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首页> 美国卫生研究院文献>other >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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Olanzapine and risperidone disrupt conditioned avoidance responding in phencyclidine-pretreated or amphetamine-pretreated rats by selectively weakening motivational salience of conditioned stimulus

机译：奥氮平和利培酮通过选择性减弱条件刺激的刺激性来破坏苯环利定预处理或苯丙胺预处理大鼠中的条件回避反应

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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.
机译：大鼠条件回避反应模型是建立良好的临床前行为模型，可预测抗精神病药的疗效。所有临床批准的抗精神病药物都会破坏条件回避反应，这一功能使它们与其他心理治疗药物区别开来。我们以前显示典型的抗精神病药物氟哌啶醇通过逐渐减弱正常大鼠中条件刺激（CS）的动机显着性来破坏回避反应。在这项研究中，使用了两种精神分裂症的药理大鼠模型[例如苯环利定（PCP）或苯丙胺敏化]，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了回避反应。首先在两种不同的注射方案之一下，用PCP，苯丙胺或盐水对大鼠进行1或3周的预处理。然后对他们进行训练，以逃避对两种类型的CS（CS1和CS2）的反应，这两种类型的CS预测无条件刺激的发生能力不同。最后，每天在奥氮平（1.0 mg / kg，皮下）或利培酮（0.33 mg / kg，皮下）下重复测试大鼠，连续5或7天。我们发现，反复使用奥氮平或利培酮治疗可避免CS1和CS2的发生，从而使整个疗程的回避逐渐减少。与CS1规避相比，奥氮平和利培酮对CS2规避（显着性CS规避）的破坏程度更大。用五氯苯酚和苯丙胺预处理不会影响奥氮平或利培酮对避免反应的破坏作用。根据这些发现，我们建议非典型药物olanzapine和risperidone像典型的药物氟哌啶醇一样，也主要通过减弱CS的动机显着性来破坏回避反应。

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