Olanzapine and risperidone disrupt conditioned avoidance responding in phencyclidine-pretreated or amphetamine-pretreated rats by selectively weakening motivational salience of conditioned stimulus.
Olanzapine and risperidone disrupt conditioned avoidance responding in phencyclidine-pretreated or amphetamine-pretreated rats by selectively weakening motivational salience of conditioned stimulus.
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奥氮平和利培酮和利培酮通过选择性削弱条件刺激的动机显着性，破坏了苯二酮预测或苯丙胺预处理大鼠的条件回避。
DOI：
10.1097/fbp.0b013e3283243008
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发表时间：
2009-02
影响因子：
1.6
通讯作者：
Mead A
中科院分区：
文献类型：
--
作者：
Li M;He W;Mead A
大鼠条件性回避反应模型是一种成熟的预测抗精神病药疗效的临床前行为模型。所有临床批准的抗精神病药物都会破坏条件性回避反应——这是它们与其他心理治疗药物的区别所在。我们之前表明，典型的抗精神病药物氟哌啶醇通过逐渐减弱正常大鼠条件刺激（CS）的动机显着性来破坏回避反应。在这项研究中，使用两种精神分裂症药理学大鼠模型[例如苯环己哌啶（PCP）或安非他明致敏]，我们检查了奥氮平或利培酮等非典型药物是否通过相同的行为机制破坏回避反应。首先按照两种不同的注射方案之一，用 PCP、安非他明或盐水对大鼠进行预处理，持续 1 周或 3 周。然后，他们接受训练，获得对两种类型的 CS（CS1 和 CS2）的回避反应，这两种类型的 CS 预测无条件刺激发生的能力不同。最后，每天对大鼠进行奥氮平（1.0 mg/kg，皮下注射）或利培酮（0.33 mg/kg，皮下注射）的重复测试，连续 5 或 7 天。我们发现，重复奥氮平或利培酮治疗会导致对 CS1 和 CS2 的回避反应逐渐下降。奥氮平和利培酮对 CS2（不太显着的 CS）回避的破坏程度比 CS1 回避更大。用 PCP 和安非他明预处理不影响奥氮平或利培酮对回避反应的破坏作用。基于这些发现，我们认为非典型药物奥氮平和利培酮，就像典型药物氟哌啶醇一样，也主要通过减弱 CS 的动机显着性来破坏回避反应。
The rat conditioned avoidance response model is a well-established preclinical behavioral model predictive of antipsychotic efficacy. All clinically approved antipsychotic drugs disrupt conditioned avoidance responding – a feature that distinguishes them from other psychotherapeutics. We previously showed that the typical antipsychotic drug haloperidol disrupts avoidance responding by progressively attenuating the motivational salience of the conditioned stimulus (CS) in normal rats. In this study, using two pharmacological rat models of schizophrenia [e.g. phencyclidine (PCP) or amphetamine sensitization], we examined whether atypicals such as olanzapine or risperidone disrupt avoidance responding through the same behavioral mechanism. Rats were first pretreated with PCP, amphetamine, or saline under one of two different injection schedules for either 1 or 3 weeks. They were then trained to acquire avoidance responding to two types of CS (CS1 and CS2) that differed in their ability to predict the occurrence of the unconditioned stimulus. Finally, rats were tested repeatedly under olanzapine (1.0 mg/kg, subcutaneously) or risperidone (0.33 mg/kg, subcutaneously) daily for 5 or 7 consecutive days. We found that repeated olanzapine or risperidone treatment produced a progressive across-session decline in avoidance responding to both CS1 and CS2. Olanzapine and risperidone disrupted the CS2 (a less salient CS) avoidance to a greater extent than the CS1 avoidance. Pretreatment with PCP and amphetamine did not affect the disruptive effect of olanzapine or risperidone on avoidance responding. On the basis of these findings, we suggest that the atypical drugs olanzapine and risperidone, like the typical drug haloperidol, also disrupt avoidance responding primarily by attenuating the motivational salience of the CS.