Cools A R, Prinssen E P, Ellenbroek B A
Department of Psycho- and Neuropharmacology, Faculty of Medical Sciences, Catholic University of Nijmegen, The Netherlands.
Psychopharmacology (Berl). 1995 Jun;119(4):428-39. doi: 10.1007/BF02245859.
The paw test was used to detect the preclinical profile (classical versus atypical) of five putative, atypical neuroleptics, namely olanzapine, sertindole, risperidone, prothipendyl and ORG 5222. In the paw test classical neuroleptics increase the hindlimb reaction time (HRT), a parameter with predictive validity for antipsychotic efficacy, at doses comparable to those necessary for increasing forelimb reaction time (FRT), a parameter with predictive validity for extrapyramidal side-effects, whereas atypical neuroleptics increase HRT at doses that are much smaller than those increasing FRT. All tested compounds showed the profile of atypical neuroleptics in the paw test. Using the FRT/HRT ratio of minimum effective doses as overall predictor of a favourable ratio of extrapyramidal and therapeutic effects of these drugs, the following order was found: olanzapine (20) > sertindole = risperidone = prothipendyl (10) > ORG 5222 (3). The ability of compounds to attenuate locomotor activity elicited either from the olfactory tubercle (10 micrograms dopamine: OT test) or from the nucleus accumbens (1 microgram ergometrine: ACC test) was used to establish whether the compounds preferentially act in one of these structures. Previous research has shown that classical neuroleptics are far less potent in the OT test than in the ACC test, whereas atypical neuroleptics are far more potent in the OT test than in the ACC test. All five agents preferentially acted in the olfactory tubercle. The order of potency in the olfactory tubercle was as follows: sertindole > ORG 5222 > risperidone > olanzapine > prothipendyl. It is concluded that risperidone, prothipendyl, ORG 5222, sertindole and olanzapine not only show the profile of atypical neuroleptics in the paw test, but also preferentially act in the olfactory tubercle, but not in the nucleus accumbens, viz. two features that they share with the atypical neuroleptics clozapine and thioridazine and with the putative, atypical neuroleptics raclopride and remoxipride.
采用爪部试验来检测5种假定的非典型抗精神病药物，即奥氮平、舍吲哚、利培酮、丙硫喷地和ORG 5222的临床前特征（经典型与非典型型）。在爪部试验中，经典抗精神病药物在增加前肢反应时间（FRT，对锥体外系副作用具有预测效度的参数）所需剂量相当的情况下，会增加后肢反应时间（HRT，对抗精神病疗效具有预测效度的参数），而非典型抗精神病药物在增加HRT时的剂量远小于增加FRT时的剂量。所有受试化合物在爪部试验中均呈现非典型抗精神病药物的特征。以最小有效剂量的FRT/HRT比值作为这些药物锥体外系和治疗作用良好比值的总体预测指标，得出以下顺序：奥氮平（20）>舍吲哚 = 利培酮 = 丙硫喷地（10）> ORG 5222（3）。利用化合物减弱由嗅结节（10微克多巴胺：OT试验）或伏隔核（1微克麦角新碱：ACC试验）引发的运动活性的能力，来确定这些化合物是否优先作用于其中一个结构。先前的研究表明，经典抗精神病药物在OT试验中的效力远低于在ACC试验中的效力，而非典型抗精神病药物在OT试验中的效力远高于在ACC试验中的效力。所有5种药物均优先作用于嗅结节。在嗅结节中的效力顺序如下：舍吲哚 > ORG 5222 > 利培酮 > 奥氮平 > 丙硫喷地。得出结论，利培酮、丙硫喷地、ORG 5222、舍吲哚和奥氮平不仅在爪部试验中呈现非典型抗精神病药物的特征，而且优先作用于嗅结节，而非伏隔核，即它们与非典型抗精神病药物氯氮平和硫利达嗪以及假定的非典型抗精神病药物雷氯必利和瑞莫必利共有这两个特征。
