Schizophrenic sympyoms-related disturbance of cerebral neurotransmission

为了了解精神分裂症患者脑神经传递和神经网络可能的紊乱，我们观察了甲基苯丙胺(MAP)、可卡因和苯环利定(PCP)等拟精神分裂症药物对大鼠脑内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，能拮抗PCP和MAP在大鼠体内的拟精神行为，因此研究了D-氨基酸在大鼠、小鼠和人组织中的解剖分布。急性给予MAP可在出生后56-80天在大鼠脑内广泛诱导c-Fos蛋白样免疫反应。C-fos阳性细胞密度在梨状皮质和嗅结节最高，其次是新皮质、隔区、纹状体等的II-VI层。在8日龄新生大鼠，急性注射MAP未能引起新皮质II-V层c-fos的表达，但对…原癌基因产物更多地出现在新皮质、古皮质包括梨状皮质和皮质下区域的第VI层更深的部分。MAP诱导的c-Fos阳性细胞在新皮质内的数量和分布随出生后发育而增加，并在出生后21~23天呈成人型。与免疫组织化学结果一致的是，Norten印迹分析显示，在新皮质中，注射MAP后21、23、25、30和49天有明显的c-fos诱导，而MAP处理导致即刻早期基因在出生后8和14天低表达。C-fos在新皮质区域的这种不同的表达模式可能反映了新生和青年时期对药物反应的神经元回路的不同，因为药物、电和生理刺激的影响被认为是由神经系统中的原癌基因表达来追踪的。因此，本研究结果提示，MAP和可卡因的行为敏化可能需要大脑皮层某些神经元回路的成熟。在出生后8天和56天，MAP后c-Fos阳性细胞的分布模式与DA激动剂、可卡因和阿朴吗啡相似，但明显不同于NMDA拮抗剂PCP和地佐西平。此外，MAP以河豚毒素不敏感的方式显著增加成年大鼠额叶皮质和纹状体细胞外DA的释放，而PCP则使额叶皮质偏爱和河豚毒素敏感的DA释放增加。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。在大鼠、小鼠和人的大脑中，发现一种内源性的抗PCP和MAP物质D-丝氨酸仅存在于大脑中，并在一生中持续高含量。脑D-丝氨酸的区域变异模式与NMDA型谷氨酸受体的区域变异模式密切相关。结合D-丝氨酸对NMDA相关甘氨酸位点的选择性分布，这些数据表明D-氨基酸是一种新的甘氨酸作为NMDA受体甘氨酸调节区的内在配体，可能参与包括精神分裂症亚型在内的某些神经精神障碍的病理生理学。较少

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