Psilocybin prevents activity-based anorexia in female rats by enhancing cognitive flexibility: contributions from 5-HT1A and 5-HT2A receptor mechanisms
Kyna‐anne Conn, Lk Milton, Kaixin Huang, Hermany Munguba, Janika Ruuska, M. B. Lemus, Erin Greaves, Jihane Homman‐ludiye, Brian J. Oldfield, Claire J. Foldi
bioRxiv (Cold Spring Harbor Laboratory) December 13, 2023 preprint DOI: 10.1101/2023.12.12.571374 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal study |
|---|---|
| Population | Female rats in the activity-based anorexia (ABA) model |
| Intervention | Psilocybin |
| Topics | Psilocybin Serotonin |
| Keywords | Cognitive flexibility Cognition Flexibility engineering Hallucinogen Anorexia Context archaeology Clinical psychology Cognitive psychology |
| Citations | 6 |
| Key points | Psilocybin improved body weight maintenance and cognitive flexibility in anorexic rats, an effect dependent on 5-HT1A receptor signaling. |
Abstract
Abstract Psilocybin has shown promise for alleviating symptoms of depression and is currently in clinical trials for the treatment of anorexia nervosa (AN), a condition that is characterised by persistent cognitive inflexibility. Considering that enhanced cognitive flexibility after psilocybin treatment is reported to occur in individuals with depression, it is plausible that psilocybin could improve symptoms of AN by breaking down cognitive inflexibility. A mechanistic understanding of the actions of psilocybin is required to tailor the clinical application of psilocybin to individuals most likely to respond with positive outcomes. This can only be achieved using incisive neurobiological approaches in animal models. Here, we use the activity-based anorexia (ABA) rat model and comprehensively assess aspects of reinforcement learning to show that psilocybin (post-acutely) improves body weight maintenance in female rats and facilitates cognitive flexibility, specifically via improved adaptation to the initial reversal of reward contingencies. Further, we reveal the involvement of signalling through the serotonin (5-HT) 1A and 5-HT2A receptor subtypes in specific aspects of learning, demonstrating that 5-HT1A antagonism negates the cognitive enhancing effects of psilocybin. Moreover, we show that psilocybin elicits a transient increase and decrease in cortical transcription of these receptors ( Htr2a and Htr1a , respectively), and a further reduction in the abundance of Htr2a transcripts in rats exposed to the ABA model. Together, these findings support the hypothesis that psilocybin could ameliorate cognitive inflexibility in the context of AN and highlight a need to better understand the therapeutic mechanisms independent of 5-HT2A receptor binding.
Comparable studies
Other preclinical and animal studies on serotonin, 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 | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 5
- Do the therapeutic effects of psilocybin involve actions in the gut? TIPS - Trends in Pharmacological Sciences February 1, 2024
- A dual-receptor model of serotonergic psychedelics bioRxiv (Cold Spring Harbor Laboratory) April 15, 2024
- Short- and long-term reconfiguration of rat prefrontal cortical networks following single doses of psilocybin bioRxiv (Cold Spring Harbor Laboratory) December 13, 2024
- Psilocybin exerts differential effects on social behaviour and inflammation in mice in contexts of activity-based anorexia (ABA) bioRxiv (Cold Spring Harbor Laboratory) October 15, 2025
- Do Cognitive Enhancers Have the Potential to Change the Structure of Harm Reduction in the Future? Archives of Neuroscience December 9, 2024
Cites 38
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology November 8, 2017
- Safety, Tolerability, and Efficacy of Psilocybin in 9 Patients With Obsessive-Compulsive Disorder The Journal of Clinical Psychiatry November 15, 2006
- Long-term follow-up of psilocybin-facilitated smoking cessation The American Journal of Drug and Alcohol Abuse July 21, 2016
and 33 more in the library