Neural mechanisms of prefrontal dysfunction in animal models of schizophrenia

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Phencyclidine (PCP) is a well-known psychotomimetic drug, which induces schizophrenia-like symptoms in healthy individuals. PCP-administered animals are now considered as the most reliable pharmachological model of schizophrenia. This study aimed to investigate the neural mechanisms of prefrontal dysfunctions in rats with acute administration of PCP. Following four experiments were conducted. In the first experiment the single unit activity of medial prefrontal cortex (mPFC) neurons was recorded in freely moving rats before and after intraperitoneal injection of either PCP or saline. In the second experiment PCP was iontophoretically applied on mPFC neurons to examine the direct effects of PCP on firing activity of a single mPFC neuron in anesthetized rats. In the third experiment the single unit activity of mPFC neurons was recorded for systemic injection of a psychomotor stimulant, methamphetamine (MAP), to compare with the effects of PCP on firing activity of mPFC neurons. In the last experiment PCP or MK801 was locally perfused with a reverse microdyalysis method in the ventral hippocampus to examine the possible origin of excitatory inputs to the mPFC in freely moving rats. The results of these experiments were as follows. (1) Systemically-applied PCP produces long-lasting activation (> 70 min) of mPFC neurons (2) Microiontophoretically-applied PCP produces little change in firing activity of mPFC neurons (3) Systemically-applied MAP does not alter the firing rate in almost all mPFC neurons recorded, although locomotor activity are markedly increased (4) Relatively short-lasting activation of mPFC neurons is induced by local perfusion of PCP or MK801 in the ventral subiculum, but not in the ventral CA1 area. These results suggest that systemic PCP may induce tonic activation of mPFC neurons through excitatory inputs from the ventral subiculum.