The Combination of Long-term Ketamine and Extinction Training Contributes to Fear Erasure by Bdnf Methylation
Ling-Sha Ju, Jiao-Jiao Yang, Lei Lei, Jiang-Yan Xia, Dan Luo, M. Ji, A. Martynyuk, Jian-Jun Yang
Frontiers in Cellular Neuroscience April 20, 2017 DOI: 10.3389/fncel.2017.00100 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Male mice subjected to inescapable electric foot shocks as a model of PTSD |
| Interventions | Ketamine extinction training |
| Duration | Long-term ketamine for 22 consecutive days starting 1 h after inescapable foot shock; short-term ketamine 2 h before extinction training on days 15 and 16 after shock; behavioral tests on days 18, 20, and 23 |
| Measures | Open Field (OF), Elevated Plus Maze (EPM), spontaneous recovery test, fear renewal test, DNA methyltransferase levels, Bdnf gene methylation, BDNF mRNA expression |
| Topics | Esketamine Ketamine |
| Key points | Mice given inescapable foot shocks showed anxiety-like behavior and fear relapse with increased DNA methyltransferases, Bdnf hyper-methylation, and reduced BDNF mRNA in the medial prefrontal cortex and hippocampus. Long-term ketamine combined with extinction training alleviated these abnormalities, suggesting the combination may reduce fear relapse at least partly by normalizing Bdnf DNA methylation. |
Abstract
A combination of antidepressant drugs and psychotherapy exhibits more promising efficacy in treating fear disorders than either treatment alone, but underlying mechanisms of such treatments remain largely unknown. Here we investigated the role of DNA methylation of the brain-derived neurotrophic factor (Bdnf) gene in the therapeutic effects of ketamine in combination with extinction training in a mouse model of post-traumatic stress disorder (PTSD) induced by inescapable electric foot shocks (IFS). Male mice received ketamine for 22 consecutive days starting 1 h after the IFS (long-term ketamine treatment) or 2 h prior to the extinction training on days 15 and 16 after the IFS (short-term ketamine treatment). The Open Field (OF) and Elevated Plus Maze (EPM) tests were conducted on days 18 and 20. The spontaneous recovery and fear renewal tests were performed on day 23. Mice, subjected to IFS, exhibited anxiety-like behavior and fear relapse, accompanied by the increased levels of DNA methyltransferases, hyper-methylation of Bdnf gene, and decreased BDNF mRNA expression in the medial prefrontal cortex (mPFC) and hippocampus (HIP). Long-term treatment with ketamine combined with extinction training alleviated the IFS-induced abnormalities. These results suggest that long-term ketamine treatment in combination with extinction training may ameliorate fear relapse in the murine model of PTSD, at least in part, by normalizing DNA methylation of Bdnf gene.
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
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- Modulation of DNA methylation and protein expression in the prefrontal cortex by repeated administration of D-lysergic acid diethylamide (LSD): Impact on neurotropic, neurotrophic, and neuroplasticity signaling Progress in Neuro-Psychopharmacology and Biological Psychiatry June 28, 2022
- Repeated oral esketamine in patients with treatment resistant depression and comorbid posttraumatic stress disorder Heliyon May 1, 2023
- Epigenetic mechanisms of rapid-acting antidepressants Translational Psychiatry September 4, 2024
- Hallucinogenic drugs and their potential for treating fear-related disorders: Through the lens of fear extinction. Journal of Neuroscience Research April 1, 2022
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Cites 7
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- BDNF Release Is Required for the Behavioral Actions of Ketamine The International Journal of Neuropsychopharmacology October 31, 2014
- Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in treatment-resistant depression The International Journal of Neuropsychopharmacology October 8, 2013
- Role of hippocampal p11 in the sustained antidepressant effect of ketamine in the chronic unpredictable mild stress model Translational Psychiatry February 23, 2016
- Ketamine as a prophylactic against stress-induced depressive-like behavior Biological Psychiatry May 4, 2015
and 2 more in the library