Acute psilocybin robustly improves cognitive flexibility in male and female rats, enhancing their ability to switch between previously learned strategies in response to uncued environmental changes. Psilocybin did not affect Pavlovian reversal learning, indicating its cognitive effects are selective to strategy switching. The serotonin 5HT2A receptor antagonist ketanserin blocked psilocybin's effect on set-shifting, while a 5HT2C-selective antagonist did not; ketanserin alone also improved set-shifting performance, suggesting a complex pharmacological relationship. The psychedelic DOI impaired cognitive flexibility in the same task, showing this effect does not generalize to all serotonergic psychedelics. These findings provide a behavioral model for investigating psilocybin's neuronal effects relevant to its clinical outcomes.
Substituted tryptamines show varying potency and selectivity at serotonin receptors and the serotonin transporter. Several compounds, including 5-MeO-DMT and 5-MeO-tryptamine, are potent 5-HT2AR agonists, while others like 5-MeO-NMT and bufotenine have lower activity. At 5-HT2CR, 5-MeO-DMT and 5-MeO-tryptamine are also potent, but bufotenine is inactive. Most tryptamines have weak or no activity at 5-HT1AR and the serotonin transporter. The findings indicate that the 5-methoxy substitution enhances 5-HT2AR and 5-HT2CR potency, while the N,N-dimethyl group is important for high efficacy.