Melatonin exerts an antidepressant-like effect in the tail suspension test in mice: evidence for involvement of N-methyl-D-aspartate receptors and the L -arginine-nitric oxide pathway Michela Mantovani a , Roberto Pe ´rtile a , Joa ˜o B. Calixto b , Adair R.S. Santos c , Ana Lu ´cia S. Rodrigues a, * a Departamento de Bioquı ´mica, Centro de Cie ˆncias Biolo ´gicas, Universidade Federal de Santa Catarina, Floriano ´polis, SC 88040-900, Brazil b Departamento de Farmacologia, Centro de Cie ˆncias Biolo ´gicas, Universidade Federal de Santa Catarina, Floriano ´polis, SC 88040-900, Brazil c Departamento de Cie ˆncias Fisiolo ´gicas, Centro de Cie ˆncias Biolo ´gicas, Universidade Federal de Santa Catarina, Floriano ´polis, SC 88040-900, Brazil Received 9 December 2002; received in revised form 27 January 2003; accepted 11 February 2003 Abstract This study investigated the effect of melatonin in the mouse tail suspension test (TST), and the contribution of N-methyl-D-aspartate (NMDA) receptors and the L-arginine-nitric oxide (NO) pathway to its antidepressant-like effect. The immobility time in the TST was reduced by melatonin given either by intraperitoneal (0.1 – 30 mg/kg) or intracerebroventricular (0.001 – 0.1 nmol/site) route. The anti- immobility effect of melatonin (1 mg/kg, intraperitoneal, i.p.) was prevented by pre-treatment with guanosine 5 0 -monophosphate (GMP), ascorbic acid, L-arginine or S-nitroso-N-acetyl-penicillamine, but not with D-arginine. Pre-treatment with melatonin (100 mg/kg, i.p.) prevented the anti-immobility effect of MK-801, ketamine or zinc chloride, but did not alter the effect of imipramine. Furthermore, a sub- effective dose of melatonin (0.001 mg/kg, i.p.) produced a synergistic antidepressant-like effect with MK-801, ketamine, zinc chloride and imipramine in the TST. Taken together these data indicate that the effect of melatonin in the TST seems to be mediated through an interaction with NMDA receptors and the L-arginine-NO pathway. q 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Depression; Melatonin; NMDA; L-Arginine; Nitric oxide; Tail suspension test Melatonin is a neurohormone produced mainly by the pineal gland from the amino acid precursor L-tryptophan in most vertebrate species, including humans. Despite a great number of studies, the physiological significance of melatonin is not yet fully understood [11]. Apart from its known involvement in circadian rhythms, melatonin is thought to influence physiological and behavioural pro- cesses, as well as neuroendocrine function [9]. Melatonin has been implicated in several pathological states, including psychiatric disorders. The majority of the studies dealing with the secretory pattern of melatonin in depressed patients have shown that the daily secretion of this hormone is reduced [11]. Moreover, preclinical studies indicate that melatonin possesses putative antidepressant properties. For example, it has been shown that melatonin exerts an antidepressant-like action when assessed in the tail suspen- sion test (TST) and forced swimming test (FST), which are animal models predictive of antidepressant action of drugs in humans [13,14,18]. However, the mechanisms under- lying the antidepressant effect of melatonin remain unclear. Recent evidence indicates that the N-methyl-D-aspartate (NMDA) receptor complex is involved in the pathogenesis of depression, as shown by the fact that NMDA receptor antagonists exert antidepressant-like effects both in pre- clinical and clinical tests [16]. Moreover, there are findings indicating that the L-arginine-nitric oxide pathway is also involved in the modulation of depression [3,19]. Consider- ing that melatonin possesses an antidepressant-like effect in animal models, and since it has been shown to block some of the excitatory effects elicited by glutamate itself and its receptor agonists [5,8] as well as inhibiting cerebellar nitric 0304-3940/03/$ - see front matter q 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0304-3940(03)00306-9 Neuroscience Letters 343 (2003) 1–4 www.elsevier.com/locate/neulet * Corresponding author. Tel.: þ 55-48-331-9795; fax: þ55-48-331-9672. E-mail address: analucia@mbox1.ufsc.br (A.L.S. Rodrigues).