Wadenberg M L, Kapur S, Soliman A, Jones C, Vaccarino F
Section of Biopsychology, CAMH, University of Toronto, Canada.
Psychopharmacology (Berl). 2000 Jul;150(4):422-9. doi: 10.1007/s002130000466.
Human positron emission tomography (PET) shows that striatal dopamine D2 receptor occupancy predicts extrapyramidal side effects (EPS). Patients showed a clinical response with > or = 65% D2 occupancy, but EPS only when D2 occupancy >78%. Catalepsy and the selective suppression of conditioned avoidance response (CAR) are often used as animal models to predict EPS and antipsychotic effect, respectively. However, the quantitative relationship between striatal D2 occupancy and effects in these models is not known.
The present study intended to investigate the relationship between animal catalepsy, suppression of CAR, and D2 receptor blockade using a method of evaluating D2 receptor occupancy similar in principle to that used in patients.
In vivo binding of [11C]-raclopride and [3H]-raclopride was compared. Doses of cold raclopride were chosen to provide a D2 occupancy from 0 to 95%. The relationship between dose/time course of catalepsy and D2 occupancy was assessed. Effects of raclopride on conditioned avoidance response (CAR) behavior were tested.
In vivo binding of [11C]-raclopride compared to [3H]-raclopride was virtually the same. Using [3H]-raclopride, cold raclopride (0.01-0.2 mg/kg) produced 16-77% D2 receptor occupancy and no catalepsy. Raclopride (0.5-2 mg/kg) produced 83-95% D2 occupancy and significant catalepsy. Raclopride (2 mg/kg) produced on average 95% and 87% D2 receptor occupancy 1 and 2 h after administration, respectively, and maximum catalepsy. D2 occupancy at 4, 8 and 24 h was on average 58%, 46%, and 4%, respectively. No catalepsy was observed. Raclopride (0.2 mg/kg), estimated at 70-75% D2 occupancy, produced suppression of CAR.
In vivo D2 occupancy measurements in rats using [3H]-raclopride is analogous to using [11C]-raclopride in human PET scanning. Suppression of CAR occurred at a D2 occupancy of around 70-75%, and catalepsy at D2 occupancy >80%. Results closely resembled human studies where 65-70% D2 occupancy was required for antipsychotic response, while > or = 80% D2 occupancy led to EPS. Brain mechanisms involved in mediation of catalepsy in rats and EPS in humans might indeed be similar. Both suppression of CAR in rats and antipsychotic response in humans might share an underlying construct, i.e. the need for around 70% D2 receptor blockade.
人体正电子发射断层扫描（PET）显示，纹状体多巴胺D2受体占有率可预测锥体外系副作用（EPS）。患者在D2占有率≥65%时出现临床反应，但仅当D2占有率>78%时才会出现EPS。僵住症和条件性回避反应（CAR）的选择性抑制常分别用作预测EPS和抗精神病作用的动物模型。然而，纹状体D2占有率与这些模型中的效应之间的定量关系尚不清楚。
本研究旨在使用一种原理上与用于患者的方法类似的评估D2受体占有率的方法，研究动物僵住症、CAR抑制与D2受体阻断之间的关系。
比较了[11C] - 雷氯必利和[3H] - 雷氯必利的体内结合情况。选择冷雷氯必利的剂量以提供0至95%的D2占有率。评估僵住症的剂量/时间进程与D2占有率之间的关系。测试了雷氯必利对条件性回避反应（CAR）行为的影响。
与[3H] - 雷氯必利相比，[11C] - 雷氯必利的体内结合情况基本相同。使用[3H] - 雷氯必利时，冷雷氯必利（0.01 - 0.2 mg/kg）产生16 - 77%的D2受体占有率且无僵住症。雷氯必利（0.5 - 2 mg/kg）产生83 - 95%的D2占有率并导致明显的僵住症。雷氯必利（2 mg/kg）给药后1小时和2小时平均产生95%和87%的D2受体占有率，并出现最大程度的僵住症。4小时、8小时和24小时的D2占有率平均分别为58%、46%和4%。未观察到僵住症。估计D2占有率为70 - 75%的雷氯必利（0.2 mg/kg）可抑制CAR。
使用[3H] - 雷氯必利在大鼠中进行的体内D2占有率测量类似于在人体PET扫描中使用[11C] - 雷氯必利。CAR抑制发生在D2占有率约为70 - 75%时，僵住症发生在D2占有率>80%时。结果与人体研究非常相似，人体研究中抗精神病反应需要65 - 70%的D2占有率，而≥80%的D2占有率会导致EPS。大鼠僵住症和人类EPS介导过程中涉及的脑机制可能确实相似。大鼠中CAR的抑制和人类中的抗精神病反应可能具有共同的潜在机制，即需要约70%的D2受体阻断。
