Psilocybin exerts distinct effects on resting state networks associated with serotonin and dopamine in mice.

Psilocybin, a serotonin 2A receptor agonist, alters functional connectivity across the mouse brain in two distinct ways: it increases connectivity between serotonin-associated networks and cortical areas including the default-mode network, thalamus, and midbrain, while decreasing connectivity within dopamine-associated striatal networks. These opposing effects, observed in lightly-anesthetized mice using resting-state fMRI, suggest that interactions between serotonin- and dopamine-regulated neural networks contribute to psilocybin's neural and psychological effects. The findings also demonstrate how gene expression maps and viral tracer projection fields can help interpret pharmaco-fMRI results.

Study at a glance

Abstract

Hallucinogenic agents have been proposed as potent antidepressants; this includes the serotonin (5-HT) receptor 2A agonist psilocybin. In human subjects, psilocybin alters functional connectivity (FC) within the default-mode network (DMN), a constellation of inter-connected regions that displays altered FC in depressive disorders. In this study, we investigated the effects of psilocybin on FC across the entire brain with a view to investigate underlying mechanisms. Psilocybin effects were investigated in lightly-anaesthetized mice using resting-state fMRI. Dual-regression analysis identified reduced FC within the ventral striatum in psilocybin- relative to vehicle-treated mice. Refinement of the analysis using spatial references derived from both gene expression maps and viral tracer projection fields revealed two distinct effects of psilocybin: it increased FC between 5-HT-associated networks and cortical areas, including elements of the murine DMN, thalamus, and midbrain; it decreased FC within dopamine (DA)-associated striatal networks. These results suggest that interactions between 5-HT- and DA-regulated neural networks contribute to the neural and therefore psychological effects of psilocybin. Furthermore, they highlight how information on molecular expression patterns and structural connectivity can assist in the interpretation of pharmaco-fMRI findings.