Identification of Abnormal expression of proteins in psychotomimetic-treated animals using molecular biological methods

使用分子生物学方法鉴定拟精神病治疗动物中蛋白质的异常表达

• 批准号: 05670810
• 负责人: SHIRAKAWA Osamu
• 金额: $ 1.22万
• 依托单位: Kobe University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05670810/
• 关键词: schizophrenia; phencyclidine; methanphetamine; glutamate; transporter; 動物モデル

1. To study the roles of Ca^<2+>-binding proteins in the pathology of schizophrenia, we determined the acute (1h) and delayd (24h) effects of PCP (8mg/kg, s.c.) on the gene expression of NVP (neural visinin-like Ca^<2+>-binding protein) -1 in the rat brain. After 24 hours, the NVP-1 mRNA level in the nucleus accumbens showed a significant decrease of 42%.2. To examine the possible involvement of glutamate in the pathology of schizophrenia, we studied in the discrete rat brain regions the effect of methamphetamine (MAP) and phencyclidine (PCP) treatments on GLT-1 immunoreactivities (GLT-1-IR) , one of the glutamate transporter proteins specifically expressed in the brain, by western blot analysis. Single dose of MAP (4 mg/kg, s.c.) produced no significant changes in GLT-1-IR either one hour or 24 hours after the injection. Repetitive injections of MAP (each dose of 4 mg/kg, s.c., 5 times/week for three weeks) to rats in which we confirmed development of behavioral reverse tolerance to MAP produced a significant increase in GLT-1-IR in the caudate-putamen by about 50% (p<0.05). Single dose of PCP (8mg/kg, s.c.) produced no changes in GLT-1-IR studied one hour after the injection. Whereas, 24 hr after the injection GLT-1-IR decreased significantly in the hippocampus by about 30% (p<0.005) , with no changes in immunoreactivities of glial fibrillary acidic protein (GFAP) , a cell marker for astroglia. The increased GLT-1-IR in the caudate-putamen of rats which developed reverse tolerance to MAP suggests the relation of brain region-specific changes in glutamatergic neurotransmission to vulnerability to relapse in schizophrenic patients. The delayd response of GLT-1-IR in the hippocampus to PCP treatment may well explain an involvement of hippocampal glutamatergic abnormalities in the pathophysiology ofschizophrenia as well as the time latency in the development of human PCP psychosis.

1.为探讨钙离子结合蛋白在精神分裂症发病机制中的作用，我们测定了PCP(8 mg/kg，S.C.)的急性(1小时)和延迟(24小时)效应。大鼠脑内神经粘蛋白样钙结合蛋白-1基因表达的研究24小时后，伏隔核内NVP-1基因表达水平明显下降，降幅达42%。为了探讨谷氨酸在精神分裂症病理中的可能作用，我们在大鼠不同的脑区用蛋白质印迹法研究了甲基苯丙胺(MAP)和苯环利定(PCP)对GLT-1免疫反应性(GLT-1-IR)的影响，GLT-1-IR是谷氨酸转运蛋白之一。单剂量MAP(4 mg/kg，S.C.)GLT-1-IR在注射后1小时和24小时均无明显变化。重复注射MAP(每次4 mg/kg，皮下注射，每周5次，共三周)，我们证实了对MAP行为的反向耐受，使尾壳核GLT-1-IR显著增加约50%(p&lt；0.05)。PCP单剂(8 mg/kg，S.C.)注射后1小时GLT-1-IR无明显变化。然而，注射GLT-1-IR 24小时后，海马区GLT-1-IR显著减少约30%(p&lt；0.005)，而星形胶质细胞的细胞标志物--胶质纤维酸性蛋白的免疫反应性没有变化。对MAP产生反向耐受的大鼠尾壳核中GLT-1-IR的增加表明，精神分裂症患者谷氨酸能神经传递的脑区特异性变化与复发的易感性有关。海马区GLT-1-IR对PCP治疗的延迟反应可以很好地解释海马区谷氨酸能异常参与精神分裂症的病理生理，以及时间潜伏期在人类PCP精神病的发生发展中的作用。

项目成果

梶本康雄、ほか: "ラット脳における神経特異的ビジニン類似カルシウム結合蛋白質(NVP)mRNAの発現に対するフェンサイクリジンの急性及び遅延性の効果" 神経化学. 33. 384-385 (1994)

Yasuo Kajimoto 等人：“苯环己哌啶对大鼠大脑中神经元特异性维吉宁样钙结合蛋白 (NVP) mRNA 表达的急性和延迟影响。神经化学”33. 384-385 (1994)。

Kajimoto,Y.et al.: "Delayed changes in neural visinin‐like calcium‐binding protein gene expression caused by acute phencyclidine administration." Journal of Neural Transmission(in press).

Kajimoto, Y. 等人：“急性苯环己哌啶给药引起神经维西宁样钙结合蛋白基因表达的延迟变化。”

Gao, X. M. et al.: "Delayed regional metabolic actions of phencyclidine." European J. of Pharmacol.241. 7-15 (1993)

高，X.M.等人：“苯环己哌啶的局部代谢作用延迟。”

Kajimoto, Y.et al.: "Acute and delayd effects of phencyclidine in neural visinin-like calcium-binding protein mRNA in rat brain" Shinkeikagaku. 33,1. 384-385 (1994)

Kajimoto, Y.等人：“苯环己哌啶对大鼠脑中神经维西宁样钙结合蛋白 mRNA 的急性和延迟影响”Shinkeikagaku。

Gao, X.M.et al.: "Delayd regional metabolic actions of phencyclidine." European J.of Pharmacol.241. 7-15 (1993)

高，X.M.等人：“苯环己哌啶的延迟局部代谢作用。”