Psychedelic 5-HT2A receptor agonism: neuronal signatures and altered neurovascular coupling.
Xiaodan Wang, Jonah A. Padawer-Curry, Oliver J. Krentzman, Chao‐cheng Kuo, Annie R. Bice, Ginger E. Nicol, Abraham Z. Snyder, Joshua S. Siegel, Jordan G. Mccall, Adam Q. Bauer
bioRxiv (Cold Spring Harbor Laboratory) September 24, 2023 preprint DOI: 10.1101/2023.09.23.559145 via OpenAlex
Summary
AI-generated from the abstractPsychedelics show promise for treating mood disorders, but their effects on brain blood vessels have been overlooked. Psilocybin altered hemodynamic response functions in humans, suggesting changes in neurovascular coupling (NVC). Using wide-field optical imaging in awake mice, the psychedelic DOI (a serotonin-2A receptor agonist) partially altered task-based NVC but caused more pronounced NVC changes during rest, especially in association brain regions. Calcium and hemodynamic signals gave different accounts of resting-state functional connectivity under DOI. Co-administration with a 5-HT2A antagonist reversed many effects. The dissociation between neuronal and hemodynamic signals highlights the need to consider neurovascular effects when interpreting fMRI measures in psychedelic studies.
Study at a glance
| Characteristics | Experimental study |
|---|---|
| Population | Awake Thy1-jRGECO1a mice |
| Interventions | 2 5-Dimethoxy-4-iodoamphetamine (DOI) MDL100907 |
| Topics | Serotonin |
| Keywords | Neuroimaging Neuroscience Agonist Periaqueductal gray Brainstem |
| Citations | 9 |
| Key finding | The psychedelic DOI alters neurovascular coupling in awake mice, with stronger effects during rest than during tasks, and calcium and hemodynamic signals report different resting-state functional connectivity changes. |
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.