Blockade of phencyclidine‐induced effects by a nitric oxide donor

Abstract

1 Phencyclidine (PCP) is widely used as an animal model of schizophrenia. The aim of this study was to better understand the role of nitric oxide (NO) in the mechanism of action of PCP and to determine whether positive NO modulators may provide a new approach to the treatment of schizophrenia. 2 The eects of the NO donor, sodium nitroprusside (SNP), were studied in PCP-treated rats. Following drug administration, behavioural changes and the expression of c-fos, a metabolic marker of functional pathways in the brain, were simultaneously monitored. 3 Acute PCP (5 mg kg 71 , i.p.) treatment induced a complex behavioural syndrome, consisting of hyperlocomotion, stereotyped behaviours and ataxia. Treatment with SNP (2 ± 6 mg kg 71 , i.p.) by itself produced no eect on any behaviour studied but completely abolished PCP-induced behaviour in a dose-and time-dependent manner. 4 PCP had dierential regional eects on c-fos expression in rat brain, suggesting regionally dierent patterns of neuronal activity. The most prominent immunostaining was observed in the cortical regions. Pre-treatment with SNP blocked PCP-induced c-fos expression at doses similar to those that suppress PCP-induced behavioural eects. 5 These results implicate the NO system in the mechanism of action of PCP. The fact that SNP abolished eects of PCP suggests that drugs targeting the glutamate-NO system may represent a novel approach to the treatment of PCP-induced psychosis and schizophrenia.

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

“…The nNOS converts L-arginine to NO, thus increased levels of L-arginine may increase nNOS dysfunctional in schizophrenia. However, the administration of L-arginine does not interfere with PCP-induced behavioral effects nor does it alter PCP-induced cfos expression (Bujas-Bobanovic et al 2000a). But this could be due to NO production not being dependent upon the extracellular substrate (Szabó 1996).…”

A neuronal nitric oxide synthase (NOS-I) haplotype associated with schizophrenia modifies prefrontal cortex function

“…Accordingly, a rapidly increasing body of evidence coming from pharmacological studies in animals argues in favour of this hypothesis. [26][27][28][29][30][31][32][33][34][35] Finally, a landmark study by Akbarian et al, 36,37 followed by further histopathological investigations, 38 argues that nitrinergic neurons are pathologically altered in SCZ.…”

Effects of sodium nitroprusside in the prevention of schizophrenia-like symptoms induced by ketamine – A translational double-blind study

“…Bujas-Bobanovic et al 4 described that SNP was able to inhibit the schizophrenia-like behavior and brain c-fos expression in rats induced by PCP, an NMDA receptor antagonist. Also, Issy et al 20 reported that SNP attenuated the schizophrenia-like changes in prepulse inhibition in rats induced by amphetamine, a dopaminergic agonist.…”

“…Phencyclidine (PCP) and ketamine are widely used in animal models of schizophrenia, and both drugs act by blocking the action of glutamate on N-methyl-D-aspartate (NMDA) receptors 3,4 . These receptors mediate the production of neuronal nitric oxide (NO) and, therefore, the hypothesis was raised that schizophrenia could be related to decreased levels of NO in the brain.…”