Melatonin attenuated the behavioral despair induced by acute neurogenic stress through blockade of N-methyl D-aspartate receptors in mice

Abstract

It has been well documented that administration of melatonin could reveal antidepressant-like effect in rodents. However, the protective effect of melatonin on stress-induced depression/anxiety and its underlying mechanism is yet to be understood. In this regard, in the current study, acute foot-shock stress (FSS) was used to evaluate the antidepressant-like effect of melatonin on neurogenic stress-induced depression in mice. Behavioral evaluation was done by using the forced swimming test (FST) and Open-field test (OFT). Melatonin, MK-801, and ketamine (NMDA receptor antagonists), and NMDA (NMDA receptor agonist) were used to elucidate any association between melatonin and NMDA pathway in behavioral despair induced by acute-FSS. Applying acute-FSS to mice significantly induced depressant-like behavior in FST without any significant impact on locomotor activity in the OFT. We observed that melatonin (dose-dependently) significantly improved the depressant-like effect of FSS, but it did not impact the locomotion in animals. Acute injection of MK-801 at sub-effective doses (0.01 mg/kg) or ketamine (0.1 mg/kg) potentiated the antidepressant-like effect of a sub-effective dose of melatonin. However, the sub-effective dose of NMDA (30 mg/kg) abolished the protective effect of melatonin on the behavioral profile of stressed animals. Our results could reflect the antidepressant-like effect of melatonin on neurogenic stress-induced depressive behaviors in mice. Also, our results showed that NMDA receptors could be involved in the antidepressant-like effect of melatonin.

Keywords: Acute foot shock stress; Behavioral despair; Melatonin; Mice; NMDA receptor.

Figure 1

Effect of acute-FSS on animals' behavior. Immobility time in FST (a), distance moved in OFT (b) and number of rearings in OFT (c). Date presented as the mean ± S.E.M.; ∗∗p < 0.01 compared with control (non-stressed) group.

Figure 2

Effect of melatonin on the duration of immobility in FST after treating animals with melatonin based on time and dose of injection. Immobility of non-stressed (a and b) and stressed (c and d) mice in FST. Date presented as the mean ± S.E.M and were analyzed using one-way ANOVA followed by tukey's post hoc test; ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001 compared with saline treated (S) group in each figure.

Figure 3

Effect of different doses of melatonin on locomotion behavior in OFT: Total distance moved of non-stressed (a) and stressed (b) mice; and number of rearings of non-stressed (c) and stressed (d) animals in OFT. Date presented as the mean ± S.E.M and were analyzed using one-way ANOVA followed by tukey's post hoc test.

Figure 4

Effect of melatonin (when was administered in different time manners) on locomotion behavior in OFT: Total distance moved of non-stressed (a) and stressed (b) mice; and number of rearings of non-stressed (c) and stressed (d) animals in OFT. Date presented as the mean ± S.E.M and were analyzed using one-way ANOVA followed by tukey's post hoc test.

Figure 5

Effect of NMDA antagonists (ketamine and MK-801) and agonist (NMDA) on the duration of immobility in FST: Effect of acute administration of ketamine (0.1, 1, and 3 mg/kg, i.p., 30 min before test) on the duration of immobility in non-stressed (a) and stressed (b) animals. Effect of acute administration of MK-801 (0.01, 0.05, and 0.1 mg/kg, i.p., 45 min before test) on the duration of immobility in non-stressed (c) and stressed (d) animals. Effect of acute administration of NMDA (30, 75, and 150 mg/kg, i.p., 45 min before test) on the duration of immobility in non-stressed (e) and stressed (f) animals. Date presented as the mean ± S.E.M and were analyzed using one-way ANOVA followed by tukey's post hoc test; ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001 compared with saline treated (S) group.

Figure 6

Effect of NMDA antagonists (ketamine and MK-801) and agonist (NMDA) on total distance moved in OFT: Effect of acute administration of ketamine (0.1, 1, and 3 mg/kg, i.p., 30 min before test) on total distance moved in non-stressed (a) and stressed (b) animals. Effect of acute administration of MK-801 (0.01, 0.05, and 0.1 mg/kg, i.p., 45 min before test) on total distance moved in non-stressed (c) and stressed (d) animals. Effect of acute administration of NMDA (30, 75, and 150 mg/kg, i.p., 45 min before test) on total distance moved in non-stressed (e) and stressed (f) animals. Date presented as the mean ± S.E.M and were analyzed using one-way ANOVA followed by tukey's post hoc test.

Figure 7

Effect of NMDA antagonists (ketamine and MK-801) and agonist (NMDA) on number of rearings in OFT: Effect of acute administration of ketamine (0.1, 1, and 3 mg/kg, i.p., 30 min before test) on number of rearings in non-stressed (a) and stressed (b) animals. Effect of acute administration of MK-801 (0.01, 0.05, and 0.1 mg/kg, i.p., 45 min before test) on number of rearings in non-stressed (c) and stressed (d) animals. Effect of acute administration of NMDA (30, 75, and 150 mg/kg, i.p., 45 min before test) on number of rearings in non-stressed (e) and stressed (f) animals. Values are expressed as the mean ± S.E.M. and were analyzed using one- way ANOVA followed by tukey’s post hoc test; There is no significant difference when compared each group with saline treated (S) group in each figure.

Figure 8

Effect of NMDA antagonists and melatonin co-treatment on the duration of immobility in FST: effect of co-administration of MK-801 (0.01 mg/kg) or ketamine (0.1 mg/kg) with melatonin (0.01 mg/kg) on duration of immobility of non-stressed (a) and stressed. (b) mice in FST. Date presented as the mean ± S.E.M and were analyzed using one-way ANOVA followed by tukey's post hoc test; ∗∗p < 0.01 and ∗∗∗p < 0.001 compared with saline treated group in each figure.

Figure 9

Effect of NMDA agonist treatment on antidepressant effect of melatonin in FST: effect of co-administration of NMDA (30 mg/kg) with melatonin (3 mg/kg) on duration of immobility of non-stressed (a) and stressed (b) mice in FST. Date presented as the mean ± S.E.M and were analyzed using one-way ANOVA followed by tukey's post hoc test; ∗p < 0.05 and ∗∗∗p < 0.001 compared with saline treated group in each figure. ns = p > 0.05 and ##p < 0.01 compared with melatonin treated group in each figure.