Research report
Involvement of NMDA receptors and l-arginine-nitric oxide pathway in the antidepressant-like effects of zinc in mice

https://doi.org/10.1016/S0166-4328(03)00069-XGet rights and content

Abstract

This study investigated the involvement of NMDA receptors and the l-arginine-nitric oxide (NO) pathway in the antidepressant-like effects of zinc in the forced swimming test (FST). The immobility times in the FST and in the tail suspension test (TST) were reduced by zinc chloride (ZnCl2, 30 and 10–30 mg/kg intraperitoneal (i.p.), respectively). The doses active in the FST and TST reduced locomotor activity in an open-field. The antidepressant-like effect of ZnCl2 in the FST was prevented by pre-treatment of animals with guanosine 5′-monophosphate (GMP), ascorbic acid, l-arginine, or S-nitroso-N-acetyl-penicillamine (SNAP), but not with d-arginine, administered at doses that per se produced no anti-immobility effect. The immobility time of mice treated with ZnCl2+MK-801 was not different from the result obtained with ZnCl2 or MK-801 alone, but ZnCl2+imipramine had a greater effect in the FST than administration of either drug alone. Pre-treatment of animals with a sub-threshold dose of ZnCl2 prevented the anti-immobility effect of MK-801, ketamine, GMP, l-arginine or NG-nitro-l-arginine (l-NNA), but did not alter the effect of imipramine or fluoxetine. Taken together, the results demonstrate that zinc produced an antidepressant-like effect that seems to be mediated through its interaction with NMDA receptors and the l-arginine-NO pathway.

Introduction

The transition metal zinc serves as a cellular signalling molecule, present at high concentrations in the central nervous system, particularly in the hippocampal mossy fibres, where it is stored in synaptic vesicles and released upon depolarisation from central nerve terminals [2], [4]. Zinc produces a wide variety of neuromodulatory effects, the most prominent of which may be upon glutamate receptors [4]. Zinc inhibits NMDA receptors by a voltage-dependent mechanism similar to that shown by magnesium, and through a voltage-independent mechanism at a distinct site [6]. Zinc has been also shown to inhibit brain constitutive nitric oxide synthase (NOS) [23].

Recently, pre-clinical and clinical data have suggested that compounds that reduce transmission at NMDA receptors exhibit antidepressant-like actions, and that chronic antidepressant treatment can, in turn, impact on NMDA receptor function [31]. Recent findings have demonstrated that NOS inhibitors exert antidepressant-like effects in animal models of depression [8], [12], [37].

The forced swimming test (FST) is a behavioural model that has a good predictive value for antidepressant potency in humans [36] and is sensitive to antidepressant drugs after acute administration [3]. Recent studies have demonstrated that acute treatments with zinc produce antidepressant-like effect in rodents in the FST [14], [15]. However, these studies did not investigate the mechanisms underlying the antidepressant-like effects of zinc. The role of zinc in the modulation of depression is also suggested by some clinical studies. It has been demonstrated that zinc is present at low blood concentrations in depressed patients [17], [18]. Moreover, chronic treatment with imipramine or citalopram or chronic electroconvulsive shock (ECS) raises hippocampal and serum zinc concentration in rats [25]. Furthermore, the plasma zinc level in depressed patients after recovery was found to be higher than in depressed patients [22], [24]. These studies are, therefore, predictive that zinc could exert a critical role in the modulation of depression.

Since zinc is known to inhibit both NMDA receptors and NOS which are believed to be important molecular targets for the antidepressants [8], [12], [31], [37] and due to the existence of clinical studies indicating alterations of zinc levels in the blood of depressed patients, we sought to investigate in the present study the involvement of NMDA receptors and the l-arginine-nitric oxide (NO) pathway in the antidepressant-like effects of zinc in the FST. We also assessed the effect of zinc in the mouse tail suspension test (TST) that, like the FST, is a reliable model of depression used to screen new antidepressant drugs [32].

Section snippets

Animals

Swiss mice of either sex, weighing 30–40 g were maintained at 22–27 °C with free access to water and food, under a 12:12 h light:dark cycle. All manipulations were carried out between 08.00 a.m. and 04.00 p.m., with each animal used only once. The experiments were performed after approval of the protocol by the Ethics Committee of the institution and all efforts were made to minimise animal suffering.

Drugs and treatment

The following drugs were used in the study: zinc chloride (Merck, Darmstadt, Germany), GMP, l

Results

The immobility time in the FST and TST of animals treated with zinc chloride is shown in Fig. 1A and B, respectively. A one-way ANOVA revealed a significant effect of zinc chloride on immobility in both the FST (F(3,26)=13.8, P<0.01) and in the TST (F(3,20)=30.5, P<0.01). Zinc chloride, at a dose of 30 mg/kg, i.p., significantly decreased the immobility time when mice were tested in the FST and, in the dose range of 10–30 mg/kg, i.p., it reduced the immobility time in the TST in comparison to the

Discussion

In the present study, the anti-immobility effect of zinc chloride in the FST is in accordance with previous studies in mice and rats [14], [15]. The antidepressant-like action of zinc chloride was also confirmed in the TST. Both the FST and the TST are widely-accepted stress models of depression used to screen new antidepressant drugs, as they are sensitive to all major classes of antidepressant drugs including tricyclics, serotonin-specific reuptake inhibitors, monoamine oxidase inhibitors,

Acknowledgements

This study was supported by CNPq (479309/01-9 and 471271/01-2), CAPES, FUNPESQUISA-UFSC, and PRONEX.

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