Inproceedings: an article in a conference proceedings.
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A prefrontal cortex defect of glutamate release capacity in the phencyclidine (PCP) model of schizophrenia
Subchronic administration of PCP, a psychotomimetic agent acting as an NMDAR channel blocker, produces in rodents a syndrome that models some aspects of schizophrenia. Our research investigates the consequences of PCP administration on glutamatergic functionality in rodents' prefrontal cortex (PFC). Rats were treated once daily for 7 or 14 days with either PCP (5 mg/kg) or saline. 24 h after the last treatment, glutamatergic functionality is evaluated in terms of glutamate release capacity in acute PFC slices stimulated with high KCl (60mM). Slices from rats pre-exposed to PCP released less glutamate than slices from saline-treated animals. Such a defect persisted 72 h after the last treatment and was not observed in a different cortical area, the visual cortex. For 14 days treatments, the adaptive changes are extinguished 7 days after the last exposure to PCP. These findings were then reproduced in mice. Furthermore, we tested the effect of antipsychotics (haloperidol and olanzapine) in PCP-treated animals. PCP treatment lasted 14 days, antipsychotics were administered in parallel starting from the 8th day (when the glutamate release defect is already established). Both antipsychotics reversed the PCP-induced defect, restoring a normal glutamate release capacity. The plastic modifications apparently occur at the level of glutamatergic terminals, as synaptosomes prepared from the PFC of PCP-treated animals showed defective glutamate release in comparison to control animals. In this preparation we are now studying the molecular target of PCP action, focusing our attention on a likely presynaptic NMDAR and the regulation of Ca__ increases leading to neurotransmitter release. Preliminar data demonstred that NMDA administration on PFC synaptosomes increases the glutamate release induced by 8mM KCl, while a pre-incubation with PCP fully blocks this effect. In parallel, we are interested in assessing the effects of PCP treatment on PFC functionality, in order to establish a possible link between glutamatergic function, performance in behavioural tests involving this region and its metabolic activity during the test determined by 2-deoxyglucose quantitative auroradiography. Thus, the 'PCP model' highlights functional anomalies that could underlie aspects of the psychopathology of schizophrenia (glutamatergic hypofunction).
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