A pharmacological approach to the molecular basis of disturbed brain information processing of schizophrenia

精神分裂症大脑信息处理紊乱的分子基础的药理学方法

• 批准号: 12470192
• 负责人: NISHIKAWA Toru
• 金额: $ 10.5万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470192/
• 关键词: Schizophrenia; Methamphetamine; Phencyclidine; Neocortex; Positive symptoms; Negative symptoms; RNA arbitrarily primed PCR; Postnatal development; 精神分裂病; phencvclidine

Schizophrenic symptoms occur after adolescence and the ability of psychotogenic drugs to induce schizophrenia-like psychosis is also age-dependent. Moreover, the behavioral responses to psychotogenic drugs in experimental animals apparently depend upon postnatal development. To obtain insight into the molecular basis of schizophrenia from a developmental point of view, we investigated in the developing rats the effects of schizophrenomimetic drugs, methamphetamine (MAP : a DA agonist which causes positive symptoms) and phencyclidine (PCP : a NMDA antagonist which causes positive and negative symptoms), on gene expression in the brain using a differential cloning technique and RT-PCR. We identified a developmentally-regulated and MAP-responsive (mrtl) or PCP-responsive (prtl) gene in the neocortex A selective D1 antagonist SCH23390 attenuated a MAP-induced upregulation of neocortical mrtlexpression, while a D2-preferring antagonist haloperidol failed to inhibit the increasing effects of PCP on prtl expression. Anti-mrt1 oligonucleotide blocked the ability of repeated MAP injection to produce reverse tolerance (behavioral sensitization : a model of the onset or relapse of positive symptoms of schizophrenia). The present data suggest that mrtl or prtl might be involved in the pathophysiology of positive or negative symptoms of schizophrenia, respectively.

精神分裂症症状在青春期后发生，并且精神源性药物诱导精神分裂症样精神病的能力也依赖于年龄。此外，实验动物中对精神源性药物的行为反应显然取决于产后发育。为了从发育的角度了解精神分裂症的分子基础，我们在发育中的大鼠中研究了精神分裂症药物的影响，甲基苯丙胺（地图：导致阳性症状的DA激动剂）和支出乳肽（PCP：PCP：PCP：NMDA拮抗剂，会导致阳性和阴性症状）对基因的表达，对脑脑的表达进行了不同，该症状是在脑海中使用的。我们确定了在新皮层中鉴定出一个受发展调节的（MRTL）或PCP响应性（PRTL）基因的选择性D1拮抗剂SCH23390减弱了MAP诱导的新皮层绘图型的上调，而D2 prefrerfrifferfrifferfrifferfrifferfrifferfrifferfrifferfrifferfrifferfrifferry的拮抗剂甲型卤发型载卤素的表达式构成了PCP的效果，该型生成量增加。抗MRT1寡核苷酸阻断了重复地图注射产生反向公差的能力（行为敏化：精神分裂症阳性症状的发作或复发模型）。目前的数据表明，MRTL或PRTL可能分别参与精神分裂症的阳性或阴性症状的病理生理学。

项目成果

黒田安計, 西川 徹: "DNAチップ"臨床精神医学. 29. 1310-1312 (2000)

Yasukei Kuroda，Toru Nishikawa：“DNA 芯片”临床精神病学 29. 1310-1312 (2000)。

Kurumaji A, Kuroda T, Yamada K, Yoshikawa T, Toru M:: "An association of the polymorphic repeat of tetranucleotide (TCAT) in the first intron of the human tyrosine hydroxylase gene with schizophrenia in a Japanese sample"J Neural Transm. 108. 489-495 (200

Kurumaji A、Kuroda T、Yamada K、Yoshikawa T、Toru M：“人酪氨酸羟化酶基因第一个内含子中的四核苷酸多态性重复 (TCAT) 与日本样本中的精神分裂症的关联”J Neural Transm。

Kajii Y, Toda S, Umino A and Nishikawa T: "A molecular approach to identify essential factors for establishment of psychostimulant-induced behavioral sensitization"Contemporary Neuropsychiatry (Proceedings of the 3rd International Congress of Neuropsychia

Kajii Y、Toda S、Umino A 和 Nishikawa T：“一种分子方法来识别建立精神兴奋剂诱导的行为敏化的基本因素”当代神经精神病学（第三届国际神经精神病学大会论文集）

西川徹: "D体のアミノ酸が脳ではたらく"科学. 71. 984-988 (2001)

Toru Nishikawa：“D 型氨基酸在大脑中发挥作用”《科学》71. 984-988 (2001)。

Yoshikawa T, Kikuchi M, Saito K, Watanabe A, Yamada K, Shibuya H, Nankai M, Kurumaji A, Hattori E, Ishiguro H, Shmizu H, Okubo Y, Toru.M, Detera-Wadleigh SD: "Evidence for association of the myo-inositol monophosphatase 2 (IMPA2) gene with schizophrenia i

Yoshikawa T、Kikuchi M、Saito K、Watanabe A、Yamada K、Shibuya H、Nankai M、Kurumaji A、Hattori E、Ishiguro H、Shmizu H、Okubo Y、Toru.M、Detera-Wadleigh SD：“关联的证据