Effects of nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester on phencyclidine-induced effects in rats

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Abstract

Phencyclidine (PCP) is widely used as an animal model of schizophrenia. In rats, acute PCP treatment increased locomotor activity and induced stereotyped behaviours consisting of head weaving, turning and backpedalling. PCP had differential regional effects on c-fos expression in rat brain, suggesting different patterns of neuronal activity. The most prominent immunostaining was observed in the cortical regions. To elucidate the role of nitric oxide, an important intracellular messenger, in the mechanism of action of PCP the effects of nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME) were studied in PCP-treated animals. l-NAME potentiated PCP-induced behaviours and c-fos expression in many brain regions. The greatest increases were observed in the frontal, retrosplenial granular cortex, cerebellum, thalamic and subthalamic nuclei. While PCP alone induced low c-fos expression in the entorhinal cortex, with almost no expression in the rostral part of caudate putamen, animals pretreated with l-NAME showed marked activation in these brain areas. These results strongly indicate the involvement of the nitric oxide system in the mechanism of action of PCP.

Introduction

Several lines of evidence suggest that glutamatergic mechanisms play an important role in the pathophysiology of schizophrenia Toru et al., 1994, Hirsch et al., 1997, Tamminga, 1998, Heresco-Levy and Javitt, 1998, Carlsson et al., 1999, Duncan et al., 1999. Included in this evidence is the fact that phencyclidine (PCP) and other antagonists of NMDA receptors such as ketamine and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptane-5,10-imine maleate (MK-801) have psychotomimetic effects in normal individuals Krystal et al., 1994, Duncan et al., 1999 and exacerbate pre-existing symptoms in schizophrenic patients Lahti et al., 1995, Steinpreis, 1996, Duncan et al., 1999. Since PCP can mimic the full spectrum of schizophrenic disorders Toru et al., 1994, Steinpreis, 1996, Thornberg and Saklad, 1996, Duncan et al., 1999, it has been proposed to be one of the best drug-induced models of schizophrenia. The preclinical pharmacology of PCP has been studied in animals for many years to determine potential neurochemical correlates of psychosis and to find new antipsychotic drugs Sturgeon et al., 1979, Yang et al., 1991, Corbett et al., 1995, Noda et al., 1995b, Noda et al., 1996, Gleason and Shannon, 1997, Moghaddam and Adams, 1998, Johansson et al., 1999.

Nitric oxide (NO) is an important intracellular messenger in the central nervous system and may also operate as a neurotransmitter. Release of NO occurs as a consequence of glutamate stimulation of NMDA receptors and is dependent upon calcium-calmodulin activation of the enzyme NO synthase (NOS), Ignarro and Murad, 1995, Szabo, 1996. NO mediates a range of different physiological functions. It has been implicated in various neuropathological conditions including schizophrenia Akbarian et al., 1993, Karatinos et al., 1995, Khan et al., 1995, Das et al., 1995, Karson et al., 1996. The role of NO in these central processes has been elucidated primarily through the use of NOS inhibitors, of which NG-nitro-l-arginine (l-NOARG) and its methyl ester (l-NAME) have been used most frequently. There are several reports indicating that NO may be involved in the mechanism of action of PCP, but its actual role is still unclear. Since NO may serve as an intracellular messenger for NMDA glutamatergic neurones, it is possible that NOS inhibitors may have synergistic effects with NMDA receptor antagonists. However, it has been shown that l-NAME both enhances (Noda et al., 1995a) and abolishes Johansson et al., 1997, Johansson et al., 1998 PCP-induced behavioural effects. Considering these conflicting data further studies are required to elucidate the participation of NO in the effects produced by PCP. Therefore, in the present study we investigated the effect of l-NAME on PCP-induced behaviour and c-fos expression. Increased expression of the protein product of the immediate early gene c-fos is now widely recognised as a reliable technique to identify neuronal populations of metabolically activated brain regions Sagar et al., 1988, Hughes and Dragunov, 1995, Herrera and Robertson, 1996. Some of the data reported in the present paper have been presented in abstract form (Bujas-Bobanovic et al., 1998b).

Section snippets

Subjects

Adult male Sprague–Dawley rats (Charles River, Quebec, Canada) weighing 250–300 g were used in this study. They arrived at the animal facilities at least 5 days prior to the start of the experiments. Rats were housed in groups of two on a 12-h dark–light cycle (lights on at 7:00 h) at 22°C. Food and water were available ad libitum during the time the animals were in their home cages.

Materials

Phencyclidine hydrochloride was generously donated by the Bureau of Drug Surveillance (Ottawa, Canada). l-NAME

Results

PCP (5 mg/kg) alone induced a characteristic behavioural response with a remarkable hyperactivity and stereotyped behaviours, without apparent ataxia. Animals were moving over a large area of the cage and the activity was intermittent and emitted at a moderate-rapid rate. Stereotyped behaviours included rapid rate and continuous head weaving, turning and backpedalling. All behavioural effects occurred within a few minutes and reached a maximum between 20 and 30 min after injection. Although l

Discussion

In agreement with previous findings Sturgeon et al., 1979, Castellani and Adams, 1981, Yang et al., 1991, Toru et al., 1994, Steinpreis, 1996, the present data indicate that PCP induces a complex behavioural syndrome with increased locomotor activity and stereotyped behaviours consisting of head weaving, turning and backpedalling. Although PCP activates many brain regions, the most prominent effect was observed in the cortical regions. This is particularly interesting because the cerebral

Acknowledgements

We thank K. Murphy for excellent technical assistance and D. Bird for help in preparing the manuscript. This work was supported by the grants from the Queen Elizabeth II HSC Research Fund (SMD), the MRC of Canada (HAR) and Canadian Psychiatric Foundation (SMD). SMD is a Dalhousie University Faculty of Medicine Clinical Research Scholar.

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