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Acute psilocybin enhances cognitive flexibility in rats

Gabriela Garza, Bita Moghaddam, Alejandro Torrado Pacheco, Randall J. Olson

Neuropsychopharmacology February 20, 2023 DOI: 10.1038/s41386-023-01545-z (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Experimental study Peer reviewed
Population Male and female rats
Interventions Psilocybin Ketanserin 5HT2C-selective antagonist DOI
Topics Psilocybin
Keywords Cognitive flexibility Hallucinogen Flexibility engineering Cognition Cognitive psychology Pharmacology
Citations 69
Key findings Acute psilocybin robustly improves cognitive flexibility in rats by enhancing switching between previously learned strategies, an effect blocked by a 5HT2A receptor antagonist.

Abstract

Abstract Psilocybin has been shown to improve symptoms of depression and anxiety when combined with psychotherapy or other clinician-guided interventions. To understand the neural basis for this pattern of clinical efficacy, experimental and conceptual approaches that are different than traditional laboratory models of anxiety and depression are needed. A potential novel mechanism is that acute psilocybin improves cognitive flexibility, which then enhances the impact of clinician-assisted interventions. Consistent with this idea, we find that acute psilocybin robustly improves cognitive flexibility in male and female rats using a task where animals switched between previously learned strategies in response to uncued changes in the environment. Psilocybin did not influence Pavlovian reversal learning, suggesting that its cognitive effects are selective to enhanced switching between previously learned behavioral strategies. The serotonin (5HT) 2 A 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 relationship between psilocybin’s pharmacology and its impact on flexibility. Further, the psychedelic drug 2,5-Dimethoxy-4-iodoamphetamine (DOI) impaired cognitive flexibility in the same task, suggesting that this effect of psilocybin does not generalize to all other serotonergic psychedelics. We conclude that the acute impact of psilocybin on cognitive flexibility provides a useful behavioral model to investigate its neuronal effects relevant to its positive clinical outcome.

Comparable studies

Other preclinical and animal studies on psilocybin, most cited first.

Study Year Design Participants
Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice 2021 Observational cohort
Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Mice 2021 Experimental study
Psychedelics reopen the social reward learning critical period Mice 2023 Experimental study in mice
Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice 2020 Experimental study with dose-response experiments
Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice 2013 Experimental study

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