Chronic oral ketamine prevents anhedonia and alters neuronal activation in the lateral habenula and nucleus accumbens in rats under chronic unpredictable mild stress.
Ege Kingir, Cem Sevinc, Gunes Unal
Neuropharmacology February 20, 2023 DOI: 10.1016/j.neuropharm.2023.109468 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Controlled animal experiment Peer reviewed |
|---|---|
| Population | Male Wistar rats |
| Intervention | Ketamine |
| Dose | 0.013 mg/ml ad libitum |
| Duration | 9-week CUMS protocol; ketamine for 5 weeks |
| Measures | Sucrose consumption test, forced swim test, open field test, elevated plus maze, Morris water maze, c-Fos immunoreactivity |
| Topics | Esketamine Ketamine |
| Key findings | Chronic low-dose oral ketamine prevented behavioral despair and stress-induced anhedonia in rats under chronic unpredictable mild stress without impairing spatial reference memory. The authors propose that changes in neuronal activation in the lateral habenula and nucleus accumbens shell may contribute to this preventive effect on anhedonia. |
Abstract
Acute injections of ketamine lead to rapid but transient antidepressant effects. Chronic oral treatment at low doses, a promising non-invasive alternative, may prolong this therapeutic effect. Here, we examine the antidepressant effects of chronic oral ketamine in rats under chronic unpredictable mild stress (CUMS), and reveal their neuronal correlates. Male Wistar rats were divided into control, ketamine, CUMS, and CUMS-ketamine groups. The CUMS protocol was applied to the latter two groups for 9 weeks, and ketamine (0.013 mg/ml) was provided ad libitum to the ketamine and CUMS-ketamine groups for 5 weeks. The sucrose consumption test, forced swim test, open field test, elevated plus maze, and Morris water maze were respectively used to assess anhedonia, behavioral despair, general locomotor activity, anxiety-like behavior and spatial reference memory. CUMS caused a reduction of sucrose consumption and impaired spatial memory, accompanied by increased neuronal activation in the lateral habenula (LHb) and paraventricular thalamic nucleus (PVT). Oral ketamine prevented behavioral despair and CUMS-induced anhedonia. Reward-triggered c-Fos immunoreactivity was decreased in the LHb and increased in the nucleus accumbens shell (NAcSh) in the CUMS-ketamine group compared to the CUMS group. Ketamine did not produce a differential effect in the OFT, EPM and MWM. These results show that chronic oral ketamine at low doses prevents anhedonia without impairing spatial reference memory. The observed neuronal activation changes in the LHb and NAcSh may be involved in the preventive effects of ketamine on anhedonia.
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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- The Effect of Psilocybe cubensis on Spatial Memory and BDNF Expression in Male Rats Exposed to Chronic Unpredictable Mild Stress Journal of Psychoactive Drugs November 13, 2024
- Estrogen receptor alpha (ERα) partially modulates ketamine's sustained anxiolytic effects without altering its antidepressant properties in female rats. Psychoneuroendocrinology July 1, 2025
- Ketamine differentially affects implicit and explicit memory processes in rats. Psychopharmacology June 1, 2025
- Unveiling the role of single versus repeated low-dose ketamine in attenuating doxorubicin-induced chemobrain and depression in rats: differential modulation of neuroinflammation, phosphorylated GLT-1, SERT, DAT, and BDNF/TrkB signaling. Neuropharmacology June 1, 2026
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Cites 23
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- Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression Translational Psychiatry October 14, 2014
- The effects of ketamine on dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders Molecular Psychiatry October 3, 2017
- Neural correlates of change in major depressive disorder anhedonia following open-label ketamine Journal of Psychopharmacology February 17, 2015
and 18 more in the library