Abstract

Serotonergic psychedelic drugs, such as psilocin (4-hydroxy-N,N-dimethyltryptamine), profoundly alter the quality of consciousness through mechanisms which are incompletely understood. Growing evidence suggests that a single psychedelic experience can positively impact long-term psychological well-being, with relevance for the treatment of psychiatric disorders, including depression. A prominent factor associated with psychiatric disorders is disturbed sleep, and the sleep-wake cycle is implicated in the homeostatic regulation of neuronal activity and synaptic plasticity. However, it remains largely unknown to what extent psychedelic agents directly affect sleep, in terms of both acute arousal and homeostatic sleep regulation. Here, chronic electrophysiological recordings were obtained in mice to track sleep-wake architecture and cortical activity after psilocin injection. Administration of psilocin led to delayed REM sleep onset and reduced NREM sleep maintenance for up to approximately 3 h after dosing, and the acute EEG response was associated primarily with an enhanced oscillation around 4 Hz. No long-term changes in sleep-wake quantity were found. When combined with sleep deprivation, psilocin did not alter the dynamics of homeostatic sleep rebound during the subsequent recovery period, as reflected in both sleep amount and EEG slow-wave activity. However, psilocin decreased the recovery rate of sleep slow-wave activity following sleep deprivation in the local field potentials of electrodes targeting the medial prefrontal and surrounding cortex. It is concluded that psilocin affects both global vigilance state control and local sleep homeostasis, an effect which may be relevant for its antidepressant efficacy.

Highlights

  • Induction of the psychedelic state depends on the metabolite of psilocybin, psilocin (4-hydroxy-N, N-dimethyltryptamine), which acts as a partial agonist of 5-HT2A receptors [5–7]

  • For most analyses of non-rapid eye movement (NREM) sleep, as indicated, continuous bouts of NREM sleep less than 1 min in duration were excluded, following convention, as full state transition unfolds over this approximate time course [63]

  • During the first hour following injection, the frequency of brief awakenings in NREM sleep was increased by psilocin (Vehicle: 0.60 ± 0.32 min−1; Psilocin: 1.4 ± 0.48 min−1; p = 2.0 ×10−5, n = 8, paired t-test, Fig. 2H). These results suggest that the increased wakefulness produced by psilocin is due to an increased drive to awaken from sleep, corresponding to an impairment of sleep maintenance rather than an enhanced stability of wakefulness

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Summary

Introduction

Induction of the psychedelic state depends on the metabolite of psilocybin, psilocin (4-hydroxy-N, N-dimethyltryptamine), which acts as a partial agonist of 5-HT2A receptors [5–7]. Psychedelics act on 5-HT2A receptors on layer V pyramidal neurones, inhibitory interneurones, and presynaptic thalamocortical afferents across the cortex, most notably prefrontal cortex [8–11], modulating glutamate transmission [12–14] and disrupting neural dynamics and functional networks on a brain-wide scale [15–23]. The challenge remains to dissect which neuronal effects are specific to, and necessarily characteristic of, the psychedelic state [24, 25]. While the evidence demonstrates that psychedelics can induce structural and functional synaptic plasticity in vivo [27–29], facilitate learning and memory [30–32], and exert long-lasting behavioural effects [33, 34] in rodents, the specific underlying neurophysiology remains unclear, especially regarding the relevance to psychiatric disorders in humans

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