Cognitive flexibility of male rats is increased by augmented punishment in a reversal learning task but ketamine has no detectable long-term effects.
Anthony N Nist, Stephen J Walsh, Timothy A Shahan
Psychopharmacology April 22, 2025 DOI: 10.1007/s00213-025-06794-y (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Sample size | 40 |
| Population | Rats |
| Interventions | Ketamine electric footshock |
| Dose | single dose |
| Topics | Ketamine Esketamine |
| Keywords | Cognitive flexibility Rats Reinforcement learning Learning psychology Punishment methods Animal behavior |
| Key findings | Shock punishment increased behavioral persistence and cognitive flexibility, but ketamine had no effect beyond acute impairments. |
Abstract
The probabilistic reversal learning task (PRL) is sometimes used in the context of major depressive disorder (MDD) to assess impairments in cognitive flexibility and feedback sensitivity because behavior in the task is sensitive to pharmacological interventions. Because traditional antidepressants are limited in their effectiveness, new drugs are needed to combat MDD. Ketamine has recently been investigated in the context of probabilistic reversal learning (PRL), but findings regarding its therapeutic efficacy have been mixed. One reason for this could be that almost all non-human versions of the PRL use signaled reward omission (i.e., timeout) as the punishing stimulus. It has long been known that timeout periods do not always function as punishers, and the inclusion of a known effective punishing stimulus could help to produce results of improved translational value. The present experiment sought to examine the effects of ketamine in the PRL when electric footshocks accompanied timeout periods or not. A baseline of PRL performance was established with 40 rats in which typical timeouts followed non-rewarded trials. In Phase 2, half the rats also received probabilistic footshock punishment for non-rewarded trials, while the other half continued under baseline conditions. Finally, a single dose of ketamine was administered to half of the rats (n = 10) in each condition (i.e., shock and no shock). Shock punishment increased behavioral persistence and cognitive flexibility in the PRL, but ketamine had no effect beyond causing acute impairments. These results suggest that the conditions of punishment during the PRL can have a significant impact on performance in the task and corroborate previous findings that ketamine may not impact cognitive flexibility or reward processing in healthy rats.
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
Cites 8
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- 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
- Rodent ketamine depression-related research: Finding patterns in a literature of variability Behavioural Brain Research August 13, 2019
- Effect of lysergic acid diethylamide (LSD) on reinforcement learning in humans. Psychological Medicine October 1, 2023
- Registered clinical trials investigating ketamine and esketamine for treatment-resistant depression: A systematic review Journal of Psychedelic Studies January 16, 2023
and 3 more in the library