Rapid and long-lasting antidepressant-like effects of ketamine and their relationship with the expression of brain enzymes, BDNF, and astrocytes
G.S.B. Viana, E.M. Do Vale, Ana Giullia de Alencar Araújo, N. C. Coêlho, S. M. Andrade, R. O. Costa, P. Aquino, C. Sousa, I.S. de Medeiros, S. Vasconcelos, K.R.T. Neves
Brazilian Journal of Medical and Biological Research December 18, 2020 DOI: 10.1590/1414-431x202010107 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Peer reviewed |
|---|---|
| Population | Male Swiss mice |
| Interventions | Ketamine Imipramine |
| Dose | 2, 5, or 10 mg/kg |
| Duration | 30-minute, 15-day, and 30-day time points after single administration |
| Topics | Esketamine Ketamine |
| Post-publication review | 2 comments on PubPeer (opens in new tab) · last active May 2021 |
| Key findings | A single oral dose of ketamine (5 or 10 mg/kg) produced rapid and long-lasting antidepressant-like effects in mice, associated with decreased GSK-3 and HDAC immunoreactivity and increased BDNF and GFAP expression in brain regions up to 30 days later. |
Abstract
Ketamine (KET) is an N-methyl-D-aspartate (NMDA) antagonist with rapid and long-lasting antidepressant effects, but how the drug shows its sustained effects is still a matter of controversy. The objectives were to evaluate the mechanisms for KET rapid (30 min) and long-lasting (15 and 30 days after) antidepressant effects in mice. A single dose of KET (2, 5, or 10 mg/kg, po) was administered to male Swiss mice and the forced swim test (FST) was performed 30 min, 15, or 30 days later. Imipramine (IMI, 30 mg/kg, ip), a tricyclic antidepressant drug, was used as reference. The mice were euthanized, separated into two time-point groups (D1, first day after KET injection; D30, 30 days later), and brain sections were processed for glycogen synthase kinase-3 (GSK-3), histone deacetylase (HDAC), brain-derived neurotrophic factor (BDNF), and glial fibrillary acidic protein (GFAP) immunohistochemical assays. KET (5 and 10 mg/kg) presented rapid and long-lasting antidepressant-like effects. As expected, the immunoreactivities for brain GSK-3 and HDAC decreased compared to control groups in all areas (striatum, DG, CA1, CA3, and mainly pre-frontal cortex, PFC) after KET injection. Increases in BDNF immunostaining were demonstrated in the PFC, DG, CA1, and CA3 areas at D1 and D30 time-points. GFAP immunoreactivity was also increased in the PFC and striatum at both time-points. In conclusion, KET changed brain BDNF and GFAP expressions 30 days after a single administration. Although neuroplasticity could be involved in the observed effects of KET, more studies are needed to explain the mechanisms for the drug’s sustained antidepressant-like effects.
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
Cited by 8
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- New perspective on sustained antidepressant effect: focus on neurexins regulating synaptic plasticity Cell Death Discovery May 1, 2024
- Divergent Effects of Ketamine and the Serotoninergic Psychedelic 2,5-Dimethoxy-4-Iodoamphetamine on Hippocampal Plasticity and Metaplasticity. Psychedelic Medicine September 1, 2024
- From antidepressants and psychotherapy to oxytocin, vagus nerve stimulation, ketamine and psychedelics: how established and novel treatments can improve social functioning in major depression. Frontiers in Psychiatry 2024
- Temporal Immune Effects of Oral Ketamine on PTSD: Transcriptomic Evidence of Short-Term Inflammation Suppression and Long-Term Immune Remodelling medRxiv Preprint Server May 26, 2025
and 3 more in the library
Cites 13
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- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
- Efficacy of ketamine therapy in the treatment of depression Indian Journal of Psychiatry 2019
- Antidepressant mechanism of ketamine: perspective from preclinical studies Frontiers in Neuroscience July 21, 2015
- The monoaminergic pathways and inhibition of monoamine transporters interfere with the antidepressive-like behavior of ketamine IBRO Reports June 13, 2018
and 8 more in the library