Molecular pharmacological approach to the disturbances of brain neuron circuits involved in schizophrenia

精神分裂症脑神经元回路紊乱的分子药理学方法

• 批准号: 06670993
• 负责人: NISHIKAWA Toru
• 金额: $ 1.41万
• 依托单位: National Center of Neurology and Psychiatry
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06670993/
• 关键词: Schizophrenia; Methamphetamine; Phencyclidine; c-fos expression; Development; Neocortex; RNA arbitrarily primed PCR; Neuron circuits; c-fos遺伝子発現; 異常行動; ラット; Cocaine; SCH23390; GAP43遺伝子

A psychotomimetic drug methamphetamine (MAP) produces a neuroleptic-responsive schizophreniform psychosis in humans while phencyclidine (PCP) psychosis includes neuroleptic-resistant symptoms which are indistinguishable from those of schizophrenis. Acute administration of MAP (4.8 mg/kg, subcutaneously (s.c.)) caused a widespread induction of nuclear c-Fos-like immunoreactivity in rat brain at 56-80 postnatal days in a dopamine antagonist-sensitive manner. The greatest density of c-Fos positive cells was found in the pyriform cortex and olfactory tubercle followed by the entorhinal cortex, II-VI layrs of the neocortex, striatum, amygdala, nucleus accumbens, septal unclei, granular cell layr of the cerebellum, thalamus, hypothalamus, substantia nigra, etc. In 8-day-old neonatal rats, acute injection of these drugs failed to cause c-fos expression from the laver II htrough V of the neocortex, but induced the proto-oncogene product in a deeper aprt of the layr VI of the neocortex, the pal … More eocortex (including the pyriform and entorhinal cortex) and the above subcortical areas. MAP-induced c-Fos positive cells in the neocortex increased in number and distribution with postnatal development and showed the adult pattern after 21-23 postnatal days. The distribution patterns of c-Fos-positive cells after PCP treatment were different from those after MAP.Thus, a single injection of PCP (5-10mg/kg, s.c.) produced the dense expression of c-Fos-like immunoreactivity in the deeper layrs (IV-VI) of the neocortex and pyriform cortex, but the very sparse expression in the striatum, olfactory tubercle and superficial layrs (I-III) of the necortex in the young adult periods in a dopamine antagonist-resistant fashion. These expression patterns were similar to those of a selective NMDA receptor antagonist dizocilpine. In the neonatal periods, PCP induced very low levels of c-Fos-like immunoreactivity in the neocortex while the pyriform cortex was dense with c-Fos positive cells. PCP-induced c-Fos-immunostaining in th brain showed the adult pattern after 21-25 postnatal days. The above developmental changes in the patterns of c-fos expression in the neocortical areas might reflect differences in responsive neuronal circuits to the drugs between the neonatal and young adult periods. Because acute or long-term behavioral effects of these drugs alter around the third week of postnatal life, these results suggest that the maturation of certain neuronal circuits in the neocortex might be crucial for the acquisition of the adult patterns of behavioral responses or motor functions. We have nowtried to identify molecules contributing to such developmental changes in the discrete brain regions because these molecules should play a pivotal role in expression and regulation of psychomotor functions that may be disturbed in schizopherenic patients. To this end, we have employed a RNA arbitarily primed PCR technique for the detection of cDNAs that represent developmentally regulate Less

一种拟精神药物甲基苯丙胺（MAP）在人类中产生一种抗精神病药反应性精神分裂症样精神病，而苯环利定（PCP）精神病包括与精神分裂症难以区分的抗精神病药症状。急性给药MAP （4.8 mg/kg，皮下注射）在大鼠出生后56-80天以多巴胺拮抗剂敏感的方式广泛诱导核c- fos样免疫反应性。c-Fos阳性细胞密度最大的部位为梨状皮质和嗅结节，其次为内嗅皮质、新皮层II-VI层、纹状体、杏仁核、伏隔核、隐隔、小脑颗粒细胞层、丘脑、下丘脑、黑质等。在8日龄的新生大鼠中，急性注射这些药物并没有引起新皮层laver II - V层的c-fos表达，而是在新皮层第6层更深的部分，即pal…More皮层（包括梨状皮层和内嗅皮层）和以上皮层下区域诱导原癌基因产物。随着出生后发育，map诱导的新皮层c-Fos阳性细胞数量和分布增加，并在出生后21-23天呈现成体模式。PCP处理后的c- fos阳性细胞分布模式与MAP处理后的不同。因此，单次注射PCP （5-10mg/kg, s.c）在青壮年时期新皮层和梨状皮层的较深层（IV-VI）产生密集的c- fos样免疫反应性表达，但在纹状体、嗅结节和皮层的浅层（I-III）以多巴胺拮抗剂耐药的方式表达非常稀疏。这些表达模式与选择性NMDA受体拮抗剂二唑西平相似。在新生儿期，PCP诱导的新皮层中c-Fos样免疫反应性非常低，而梨状皮层中c-Fos阳性细胞密集。pcp诱导的脑c- fos免疫染色在出生后21-25天呈现成体模式。上述新皮质区c-fos表达模式的发育变化可能反映了新生儿期和青年期神经回路对药物反应的差异。由于这些药物的急性或长期行为影响在出生后的第三周左右发生改变，这些结果表明，新皮层中某些神经元回路的成熟可能对获得成人行为反应或运动功能的模式至关重要。我们现在已经试图在离散的大脑区域中识别有助于这种发育变化的分子，因为这些分子应该在精神分裂症患者可能受到干扰的精神运动功能的表达和调节中发挥关键作用。为此，我们采用了RNA任意引物PCR技术来检测代表发育调节Less的cdna

项目成果

Kashiwa A, Nishikawa T, Nishijima K, Umino A and Takahashi K.: "Dizocilpine(MK-801)elicits a tetrodotoxin-sensitive increase in extracellular release of dopamine in rat medial frontal cortex." Neurochem. Int.26. 85-90 (1995)

Kashiwa A、Nishikawa T、Nishijima K、Umino A 和 Takahashi K.：“地佐环平 (MK-801) 会引起大鼠内侧额叶皮层细胞外多巴胺释放对河豚毒素敏感的增加。”

Tanii Y,Nishikawa T,Hashimoto A and Takahashi K: "Stereoselective antagonism by enantiomers of alanine and serine of phencyclidine-induced hyperactiviy, stereotypy and ataxia in the rat." J.Pharmacol.EXP.Ther.269. 1040-1048 (1994)

Tanii Y、Nishikawa T、Hashimoto A 和 Takahashi K：“丙氨酸和丝氨酸对映体对苯环己哌啶诱导的大鼠多动症、刻板性和共济失调的立体选择性拮抗作用。”

Nishikawa T and Scatton B:"GABAergic inhibition of ascending serotonergic neurons in rat brain. In Serotonin in the Central Nervous System and Periphery(eds. A. Takada and G. Curzon)," Elsevier, Amsterdam,6 (1995)

Nishikawa T 和 Scatton B：“GABA 能抑制大鼠大脑中的上行血清素能神经元。中枢神经系统和外周的血清素（A. Takada 和 G. Curzon 编辑）”，Elsevier，阿姆斯特丹，6 (1995)

Hashimoto,A.et al.: "Extracellular concentration of endogenous free D-serine in the rat brain as revealed by in vivo microdialysis" Neurosuience. (印刷中).

Hashimoto, A. 等人：“通过体内微透析揭示的大鼠脑中内源性游离 D-丝氨酸的细胞外浓度”Neurosuience（正在出版）。

岩間久行・西川徹: "精神分裂病II-おもに病因・病態論の立場から-(シリーズ精神科症例集2)" 佐藤光源編集,中山書店,東京, 396 (1994)

岩间久之和西川彻：《精神分裂症 II - 主要从病因学和病理生理学的角度 - (系列精神病病例集 2)》由佐藤光编辑，中山书店，东京，396 (1994)