The Antidepressant-Like Effects of a Clinically Relevant Dose of Ketamine Are Accompanied by Biphasic Alterations in Working Memory in the Wistar Kyoto Rat Model of Depression
Conor McDonnell, F. Dunphy-Doherty, J. Rouine, Massimiliano Bianchi, N. Upton, E. Sokołowska, J. Prenderville
Frontiers in Psychiatry January 20, 2021 DOI: 10.3389/fpsyt.2020.599588 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Wistar Kyoto (WKY) rats and Sprague Dawley rats |
| Intervention | Ketamine |
| Dose | 5 mg/kg |
| Topics | Depression Esketamine Ketamine |
| Key points | Single subcutaneous 5 mg/kg ketamine rescued depressive-like behaviors in WKY rats while inducing transient dissociative-like side effects. |
Abstract
Major depressive disorder (MDD) is the leading cause of disability worldwide. The majority of antidepressant drugs require several weeks or months of treatment to demonstrate efficacy and a subset of patients are resistant to such interventions. Ketamine demonstrates rapid and long-lasting antidepressant effects in treatment resistant patients; however, side effects may limit its widespread clinical utility. The pharmaceutical industry is engaged in developing novel rapid-acting antidepressant drugs and the establishment of clinically relevant assays are needed to advance this process. Wistar Kyoto (WKY) rats are a valuable model of many of the characteristics of MDD and their resistance to selective serotonin reuptake inhibitors (SSRIs) in several behavioral paradigms emulates treatment resistance in clinical populations. Here, we confirmed the depressive-like phenotype of WKY rats in comparison to Sprague Dawley rats, characterized by increased immobility in the forced swim test, decreased locomotor activity and entries to the centre in the open field test, anhedonia in the female urine sniffing test and working memory deficits in the delayed non-match to position task. Single subcutaneous administration of 5 mg/kg ketamine in WKY rats mirrored the plasma exposure produced by the antidepressant dose in the clinic and rescued depressive-like behaviors. The same dose induced transient side effects, including decreased locomotor activity and reduced positive affect-associated vocalizations. Furthermore, ketamine acutely impaired working memory but induced pro-cognitive effects at a later time point. These data confirm the WKY rat as a preclinical model of depression. Ketamine's efficacy in recovering this depressive-like phenotype while inducing transient dissociative-like effects supports this as a translational model suitable for investigating novel antidepressant drugs.
Comparable studies
Other preclinical and animal studies on ketamine for depression, most cited first.
Citations in the library
Cited by 11
- The abuse liability of ketamine: A scoping review of preclinical and clinical studies. Journal of Psychiatric Research May 1, 2022
- Rapid-acting antidepressant drugs modulate affective bias in rats Science Translational Medicine January 10, 2024
- Preclinical models of treatment-resistant depression: challenges and perspectives. Pharmacological Reports December 1, 2023
- Behavioral sensitization and tolerance induced by repeated treatment with ketamine enantiomers in male Wistar rats. PLoS One 2024
- Increased sensitivity to psychomotor effects of ketamine enantiomers in the Wistar-Kyoto depression model. Journal of Psychiatric Research April 1, 2025
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Cites 20
- 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
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
and 15 more in the library