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

拟精神病药物甲基苯丙胺（MAP）在人类中产生抗精神病药反应性精神分裂症样精神病，而苯环己哌啶（PCP）精神病包括与精神分裂症难以区分的抗精神病药耐药症状。急性施用MAP（4.8mg/kg，皮下（s.c.））在出生后56-80天，以多巴胺拮抗剂敏感的方式在大鼠脑中引起广泛的核c-Fos样免疫反应性诱导。在梨状皮质和嗅结节中c-Fos阳性细胞密度最大，其次是内嗅皮质、新皮质的Ⅱ-Ⅵ层、纹状体、杏仁核、隔核、小脑颗粒细胞层、丘脑、下丘脑、黑质等。急性注射这些药物不能引起c-fos在新皮层第II层至第V层的表达，但诱导了原癌基因产物在新皮层第VI层更深的部位，即pal ...更多信息 皮质（包括梨状皮质和内嗅皮质）和上述皮质下区域。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。PCP处理后c-Fos阳性细胞的分布模式与MAP处理后不同，单次注射PCP（5- 10 mg/kg，s.c.）结果表明，在青年期，c-Fos样免疫反应性在新皮质和梨状皮质的深层（IV-VI）表达较强，而在纹状体、嗅结节和皮层浅层（I-III）表达较弱，呈多巴胺拮抗剂抵抗性。这些表达模式与选择性NMDA受体拮抗剂地佐环平的表达模式相似。在新生儿期，PCP诱导非常低水平的c-Fos样免疫反应的新皮质，而梨状皮质密集的c-Fos阳性细胞。PCP诱导的脑内c-Fos免疫组化染色在出生后21-25天呈现成年模式。上述c-fos表达模式的发育变化可能反映了新生期和青年期对药物反应神经回路的差异。由于这些药物的急性或长期行为效应在出生后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年人的行为反应或运动功能模式至关重要。我们现在已经试图确定分子有助于这种发展变化的离散的大脑区域，因为这些分子应该发挥关键作用的表达和调节的精神功能，可能会受到干扰，在精神分裂症患者。为此，我们采用了RNA任意引物PCR技术检测代表发育调节的cDNA。

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