Catalepsy induced by intra-striatal administration of nitric oxide synthase inhibitors in rats

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Abstract

Systemic administration of nitric oxide synthase (NOS) inhibitors induces catalepsy in a dose-dependent manner in male Albino-Swiss mice. The objective of the present work was to investigate if similar effects occur in rats and if these effects are centrally mediated. The results showed that systemic administration of NG-nitro-l-arginine (l-NOARG, 40–160 mg/kg, i.p.), a non-selective NOS inhibitor, induced catalepsy in rats. Similar effects were found after intracerebroventricular (i.c.v.) injection of l-NOARG (50–200 nmol) or NG-nitro-l-arginine methylester (l-NAME, 100–200 nmol). The dose–response curve of the former compound, however, had an inverted U shape. The effect of l-NOARG (100 nmol, i.c.v.) was completely prevented by pre-treatment with l-arginine (300 nmol, i.c.v.) but not by d-arginine (300 nmol, i.c.v.). Intra-striatal injection of NG-monomethyl-l-arginine (l-NMMA, 100 nmol), 7-nitroindazole (7-NIO, 100 nmol), l-NOARG (25–100 nmol) or l-NAME (50–200 nmol) also induced catalepsy. Similar to i.c.v. administration, the latter two compounds produced bell-shaped dose–response curves. The cataleptic effect of intra-striatal administration of l-NAME (100 nmol) was reversed by local treatment with l-arginine (100 nmol). These results suggest that interference with the striatal formation of nitric oxide may induce significant motor effects in rats.

Introduction

Nitric oxide (NO) is a short-lived, highly liposoluble molecule, produced from the amino acid l-arginine by a family of enzymes called NO synthases (NOS; Moncada and Higgs, 1993). It acts as a signalling molecule in the central nervous system and has been related to several physiological or pathological conditions (for review, see Bredt, 1999, Esplugues, 2002).

NO seems to play a role in the control of motor behaviour. Mice mutant for the neuronal NOS isoform have altered locomotor abilities (Kriegsfeld et al., 1999) and rats and mice treated with various NOS inhibitors show problems with fine motor control Star and Star, 1995, Dzoljic et al., 1997, Araki et al., 2001, Uzbay, 2001, Dall'Igna et al., 2001, Del Bel et al., 2002. Systemic administration of NG-nitro-l-arginine (l-NOARG), an inhibitor of NOS, induces catalepsy in mice Marras et al., 1995, Navarro et al., 1997, Cavas and Navarro, 2002, Del Bel et al., 2002. This effect is attenuated by previous treatment with l-arginine and suffers tolerance after four days of subchronic (twice a day, 4 days) administration Marras et al., 1995, Navarro et al., 1997.

The cataleptic effect of NOS inhibitors may involve the striatum. NOS positive neurons are located throughout this structure (Vincent and Kimura, 1992) and NO is proposed to regulate dopamine neurotransmission in the striatum (West et al., 2002). Although there are contradictory results (Silva et al., 1995) most studies suggest that, under physiological conditions, NO increases striatal dopamine by facilitating its release Hanbauer et al., 1992, Black et al., 1994, Stewart et al., 1996, West and Galloway, 1998, Iravani et al., 1998, West et al., 2002 and/or by decreasing its reuptake Guevara-Guzman et al., 1994, Kiss and Vizi, 2001. However, the possible participation of the striatum on the cataleptic effects of NOS inhibition has not yet been directly tested nor has the presence of these effects in other rodent species such as the rat.

The objective of the present study, therefore, was to verify if NOS inhibition can also induce catalepsy in rats and if this effect involves inhibition of NO formation in the central nervous system, particularly in the striatum.

Section snippets

Animals

Male Albino Wistar rats (200–250 g) were housed in groups of five or eight per cage in a temperature-controlled room (24±1 °C) under standard laboratory conditions. They had free access to food and water and remained on a 12 h light/12 h dark cycle (lights on at 06:30 a.m.). Procedures were conducted in conformity with the Brazilian Society of Neuroscience and Behaviour guidelines for the care and use of laboratory animals, which are in compliance with international laws and politics. All

Experiment 1

Results are in Fig. 1. There were significant general effects of treatment (F(3,40)=57.47, P<0.001), time (F(2,39)=13.96, P<0.001) and treatment×time (F(6,76)=3.04, P=0.01). All doses of l-NOARG increased catalepsy time along the whole experiment as compared to saline group (Duncan test, P<0.05). The dose of 160 mg/kg, in addition, produced greater catalepsy than the 40 and 80 mg/kg doses 2 and 4 h after injection (Duncan, P<0.05).

Experiment 2

All doses of l-NAME and l-NOARG increased catalepsy time

Discussion

Catalepsy is defined as a failure to correct an externally imposed posture. Drugs that decrease dopaminergic neurotransmission in the striatum, such as neuroleptics, induce catalepsy in rodents and Parkinson symptoms in humans Koffer et al., 1978, Sanberg et al., 1988. This test is widely used to evaluate motor effects of drugs that act on the extrapyramidal system Sanberg et al., 1988, Hauber, 1998.

Similar to previous results obtained in mice Marras et al., 1995, Del Bel and Guimarães, 2000,

Acknowledgments

Research supported by grants from FAPESP, CAPES and CNPq. The authors are recipients of CNPq fellowships.

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