Environmental determinants of ketamine's prohedonic and antianhedonic efficacy: Persistence of enhanced reward responsiveness is modulated by chronic stress.
Amaya R Jenkins, Daniela B Radl, Thomas J Kornecook, Diego A. Pizzagalli, Jack Bergman, Derek L Buhl, Patricio O'Donnell, Brian D Kangas
Journal of Pharmacology and Experimental Therapeutics May 1, 2025 DOI: 10.1016/j.jpet.2025.103572 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rats |
| Intervention | Ketamine |
| Dose | 3.2-32.0 mg/kg (without stress), 10.0 mg/kg (with stress) |
| Duration | Within 24 hours (prohedonic), nearly 1 week (antianhedonic) |
| Topics | Ketamine Esketamine |
| Keywords | Anhedonia Probabilistic reward task Rats Reverse translation Touchscreen methods Stress response Reward processing Depression treatment Animal behavior research Psychopharmacology |
| Citations | 8 |
| Key findings | Ketamine produced short-lived prohedonic effects under nonstressful conditions and persistent antianhedonic effects under chronic stress. |
Abstract
Ketamine, a dissociative anesthetic with well documented abuse liability, can also provide rapid-onset and persistent antidepressant effects and is currently used for the management of treatment-resistant depression. Although the precise neurobiological mechanisms underlying its antidepressant actions are not fully determined, a critical feature of ketamine's clinical efficacy may be its antianhedonic action. Anhedonia is an endophenotype of depression defined by decreased responsivity to previously rewarding stimuli and is generally not ameliorated by conventional antidepressants, emphasizing the need to examine underlying behavioral mechanisms of action. In this study, the probabilistic reward task, a reverse-translated assay originally designed to objectively quantify anhedonic phenotypes in human subjects, was used in rats to examine ketamine's effects on reward responsiveness under conditions without programmed stressors (3.2-32.0 mg/kg) or during ongoing chronic exposure to ecologically relevant stress (10.0 mg/kg). Results showed that under conditions without programmed stress, ketamine produced significant prohedonic effects in the probabilistic reward task, defined by increases in reward responsiveness that dissipated within 24 hours. In rats exposed to ongoing chronic stress, ketamine produced significant antianhedonic effects, defined by the rescue of blunted reward responsiveness, that persisted for nearly 1 week. Taken together, the prolonged antianhedonic effects of ketamine in rats experiencing chronic stress, compared with the shorter-lived prohedonic effects in subjects without exposure to programmed stressors, are striking and highlight the role of environmental determinants in the effects of ketamine on behavioral processes. Moreover, the translational nature of this experimental design may offer the opportunity to accelerate development of novel antianhedonic therapeutics. SIGNIFICANCE STATEMENT: Although ketamine is used for the management of treatment-resistant depression, its precise behavioral mechanisms of action are not fully delineated. Emerging evidence suggests the attenuation of anhedonia plays a key role in its rapid-acting therapeutic efficacy. To evaluate this possibility, the effects of ketamine were studied using a reverse-translated assay of reward responsiveness in rats and documented to be short-lived (prohedonic) under nonstressful conditions and persistent (antianhedonic) under stressful conditions, informing ketamine effects in healthy versus depressed individuals.
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 3
- The cognitive neuroscience of ketamine in major depression. Brain June 30, 2025
- Ketamine Improves Anhedonic Phenotypes Across Species: Translational Evidence From the Probabilistic Reward Task. Biological Psychiatry Global Open Science May 1, 2026
- Psychedelics produce enduring enhancement of reward responsiveness in male rats Neuropsychopharmacology July 10, 2026
Cites 17
- Single-dose infusion ketamine and non-ketamine N-methyl-D-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories Psychological Medicine February 12, 2016
- Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression Translational Psychiatry October 14, 2014
- Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms Neuropsychopharmacology July 24, 2023
- Neural correlates of change in major depressive disorder anhedonia following open-label ketamine Journal of Psychopharmacology February 17, 2015
- A Single Subanesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats Anesthesiology October 1, 2011
and 12 more in the library