Clozapine but not haloperidol treatment reverses sub-chronic phencyclidine-induced disruption of conditional discrimination performance
Clozapine but not haloperidol treatment reverses sub-chronic phencyclidine-induced disruption of conditional discrimination performance
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DOI：
10.1016/j.bbr.2006.08.028
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发表时间：
2006-12-15
影响因子：
2.7
通讯作者：
Killcross, Simon
中科院分区：
文献类型：
--
作者：
Dunn, Michael J.;Killcross, Simon
苯环利定(PCP)的滥用者通常表现出与精神分裂症患者相似的症状。利用这种精神分裂学的动物模型目前正在为对这种情况的研究提供信息。越来越多的证据表明，精神分裂症的一个中心认知缺陷是无法使用任务设置线索来指导目标导向行为，而且这种能力是由前额叶多巴胺(DA)介导的。本研究使用非竞争性NMDA拮抗剂苯环利定(PCP)、Hatperidol(典型抗精神病药物)和Clozapine(非典型抗精神病药物)，以进一步研究DA能操纵对一项需要使用条件信息来告知目标定向操作的任务的影响。采用工具性条件辨别任务，让大鼠学习根据特定听觉条件刺激的存在做出适当的反应。探针试验I显示，与对照组相比，亚慢性给药(每天两次注射七次)后条件辨别能力受损，而用氯氮平(5 mg/kg)急性治疗而不是氟哌啶醇(0.1 mg/kg)急性治疗后，这一情况被逆转，这两种药物都用了60分钟的预测试。探查试验2(治疗后8天)显示条件辨别能力的持久缺陷，氯氮平但不能逆转这一缺陷(注射程序如上)。这些结果表明，依赖条件关系的任务对多巴能系统的操纵特别敏感，因为PCP的长期治疗被证明可以选择性地降低前额叶皮质(PFC)的DA活性，而氯氮平(已知可以改善认知障碍)治疗可以选择性地恢复PFC DA的水平，但氟哌啶醇不能。(C)2006爱思唯尔B.V.保留所有权利。
Abusers of phencyclidine (PCP) often present with a symptom profile similar to that exhibited by schizophrenia patients. Animal models utilising such psychotomimetics are currently informing research into the condition. Accumulating evidence suggests that a central cognitive deficit in schizophrenia is the inability to use task-setting cues to guide goal directed behaviour and that this ability is mediated by prefrontal dopamine (DA). The current study used the non-competitive NMDA antagonist phencyclidine (PCP) and Hatoperidol (typical antipsychotic) and Clozapine (atypical antipsychotic) in order to further investigate the influence of DAergic manipulation on a task that requires the use of conditional information to inform goal-directed performance. An instrumental conditional discrimination task was employed in which rats learn to respond appropriately according to the presence of specific auditory conditional stimuli. Probe test I showed impaired conditional discrimination performance following sub-chronic PCP administration (seven twice-daily injection protocol) compared to control which was reversed by acute treatment with clozapine (5 mg/kg) but not haloperidol (0.1 mg/kg) both administered 60 min pre-test. Probe test 2 (8 days post-treatment) showed enduring deficits to conditional discrimination performance that were again reversed by clozapine but not haloperidol (injection procedures as above). These results show that tasks dependent upon conditional relationships are particularly sensitive to manipulation of DAergic systems as prolonged treatment with PCP has been shown to selectively reduce prefrontal cortex (PFC) DA activity and treatment with clozapine (known to ameliorate cognitive deficits) but not haloperidol has been shown to selectively restore PFC DA levels. (c) 2006 Elsevier B.V. All rights reserved.