Psychedelic enhancement of flexible learning weeks after a single dose

Psychedelic drugs have shown therapeutic potential for the treatment of multiple neuropsychiatric disorders chiefly by promoting long-lasting plasticity in the prefrontal cortex (PFC). A critical function of the PFC is the ability to apply previously learned rules to novel scenarios, a skill known as cognitive flexibility. Here, we show that a single dose of 25CN-NBOH, a serotonin 2A receptor-preferring psychedelic, improves performance on a relatively complex flexible reversal learning task in mice, measured 2-3 weeks after the dose. This effect was seen in both male and female mice. This behavioral finding complements previous cellular results showing that a single psychedelic dose induces long-term structural changes in the PFC and uniquely demonstrates sustained improvements in cognitive flexibility in a novel behavioral paradigm weeks after the initial psychedelic dose in mice. This high throughput task also provides a rapid, automated way to assess other candidate psychedelics for their impact on cognitive flexibility in mice.