Acute psilocybin enhances cognitive flexibility in rats

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.

Medial Prefrontal Cortex Serotonin Input Regulates Cognitive Flexibility in Mice

“…We speculate that serotonergic prescription drugs (such as serotonin reuptake inhibitors) and recreational drugs (such as psychedelics) may improve cognitive flexibility by interacting with serotonin signaling in the mPFC (Davis et al, 2020, Dos Santos et al, 2018, Murphy-Beiner et al, 2020, Torrado Pacheco et al, 2023, Winkelman, 2014. Our data provide a mechanistic foundation to investigate such relationships which will ultimately improve diagnosis and treatment approaches in psychiatry.…”

Psilocybin prevents activity-based anorexia in female rats by enhancing cognitive flexibility: contributions from 5-HT1A and 5-HT2A receptor mechanisms

“…Not only does ketanserin bind multiple serotoninergic and non-serotonergic receptors but it also only blocks ~30% of 5-HT2AR in the rat cortex 76 . It is plausible, therefore, that partial blockade with ketanserin shifts the binding of psilocybin to other 5-HTR subtypes, including 5-HT1A, which may explain the acute improvement in reversal learning after ketanserin alone previously reported in rats 38 .…”

“…If adaptive cognition requires an appropriate balance between 5-HT1A and 5-HT2A receptor function 47 , our molecular findings suggest that individuals (humans or rats) exhibiting elevated 5-HT1AR function (or for that matter reduced 5-HT2AR function) may not respond positively (since further elevation or reduction elicited by psilocybin would push them into the tail ends of the inverted “U”). It is also important to note, in light of the recent observation that psilocybin, administered acutely, did not facilitate flexibility 36 , that there are important methodological differences that may explain this discordance. Specifically, we examined effects of psilocybin post-acutely, using a single administration paradigm, and the reversal learning task used in the present study relied on action-outcome learning rather than Pavlovian cue-outcome learning.…”

“…the forced swim test) do not reliably translate to human depressive syndromes 33 and that reinforcement learning tasks offer key advantages including more relevant clinical links and repeatability 34 , these early approaches clearly need to be redressed. Other key methodological details in prior studies need to be considered, particularly the role of multiple dosing (cross-over) designs, antagonising 5-HT2AR with ketanserin (a compound with many known non-serotonergic binding sites 35 ), and the measurable motoric side effects of acute psilocybin administration 36 .…”

A dual-receptor model of serotonergic psychedelics

“…Within this framework, 5-HT neuromodulation then serves a role in responding to stress by improving the computational efficiency of the processes required to learn and maintain such successful representations. The ability to efficiently learn and maintain adaptive predictive representations is precisely the construct of cognitive flexibility (Ionescu, 2012)—the characteristic that enables animals or humans to adaptively generate appropriate behavioral responses based on changing sensory stimuli—which psychedelics have been demonstrated to improve (Doss et al, 2021; Torrado Pacheco, Olson, Garza, & Moghaddam, 2023), and is believed to be generally associated with serotonin signalling (Matias et al, 2017).…”