Antidepressant, anxiolytic and procognitive effects of subacute and chronic ketamine in the chronic mild stress model of depression.
Mariusz Papp, Piotr Gruca, Magdalena Lason-Tyburkiewicz, Paul Willner
Behavioural Pharmacology February 2017 DOI: 10.1097/fbp.0000000000000259 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Population | Wistar rats exposed to chronic mild stress |
| Interventions | Ketamine Imipramine |
| Dose | 5-30 mg/kg; optimum 10 mg/kg |
| Duration | 2 weeks chronic mild stress before treatment; 5 weeks chronic treatment; subacute treatment 3-5 days |
| Measures | Sucrose intake test, elevated plus maze, novel object recognition test |
| Topics | Depression Esketamine Ketamine |
| Key findings | Daily ketamine in the chronic mild stress model produced sustained antidepressant-like effects on sucrose intake, with onset around one week and an optimal dose of 10 mg/kg, faster than imipramine. Subacute and chronic ketamine fully reversed stress-induced anxiety-like and cognitive deficits. The authors suggest the cognitive-enhancing effect may have particular translational value. |
Abstract
Ketamine is the prototype of a new generation of antidepressant drugs, which is reported in clinical studies to be effective in treatment-resistant patients, with an effect that appears within hours and lasts for a few days. Chronic mild stress (CMS) is a well-established and widely used animal model of depression, in which anhedonia, anxiogenesis and cognitive dysfunction can be observed reliably. Studies using acute or brief ketamine treatment following withdrawal from CMS have replicated the clinical finding of a rapid onset of antidepressant action. However, there have been no CMS studies of chronic daily ketamine treatment or continued stress following ketamine treatment, which would have greater translational potential in relation to the long-term maintenance of antidepressant effects. Wistar rats were drug treated following an initial 2 weeks of CMS exposure, which continued alongside daily drug treatment. A first experiment tested a range of chronic (5 weeks) ketamine doses (5-30 mg/kg); a second compared the effects of subacute (3-5 days) and chronic (5 weeks) treatment. CMS-induced anhedonic, anxiogenic and dyscognitive effects, as measured, respectively, by decreased sucrose intake, avoidance of open arms in the elevated plus maze and loss of discrimination in the novel object recognition test. A sustained antidepressant-like effect of ketamine in the sucrose intake test was observed in both experiments, with an onset at around 1 week, faster than imipramine, and an optimum dose of 10 mg/kg. Anxiogenic and dyscognitive effects of CMS, in the elevated plus maze and novel object recognition test, respectively, were fully reversed by both subacute and chronic ketamine treatment. Daily treatment with ketamine in the CMS model causes sustained long-term antidepressant, anxiolytic and procognitive effects. The demonstration of a procognitive effect of ketamine may have particular translational value.
Comparable studies
Other preclinical and animal studies on ketamine for depression, most cited first.
Citations in the library
Cited by 19
- Glutamatergic Neurotransmission: Pathway to Developing Novel Rapid-Acting Antidepressant Treatments The International Journal of Neuropsychopharmacology November 14, 2018
- Cognitive Behavior Therapy May Sustain Antidepressant Effects of Intravenous Ketamine in Treatment-Resistant Depression Psychotherapy and Psychosomatics 2017
- NMDA Receptor Activation-Dependent Antidepressant-Relevant Behavioral and Synaptic Actions of Ketamine Journal of Neuroscience January 3, 2023
- Ketamine and its metabolite, (2R,6R)-HNK, restore hippocampal LTP and long-term spatial memory in the Wistar-Kyoto rat model of depression Molecular Brain June 16, 2020
- Comparison of the Psychopharmacological Effects of Tiletamine and Ketamine in Rodents Neurotoxicity Research June 2, 2017
and 14 more in the library
Cites 11
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Ketamine as a promising prototype for a new generation of rapid‐acting antidepressants Annals of the New York Academy of Sciences February 27, 2015
- Long-Lasting Antidepressant Action of Ketamine, but Not Glycogen Synthase Kinase-3 Inhibitor SB216763, in the Chronic Mild Stress Model of Mice PLoS One February 4, 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: stimulating antidepressant treatment? BJPsych Open May 1, 2016
and 6 more in the library