Serotonin receptor mechanisms mediate the discriminative stimulus properties of the atypical antipsychotic clozapine in C57BL/6 mice.
Serotonin receptor mechanisms mediate the discriminative stimulus properties of the atypical antipsychotic clozapine in C57BL/6 mice.
复制标题
5-羟色胺受体机制介导非典型抗精神病药物氯氮平在 C57BL/6 小鼠中的辨别刺激特性。
DOI：
10.1007/s00213-005-2147-0
复制
发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Porter,JosephH
中科院分区：
文献类型：
--
作者：
Philibin,ScottD;Prus,AdamJ;Pehrson,AlanL;Porter,JosephH
非典型抗精神病药物（APD）氯氮平（CLZ）已被证明在大鼠，鸽子，目的本研究旨在探讨CLZ在C57 BL/6小鼠中能否建立一种双选择药物辨别程序，以及该程序能否区分典型APD和非典型APD。6只雄性小鼠进行了训练，以区分2.5 mg/kg CLZ从车辆在一个两个杠杆的药物discriminationprocedure.ResultsGeneralization测试与CLZ产生完全取代在2.5-和5.0-mg/kg剂量与ED 50为1.14 mg/kg。非典型APD奥氮平（ED 50 =0.24 mg/kg）、利培酮（ED 50 =0.072 mg/kg）和齐拉西酮（ED 50 =0.33 mg/kg）完全替代CLZ的辨别线索，而典型APD氟哌啶醇未能替代CLZ。用选择性配体进行的泛化试验表明，5-羟色胺（5-HT）2A/2B/2Cantagonist ritanserin完全取代了CLZ（ED 50 =2.08 mg/kg），5-HT受体激动剂quipazine显著减弱了CLZ的辨别线索，但不破坏应答率。毒蕈碱受体拮抗剂东莨菪碱，多巴胺激动剂安非他明，和5-HT激动剂quipazine未能取代CLZ.ConclusionsThese结果表明，5-HT受体的拮抗作用起着重要的作用，在介导的非典型APD CLZ在C57 BL/6小鼠的辨别刺激特性。非典型APD奥氮平、利培酮和齐拉西酮完全替代CLZ，而典型APD氟哌啶醇不能。这些结果表明，CLZ药物辨别在C57 BL/6小鼠可能是一个有效的临床前行为检测筛选典型的抗精神病药物的非典型。
RationaleThe atypical antipsychotic drug (APD) clozapine (CLZ) has been shown to have a robust discriminative cue in rats, pigeons, and monkeys in two-choice drug discrimination procedures.ObjectivesThe present study determined whether a two-choice drug discrimination procedure with CLZ could be established in C57BL/6 mice and whether this procedure could distinguish between atypical and typical APDs.MethodsC57BL/6 male mice were trained to discriminate 2.5 mg/kg CLZ from vehicle in a two-lever drug discrimination procedure.ResultsGeneralization testing with CLZ produced full substitution at the 2.5- and 5.0-mg/kg doses with an ED50of 1.14 mg/kg. The atypical APDs olanzapine (ED50=0.24 mg/kg), risperidone (ED50=0.072 mg/kg), and ziprasidone (ED50=0.33 mg/kg) fully substituted for CLZ’s discriminative cue, while the typical APD haloperidol failed to substitute for CLZ. Generalization testing with selective ligands showed that the serotonin (5-HT)2A/2B/2Cantagonist ritanserin fully substituted for CLZ (ED50=2.08 mg/kg) and that the 5-HT receptor agonist quipazine significantly attenuated CLZ’s discriminative cue without disrupting response rates. The muscarinic receptor antagonist scopolamine, the dopamine agonist amphetamine, and the 5-HT agonist quipazine failed to substitute for CLZ.ConclusionsThese results demonstrated that antagonism of 5-HT receptors plays an important role in mediating the discriminative stimulus properties of the atypical APD CLZ in C57BL/6 mice. The atypical APDs olanzapine, risperidone, and ziprasidone fully substituted for CLZ, while the typical APD haloperidol did not. These results suggest that CLZ drug discrimination in C57BL/6 mice may be an effective preclinical behavioral assay for screening atypical from typical antipsychotic drugs.