“Paradoxical wakefulness” induced by psychedelic 5-methoxy-N,N-dimethyltryptamine in mice

Abstract

Vigilance states - waking, slow-wave sleep (SWS) and paradoxical sleep, are thought to be controlled by several cortical and subcortical neuromodulatory circuits, among which the serotonergic (5-HT) system plays an important role. Recently, serotonergic psychedelics have attracted attention as potent antidepressants. While they are known to induce profound changes in subjective experience, the immediate and delayed effects of psychedelics on classical signatures of sleep-wake states remain under-investigated. To address this, we performed chronic electrophysiological recordings in the cortex of freely moving adult male mice following an injection of a short-acting psychedelic 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). The most noticeable effect of 5-MeO-DMT administration was the suppression of paradoxical sleep and an acute induction of a mixed state of vigilance, characterised instead by prominent SWS-like slow waves on the EEG and LFP in awake, moving animals. We posit that the occurrence of this state in mice, which we refer to as 'paradoxical wakefulness', may be a rodent equivalent of the altered state of consciousness induced by psychedelics in humans.

Deficient synaptic neurotransmission results in a persistent sleep-like cortical activity across vigilance states in mice

“…Yet, these observations start from the premise that sleep and wake are mutually exclusive states between which animals switch in a clear-cut manner, which is now acknowledged to be more complex (Nir and de Lecea, 2023). Indeed, this may not always be the case, as clearly shown by several studies (Bréant et al, 2022;Jang et al, 2022;Vyazovskiy et al, 2007), and states may indeed be viewed on a continuum, with some feature overlap. This is indeed what we see in rlss mice with an intrusion of NREMS-like features in REMS and wake states.…”

“…Just as the occurrence of slow-waves or decreased neuronal activity which have been previously described in waking and not only in sleep (Fisher et al, 2016;Vanderwolf and Robinson, 1981;Vyazovskiy and Tobler, 2012), our findings further support that vigilance states are not necessarily separate phenomena with unambiguous boundaries, but can share characteristics. Such overlapping features may thus fluctuate depending on specific waking behaviour (Fisher et al, 2016), chemical manipulations (Bréant et al, 2022) or genetic alterations (Funato et al, 2016).…”