King's College London, Department of Psychosis Studies, Institute of Psychiatry, London, UK.
Int J Neuropsychopharmacol. 2011 Oct;14(9):1165-78. doi: 10.1017/S1461145710001343. Epub 2010 Nov 19.
While dopamine D2 receptor partial agonists (PAs) have been long considered for treating schizophrenia, only one, aripiprazole, is clinically available for therapeutic use. This raises critically important questions as to what is unique about aripiprazole and to what extent animal models can predict therapeutic success. A number of PAs whose clinical fate is known: aripiprazole, preclamol, terguride, OPC-4392 and bifeprunox were compared to haloperidol (a reference antipsychotic) in several convergent preclinical animal models; i.e. amphetamine-induced locomotion (AIL) and conditioned avoidance response (CAR), predictive of antipsychotic effects; unilateral nigrostriatal lesioned rats, a model of hypo-dopaminergia; striatal Fos induction, a molecular marker for antipsychotic activity; and side-effects common to this class of drugs: catalepsy (motor side-effects) and prolactaemia. The results were compared across drugs with reference to their measured striatal D2 receptor occupancy. All the PAs occupied striatal D2 receptors in a dose dependent manner, inhibited AIL and CAR, and lacked motor side-effects or prolactinaemia despite D2 receptor occupancy exceeding 80%. At comparative doses, aripiprazole distinguished itself from the other PAs by causing the least rotation in the hypo-dopaminergic model (indicating the least intrinsic activity) and showed the highest Fos expression in the nucleus accumbens (indicating functional D2 antagonism). Although a number of PAs are active in antipsychotic animal models, not all of them succeed. Given that only aripiprazole is clinically available, it can be inferred that low functional intrinsic activity coupled with sufficient functional antagonism as reflected in the animal models may be a marker of success.
虽然多巴胺 D2 受体部分激动剂 (PAs) 长期以来一直被认为可用于治疗精神分裂症，但目前临床上仅阿立哌唑一种可用于治疗。这就提出了一个非常重要的问题，即阿立哌唑有何独特之处，以及动物模型在多大程度上可以预测治疗效果。一些已明确临床命运的 PAs，包括阿立哌唑、普拉克索、曲格列酮、OPC-4392 和 bifeprunox，与氟哌啶醇（一种参考抗精神病药）在几种趋同的临床前动物模型中进行了比较；即安非他命诱导的运动（AIL）和条件回避反应（CAR），这两种反应可预测抗精神病作用；单侧黑质纹状体损伤大鼠，一种低多巴胺能模型；纹状体 Fos 诱导，一种抗精神病活性的分子标志物；以及该类药物常见的副作用：僵住（运动副作用）和催乳素血症。结果与药物的测量纹状体 D2 受体占有率进行了比较。所有 PAs 均以剂量依赖的方式占据纹状体 D2 受体，抑制 AIL 和 CAR，且尽管 D2 受体占有率超过 80%，但无运动副作用或催乳素血症。在比较剂量下，阿立哌唑与其他 PAs 不同之处在于，它在低多巴胺能模型中引起的旋转最少（表明内在活性最低），并且在伏隔核中表现出最高的 Fos 表达（表明功能拮抗 D2）。尽管许多 PAs 在抗精神病动物模型中具有活性，但并非所有 PAs 都成功。鉴于临床上仅阿立哌唑可用，因此可以推断，低功能内在活性与动物模型中反映出的足够功能拮抗作用可能是成功的标志。
