The Timing of Melatonin Administration Is Crucial for Its Antidepressant-Like Effect in Mice

Abstract

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.

Low Doses of Ketamine and Melatonin in Combination Produce Additive Antidepressant-like Effects in Mice

“…To examine whether the KET/MEL combination would be more effective than either drug alone in reducing the immobility behavior, we administered sub-effective doses of KET (1.5 mg/kg) and MEL (4 or 16 mg/kg, i.p.) simultaneously, 30 min before the FST [15]. KET at 1.5 mg/kg did not reduce the immobility time in mice summited to the FST (Figure 1A).…”

“…In addition, we have previously shown that a single administration of MEL (4 or 16 mg/kg i.p.) 30 min before the FST does not reduce the immobility time in this test [15]. To examine whether the KET/MEL combination would be more effective than either drug alone in reducing the immobility behavior, we administered sub-effective doses of KET (1.5 mg/kg) and MEL (4 or 16 mg/kg, i.p.)…”

“…(2) Mice received MEL (16 mg/kg) or FLX at ZT 18 (middle of the dark phase) and at ZT 11 (one hour before the beginning of the next dark phase), and then the KET/MEL combination was administered at the next ZT 18. Behavioral tests were performed 30 min later, at ZT 18.5 (Figure 2, upper scheme) [15].…”

“…Single Administration of Ketamine/Melatonin Combination Increases the Expression of Doublecortin and Ki67 in the Mice HippocampusNeurogenesis occurs after antidepressant administration[32]. Thus, we explored if the KET/MEL combination was able to increase this process after a single administration, using MEL at a dose that produces antidepressant-like effects in mice (4 mg/kg) in the FST[15] and KET at non-effective doses[33]. Brain slices including the hippocampal dentate gyrus were labeled with a specific anti-doublecortin antibody.…”

Further Evidence of the Melatonin Calmodulin Interaction: Effect on CaMKII Activity

“…Evidence from nuclear magnetic resonance-based studies and ligand-binding assays have shown that MEL can bind to Ca 2+ -CaM [ 10 , 16 , 17 ]. Exogenous MEL antidepressant-like effects in mice have been recently described [ 25 , 26 ], and modulation of neuroplasticity may underlie this effect. CaMKII plays a key role in neurogenesis and dendritogenesis which are processes stimulated by antidepressants and MEL [ 27 ].…”