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) 1 A 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.

裸盖菇素已显示出缓解抑郁症状的前景，目前正处于治疗神经性厌食症 (AN) 的临床试验中，神经性厌食症是一种以持续认知不灵活为特征的疾病。考虑到据报道，抑郁症患者在接受裸盖菇素治疗后认知灵活性有所增强，因此裸盖菇素可能通过打破认知僵化来改善 AN 症状，这是合理的。需要对裸盖菇素作用的机制有了解，才能将裸盖菇素的临床应用调整到最有可能产生积极结果的个体。这只能在动物模型中使用深入的神经生物学方法来实现。在这里，我们使用基于活动的厌食症（ABA）大鼠模型，并全面评估强化学习的各个方面，以表明裸盖菇素（急性后）可改善雌性大鼠的体重维持并促进认知灵活性，特别是通过改善对初始逆转的适应奖励意外事件。此外，我们揭示了通过血清素 (5-HT) 1 A 和 5-HT2A 受体亚型的信号传导在学习的特定方面的参与，证明 5-HT1A 拮抗作用抵消了裸盖菇素的认知增强作用。此外，我们发现裸盖菇素会引起这些受体（分别为Htr2a和Htr1a ）的皮质转录的短暂增加和减少，并且在暴露于 ABA 模型的大鼠中Htr2a转录物的丰度进一步减少。总之，这些发现支持了裸盖菇素可以改善 AN 背景下认知僵化的假设，并强调需要更好地了解独立于 5-HT2A 受体结合的治疗机制。