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Phencyclidine (PCP) is a non-competitive NMDA glutamate receptor antagonist that induces psychotomimetic effects in humans and experimental animals. Chronic PCP exposure elicits signs of persistently altered frontal brain activity and related behaviors which are also seen in patients with schizophrenia. Secretogranin II (sg II) belongs to the chromogranin family of proteins that exist in large dense core vesicles in nervous tissue. In the brain, 90% of sg II is processed to the small peptide secretoneurin. We previously detected differential effects of single-dose and subchronic PCP administration on sg II expression in the rat prefrontal cortex (PFC). In the present study, we applied PCP to organotypic PFC slices. PCP application for 28 h induced decreased tissue and culture medium secretoneurin content. In contrast, incubation with the adenylate cyclase activator forskolin caused significantly increased secretoneurin levels after 8 h. PCP for 4 h followed by 24 h without PCP resulted in increased culture medium secretoneurin content but no change in tissue levels. sg II mRNA expression was decreased after 28 h PCP application in cortical neurons. Immunohistochemical and TUNEL staining profiles indicated that the alterations were not due to neurodegeneration. PCP for 5 days changed neither the secretoneurin tissue or culture medium levels, nor the sg II mRNA expression. These results demonstrate that PCP modulates sg II expression in PFC tissue in the absence of afferent inputs and that the nature of these changes is dependent upon the duration of exposure to and/or withdrawal from PCP. Keywords: gene expression, in vitro, neuropeptides, NMDA antagonist, prefrontal cortex, schizophrenia. J. Neurochem. (2003) 87, 13-21. Noncompetitive antagonists of the NMDA glutamate receptor, including the dissociative anesthetic phencyclidine (PCP), cause a psychotic reaction in humans comprising many of the positive and negative symptoms of schizophrenia (Tamminga 1998). Chronic PCP exposure elicits a schizophrenia-like pattern of impairment in social and cognitive performance that is thought to result from disturbed prefrontal cortical function (Andreasen et al. 1997;Bunney and Bunney 2000). NMDA glutamate receptor antagonism exerts effects on prefrontal cortical metabolism and neurotransmitter tone the quality and duration of which varies considerably depending on dosing regimen (for review, see Jentsch and Roth 1999). Specifically, chronic PCP exposure induces lasting cognitive impairment (Jentsch et al. 2000) as well as reduced frontal blood flow in humans (Hertzmann et al. 1990) and persistent deficits in prefrontal cortical dopamine utilization and prefrontal cortex (PFC)-dependent cognitive function in rats and monkeys (Balla et al. 2001).The chromogranins comprise a group of acidic secretory proteins which are stored with other neuropeptides in secretory large dense core vesicles (Winkler and Fischer-Colbrie 1992). Chromogranins are involved in the sorting, processing, Received April 23, 2003; accepted May...

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