Effects of withdrawal from repeated phencyclidine administration on behavioural function and brain arginine metabolism in rats.

Phencyclidine (PCP) induces behavioural changes in humans and laboratory animals that resemble positive and negative symptoms, and cognitive impairments in schizophrenia. It has been shown repeated treatment of PCP leading to persistent symptoms even after the drug discontinuation, and there is a growing body of evidence implicating altered arginine metabolism in the pathogenesis of schizophrenia. The present study investigated the effects of withdrawal from repeated daily injection of PCP (2mg/kg) for 12 consecutive days on animals'behavioural performance and arginine metabolism in the hippocampus and prefrontal cortex in male young adult rats. Repeated PCP treatment reduced spontaneous alternations in the Y-maze and exploratory and locomotor activities in the open field under the condition of a washout period of 24h, but not 4days. Interestingly, the PCP treated rats also displayed spatial working memory deficits when tested 8-10days after withdrawal from PCP and showed altered levels of arginase activities and eight out of ten l-arginine metabolites in neurochemical- and region-specific manner. Cluster analyses showed altered relationships among l-arginine and its three main metabolites as a function of withdrawal from repeated PCP treatment in a duration-specific manner. Multiple regression analysis revealed significant neurochemical-behavioural correlations. Collectively, the results suggest both the residual and long-term effects of withdrawal from repeated PCP treatment on behavioural function and brain arginine metabolism. These findings demonstrate, for the first time, the influence of the withdrawal duration on animals' behaviour and brain arginine metabolism.

Effects of acute phencyclidine administration on arginine metabolism in the hippocampus and prefrontal cortex in rats.

Phencyclidine (PCP), a non-competitive N-methyl-d-aspartate glutamate receptor antagonist, induces schizophrenic symptoms in healthy individuals, and altered arginine metabolism has been implicated in schizophrenia. The present study investigated the effects of a single subcutaneous injection of PCP (2, 5 or 10 mg/kg) on arginine metabolism in the sub-regions of the hippocampus and prefrontal cortex in male young adult Sprague-Dawley rats. Animals' general behaviour was assessed in the open field apparatus 30 min after the treatment, and the brain tissues were collected at the time point of 60 min post-treatment. 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 nitric oxide synthase and arginase activities, the l-arginine, agmatine, spermine, glutamate and GABA levels, and the glutamine/glutamate and glutamate/GABA ratios in a dose-dependent and/or region-specific manner. Cluster analyses showed that l-arginine and its main metabolites l-citrulline, l-ornithine and agmatine formed distinct groups, which changed as a function of PCP mainly in the hippocampus. Multiple regression analysis revealed significant neurochemical-behavioural correlations. These results demonstrate, for the first time, that a single acute administration of PCP affects animals' behaviour and arginine metabolism in the brain.

Scopolamine impairs behavioural function and arginine metabolism in the rat dentate gyrus.

Alzheimer's disease (AD) is a neurodegenerative disorder with progressive memory loss. It has been shown that the cholinergic neurotransmission deficit is one of the neurochemical characteristics of AD, and that L-arginine and its metabolites also play a prominent role in AD pathogenesis. Scopolamine, a non-selective muscarinic receptor antagonist, blocks cholinergic neurotransmission and impairs behavioural function, including learning and memory. This study investigated the effects of scopolamine on animals' behavioural performance and L-arginine metabolism in the hippocampus and prefrontal cortex. Rats were given intraperitoneal injections of scopolamine (0.8 mg/kg) or saline (1 ml/kg) and tested in the Y-maze, open field, water maze and elevated plus maze 30 min post-treatment. After completion of the behavioural testing, the CA1, CA2/3 and dentate gyrus (DG) sub-regions of the hippocampus and the prefrontal cortex were harvested to measure the activity and protein expression of nitric oxide synthase (NOS) and arginase, and the levels of L-arginine, L-citrulline, L-ornithine, agmatine, putrescine, spermidine, spermine, glutamate and GABA. Scopolamine treated rats displayed reduced alternation and exploratory behaviour, increased swimming speed and impaired spatial learning and memory. There were significantly decreased NOS activity, increased arginase activity, and increased L-ornithine and putrescine levels in the DG, but not other regions examined, in the scopolamine treated rats as compared to the controls. These findings suggest that scopolamine impairs behavioural function and alters L-arginine metabolism in the DG sub-region of the hippocampus specifically. The underlying mechanisms of it remain to be explored further.