACh) receptor occupancies by these drugs in the striatum were also examined. The in vitro binding affinities (K_i values) of amoxapine and cinnarizine to dopamine D₁, D₂ and mACh receptors in rat striatal synaptic membrane were 200 and 2900 nM, 58.4 and 76.4 nM and 379 and 290 nM, respectively. Cyclophosphamide did not bind to these receptors at concentrations up to 100 μM. Twenty drugs, including those mentioned above, showed a significant correlation between the observed intensity of catalepsy and the values predicted with a pharmacodynamic model (Haraguchi K, Ito K, Kotaki H, Sawada Y, Iga T. Prediction of drug-induced catalepsy based on dopamine D₁, D₂, and muscarinic acetylcholine receptor occupancies. Drug Metab Disp 1997; 25: 675-684) based on in vivo occupancy of dopamine D₁, D₂ and mACh receptors. We conclude that occupancy of dopamine D₁ and D₂ receptors contributes to catalepsy induction by amoxapine and cinnarizine.