Psychedelic-mediated Reversal of General Anesthesia and Restoration of Brain Dynamics in Rat
Emma R. Huels, Nicholas Kolbman, Christopher W. Fields, Amanda G. Nelson, Hazel Jackson, Tiecheng Liu, George A. Mashour, Dinesh Pal
bioRxiv Preprint Server January 22, 2025 preprint DOI: 10.1101/2025.01.22.632279 via bioRxiv
Summary
A serotonergic psychedelic, DOI, reverses general anesthesia in rats, restoring wakefulness and brain dynamics even while anesthetics continue. DOI triggered behavioral arousal and recovered high gamma functional connectivity and brain network structure. These effects were blocked by a 5-HT2A antagonist, and a non-psychedelic 5-HT2A agonist did not produce similar results. This is the first evidence that a psychedelic can reverse anesthesia and restore normal wakefulness-related brain activity.
Study at a glance
| Design | experimental study |
|---|---|
| Population | rats |
| Key finding | Intravenous DOI reversed general anesthesia in rats, restoring wakefulness and high gamma functional connectivity, effects blocked by a 5-HT2A antagonist. |
Abstract
Serotonergic psychedelics enhance neurophysiological complexity and the repertoire of brain states, whereas general anesthetics produce opposite effects. Serotonergic psychedelics are also known to increase wakefulness and reduce sleep time in rodents. Therefore, we hypothesized that 2,5-dimethoxy-4-iodopamphetamine (DOI), a serotonergic psychedelic, will reverse general anesthesia and restore neurophysiological conditions associated with normal wakefulness. We demonstrate that intravenous administration of DOI in rats under general anesthesia induced wakefulness despite ongoing delivery of the anesthetics, propofol or isoflurane. Behavioral arousal was accompanied by recovery of directional and non-directional high gamma (125-165Hz) functional connectivity and restoration of functional brain network structure. These behavioral and neurophysiological effects were blocked by a 5-HT2A antagonist, volinanserin. Intravenous administration of a non-psychedelic 5-HT2A agonist, lisuride, failed to restore wakefulness or brain dynamics in anesthetized rats. To our knowledge, these results provide the first evidence of psychedelic-mediated reversal of general anesthesia and concurrent restoration of brain dynamics associated with normal wakefulness.