Chronic administration of ketamine elicits antidepressant-like effects in rats without affecting hippocampal brain-derived neurotrophic factor protein levels.
Lêda S B Garcia, Clarissa M Comim, Samira S Valvassori, Gislaine Z Réus, Ana Cristina Andreazza, Laura Stertz, Gabriel R Fries, Elaine Cristina Gavioli, Flávio Kapczinski, João Quevedo
Basic & Clinical Pharmacology & Toxicology December 2008 DOI: 10.1111/j.1742-7843.2008.00210.x (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Controlled animal experiment Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | Ketamine Imipramine |
| Dose | Ketamine 5, 10, and 15 mg/kg; imipramine 10, 20, and 30 mg/kg |
| Duration | 14 days of treatment, once daily |
| Measures | Forced swimming test, open-field test, ELISA sandwich assay for BDNF |
| Topics | Esketamine Ketamine |
| Key findings | Chronic ketamine and imipramine reduced immobility and increased climbing and swimming in the forced swimming test without affecting locomotor activity, but neither drug changed hippocampal BDNF protein levels. The authors report that a chronically administered 5 mg/kg ketamine dose, inactive acutely, became active, with no tolerance at 10 and 15 mg/kg, and argue that NMDA receptor blockade may be a target for mood disorders. |
Abstract
A growing body of evidence has pointed to the blockade of the N-methyl-d-aspartate (NMDA) receptor signaling as a potential therapeutic target for the treatment of major depression. The present study was aimed to evaluate behavioural and molecular effects of the chronic treatment with ketamine and imipramine in rats. To this aim, rats were 14 days treated once a day with ketamine (5, 10 and 15 mg/kg) and imipramine (10, 20 and 30 mg/kg) and then subjected to the forced swimming and open-field tests. Ketamine and imipramine, at the all doses tested, reduced immobility time, and increased both climbing and swimming time of rats compared to the saline group, without affecting spontaneous locomotor activity. Brain-derived neurotrophic factor (BDNF) hippocampal levels were assessed in imipramine- and ketamine-treated rats by ELISA sandwich assay. Chronic administration of both drugs, ketamine and imipramine, did not modify BDNF protein levels in the rat hippocampus. In conclusion, our findings demonstrate for the first time that chronic administration of acute inactive doses of ketamine (5 mg/kg) becomes active after chronic treatment, while no signs of tolerance to the behavioural effects of ketamine were observed after chronic administration of acute active doses (10 and 15 mg/kg). Finally, these findings further support the hypothesis that NMDA receptor could be a new pharmacological target for the treatment of mood disorders.
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 24
- Ketamine treatment for depression: a review Discover Mental Health April 15, 2022
- Rodent ketamine depression-related research: Finding patterns in a literature of variability Behavioural Brain Research August 13, 2019
- Effects of subanesthetic intravenous ketamine infusion on neuroplasticity-related proteins in the prefrontal cortex, amygdala, and hippocampus of Sprague-Dawley rats IBRO Reports January 16, 2019
- Repeated Dosing of Ketamine in the Forced Swim Test: Are Multiple Shots Better Than One? Frontiers in Psychiatry May 11, 2021
- Advances in the study of NMDA receptors in depression pathogenesis and the antidepressant efficacy of their antagonists. Asian Journal of Psychiatry June 1, 2025
and 19 more in the library
Cites 4
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Intravenous ketamine therapy in a patient with a treatment-resistant major depression Swiss Medical Weekly April 21, 2007
- 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
- Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Progress in Neuro-Psychopharmacology and Biological Psychiatry January 1, 2008