Behavioral and biochemical effects of ketamine and dextromethorphan relative to its antidepressant-like effects in Swiss Webster mice
Linda Nguyen, Brandon P Lucke-Wold, A. Logsdon, Anna L. Scandinaro, J. D. Huber, R. Matsumoto
Neuroreport September 28, 2016 DOI: 10.1097/wnr.0000000000000646 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Proof-of-concept animal study Peer reviewed |
|---|---|
| Population | Male Swiss Webster mice |
| Interventions | Dextromethorphan Ketamine Imipramine |
| Duration | 40 minutes |
| Measures | Forced-swim test, Open-field test, Western blots |
| Topics | Esketamine Ketamine |
| Key points | DM and imipramine reduced forced-swim immobility without affecting locomotion, whereas ketamine reduced immobility and increased locomotion. Ketamine rapidly increased hippocampal pro-BDNF in an AMPA-receptor-dependent manner; DM and imipramine did not alter BDNF or pro-BDNF in hippocampus or frontal cortex within 40 minutes. The authors argue DM shares features with both ketamine and imipramine. |
Abstract
Ketamine has been shown to produce rapid and robust antidepressant effects in depressed individuals; however, its abuse potential and adverse psychotomimetic effects limit its widespread use. Dextromethorphan (DM) may serve as a safer alternative on the basis of pharmacodynamic similarities to ketamine. In this proof-of-concept study, behavioral and biochemical analyses were carried out to evaluate the potential involvement of brain-derived neurotrophic factor (BDNF) in the antidepressant-like effects of DM in mice, with comparisons to ketamine and imipramine. Male Swiss, Webster mice were injected with DM, ketamine, or imipramine and their behaviors were evaluated in the forced-swim test and the open-field test. Western blots were used to measure BDNF and its precursor, pro-BDNF, protein expression in the hippocampus and the frontal cortex of these mice. Our results show that both DM and imipramine reduced immobility time in the forced-swim test without affecting locomotor activity, whereas ketamine reduced immobility time and increased locomotor activity. Ketamine also rapidly (within 40 min) increased pro-BDNF expression in an &agr;-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-dependent manner in the hippocampus, whereas DM and imipramine did not alter pro-BDNF or BDNF levels in either the hippocampus or the frontal cortex within this timeframe. These data show that DM shares some features with both ketamine and imipramine. Additional studies examining DM may aid in the development of more rapid, safe, and efficacious antidepressant treatments.
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 6
- Efficacy of dextromethorphan for the treatment of depression: a systematic review of preclinical and clinical trials Expert Opinion on Emerging Drugs January 2, 2021
- Modulating tonic NMDA receptor currents: mechanistic insights into ketamine, esketamine, and dextromethorphan for major depressive disorder and implications for the discovery and development of investigational agents. Expert Opinion on Therapeutic Targets January 28, 2026
- The N-methyl-d-aspartate receptor hypothesis of ketamine's antidepressant action: evidence and controversies. Philosophical transactions of the Royal Society of London. Series B, Biological sciences July 29, 2024
- Ketamine alleviates fear memory and spatial cognition deficits in a PTSD rat model via the BDNF signaling pathway of the hippocampus and amygdala Research Square July 3, 2023
- All roads lead to glutamate: NMDA and AMPA receptors as targets for rapid-acting antidepressants. Pharmacological Research October 1, 2025
and 1 more in the library
Cites 10
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
- A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression Archives of General Psychiatry August 1, 2010
- Pathophysiology of depression and innovative treatments: remodeling glutamatergic synaptic connections Dialogues in Clinical Neuroscience March 31, 2014
- Evaluation of sigma (σ) receptors in the antidepressant-like effects of ketamine in vitro and in vivo. European Neuropsychopharmacology April 2012
- The antidepressant-like effects of glutamatergic drugs ketamine and AMPA receptor potentiator LY 451646 are preserved in bdnf⁺/⁻ heterozygous null mice. Neuropharmacology January 2012
and 5 more in the library