Psilocybin prevents activity-based anorexia in female rats by enhancing cognitive flexibility: contributions from 5-HT1A and 5-HT2A receptor mechanisms
OpenAlex – December 13, 2023
Source: OpenAlex
Summary
Psilocybin, a potent hallucinogen, significantly improved body weight maintenance and cognitive flexibility in female rats modeling anorexia. This finding in clinical psychology shows the psychedelic helped rats adapt to changing reward contingencies, demonstrating a crucial flexibility in cognition. Neuroscience revealed serotonin 1A receptor activity was vital for these cognitive enhancements, highlighting neurotransmitter receptor influence on behavior and neuroendocrine regulation. Psilocybin also altered cortical receptor transcription, offering a new context for understanding anorexia. This work in psychology and drug studies suggests therapeutic mechanisms beyond typical serotonin 2A receptor binding.
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.