Study on Molecular Pathophysiology of Schizophrenia

精神分裂症分子病理生理学研究

• 批准号: 17390316
• 负责人: HASHIMOTO Kenji
• 金额: $ 9.28万
• 依托单位: Chiba University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390316/
• 关键词: NMDA receptor; Schizophrenia; Nicotine Receptor; Sigma Receptor; Tropisetron; Glutamate; Cognitive deficits; Fluvoxamine; グリア細胞; フャンサイクルジン; グリシントランスポーター

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

几条证据表明，通过NMDA受体传播的谷氨酸能传播功能障碍在精神分裂症的病理生理中起作用。因此，NMDA受体拮抗剂苯基酮（PCP）已被广泛用作精神分裂症的动物模型。我们报道说，随后的氯氮平下慢速给药可以减弱PCP诱导的小鼠的认知缺陷，但不进行氟哌啶醇。这项研究是为了检查选择性羟色胺再摄取抑制剂氟伏氧胺对nmdagogogation inmdagogogation inmdagogogation pciption pciptanction的认知缺陷的选择性性5-羟色胺再摄取抑制剂抑制剂对认知缺陷的影响。在新的对象识别测试中，重复给药（10 mg/kg/day，10天）大大降低了保留测试会议的探索性偏好，但在培训测试课程中却没有。通过随后的亚基频率（2周）施用Fluboxamine（20 mg/kg/day），PCP诱导的认知缺陷得到了显着改善。此外，t…通过选择性Sigma-1受体拮抗剂NE-100（1 mg/kg/day）的共同给药，氟伏沙明对PCP诱导的认知缺陷的影响更大。此外，通过随后的亚基雄性（2周）给药，选择性Sigma-1受体激动剂SA4503（1 mg/kg/day）或神经类固醇脱氢蛋皮蛋皮蛋白皮蛋白酶3-硫酸盐3-硫酸盐（DHEA-S; DHEA-S; 25 mg/kg/kg）。 SA4503或DHEA-S的作用也通过NE-100的共同给药（1 mg/kg/day）拮抗，这表明Sigma-1受体在这些药物的活性机制中的作用。相比之下，单独使用这些药物的急性单一给药（氟伏沙明，帕罗西汀，SA4503）或与NE-100的组合不会改变PCP诱导的认知缺陷。 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 deficiencies in mice.Next, we examined the effects of tropisetron, a 5-hydroxytryptamine (5-HT3) receptor antagonist and α7 nicotinic receptor agonist, on cognitive deficiencies在重复给药NMDA受体拮抗剂苯基酮（PCP）后，小鼠中的小鼠。 PCP（10天/千克/天10天）通过随后的亚慢性（2周）给药，可显着提高Tropisetron的认知缺陷，但不能改善ondansetron。通过α7烟碱受体拮抗剂甲基甲苯胺的共同给药来显着拮抗热带酮的作用，这表明α7烟碱受体在热带酮的活性机制中的作用。这些发现表明，Sigma-1受体激动剂和α7烟碱受体激动剂（如热杆）可能是精神分裂症患者认知缺陷的潜在治疗药物。较少的

项目成果

Sigma receptor ligands : Possible applications as therapeutic drugs and as radiopharmaceuticals.

Sigma 受体配体：作为治疗药物和放射性药物的可能应用。

• 发表时间: 2006
• 期刊: Curr Pharm Des 12・30
• 作者: 熱田英範;他;須磨崎亮;須磨崎 亮;柏 淳 他;Hashimoto K. et al.
• 通讯作者: Hashimoto K. et al.