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

有证据表明，NMDA受体介导的多巴胺能传递功能障碍在精神分裂症的病理生理中发挥作用。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。我们报告，PCP诱导的认知功能障碍小鼠可以减轻随后的亚慢性给药氯氮平，但不是氟哌啶醇。本研究进行了检查的影响，选择性5-羟色胺再摄取抑制剂氟伏沙明对认知功能障碍小鼠重复给药后的NMDA受体拮抗剂苯环己哌啶（PCP）。在新物体识别试验中，重复给予PCP（10 mg/kg/天，10天）显著降低了保持试验阶段的探索偏好，但在训练试验阶段没有。PCP诱导的认知缺陷显着改善随后亚慢性（2周）给药氟伏沙明（20毫克/公斤/天）。此外，t ...更多信息 氟伏沙明对PCP诱导的认知缺陷的作用通过共同施用选择性σ-1受体拮抗剂NE-100（1 mg/kg/天）来拮抗。此外，PCP诱导的认知缺陷也通过随后亚慢性（2周）给予选择性σ-1受体激动剂SA 4503（1 mg/kg/天）或神经类固醇脱氢表雄酮3-硫酸酯（DHEA-S ; 25 mg/kg/天）得到显著改善。SA 4503或DHEA-S的作用也被NE-100（1 mg/kg/天）的共同给药拮抗，表明σ-1受体在这些药物的活性机制中的作用。相比之下，急性单次给药这些药物（氟伏沙明，帕罗西汀，SA 4503）单独或与NE-100的组合并没有改变PCP诱导的认知缺陷。本研究表明氟伏沙明对sigma-1受体的激动作用在其抗PCP诱导的小鼠认知障碍的作用机制中起重要作用。接下来，我们研究了托烷司琼（5-HT 3受体拮抗剂和α7烟碱受体激动剂）对重复给予NMDA受体拮抗剂苯环己哌啶（PCP）后小鼠认知障碍的影响。随后亚慢性（2周）给予托烷司琼可显著改善PCP（10 mg/kg/天，持续10天）诱导的认知缺陷，但昂丹司琼无效。与α7烟碱受体拮抗剂甲基利卡尼汀合用可明显拮抗托烷司琼的作用，提示α7烟碱受体在托烷司琼的作用机制中起作用。这些发现表明，σ-1受体激动剂和α7烟碱受体激动剂如托烷司琼可能是精神分裂症患者认知缺陷的潜在治疗药物。少

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.

The NMDA Receptor Hypofunction Hypothesis for Schizophrenia and Glycine Modulatory Sites on the NMDA Receptors as Potential Therapeutic Drugs

• 发表时间: 2006
• 作者: K. Hashimoto

Identification of Multiple Serine Racemase (SRR) mRNA Isoforms and Genetic Analyses of SRR and DAO in Schizophrenia and d-Serine Levels

• DOI: 10.1016/j.biopsych.2005.03.018
• 发表时间: 2005-06
• 期刊: Biological Psychiatry
• 影响因子: 10.6
• 作者: Kazuo Yamada;T. Ohnishi;K. Hashimoto;Hisako Ohba;Y. Iwayama-Shigeno;Manabu Toyoshima;Akira Okuno;Hitomi Takao;T. Toyota;Y. Minabe;Kazuhiko Nakamura;E. Shimizu;M. Itokawa;N. Mori;M. Iyo;T. Yoshikawa