Developing Translational Methods for Unlocking the Psychopharmacology of Psilocybin

Abstract

Psilocybin is a psychedelic which has gained attention for its rapid and sustained antidepressant effects, particularly in treatment-refractory patients. However, its therapeutic mechanism of action remains unclear. Preclinical animal studies are critical for understanding the neurobiological mechanisms underlying psilocybin treatment effects and guiding the development of psilocybin and related antidepressants. However, for these studies to be informative, they must be translational. Thus, this thesis aimed to develop and assess translationally valid methods for investigating psilocybin’s antidepressant effects in rodents. Psilocybin was first assessed in two variants of a translationally relevant task assessing cognitive flexibility, the Probabilistic Reversal Learning Task (PRLT). Acutely, 1mg/kg psilocybin appeared to facilitate reward learning in a touchscreen PRLT, but also reduced learning rates and impaired task performance, indicating generalised behavioural disruption. Psilocybin showed no post-acute effects in either PRLT variant, questioning the appropriateness of this assay for assessing sustained psilocybin effects on cognitive flexibility. Next, acute psilocybin effects on regional neuronal activation were assessed using TRAP2 mice. Psilocybin exhibited dose-dependent effects in medial prefrontal cortex, while 3 mg/kg psilocybin increased sensorimotor and claustral activity. The effect of administration route (subcutaneous vs oral) on acute psilocybin modulation of broadband spectral power was then assessed using rodent electroencephalography (EEG). Psilocybin dose-dependently desynchronised cortical oscillatory activity, however cortical synchrony was paradoxically increased following 0.3 and 1 mg/kg oral psilocybin. Finally, psilocybin effects on oxygen dynamics were assessed using constant potential amperometry (CPA). Psilocybin acutely disrupted circuitry involving the prelimbic cortex (PL), amygdala (AMG), and nucleus accumbens core (ACB), which was followed by post-acute changes in PL-ACB connectivity. Ultimately, this thesis demonstrates time-, dose- and route-dependent effects of psilocybin on behaviour and neural activity, while highlighting the translational utility of EEG, CPA, and TRAP2. It also raises important implications for future preclinical development of psilocybin and related compounds.

Date of Award	20 Jan 2026
Original language	English
Awarding Institution	University of Bristol
Sponsors	Compass Pathways plc
Supervisor	Emma S J Robinson (Supervisor), Zuner A Bortolotto (Supervisor) & Gary Gilmour (Supervisor)