Ketamine produces no detectable long-term positive or negative effects on cognitive flexibility or reinforcement learning of male rats.

Abstract

Patients with major depressive disorder (MDD) often experience abnormalities in behavioral adaptation following environmental changes (i.e., cognitive flexibility) and tend to undervalue positive outcomes but overvalue negative outcomes. The probabilistic reversal learning task (PRL) is used to study these deficits across species and to explore drugs that may have therapeutic value. Selective serotonin-reuptake inhibitors (SSRIs) have limited effectiveness in treating MDD and produce inconsistent effects in non-human versions of the PRL. As such, ketamine, a novel and potentially rapid-acting therapeutic, has begun to be examined using the PRL. Two previous studies examining the effects of ketamine in the PRL have shown conflicting results and only examined short-term effects of ketamine. This experiment examined PRL performance across a 2-week period following a single exposure to a ketamine dose that varied across groups. After five sessions of PRL training, groups of rats received an injection of either 0, 10, 20 or 30 mg/kg ketamine. One-hour post-injection, rats engaged in the PRL, and subsequently sessions continued daily for 2 weeks. Traditional behavioral and computational reinforcement learning-derived measures were examined. Results showed that ketamine had acute effects 1-h post-injection, including a significant decrease in the value of the punishment learning rate. Beyond 1 h, ketamine produced no detectable improvements nor decrements in performance across 2 weeks. Overall, the present results suggest that the range of ketamine doses examined do not have long-term positive or negative effects on cognitive flexibility or reward processing in healthy rats as measured by the PRL.