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

多项证据表明，通过 NMDA 受体功能障碍进行的谷氨酸传递在精神分裂症的病理生理学中发挥作用，因此，NMDA 受体拮抗剂苯环己哌啶 (PCP) 已被广泛用作精神分裂症的动物模型。小鼠可以通过随后亚慢性施用氯氮平而不是氟哌啶醇来减弱效果。本研究旨在检验选择性5-羟色胺再摄取抑制剂氟伏沙明对重复施用 NMDA 受体拮抗剂苯环己哌啶 (PCP) 后小鼠认知缺陷的影响在新的物体识别测试中，重复施用 PCP（10 毫克/公斤/天，10 天）显着降低了小鼠的探索偏好。随后的亚慢性（两周）氟伏沙明给药显着改善了记忆测试课程中的认知缺陷，但 PCP 引起的认知缺陷并未显着改善（20）。此外，氟伏沙明对 PCP 引起的认知缺陷的作用可通过与选择性 sigma-1 受体拮抗剂 NE-100（1 mg/kg/天）共同给药来拮抗。随后亚慢性（两周）施用选择性 sigma-1 受体激动剂 SA4503（1 毫克/公斤/天）或神经类固醇也显着改善了诱发的认知缺陷脱氢表雄酮 3-硫酸盐（DHEA-S；25 mg/kg/天） SA4503 或 DHEA-S 的作用也被 NE-100（1 mg/kg/天）的共同给药所拮抗，表明 sigma 的作用。 -1 受体在这些药物的活性机制中相反，单独急性单次施用这些药物（氟伏沙明、帕罗西汀、SA4503）。或与 NE-100 组合不会改变 PCP 诱导的认知缺陷。本研究表明，氟伏沙明对 sigma-1 受体的激动活性在氟伏沙明对 PCP 诱导的小鼠认知缺陷的活性机制中发挥作用。检查了托烷司琼（一种 5-羟色胺 (5-HT3) 受体拮抗剂和 α7 烟碱受体激动剂）对重复给药后小鼠认知缺陷的影响NMDA 受体拮抗剂苯环己哌啶（PCP）（10 mg/kg/天，持续 10 天）引起的认知缺陷可通过随后亚慢性（2 周）给予托烷司琼显着改善，但托烷司琼不会显着拮抗托烷司琼的作用。 α7 烟碱受体拮抗剂甲基乌头碱的共同给药，表明 α7 烟碱受体在活性机制中的作用这些研究结果表明，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缺陷的潜在药物。

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.