Psilocybin Impairs Short-Term Cognitive Flexibility but Indicates Long-Term Benefits in a Rodent Three-Choice Reversal Learning Task

IntroductionCognitive flexibility is essential for adapting behavior in response to environmental changes and is implicated in various neuropsychiatric disorders. Psilocybin, a serotonergic psychedelic, has shown potential in enhancing cognitive flexibility, though results are mixed. This study investigates the effects of psilocybin on cognitive flexibility using a three-choice visual reversal learning task in rats.MethodsSixteen Long-Evans rats were trained on a three-choice touchscreen-based reversal learning task. Following training and initial reversal testing, psilocybin (COMP360, 1 mg/kg, subcutaneous) or saline was administered in a cross-over design. Behavioral performance was assessed through time to learning criteria, reaction times, and interaction patterns with image choices, focusing on both short-term effects (days after administration during the cross-over interventions) and trends over following reversals (weeks). Computational reinforcement learning models analyzed development in latent cognitive parameters, such as learning rate and value sensitivity.ResultsFive rats successfully completed all six reversal learning protocols, demonstrating significant learning and de-learning dynamics. Number of sessions to learning criteria and reaction time for the touchscreen decreased significantly across protocols. Psilocybin administration impaired the rate of learning and de-learning across sessions during the first reversal following intervention. Computational modeling identified low learning rates, with no significant differences between psilocybin and placebo conditions on any parameters. However, exploratory analysis revealed en-hanced rates of both learning and de-learning over session in the second reversal following inter-vention compared to before intervention.ConclusionsA subset of rats effectively engaged in this complex three-choice visual reversal learning task, demonstrating learning and de-learning over time. Psilocybin impaired short-term performance in both learning and de-learning speed, while exploratory findings suggested long-term enhancements in learning dynamics. These results show a nuanced effect of psilocybin on cognitive flexibility and its potential relevance as an intervention in neuropsychiatric disorders. Further research should explore long-term outcomes and refine computational models for complex tasks.