Abstract
Psychedelics hold therapeutic promise for mood disorders due to rapid, sustained results. Human neuroimaging studies have reported dramatic serotonin-2A receptor-(5-HT2AR)-dependent changes in functional brain reorganization that presumably reflect neuromodulation. However, the potent vasoactive effects of serotonin have been overlooked. We found psilocybin-mediated alterations to fMRI-HRFs in humans, suggesting potentially altered NVC. To assess the neuronal, hemodynamic, and neurovascular coupling (NVC) effects of the psychedelic 5-HT2AR agonist, 2,5-Dimethoxy-4-iodoamphetamine (DOI), wide-field optical imaging (WFOI) was used in awake Thy1-jRGECO1a mice during stimulus-evoked and resting-state conditions. While DOI partially altered tasked-based NVC, more pronounced NVC alterations occurred under resting-state conditions and were strongest in association regions. Further, calcium and hemodynamic activity reported different accounts of RSFC changes under DOI. Co-administration of DOI and the 5-HT2AR antagonist, MDL100907, reversed many of these effects. Dissociation between neuronal and hemodynamic signals emphasizes a need to consider neurovascular effects of psychedelics when interpreting blood-oxygenation-dependent neuroimaging measures.
Competing Interest Statement
Author JSS has received consulting fees from Forbes Manhattan. In the past 36 months, author GEN has served as a Co-Investigator or as Principal Investigator for studies funded by COMPASS Pathways, LB Pharmaceuticals, Inc., Usona Institute, and Alkermes, Inc., and has received personal fees as a consultant for Carelon, Novartis and Alkermes, Inc. These potential conflicts of interest have been reviewed and are managed by Washington University School of Medicine. The other authors declare no competing interests. All authors report no financial interest in psychedelics companies.
Footnotes
Inclusion of many new data sets (e.g., non-hallucinogenic, 5-HT2A receptor agonist, Lisuride; arousal measures such as pupil-dynamics) and analysis to support the claim of hallucinogenic, 5-HT2A receptor activity altering neurovascular coupling.
