Psychedelic-mediated Reversal of General Anesthesia and Restoration of Brain Dynamics in Rat

A serotonergic psychedelic, DOI, can reverse general anesthesia and restore wakefulness in rats, even while anesthetics like propofol or isoflurane continue to be delivered. Behavioral arousal was accompanied by recovery of high gamma functional connectivity and restoration of brain network structure. These effects were blocked by a 5-HT2A antagonist, volinanserin, and a non-psychedelic 5-HT2A agonist, lisuride, failed to produce similar results. This provides the first evidence of psychedelic-mediated reversal of general anesthesia and concurrent restoration of brain dynamics associated with normal wakefulness.

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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.