Drug Research Ikeda Laboratory, Dainippon Sumitomo Pharma Co. Ltd., 33-94 Enoki-cho, Suita, Osaka, Japan.
Behav Brain Res. 2013 Jun 1;246:125-31. doi: 10.1016/j.bbr.2013.02.019. Epub 2013 Feb 27.
Cognitive impairment is one of the major symptoms of schizophrenia, and is considered largely due to dysfunctions in the prefrontal cortex (PFC). Lurasidone, a novel atypical antipsychotic agent with high binding affinity for dopamine D2, serotonin 5-HT7, 5-HT2A and 5-HT1A receptors has been reported to have superior efficacy in rodents' models of cognitive impairment. However, the beneficial effect of lurasidone on cognitive impairment has not been evaluated in non-human primates. In this study, we investigated the effect of lurasidone on executive function, which is one of the cognitive domains, in common marmosets and compared the results to those of other antipsychotics. The effects of lurasidone, haloperidol, olanzapine, risperidone, quetiapine and clozapine on executive function were evaluated in naïve marmosets using the object retrieval with detours (ORD) task. Before drug treatment, marmosets' success rates in the easy trial of the test were almost 90%. However, maximum success in the difficult trial of the task reached only 50% after 8 days of training. Haloperidol, olanzapine and risperidone decreased correct performance even in the easy trial of the task. All drugs, except lurasidone, impaired success rate in the difficult trial. On the other hand, lurasidone dose-dependently increased marmosets' success rates in the difficult trial with significant effect at 10mg/kg. In conclusion, we have shown in this study that lurasidone, unlike conventional antipsychotics, improves cognition associated with executive function in common marmosets. These findings suggest that lurasidone would be more useful for treatment of schizophrenia cognitive impairment than other antipsychotics.
认知障碍是精神分裂症的主要症状之一，主要被认为是由于前额叶皮层（PFC）的功能障碍所致。鲁拉西酮是一种新型的非典型抗精神病药物，对多巴胺 D2、5-羟色胺 5-HT7、5-HT2A 和 5-HT1A 受体具有高亲和力，已被报道在认知障碍的啮齿动物模型中具有更好的疗效。然而，鲁拉西酮对非人类灵长类动物认知障碍的有益作用尚未得到评估。在这项研究中，我们研究了鲁拉西酮对常见猕猴执行功能的影响，这是认知领域之一，并将结果与其他抗精神病药物进行了比较。在未经处理的猕猴中，使用迂回物体检索（ORD）任务评估了鲁拉西酮、氟哌啶醇、奥氮平、利培酮、喹硫平和氯氮平对执行功能的影响。在药物治疗之前，猕猴在测试的简单试验中的成功率几乎为 90%。然而，经过 8 天的训练，在任务的困难试验中，最大成功率仅达到 50%。氟哌啶醇、奥氮平和利培酮甚至在简单试验中也降低了正确表现。除了鲁拉西酮之外，所有药物都损害了在困难试验中的成功率。另一方面，鲁拉西酮剂量依赖性地增加了猕猴在困难试验中的成功率，在 10mg/kg 时具有显著效果。总之，在这项研究中，我们表明鲁拉西酮与传统抗精神病药不同，可改善常见猕猴与执行功能相关的认知。这些发现表明，与其他抗精神病药相比，鲁拉西酮在治疗精神分裂症认知障碍方面可能更有用。
