Psychedelic 5-HT2A receptor agonism alters neurovascular coupling and differentially affects neuronal and hemodynamic measures of brain function.

Human neuroimaging studies report that psychedelics induce serotonin-2A receptor-dependent changes in functional brain reorganization, presumably reflecting neuromodulation. However, these studies often overlook the potent vasoactive effects of serotonin. Here we identified psilocybin-induced alterations in hemodynamic response functions during human functional magnetic resonance imaging, suggesting potential disruptions in neurovascular coupling. We then used wide-field optical imaging in awake Thy1-jRGECO1a mice to determine whether psychedelic-induced changes in hemodynamics arise from neuronal, vascular or neurovascular effects. Exposure to the psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) differentially altered coupling between cortical excitatory neuronal versus hemodynamic activity, both during whisker stimulation and in the resting state. Furthermore, DOI resulted in discordant changes between neuronal-based versus hemodynamic-based assessments of functional connectivity. A selective serotonin-2A receptor antagonist (MDL100907) reversed many of the effects of DOI. Our results demonstrate a dissociation between DOI-induced neuronal and hemodynamic signals, indicating a need to consider neurovascular effects of psychedelics when interpreting blood-based measures of brain function.