Appetite for change: How psilocybin reshapes food reward learning through striatal dopamine function

Psilocybin has emerged as a promising therapeutic agent for psychiatric disorders characterised by cognitive rigidity and disrupted reward processing, including anorexia nervosa. While its pro-cognitive effects have been mechanistically probed almost exclusively through serotonin receptor subtype antagonism, the downstream contributions of dopaminergic systems to these outcomes remain poorly understood. Here, we examined how psilocybin (1.5 mg/kg) modulates striatal dopamine dynamics and cognitive flexibility across multiple operant paradigms in female rats, and whether nutritional state or prior activity-based anorexia (ABA) exposure moderate these effects. Calorie restriction selectively attenuated psilocybin-enhanced reversal learning, shifting the temporal profile of benefit without abolishing it, and was associated with exacerbated nucleus accumbens (NAc) cFos+ expression relative to ad libitum fed animals. In vivo fiber photometry revealed that psilocybin broadly amplified NAc dopamine transients time-locked to expected and unexpected outcomes during probabilistic reversal learning across 7 days. Computational modelling identified psilocybin-specific increases in learning rate and reductions in prior value weighting, consistent with strengthened feedback-driven updating. In touchscreen paradigms, psilocybin enhanced discrimination accuracy and accelerated reversal learning acquisition when administered prior to initial discrimination, but impaired serial reversal accuracy when administered at a later training stage. ABA exposure constrained psilocybin’s pro-cognitive effects, abolishing discrimination accuracy benefits and trending toward worsened reversal learning, likely reflecting ABA-induced reductions in cortical 5-HT2A receptor availability. These findings provide the first direct evidence that psilocybin modulates striatal dopamine prediction error signalling in a behaving animal and demonstrate that nutritional state and prior ABA exposure critically moderate its cognitive effects.