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

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 (Htr2aandHtr1a, respectively), and a further reduction in the abundance ofHtr2atranscripts 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.

Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles

“…In this study, we combined in- vivo single cell calcium imaging of cortical ensembles with behavioral pharmacology to elucidate the neural correlates of psilocybin-enhanced extinction. The existence psilocybin-responsive and non-responsive subpopulations of humans and rats has been the subject of recent investigation 28,75 . Here, we report for the first time that mice are divided into psilocybin responsive and non-responsive groups with respect to post-acute enhancement of TFC extinction.…”

“…Clinical researchers found that therapeutic effects of serotonergic psychedelics in humans are mediated by increased cognitive flexibility following drug experience, a finding recapitulated in rodent models [25][26][27][28] . Evidence from human, rodent, and molecular research converges on the hypothesis that psilocybin generates highly plastic brain states conducive to modifying circuits that underlie inflexible, maladaptive behaviors via 5HT2R and TrkB activation 2,17,[29][30][31][32][33][34][35][36] .…”

“…Clinical researchers have demonstrated that the therapeutic effects of serotonergic psychedelics in humans are mediated by increased cognitive flexibility following drug experience, a finding recapitulated in rodent models [31][32][33][34] . Cognitive inflexibility, or the inability to adapt thought or behavior to new environmental demands, is central to a wide range of neuropsychiatric disease 35,36 .…”