The role of M1 muscarinic cholinergic receptors in the discriminative stimulus properties of N-desmethylclozapine and the atypical antipsychotic drug clozapine in rats.
The role of M1 muscarinic cholinergic receptors in the discriminative stimulus properties of N-desmethylclozapine and the atypical antipsychotic drug clozapine in rats.
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M1 毒蕈碱胆碱能受体在 N-去甲基氯氮平和非典型抗精神病药物氯氮平在大鼠中的辨别刺激特性中的作用。
DOI：
10.1007/s00213-008-1262-0
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发表时间：
2009
影响因子：
3.4
通讯作者：
Porter,JosephH
中科院分区：
文献类型：
--
作者：
Prus,AdamJ;Pehrson,AlanL;Philibin,ScottD;Wood,JesseT;Vunck,SarahA;Porter,JosephH
氯氮平(CLZ)的歧视性刺激特性已经研究了几十年，因为它仍然是非典型抗精神病药物作用的原型，但在许多方面是独一无二的，包括提高治疗难治性精神分裂症的疗效和减少自杀。最近的研究表明，活性的CLZ代谢物N-去甲基氯氮平(NDMC)可能在介导CLZ的认知效能中发挥作用，并可能具有非典型的抗精神病作用。目的本研究旨在确定NDMC是否具有与其母药CLZ相似的辨别刺激特性。材料和方法在双选择药物辨别任务中，大鼠被训练从车辆中辨别1.25 mg/kg的CLZ。结果尽管NDMC(2.5-20.0 mg/kg)不能替代CLZ，NDMC(5.0和10.0 mg/kg)与低剂量(0.3125 mg/kg)的CLZ组合可产生完全替代(>；对于1.25 mg/kg的CLZ训练量，80%的CLZ-适当反应)。联合给予M1受体拮抗剂苯海索(6.0 mg/kg)和5.0 mg/kg的NDMC可部分替代CLZ(相当于CLZ的60%和80%)，而单独给予苯海索(0.3-12.0 mg/kg)则不能替代CLZ。结论NDMC产生与母药CLZ不同的区分性刺激效应。这种差异可能是由于NDMC在M1胆碱能受体上的激动剂特性所致。
RationaleThe discriminative stimulus properties of clozapine (CLZ) have been studied for decades because it remains the prototype for atypical antipsychotic drug effects and yet is unique in many ways, including increased efficacy in treatment-resistant schizophrenia and in reducing suicidality. Recent studies have indicated that the active CLZ metaboliteN-desmethylclozapine (NDMC) may play a role in mediating the cognitive efficacy of CLZ and may also have atypical antipsychotic properties.ObjectivesThe present study sought to determine if NDMC has discriminative stimulus properties similar to that of its parent drug CLZ.Materials and methodsRats were trained to discriminate 1.25 mg/kg CLZ from vehicle in a two-choice drug discrimination task.ResultsAlthough NDMC (2.5–20.0 mg/kg) failed to substitute for CLZ, the combination of NDMC (5.0 and 10.0 mg/kg) with a low dose (0.3125 mg/kg) of CLZ produced full substitution (>80% CLZ-appropriate responding) for the 1.25 mg/kg CLZ training dose. Co-administration of the M1-preferring receptor antagonist trihexyphenidyl (6.0 mg/kg) with a 5.0 mg/kg dose of NDMC produced partial substitution (>60% to <80% CLZ-appropriate responding) for CLZ, while administration of trihexyphenidyl alone (0.3–12.0 mg/kg) failed to substitute for CLZ.ConclusionsThese findings suggest that NDMC produces discriminative stimulus effects that are different from those elicited by its parent drug CLZ. This difference may be due to the agonist properties of NDMC at M1muscarinic cholinergic receptors.