Opposite effect of phencyclidine on activity-regulated cytoskeleton-associated protein (Arc) in juvenile and adult limbic rat brain regions

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 (5 mg/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.