Mood disorders are a spectrum of neuropsychiatric disorders characterized by changes in the emotional state. In particular, major depressive disorder is expected to have a worldwide prevalence of 20% in 2020, representing a huge socio-economic burden. Currently used antidepressant drugs have poor efficacy with only 30% of the patients in remission after the first line of treatment. Importantly, mood disorder patients present uncoupling of circadian rhythms. In this regard, melatonin (5-methoxy-N-acetyltryptamine), an indolamine synthesized by the pineal gland during the night, contributes to synchronization of body rhythms with the environmental light/dark cycle. In this review, we describe evidence supporting antidepressant-like actions of melatonin related to the circadian modulation of neuroplastic changes in the hippocampus. We also present evidence for the role of melatonin receptors and their signalling pathways underlying modulatory effects in neuroplasticity. Finally, we briefly discuss the detrimental consequences of circadian disruption on neuroplasticity and mood disorders, due to the modern human lifestyle. Together, data suggest that melatonin's stimulation of neurogenesis and neuronal differentiation is beneficial to patients with mood disorders.
Abstract:We evaluated the antidepressant-like effect of kaempferitrin (Km) isolated from the plant Justicia spicigera (Asteraceae), which is used in traditional medicine for relieving emotional disorders, such as "la tristeza" (sadness or dysthymia) and "el humor" (mood changes). The actions of Km were evaluated in a forced swimming test (FST) and a suspension tail test (TST) in mice. We explored the involvement of the serotonergic system and the hypothalamic-hypophysis-adrenal axis (HPA) in the antidepressant-like effect of Km. To evaluate nonspecific effects of Km on general activity, the open field test (OFT) was
OPEN ACCESSMolecules 2014, 19 21443 performed. Km at 5, 10, and 20 mg/kg induced an antidepressant-like effect. Sub-effective dose of Km (1 mg/kg) produced a synergistic effect with imipramine (6.25 mg/kg) and fluoxetine (10 mg/kg) but not with desipramine (3.12 mg/kg). Pretreatment with p-chlorophenylalanine methyl ester (PCPA), a serotonin synthesis inhibitor, N-{2-(4-(2-methoxyphenyl)-1-piperazinyl}-N-(2-pyridinyl)cyclohexecarboxamide (WAY-100635), a selective 5-HT1A receptor antagonist, and 8OH-DPAT, a selective 5-HT1A agonist, but not pindolol (10 mg/kg) blocked the anti-immobility effect induced by Km. Taken together, these results indicate that the antidepressant-like effect of Km is related to the serotonergic system, principally 5-HT1A. This effect was not related to changes in locomotor activity.
Melatonin is synthesized by the pineal gland with a circadian rhythm in synchrony with the environmental light/dark cycle. A gradual increase in circulating levels of melatonin occur after lights off, reaching its maximum around the middle of the dark phase. Agonists of melatonin receptors have proved effectiveness as antidepressants in clinical trials. However, there is contradictory evidence about the potential antidepressant effect of melatonin itself. Herein we studied melatonin administration in mice at two zeitgeber times (ZT; ZT = 0 lights on; 12:12 L/D), one hour before the beginning (ZT11) and at the middle (ZT18) of the dark phase after either a single or a three-dose protocol. Behavioral despair was assessed through a forced-swimming test (FST) or a tail suspension test (TST), at ZT18.5. A single dose of 4 mg/kg melatonin at ZT11 was effective to reduce the immobility time in both tests. However, acute administration of melatonin at ZT18 was not effective in mice subjected to FST, and a higher dose (16 mg/kg) was required to reduce immobility time in the TST. A three-dose administration protocol of 16 mg/kg melatonin (ZT18, ZT11, and ZT18) significantly reduced immobility time in FST. Data indicate that the timely administration of melatonin could improve its antidepressant-like effect.
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