Copenhagen University Hospital, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
Neurochem Int. 2010 Jan;56(2):270-5. doi: 10.1016/j.neuint.2009.10.011. Epub 2009 Nov 6.
The psychotomimetic effect of NMDA antagonists such as phencyclidine (PCP) in humans spurred the hypoglutamatergic theory of schizophrenia. This theory is supported by animal studies demonstrating schizophrenia-like behavioral and molecular changes following PCP administration to adult or neonatal animals. However, schizophrenia is believed to develop in part due to neurodevelopmental dysfunction during adolescence. Therefore, the effects of PCP in juvenile animals may better reflect the pathophysiology of schizophrenia. Here, we compare the effect of PCP (5mg/kg/day for 5 days) on activity-regulated cytoskeleton-associated protein (Arc) and parvalbumin mRNA expression in juvenile and adult rats. Arc is a marker for excitatory neurotransmission. Parvalbumin is a marker for GABAergic neurotransmission, known to be reduced in postmortem brains of schizophrenics. PCP reduced parvalbumin mRNA expression in the medial prefrontal cortex (mPFC), ventrolateral orbitofrontal cortex (VLO) and shell of the nucleus accumbens (ACCshell) in both juvenile and adult rats. Contrarily, PCP produced opposite effects on Arc mRNA expression in the mPFC, VLO and ACCshell, leading to decreased expression in juvenile and increased expression in adult rats. The differential effect of PCP in juvenile and adult rats may be caused by the immature functional state of the prefrontal cortex in juvenile rats. These results demonstrate differences between the effects of PCP in juvenile and adult rats. The decrease in Arc mRNA in juvenile rats corresponds best with the proposed "hypofrontality" in schizophrenia, suggesting the merits of using PCP in juvenile animals as a model for schizophrenia, as this would relate better to the typical onset and clinical features of schizophrenia.
NMDA 拮抗剂（如苯环利定，PCP）在人类中的精神拟态效应促使人们提出了精神分裂症的谷氨酸能低下理论。该理论得到了动物研究的支持，这些研究表明，在成年或新生动物中给予 PCP 后，会出现类似精神分裂症的行为和分子变化。然而，人们认为精神分裂症部分是由于青春期的神经发育功能障碍而发展的。因此，PCP 在幼年动物中的作用可能更好地反映了精神分裂症的病理生理学。在这里，我们比较了 PCP（每天 5mg/kg，连续 5 天）对幼年和成年大鼠中活性调节细胞骨架相关蛋白（Arc）和钙结合蛋白 Parvalbumin mRNA 表达的影响。Arc 是兴奋性神经传递的标志物。钙结合蛋白 Parvalbumin 是 GABA 能神经传递的标志物，已知在精神分裂症患者的死后大脑中减少。PCP 降低了幼年和成年大鼠内侧前额叶皮层（mPFC）、腹外侧眶额皮层（VLO）和伏隔核壳（ACCshell）中的 Parvalbumin mRNA 表达。相反，PCP 对 mPFC、VLO 和 ACCshell 中的 Arc mRNA 表达产生相反的影响，导致幼年大鼠表达减少，成年大鼠表达增加。PCP 在幼年和成年大鼠中的不同作用可能是由于幼年大鼠前额叶皮层的不成熟功能状态所致。这些结果表明了 PCP 在幼年和成年大鼠中的作用存在差异。幼年大鼠中 Arc mRNA 的减少与精神分裂症中提出的“前额叶功能低下”最为吻合，这表明在幼年动物中使用 PCP 作为精神分裂症模型具有优势，因为这与精神分裂症的典型发病和临床特征更为相关。
