Anxiolytic- and antidepressant-like properties of ketamine in behavioral and neurophysiological animal models.
E Engin, D Treit, C T Dickson
Neuroscience June 30, 2009 DOI: 10.1016/j.neuroscience.2009.03.038 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Placebo-controlled Double-blind Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | Ketamine Fluoxetine MK-801 Diazepam |
| Measures | forced swim test, elevated-plus-maze, open field test, reticularly-activated theta oscillations in the hippocampus |
| Topics | Esketamine Ketamine |
| Key points | Ketamine decreased behavioral despair in the forced swim test comparably to fluoxetine, without affecting general activity, and produced anxiolytic-like effects in the elevated-plus-maze at a dose that did not alter locomotion. Ketamine also reduced reticularly-activated hippocampal theta oscillations, a signature common to anxiolytic drugs, whereas MK-801's effects were confounded by activity changes. |
Abstract
Ketamine, a dissociative anesthetic agent, appears to have rapid antidepressant effects at sub-anesthetic doses in clinically depressed patients. Although promising, these results need to be replicated in double-blind placebo-controlled studies, a strategy thwarted by the psychoactive effects of ketamine, which are obvious to both patients and clinicians. Alternatively, demonstrations of the psychotherapeutic effects of ketamine in animal models are also complicated by ketamine's side-effects on general activity, which have not been routinely measured or taken into account in experimental studies. In this study we found that ketamine decreased "behavioral despair" in the forced swim test, a widely used rats model of antidepressant drug action. This effect was not confounded by side-effects on general activity, and was comparable to that of a standard antidepressant drug, fluoxetine. Interestingly, ketamine also produced anxiolytic-like effects in the elevated-plus-maze. Importantly, the effective dose of ketamine in the plus-maze did not affect general locomotion measures, in either the plus-maze or in the open field test. While the selective N-methyl-d-aspartic acid (NMDA) receptor antagonist MK-801 also produced antidepressant-like and anxiolytic-like effects, these were mostly confounded by changes in general activity. Finally, in a neurophysiological model of anxiolytic drug action, ketamine reduced the frequency of reticularly-activated theta oscillations in the hippocampus, similar to the proven anxiolytic drug diazepam. This particular neurophysiological signature is common to all known classes of anxiolytic drugs (i.e. benzodiazepines, 5-HT1A agonists, antidepressants) and provides strong converging evidence for the anxiolytic-like effects of ketamine. Further studies are needed to understand the underlying pharmacological mechanisms of ketamine's effects in these experiments, since it is not clear they were mimicked by the selective NMDA antagonist MK-801.
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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- Psilocin and ketamine microdosing: effects of subchronic intermittent microdoses in the elevated plus-maze in male Wistar rats Behavioural Pharmacology March 13, 2018
- Efficacy of intravenous ketamine treatment in anxious versus nonanxious unipolar treatment-resistant depression Depression and Anxiety December 30, 2018
- The monoaminergic pathways and inhibition of monoamine transporters interfere with the antidepressive-like behavior of ketamine IBRO Reports June 13, 2018
- Environmental enrichment enhances the antidepressant effect of ketamine and ameliorates spatial memory deficits in adult rats. Pharmacology, Biochemistry, and Behavior July 1, 2024
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Cites 6
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- Ketamine, but not phencyclidine, selectively modulates cerebellar GABA(A) receptors containing alpha6 and delta subunits. Journal of Neuroscience May 14, 2008
- Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biological Psychiatry February 15, 2008
- Behavioral effects of ketamine and toxic interactions with psychostimulants BMC Neuroscience March 16, 2006
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