0090-9556/97/2506-0675-0684$02.00/0
DRUG METABOLISM AND DISPOSITION
Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics
Vol. 25, No. 6

Prediction of Drug-Induced Catalepsy Based on Dopamine D₁, D₂, and Muscarinic Acetylcholine Receptor Occupancies

Kaori Haraguchi, Kiyomi Ito, Hajime Kotaki, Yasufumi Sawada, and Tatsuji Iga

Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo

It is known that catalepsy serves as an experimental animal model of parkinsonism. In this study, the relationship between in vivo dopamine D₁ and D₂ receptor occupancies and catalepsy was investigated to predict the intensity of catalepsy induced by drugs that bind to D₁ and D₂ receptors nonselectively. ³H-SCH23390 and ³H-raclopride were used for the labeling of D₁ and D₂ receptors, respectively. The ternary complex model consisting of agonist or antagonist, receptor, and transducer was developed, and the dynamic parameters were determined. After coadministration of SCH23390 and nemonapride, catalepsy was stronger than sum of the values predicted by single administration of each drug, and it was intensified synergistically. This finding suggested the existence of interaction between D₁ and D₂ receptors, and the necessity for constructing the model including this interaction. To examine the validity of this model, catalepsy and in vivo dopamine receptor occupancy were measured after administration of drugs that induce or have a possibility to induce parkinsonism (haloperidol, flunarizine, manidipine, oxatomide, hydroxyzine, meclizine, and homochlorcyclizine). All of the tested drugs blocked both dopamine D₁ and D₂ receptors. Intensity of catalepsy was predicted with this dynamic model and was compared with the observed values.

In contrast with haloperidol, flunarizine, manidipine, and oxatomide (which induced catalepsy), hydroxyzine, meclizine, and homochlorcyclizine failed to induce catalepsy.

Intensities of catalepsy predicted with this dynamic model considering the interaction between D₁ and D₂ receptors overestimated the observed values, suggesting that these drugs have catalepsy-reducing properties as well. Because muscarinic acetylcholine (mACh) receptor antagonists inhibit the induction of catalepsy, the anticholinergic activities of the drugs were investigated. After SCH23390, nemonapride and scopolamine were administered simultaneously; catalepsy and in vivo mACh receptor occupancy were measured to evaluate quantitatively the anticholinergic activity. Relationship between mACh receptor occupancy and change in catalepsy was used as the measure of catalepsy-reducing effects of the drugs.

Measurement of in vivo mACh receptor occupancy revealed a significant blockade of mACh receptor by all of the tested drugs except for haloperidol. The predicted values of catalepsy, when corrected for the mACh receptor-related reduction, approached the observed values. This finding indicates the possibility that mACh receptor antagonism of drugs may contribute to the reduction of catalepsy. In conclusion, the dynamic model considering D₁, D₂, and mACh receptor occupancies and synergism between D₁ and D₂ receptors may be useful for quantitative prediction of drug-induced catalepsy.