Effects of aripiprazole, olanzapine, and haloperidol in a model of cognitive deficit of schizophrenia in rats: relationship with glutamate release in the medial prefrontal cortex
Effects of aripiprazole, olanzapine, and haloperidol in a model of cognitive deficit of schizophrenia in rats: relationship with glutamate release in the medial prefrontal cortex
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DOI：
10.1007/s00213-010-2065-7
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发表时间：
2011-04-01
影响因子：
3.4
通讯作者：
Invernizzi, Roberto W.
中科院分区：
文献类型：
--
作者：
Carli, Mirjana;Calcagno, Eleonora;Invernizzi, Roberto W.
认知障碍是精神分裂症等精神疾病的特征。对改善认知的药物的研究可能会更好地了解认知缺陷的潜在机制。我们比较了抗精神病药物阿立哌唑、奥氮平和氟哌啶醇对分离和持续视觉注意测试、五选项连续反应时间任务（5-CSRTT）中表现缺陷的影响，该测试提供了关于注意力功能（视觉辨别的准确性）、反应控制（通过预期反应和持续性反应测量）和速度的信息。用NMDA受体拮抗剂3-(R)-2- carboxypperazin -4-丙基-1-磷酸（CPP）在大鼠内侧前额叶皮层（mPFC）输注诱导认知缺陷。采用体内微透析法比较阿立哌唑、奥氮平和氟哌啶醇对清醒大鼠mPFC中cpp诱导的谷氨酸（GLU）和血清素（5-HT）释放的影响。口服阿立哌唑（1.0和3.0 mg/kg）和奥氮平（0.3和1.0 mg/kg），但氟哌啶醇（0.1 mg/kg）不能消除cpp诱导的准确性缺陷和GLU释放。氟哌啶醇和阿立哌唑减少了持续性过度反应，而奥氮平对预期反应的控制效果最好。然而，这些影响与GLU释放的变化无关。未发现这些抗精神病药物对cpp诱导的5-CSRTT和5-HT外排的注意表现缺陷的影响。数据证实，在mPFC中过量的GLU释放与注意力缺陷有关。因此，抑制GLU释放可能是开发新型抗精神病药物的目标，对认知缺陷的某些方面有更大的影响。
Disruption in cognition is characteristic of psychiatric illnesses such as schizophrenia. Studies of drugs that improve cognition might provide a better insight into the mechanisms underlying cognitive deficits.We compared the effects of the antipsychotic drugs aripiprazole, olanzapine, and haloperidol on performance deficit in a test of divided and sustained visual attention, the five-choice serial reaction time task (5-CSRTT), which provides information on attentional functioning (accuracy of visual discrimination), response control (measured by anticipatory and perseverative responses) and speed.The cognitive deficit was induced by infusion of the competitive NMDA receptor antagonist 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP) in the rat medial prefrontal cortex (mPFC). In vivo microdialysis was used to compare the effects of aripiprazole, olanzapine and haloperidol on CPP-induced glutamate (GLU) and serotonin (5-HT) release in the mPFC of conscious rats.Oral aripiprazole (1.0 and 3.0 mg/kg) and olanzapine (0.3 and 1.0 mg/kg), but not haloperidol (0.1 mg/kg), abolished the CPP-induced accuracy deficit and GLU release. Haloperidol and aripiprazole, but not olanzapine, reduced perseverative over-responding, while anticipatory responding was best controlled by olanzapine. However, these effects were not associated with changes in GLU release. No association was found between the effects of these antipsychotics on CPP-induced attentional performance deficits in the 5-CSRTT and 5-HT efflux.The data confirm that excessive GLU release in the mPFC is associated with attentional deficits. Thus, suppression of GLU release may be a target for the development of novel antipsychotic drugs with greater effect on some aspects of cognitive deficits.