PREDICTION OF DRUG-INDUCED CATALEPSY BASED ON DOPAMINE D1, D2, AND MUSCARINIC ACETYLCHOLINE RECEPTOR OCCUPANCIES

本研究旨在探讨多巴胺D_1和D_2受体在体与僵住症之间的关系，以预测非选择性结合D_1和D_2受体的药物所引起的僵住症的强度。通过使用考虑Dl和D2受体之间的相互作用的该药效学模型预测的僵住症的强度高估了观察到的值，表明这些药物也具有减少僵住症的性质。由于毒蕈碱乙酰胆碱（mACh）受体拮抗剂抑制木僵的诱导，药物的抗胆碱能活性进行了研究。mACh受体结合率与僵住症变化之间的关系被用作药物减轻僵住症作用的量度。多潘立酮和环孢素A联合给药后，僵住症的强度比每种药物给药后预测的更强。结果表明，多潘立酮对环孢素A的血脑屏障通透性发生了变化。结论：考虑D1、D2和mACh受体的占位作用以及D1和D2受体之间的协同作用的药效学模型可能有助于定量预测药物诱导的僵住症。

In this study, the relationship between in vivo dopamine Dl and D2 receptor occupancies and catalepsy was investigated to predict the intensity of catalepsy induced by drugs which bound to Dl and D2 receptors nonselectively. Intensities of catalepsy predicted by using this pharmacodynamic model considering the interaction between Dl and D2 receptors overestimated the observed values, suggesting that these drugs had catalepsy-reducing properties as well. Since muscarinic acetylcholine (mACh) receptor antagonists inhibited the induction of catalepsy, the anticholinergic activities of the drugs were investigated. Relationship between mACh receptor occupancy and change in catalepsy was used as the measure of catalepsy-reducing effects of the drugs.After coadministration of domperidone and cyclosporin A, intensity of catalepsy was stronger than that predicted after administration of each drug. It is suggested that changes in permeability of the blood-brain barrier (BBB) to domperidone following exposure to cyclosporin A.In conclusion, the pharmacodynamic model considering Dl , D2, and mACh receptor occupancies and synergism between Dl and D2 receptors may be useful for quantitative prediction of drug-induced catalepsy.