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。我们报道，PCP 诱导的小鼠认知缺陷可以通过随后亚慢性给予氯氮平而减轻，但不能减轻氟哌啶醇。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给予 NMDA 受体拮抗剂苯环己哌啶 (PCP) 后小鼠认知缺陷的影响。在新物体识别测试中，重复施用五氯苯酚（10 mg/kg/天，10 天）显着降低了保留测试阶段的探索偏好，但在训练测试阶段没有显着降低。随后亚慢性（两周）给予氟伏沙明（20 mg/kg/天）可显着改善 PCP 引起的认知缺陷。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。此外，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）或神经类固醇脱氢表雄酮 3-硫酸盐（DHEA-S；25 毫克/公斤/天）也显着改善了 PCP 引起的认知缺陷。 SA4503 或 DHEA-S 的作用也被 NE-100（1 mg/kg/天）的共同给药所拮抗，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，这些药物（氟伏沙明、帕罗西汀、SA4503）单独或与 NE-100 联合急性单次给药并不能改变 PCP 引起的认知缺陷。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。接下来，我们检查了托烷司琼（一种 5-羟色胺 (5-HT3) 受体拮抗剂和 α7 烟碱受体激动剂）对小鼠认知缺陷的影响 重复施用 NMDA 受体拮抗剂苯环己哌啶 (PCP)。随后亚慢性（2 周）给予托烷司琼（但不是昂丹司琼）可显着改善 PCP（10 mg/kg/天，持续 10 天）引起的认知缺陷。托烷司琼的作用被α7烟碱受体拮抗剂甲基乌头碱的共同给药显着拮抗，表明α7烟碱受体在托烷司琼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（例如托烷司琼）可能是治疗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.

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