Istituto di Ricerche Farmacologiche Mario Negri, Laboratory of Neurochemistry and Behavior, Via G. La Masa 19, 20156, Milan, Italy.
Psychopharmacology (Berl). 2011 Apr;214(3):625-37. doi: 10.1007/s00213-010-2066-6. Epub 2010 Nov 4.
Blockade of N-methyl-d-aspartic acid (NMDA) receptors in the rat medial prefrontal cortex (mPFC) impairs performance in the five-choice serial reaction time task (5-CSRTT) and increases glutamate (GLU) release. Recent research suggests that excessive GLU release may be critical for attention deficits.
We tested this hypothesis by investigating the effects of the atypical antipsychotics sertindole and clozapine on 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP)-induced performance deficits in the 5-CSRTT and on the CPP-induced GLU release in the mPFC.
The 5-CSRTT, a test of divided and sustained visual attention providing indices of attentional functioning (accuracy of visual discrimination), response control (anticipatory and perseverative responses) and intracortical microdialysis in conscious rats were used to investigate the effects of sertindole and clozapine.
Low doses of sertindole (0.02-0.32 mg/kg) prevented CPP-induced accuracy deficits, anticipatory over-responding and the rise in GLU release. In contrast, doses ranging from 0.6 to 2.5 mg/kg had no effect or even enhanced the effect of CPP on anticipatory responding. Similarly, 2.5 mg/kg sertindole was unable to reverse CPP-induced rise in GLU release. Clozapine (2.5 mg/kg) prevented accuracy deficits and the increase in anticipatory responding and abolished the rise in GLU release induced by CPP.
These findings show that the ameliorating effects of sertindole and clozapine on NMDA receptor dependent attention deficit is associated with suppression in GLU release in the mPFC. This supports the proposal that suppression in GLU release might be a target for the development of novel drugs aimed at counteracting some aspects of cognitive deficits of schizophrenia.
阻断大鼠内侧前额叶皮质（mPFC）中的 N-甲基-D-天冬氨酸（NMDA）受体可损害 5-选择连续反应时任务（5-CSRTT）的表现，并增加谷氨酸（GLU）释放。最近的研究表明，GLU 释放过多可能对注意力缺陷至关重要。
我们通过研究非典型抗精神病药 sertindole 和氯氮平对 3-（R）-2-羧基哌嗪-4-丙基-1-膦酸（CPP）诱导的 5-CSRTT 表现缺陷和 mPFC 中 CPP 诱导的 GLU 释放的影响，验证了这一假设。
5-CSRTT 是一种测试分裂和持续视觉注意力的测试，提供注意力功能的指标（视觉辨别准确性）、反应控制（预期和持续反应）和清醒大鼠的皮质内微透析，用于研究 sertindole 和氯氮平的作用。
低剂量 sertindole（0.02-0.32mg/kg）可预防 CPP 引起的准确性缺陷、预期过度反应和 GLU 释放增加。相比之下，0.6 至 2.5mg/kg 的剂量没有作用，甚至增强了 CPP 对预期反应的作用。同样，2.5mg/kg sertindole 无法逆转 CPP 诱导的 GLU 释放增加。氯氮平（2.5mg/kg）可预防准确性缺陷和预期反应增加，并消除 CPP 诱导的 GLU 释放增加。
这些发现表明 sertindole 和氯氮平对 NMDA 受体依赖性注意力缺陷的改善作用与 mPFC 中 GLU 释放的抑制有关。这支持了这样一种观点，即 GLU 释放的抑制可能是开发旨在对抗精神分裂症某些认知缺陷的新型药物的目标。
