Single-dose psychedelic enhances cognitive flexibility and reversal learning in mice weeks after administration.

A single dose of the selective serotonin 2A receptor agonist 25CN-NBOH produces long-lasting improvements in cognitive flexibility in both male and female mice, measured 2-3 weeks after treatment. In an automated sequential learning task, treated mice showed superior adaptability in rule reversal compared to controls, with better poke efficiency, higher correct trial percentages, and increased reward acquisition. These behavioral results extend prior cellular findings on psychedelic-induced structural remodeling in the prefrontal cortex and demonstrate sustained cognitive benefits weeks after a single dose. The automated task offers a high-throughput method for evaluating cognitive flexibility effects of psychedelic compounds, with implications for conditions like depression, PTSD, and Alzheimer's disease.

Study at a glance

Abstract

Psychedelic compounds have demonstrated remarkable therapeutic potential for treating neuropsychiatric disorders by promoting sustained neuroplasticity in the prefrontal cortex (PFC). Cognitive flexibility-the ability to adapt previously learned rules to novel situations-represents a critical PFC function that is frequently impaired in depression, PTSD, and neurodegenerative conditions. In this study, we demonstrate that a single administration of the selective serotonin 2A receptor agonist 25CN-NBOH produces significant, long-lasting improvements in cognitive flexibility in both male and female mice when measured 2-3 weeks posttreatment. Using a novel automated sequential learning paradigm, psychedelic-treated mice showed superior adaptability in rule reversal tasks compared to saline controls, as evidenced by enhanced poke efficiency, higher percentages of correct trials, and increased reward acquisition. These behavioral findings complement existing cellular research showing psychedelic-induced structural remodeling in the PFC and uniquely demonstrate sustained cognitive benefits persisting weeks after a single psychedelic dose. Our automated behavioral task provides a high-throughput method for evaluating cognitive flexibility effects of various psychedelic compounds, offering important implications for therapeutic applications in conditions characterized by cognitive rigidity, including depression, PTSD, and potentially Alzheimer's disease.