Enhanced Modulation of CaMKII in Mouse Hippocampus by an Antidepressant-like Dose of Melatonin/Ketamine Combination
Armida Miranda-Riestra, Rosa Estrada-Reyes, Luis A Constantino-Jonapa, Jesús Argueta, Julián Oikawa-Sala, Miguel A. Reséndiz-Gachús, Daniel Albarrán-Gaona, Gloria Benítez-King
Cells August 1, 2025 DOI: 10.3390/cells14151187 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | Melatonin Ketamine Luzindole |
| Dose | ketamine 10−7 M and melatonin 10−7 M (in olfactory neuronal precursor experiments); melatonin and ketamine doses in mice not specified |
| Topics | Esketamine Ketamine |
| Key findings | Melatonin combined with ketamine increased CaMKII activation and changed its subcellular distribution in the mouse hippocampal dentate gyrus, with melatonin causing nuclear translocation of active CaMKII. Luzindole, an MT1/MT2 receptor antagonist, abolished these effects, which the authors interpret as evidence that CaMKII lies downstream of the melatonin receptor pathway underlying antidepressant-like effects. |
Abstract
Forty per cent of major depression patients are resistant to antidepressant medication. Thus, it is necessary to search for alternative treatments. Melatonin (N-acetyl-5-hydroxytryptamine) enhances neurogenesis and neuronal survival in the adult mouse hippocampal dentate gyrus. Additionally, melatonin stimulates the activity of Ca2+/Calmodulin-dependent Kinase II (CaMKII), promoting dendrite formation and neurogenic processes in human olfactory neuronal precursors and rat organotypic cultures. Similarly, ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, modulates CaMKII activity. Importantly, co-treatment of low doses of ketamine (10−7 M) in combination with melatonin (10−7 M) produces additive effects on neurogenic responses in olfactory neuronal precursors. Importantly, enhanced neurogenic responses are produced by conventional antidepressants like ISSRs. The goal of this study was to investigate whether hippocampal CaMKII participates in the signaling pathway elicited by combining doses of melatonin with ketamine acutely administered to mice, 30 min before being subjected to the forced swimming test. The results showed that melatonin, in conjunction with ketamine, significantly enhances CaMKII activation and changes its subcellular distribution in the dentate gyrus of the hippocampus. Remarkably, melatonin causes nuclear translocation of the active form of CaMKII. Luzindole, a non-selective MT1 and MT2 receptor antagonist, abolished these effects, suggesting that CaMKII is downstream of the melatonin receptor pathway that causes the antidepressant-like effects. These findings provide molecular insights into the combined effects of melatonin and ketamine on neuronal plasticity-related signaling pathways and pave the way for combating depression using combination therapy.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 6
- Strategies to mitigate dissociative and psychotomimetic effects of ketamine in the treatment of major depressive episodes: a narrative review The World Journal of Biological Psychiatry January 11, 2016
- Antidepressant Low Doses of Ketamine and Melatonin in Combination Produce Additive Neurogenesis in Human Olfactory Neuronal Precursors. Molecules September 1, 2022
- Low Doses of Ketamine and Melatonin in Combination Produce Additive Antidepressant-like Effects in Mice International Journal of Molecular Sciences August 26, 2021
- Calcium/Calmodulin-Dependent Protein Kinase II and Eukaryotic Elongation Factor 2 Kinase Pathways Mediate the Antidepressant Action of Ketamine. Biological Psychiatry July 1, 2018
- Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology January 2012
and 1 more in the library