Abstract
Schizophrenia is a chronic mental disorder with prominent prefrontal and hippocampal dysfunction. Although the exact cause of schizophrenia is currently poorly understood, glutamatergic hypofunction and neurodevelopmental disruption have been linked to the etiology and/or pathophysiology of the disease. Phencyclidine (PCP), a non-competitive NMDA receptor antagonist, induces behavioural changes in humans and laboratory animals that resemble schizophrenic symptoms, suggesting NMDA receptor hypofunction as a factor in the disease. Accumulating evidence suggests the altered metabolism of L-arginine, a semi-essential amino acid with a number of bioactive metabolites, is implicated in the pathogenesis of schizophrenia. The overall aims of the present study were to develop a PCP rat model in our laboratory using different treatment regimes and to determine its effects on arginine metabolism (focusing on its main metabolic enzymes nitric oxide synthase (NOS) and arginase) in the sub-regions of the hippocampus and prefrontal cortex.
Experiment 1 assessed the dose-response effects of acute subcutaneous (s.c.) injection of PCP (2, 5 or 10 mg/kg) on general behaviour in the open field (30 min post-injection) and brain arginine metabolism (60 min post-treatment) in adult male Sprague-Dawley (SD) rats. Behaviourally, PCP resulted in reduced exploratory activity in a dose-dependent manner, and severe stereotype behaviour and ataxia at the highest dose. Neurochemically, PCP significantly altered the NOS and arginase activities mainly in the CA1 and CA2/3 sub-regions of the hippocampus in a dose-dependent manner. In Experiment 2, a single s.c. injection of PCP at 2 mg/kg produced hyperlocomotion in the open field and impaired performance in a simplified version of the water maze in adult male SD rats, however did not affect NOS and arginase activities in any regions examined. These results demonstrate that acute PCP treatment affects exploration, locomotion and spatial learning and can alter NOS and arginase activity. However, animals’ behavioural experience may influence neurochemistry.
Experiment 3 assessed the behavioural and neurochemical effects of repeated PCP (2 mg/kg, s.c., once daily for consecutive 12 days) following a washout period of 4 days (Experiment 3A) or 24 hours (Experiment 3B) in adult male SD rats. Repeated PCP treatment impaired animals’ behavioural performance in the Y-maze and open field under the 24-hour, but not 4-day, washout condition, indicating the residual effects of PCP. Interestingly, the PCP treated rats displayed spatial working memory deficits 8 days after withdrawal from PCP and showed altered arginase activities in hippocampal CA2/3 and prefrontal cortex, suggesting the long-term impact of repeated PCP treatment on behavioural function and brain arginine metabolism.
Experiment 4 assessed how perinatal treatment of PCP (10 mg/kg, s.c.) on post-natal (PN) days 7, 9 and 11 affected brain arginine metabolism on PN day 13 (Experiment 4A) and behavioural performance and brain arginine metabolism during 12-14 weeks of age (Experiment 4B) in male SD rats. Surprisingly, perinatal PCP treatment did not impair animals’ performance in a battery of behavioural tests. Neurochemically, increased arginase activity was found in the parahippocampal region in the PCP group (Experiment 4A), however there were no significant changes in NOS and arginase activity between groups in Experiment 4B.
In summary, this study has provided preliminary evidence that PCP affects animals’ behavioural function and brain arginine metabolism in a treatment regime-, dose-, task-, or region-dependant manner. Future research is required to better understand how the brain L-arginine metabolic profile changes in the PCP model of schizophrenia, as well as in schizophrenic patients.