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 homochlorcycilzine). 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.