Psychedelic 5-HT2A receptor agonism: neuronal signatures and altered neurovascular coupling.

Abstract Psychedelics are promising therapeutics for mood disorders due to their rapid, sustained results. These effects rely on serotonin (5-hydroxytryptamine) receptor agonism, especially at the 2A receptor (5-HT2AR). Human neuroimaging studies have reported dramatic 5-HT2AR-dependent changes in functional brain reorganization that presumably reflect neuromodulation. However, the potent vasoactive effects of serotonin have not been considered. We assessed neuronal, hemodynamic, and neurovascular coupling (NVC) effects of the psychedelic 5-HT2AR agonist, 2,5-Dimethoxy-4-iodoamphetamine (DOI), using wide-field optical imaging (WFOI) in awake Thy1-jRGECO1a mice during stimulus-evoked and resting-state conditions. While DOI mildly 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.