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

一种精神病药物甲基苯丙胺（MAP）在人类中产生神经诱导的精神分裂症精神病，而苯基二肽（PCP）精神病包括与精神分裂症的神经耐受性耐药性症状。急性施用MAP（4.8 mg/kg，皮下（S.C.））在56-80天气中以多巴胺拮抗剂敏感的方式在56-80天在大鼠脑中诱导了大鼠脑的核C-FOS样免疫反应性。 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, nuclear accumbens, septal unclei, granular cell layr of the cerebellum, thalamus, hypothalamus, substantia nigra, etc. In 8-day-old neonatal这些药物的急性注入大鼠未能引起新皮层的Laver II Hroth V的C表达，但在新皮层的Layr VI的更深层次中诱导了原始癌基因，PAL，PAL…MOLE EOCORTEX（包括吡张和内旋和内旋Corortex）和上述下属的区域。新皮层中MAP诱导的C-FOS阳性细胞随产后发育的数量和分布增加，并在产后21-23天后显示了成年模式。 PCP处理后C-FOS阳性细胞的分布模式与地图后的分布不同。 （I-III）在年轻人时期，以多巴胺拮抗剂的方式。这些表达模式与选择性NMDA受体拮抗剂dizocilpine的表达模式相似。在新生儿期间，PCP在新皮层中诱导了非常低的C-FOS样免疫反应性，而吡形皮层则伴有C-FOS阳性细胞致密。 PCP诱导的TH大脑中的C-FOS免疫染色显示出产后21-25天后的成人模式。上述新皮质区域中C-FOS表达模式的发育变化可能反映了新生儿和年轻人时期的药物反应性神经元回路的差异。由于这些药物的急性或长期行为作用发生了变化，因此这些结果表明，新皮层中某些神经元回路的成熟对于获取成人行为反应或运动功能的模式可能至关重要。现在，我们已经识别出导致离散大脑区域此类发育变化的分子，因为这些分子应在精神病患者中可能扭曲的精神运动功能的表达和调节中起关键作用。为此，我们采用了RNA仲裁PRCR技术来检测代表发育规范较少调节的cDNA

项目成果

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