Study on Molecular Pathophysiology of Schizophrenia

一些证据表明，通过NMDA受体的谷氨酸能传递功能障碍在精神分裂症的病理生理学中发挥了作用。因此，NMDA受体拮抗剂苯环利定(PCP)已被广泛用作精神分裂症的动物模型。我们报道了氯氮平的亚慢性给药可以减轻氯氮平所致的小鼠认知障碍，但氟哌啶醇不能。本研究旨在观察选择性5-羟色胺重摄取抑制剂氟伏沙明对反复给药NMDA受体拮抗剂苯环利定(PCP)后小鼠认知功能障碍的影响。在新的物体识别测验中，重复给予PCP(10 mg/kg/天，10天)显著降低了在保持测验阶段的探索偏好，但在训练测试阶段没有显著降低。亚慢性(2周)给予氟伏沙明(20 mg/kg/d)可显著改善PCP所致的认知障碍。此外，t…选择性Sigma-1受体拮抗剂NE-100(1 mg/kg/d)可拮抗氟伏沙明对PCP所致认知障碍的影响。此外，亚慢性(2周)给予选择性Sigma-1受体激动剂SA4503(1 mg/kg/d)或神经类固醇脱氢表雄酮3-硫酸酯(DHEA-S；25 mg/kg/d)也可显著改善PCP所致的认知障碍。NE-100(1 mg/kg/d)可拮抗SA4503或脱氢表雄酮-S的作用，提示Sigma-1受体在这些药物的作用机制中起作用。相比之下，急性单次给药(氟伏沙明、帕罗西汀、SA4503)单独或与NE-100联合应用并不能改变PCP引起的认知障碍。本研究提示氟伏沙明对5-羟色胺(5-HT3)受体拮抗剂和烟碱受体激动剂托烷司琼对α受体拮抗剂苯环利定(PCP)反复给药后小鼠认知功能障碍的改善作用可能与其在Sigma-1受体上的激活作用有关。亚慢性(2周)服用托烷司琼可显著改善PCP(10 mg/kg/d，连续10天)所致的认知障碍，但恩丹西酮未见明显改善。托烷司琼的作用可被α7烟碱受体拮抗剂甲基牡丹碱显著拮抗，提示α7烟碱受体在托烷司琼的作用机制中起重要作用。这些发现表明，Sigma-1受体激动剂和α7烟碱受体激动剂，如托烷司琼，可能是治疗精神分裂症患者认知障碍的潜在药物。较少

Several lines of evidence suggest that dysfunction of glutamatergic transmission via NMDA receptor play a role in the pathophysiology of schizophrenia. Therefore, NMDA receptor antagonist phencyclidine (PCP) have been widely used as animal model of schizophrenia. We reported that PCP-induced cognitive deficits in mice could be attenuated by subsequent subchronic administration of clozapine, but not haloperidol.This study was undertaken to examine the effects of the selective serotonin reuptake inhibitor fluvoxamine on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). In the novel object recognition test, repeated administration of PCP (10 mg/kg/day, 10 days) significantly decreased the exploratory preference in the retention test session, but not in the training test session. PCP-induced cognitive deficits were significantly improved by subsequent subchronic (2-week) administration of fluvoxamine (20 mg/kg/day). Furthermore, t … More he effect of fluvoxamine on PCP-induced cognitive deficits was antagonized by co-administration of the selective sigma-1 receptor antagonist NE-100 (1 mg/kg/day). Moreover, PCP-induced cognitive deficits were also significantly improved by subsequent subchronic (2-week) administration of the selective sigma-1 receptor agonist SA4503 (1 mg/kg/day) or neurosteroid dehydroepiandrosterone 3-sulfate (DHEA-S ; 25 mg/kg/day). The effects of SA4503 or DHEA-S were also antagonized by co-administration of NE-100 (1 mg/kg/day), suggesting the role of sigma-1 receptors in the active mechanisms of these drugs. In contrast, acute single administration of these drugs (fluvoxamine, paroxetine, SA4503) alone or combination with NE-100 did not alter PCP-induced cognitive deficits. The present study suggests that agonistic activity of fluvoxamine at sigma-1 receptors plays a role in the active mechanisms of fluvoxamine on PCP-induced cognitive deficits in mice.Next, we examined the effects of tropisetron, a 5-hydroxytryptamine (5-HT3) receptor antagonist and α7 nicotinic receptor agonist, on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). PCP (10 mg/kg/day for 10 days)-induced cognitive deficits were significantly improved by subsequent subchronic (2-weeks) administration of tropisetron, but not ondansetron. Effects of tropisetron were significantly antagonized by co-administration of the α7 nicotinic receptor antagonist methyllycaconitine, suggesting the role of α7 nicotinic receptors in the active mechanisms of tropisetron. These findings suggest that sigma-1 receptor agonists and α7 nicotinic receptor agonists such as tropisetron could be a potential therapeutic drug for cognitive deficits in schizophrenic patients. Less