Differential sleep/wake response and sex differences following acute suvorexant, MK‐1064 and zolpidem administration in the rTg4510 mouse model of tauopathy

Abstract

Background and Purpose Transgenic mouse models of tauopathy display prominent sleep/wake disturbances which manifest primarily as a hyperarousal phenotype during the active phase, suggesting that tau pathology contributes to sleep/wake changes. However, no study has yet investigated the effect of sleep‐promoting compounds in these models. Such information has implications for the use of hypnotics as potential therapeutic tools in tauopathy‐related disorders. Experimental Approach This study examined polysomnographic recordings in 6‐6.5‐month‐old male and female rTg4510 mice following acute administration of suvorexant (50 mg·kg−1), MK‐1064 (30 mg·kg−1) or zolpidem (10 mg·kg−1), administered at the commencement of the active phase. Key Results Suvorexant, a dual OX receptor antagonist, promoted REM sleep in rTg4510 mice, without affecting wake or NREM sleep. MK‐1064, a selective OX2 receptor antagonist, reduced wake and increased NREM and total sleep time. MK‐1064 normalised the hyperarousal phenotype of male rTg4510 mice, whereas female rTg4510 mice exhibited a more transient response. Zolpidem, a GABAA receptor positive allosteric modulator, decreased wake and increased NREM sleep in both male and female rTg4510 mice. Of the three compounds, the OX2 receptor antagonist MK‐1064 promoted and normalised physiologically normal sleep, especially in male rTg4510 mice. Conclusions and Implications Our findings indicate that hyperphosphorylated tau accumulation and associated hyperarousal does not significantly alter the responses of tauopathy mouse models to hypnotics. However, the sex differences observed in the sleep/wake response of rTg4510 mice to MK‐1064, but not suvorexant or zolpidem, raise questions about therapeutic implications for the use of OX2 receptor antagonists in human neurodegenerative disorders.

Orexin 2 receptor antagonism sex‐dependently improves sleep/wakefulness and cognitive performance in tau transgenic mice

“…Male and female rTg4510 transgenic mice and wild type (WT) littermate controls were used as previously described (Keenan et al, 2022; Ramsden et al, 2005; Santacruz et al, 2005). In the rTg4510 mouse, tau transgene expression is specifically restricted to the forebrain, via the CaMKII promotor, and can be repressed with doxycycline (Dox; Ramsden et al, 2005; Santacruz et al, 2005).…”

“…For EEG recordings, administration of compounds or vehicle was performed within a time window of 5–15 min before the start of the recording. The doses for suvorexant (Betschart et al, 2013; Hoyer et al, 2013; Keenan et al, 2022) and MK‐1064 (Gotter et al, 2016; Keenan et al, 2022; Roecker et al, 2014) were selected based on previous literature and preliminary in‐house data, as providing efficacious induction of sleep and receptor occupancy for the orexin receptors of ≥90%. Four weeks after treatment initiation, mice in each experiment were surgically implanted with EEG/EMG recording head mounts (Pinnacle Technology Inc., Lawrence, KS, USA).…”

“…Mice were implanted with EEG/EMG preformed head mounts (Catalogue number: #8201‐SS, Pinnacle Technology Inc., Lawrence, KS, USA) as previously described (Keenan et al, 2022). In brief, mice were anaesthetised with isoflurane (5% for induction, 2%–3% for maintenance) in oxygen and placed in a stereotaxic frame.…”

“…Excessive wakefulness (such as in sleep deprivation) increases the extracellular release of Aβ (Bero et al, 2011; Cirrito et al, 2008, 2005; Tabuchi et al, 2015) and tau (Holth et al, 2019; Pooler et al, 2013; Wang et al, 2017; Wu et al, 2016; Yamada et al, 2014). Preclinical data show that Aβ (Bero et al, 2011; Cirrito et al, 2005; Kang et al, 2009; Roh et al, 2012) and tau pathologies (Holth et al, 2017; Holton et al, 2020; Keenan et al, 2022; Koss et al, 2016; Zhu et al, 2018) are associated with reduced sleep and excessive wakefulness (hyperarousal). Common phenotypes include increases in wake and decreases in non‐rapid eye movement (NREM) and rapid eye movement (REM) sleep, and/or highly fragmented sleep with marked increases in sleep/wake transitions.…”

In Vitro and In Vivo Evaluation of Pellotine: A Hypnotic Lophophora Alkaloid

“…a similar effect on locomotion is observed (Figure 6a). 55,56 When applying a one-way ANOVA it is apparent that the effect observed from pellotine (1) is significantly different compared to the saline control. Interestingly, no significant difference between pellotine (1) and zolpidem was observed, suggesting potential hypnotic effects of pellotine (1) in mice.…”