Effects of psilocybin microdoses on serotonergic pathways and lipid signaling

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Psilocybin is the primary psychedelic component of hallucinogenic mushrooms. However, details on the mechanism of action specifically, the route of administration of psilocybin are not clear. While oral dosing is common practice with psilocybin, the effects of psilocybin in preclinical studies often varies depending on route of administration which leads to differences in onset of effects, the maximal effects, and the duration of the effect. Secondly, psilocybin research has focused on hallucinogenic doses with which effects are predominantly mediated by activation of serotonin 5-HT2A receptors (5-HT2AR) and inflammatory cytokines. Therefore, it is unknown whether microdoses of psilocybin may elicit differential sets of serotonin receptors in neurons, microglia, and astrocytes and alter brain signaling. This proposal has three major objectives: 1) to comprehensively examine expressions of serotonin receptor families and metabolites in the tryptophan-serotonin pathway after psilocybin injection through four routes of administrations (mouth, vein, abdominal cavity, brain), 2) to compare and contrast the neural networks affected by microdoses of hallucinogenic psilocybin and non-hallucinogenic 5-HT2A receptor agonist, lisuride, and 3) to investigate the effects of microdosing psilocybin on microglial and astrocytic markers of brain inflammation. These studies will build on current understanding of 5-HT2AR-mediated actions of psilocybin and provide critical discovery of novel additional mechanisms mediated by other serotonin receptors after microdosing psilocybin treatments.