Schizophrenic sympyoms-related disturbance of cerebral neurotransmission

为探讨精神分裂症患者脑内神经传递和神经网络的可能失调，本研究观察了拟精神分裂症药物甲基苯丙胺（MAP）、可卡因和苯环己哌啶（PCP）对大鼠脑内c-fos基因表达和多巴胺（DA）代谢的影响。由于D-丝氨酸是一种内源性氨基酸，它能拮抗PCP和MAP对大鼠的拟精神病作用，因此我们研究了D-丝氨酸在大鼠、小鼠和人体组织中的解剖分布，发现急性给予MAP可在出生后56-80天的大鼠脑中广泛诱导核c-Fos蛋白样免疫反应。在新生8天的大鼠中，急性MAP注射不能引起c-fos在新皮质的Ⅱ-Ⅴ层表达，但能引起c-fos在新皮质的Ⅱ-Ⅴ层表达，而在新皮质的Ⅱ-Ⅵ层，c-fos在新皮质的Ⅱ-Ⅴ层表达最强，其次是新皮质的Ⅱ-Ⅵ层、隔、纹状体等。 ...更多信息 将原癌基因产物引入新皮质VI层的更深部分、包括梨状核和皮质下区域的古皮质。MAP诱导的新皮质c-Fos阳性细胞数量和分布随生后发育而增加，在生后21-23天呈成年型。与免疫组织化学研究结果一致，Northen印迹分析显示，在新皮层，MAP注射后，在产后21，23，25，30和49天观察到一个显着的c-fos诱导，而MAP治疗引起的立即早期基因在出生后8和14天的低表达。这些不同的模式c-fos的表达在新皮质区可能反映了不同的反应神经元回路的药物在新生儿和年轻的成年人时期，因为药理学，电和生理刺激的影响已被认为是由蛋白癌基因在神经系统中的表达跟踪。本研究结果表明，在出生后第3周，刺激物诱发的致敏作用可能需要大脑皮层某些神经元回路的成熟才能产生对MAP和可卡因的行为致敏作用，在出生后第8天和第56天，MAP后c-Fos阳性细胞的分布模式与DA受体激动剂相似，可卡因和阿扑吗啡，但明显不同于PCP和地佐环平后，这是NMDA拮抗剂。此外，MAP显着增加细胞外DA释放在额叶皮层和纹状体中的河豚毒素不敏感的方式在成年大鼠，而PCP产生的额叶皮层偏好和河豚毒素敏感的增加DA释放。MAP和PCP的不同效应可以部分解释PCP和MAP诱导的精神病之间的差异。内源性抗PCP和MAP物质D-丝氨酸被发现只发生在大鼠、小鼠和人类的大脑中，并且在整个生命过程中含量持续较高。脑内D-丝氨酸的区域性变化与NMDA型谷氨酸受体的变化密切相关。结合D-丝氨酸对NMDA相关甘氨酸位点的选择性刺激，这些数据表明D-氨基酸是NMDA受体甘氨酸调节位点的一种新的候选内在配体，并可能参与某些神经精神疾病（包括精神分裂症亚型）的病理生理学。少

In order to get an insight into the possible dysregulation of cerebral neurotransmission and neural networks in schizophrenic disorders, we investigated the effects of schizophrenomimetic drugs including methamphetamine (MAP), cocaine and phencyclidine (PCP) on c-fos gene expression and dopamine (DA) metabolism in rat brain. Since D-serine, which has recently been shown to be an endogenous amino acid, antagonizes the psychotomimetic action of PCP and MAP in the rat, the anatomical distribution of the D-amino acid was examined in rat, mouse and human tissues.Acute administration of MAP caused a widespread induction of nuclear c-Fos protein-like immunoreactivity in rat brain at 56-80 postnatal days. The greatest density of c-Fos positive cells was found in the pyriform cortex and olfactory tubercle followed by the II-VI layrs of the neocortex, septum, striatum, etc.In 8-day-old neonatal rats, acute MAP injection failed to cause c-fos expression in the II-V layrs of the neocortex, but ind … More uced the proto-oncogene product in a deeper part of the layr VI of the neocortex, the paleocortex including the pyriform and the 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. In agreement with the results of immunohistochemical studies, Northen blot analysis revealed that, in the neocortex, a marked c-fos induction was observed after MAP injection at 21, 23, 25, 30 and 49 days postpartum, whereas the MAP treatment caused a low expression of the immediate early gene at 8 and 14 postnatal days. These distinct patterns of c-fos expression in the neocortical areas might reflect differences in responsive neuronal circuits to the drugs at the neonatal and young adult periods, because the effects of pharmacological, electrical and physiological stimuli have been considered to be traced by the prote-oncogene expression in the nervous system. Together with the observation that stimulant-induced sensitization occurs sometime after the third week of postnatal life, the present results, therefore, suggest that the maturation of certain neuronal circuits in the neocortex might be needed to develop behavioral sensitization to MAP and cocaine.At 8 and 56 postnatal days, the distibution patterns of c-Fos positive cells after MAP were similar to those after DA agonists, cocaine and apomorphine, but clearly distinct from those after PCP and dizocilpine which are NMDA antagonists. Moreover, MAP markedly augmented extracellular DA release in the frontal cortex and striatum in a tetrodotoxin-insensitive manner in adult rats while PCP produced a frontal cortex-preferring and tetrodotoxin-sensitive increase in DA liberation. The differential effects of MAP and PCP could, in part, explain the differences between PCP-and MAP-induced psychosis.An endogenous anti-PCP and-MAP substance D-serine was found to exclusively occur in brains with a persistent high content throughout life in the rat, mouse and human. The patterns of the regional variations in brain D-serine were closely correlated with those of the NMDA type glutamate receptor. Together with a selective stimuditribution of the NMDA-related glycine site by D-serine, these data suggest that the D-amino acid is a novel canditate as an intrinsic ligand for the glycine modulatory aite of the NMDA receptor and might be involved in pathophysiology of certain neuropsychiatric disorders including a subtype of schizophrenia. Less