The influence of oxytocin-based interventions on sleep-wake and sleep-related behaviour and neurobiology: A systematic review of preclinical and clinical studies

Highlights

• Oxytocin (OXT) interventions can influence sleep-wake behaviour and neurobiology.

• Preclinically, OXT system activation exerts wake-promoting effects at higher doses.

• Clinically, OXT seems to exert no or minor sleep-promoting effects at doses tested.

Abstract

The oxytocin (OXT) system has garnered considerable interest due to its influence on diverse behaviours. However, scant research has considered the influence of oxytocin on sleep-wake and sleep-related behaviour and neurobiology. Consequently, the objective of this systematic review was to assess the extant preclinical and clinical evidence for the influence of oxytocin-based interventions on sleep-wake outcomes. The primary search was conducted on 22/7/2020 using six electronic databases; 30 studies (19 preclinical, 11 clinical) were included based on inclusion criteria. Studies were evaluated for risk of bias using the SYRCLE tool and the Cochrane risk of bias tools for preclinical and clinical studies, respectively. Results indicated manipulation of the OXT system can influence sleep-wake outcomes. Preclinical evidence suggests a wake-promoting influence of OXT system activation whereas the clinical evidence suggests little or no sleep-promoting influence of OXT. OXT dose was identified as a likely modulatory factor of OXT-induced effects on sleep-wake behaviour. Future studies are necessary to validate and strengthen these tentative conclusions about the influence of OXT on sleep-wake behaviour.

Introduction

Sleep is a fundamental component of mammalian life (Siegel, 2005); continued survival is contingent upon sleep (Everson et al., 1989) and humans themselves tend to spend approximately 1/3 of their lives asleep (Aminoff et al., 2011). Sleep can be conceptualised as a rapidly reversible state of immobility, reduced neurophysiological arousal and behavioural responsiveness to environmental stimuli, whereas wakefulness involves high levels of arousal and activity for optimal environmental interaction (Joiner, 2016; Siegel, 2005). However, sleep is by no means a passive process; sleep plays a critical role in a multitude of physiological and psychological processes such as memory consolidation (Rasch and Born, 2013), waste metabolite homeostasis within the brain (Xie et al., 2013), and mood regulation (Vandekerckhove and Cluydts, 2010; Yoo et al., 2007). Furthermore, deficits in sleep exert an array of deleterious effects: attentional impairment, emotional lability, hyperalgesia, and dysfunction in metabolic, cardiovascular and immunological physiology (as reviewed by Joiner, 2016). Sleep problems are highly prevalent—in an Australian sample, an estimated 33−45% of adults reported experiencing inadequate sleep (duration or quality) followed by consequent impaired daytime functioning, 20% reported experiencing significant insomnia, and 8% reported experiencing diagnosed sleep apnoea (Adams et al., 2017). When the broad-spectrum importance of sleep for health is considered in conjunction with the high prevalence of sleep disturbance in society, it is evident there is a need to further understand sleep behaviour and its complex neurobiology in order to address this substantial public health concern.

Oxytocin (OXT) is a neuropeptide synthesised in the mammalian hypothalamus, predominantly within the paraventricular nucleus (PVN) and supraoptic nucleus (SON) (Althammer and Grinevich, 2018; Swaab et al., 1975). Aside from the classical peripheral endocrine functions of this peptide—uterine contractions during parturition and milk-ejection during lactation—oxytocin exerts diverse central effects on behaviour and neurobiology (for review, see Jurek and Neumann, 2018). Briefly, OXT plays a crucial role in social behaviours (e.g. pair-bonding, social interaction, aggression, and sexual behaviour; Donaldson and Young, 2008; Insel, 2010); modulates responses to stress and fear (Beurel and Nemeroff, 2014; Knobloch et al., 2012; Neumann and Landgraf, 2012); and influences processes of learning and memory (Engelmann et al., 1996; Sarnyai and Kovács, 2014), feeding and satiety (Sabatier et al., 2013), pain and nociception (Rash et al., 2014), and addiction-related behaviours (Bowen and Neumann, 2017, 2018; McGregor and Bowen, 2012). Based primarily on its role in stress-attenuation and its neurobiological proximity to sleep and arousal neurocircuitry, a putative role for oxytocin in sleep-wake behaviour has been posited on occasion within the literature (Lancel et al., 2003; Troxel, 2010). However, despite the growing body of literature exploring the neurobehavioural effects of OXT, little research has investigated the influence of OXT on sleep-wake behaviour and neurobiology.

A greater understanding of the influence that OXT exerts on sleep behaviour and neurobiology holds implications across various domains. Firstly, while sleep research has traditionally focused on sleep at the level of the individual, sleep in numerous species also takes place in the context of co-sleeping, occurring in dyads (i.e., humans) or in larger groups (Troxel, 2010). Alongside sleep itself, the plural context of co-sleeping also involves affiliative behaviours (e.g., huddling, physical intimacy, sexual intercourse) that can facilitate social bonding, pair-bonding, and feelings of safety and security (Troxel, 2010). Given the critical role OXT plays in attachment, affiliative and sexual behaviours (Argiolas and Melis, 2004; Campbell, 2008; Carter, 1992; Lim and Young, 2006; Ross and Young, 2009), OXT could also play a largely unexplored role in sleep behaviour and neurobiology (Troxel, 2010). Secondly, at present, OXT-based therapeutics are under investigation as treatments for a range of conditions; clinical trials have explored the use of intranasal (IN) OXT for autism spectrum disorder (ASD), pain, frontotemporal dementia, anxiety disorders, substance addiction and relapse (see clinicaltrials.gov). Additionally, novel therapeutics that aim to activate oxytocin receptors in the brain far more effectively than IN OXT are currently under development (Gulliver et al., 2019). Notably, as sleep disturbances have also been implicated in the aforementioned conditions (Finan et al., 2013; Kelly et al., 2011; McCarter et al., 2016; Rash et al., 2014; Richdale and Schreck, 2009; Valentino and Volkow, 2020), the effects of therapeutics targeting the OXT system on sleep may serve to improve or exacerbate existing symptomology, contributing to the overall clinical efficacy and tolerability of treatments. Lastly, alongside psychological treatments for sleep disorders (e.g. cognitive behavioural therapy for insomnia (CBT-I); Edinger et al., 2001), pharmacological therapeutics (i.e. hypnotics or wake-promoting drugs) are a common avenue for treating disordered sleep-wake behaviour (Krystal, 2020). While current first-line hypnotics (e.g., benzodiazepines and non-benzodiazepine Z-drugs) demonstrate efficacy for acute sleep-promotion, they can induce adverse side-effects (i.e. residual daytime sleepiness; Pagel and Parnes, 2001), and their continued use can lead to rapid tolerance to hypnotic effects, impaired sleep, and the development of dependency (as reviewed by Dresler et al., 2014). Similarly, some current wake-promoting medications (e.g., stimulants) for alleviating symptoms of excessive daytime drowsiness can also induce problems of dependence and withdrawal (Mitler and O’Malley, 2005). Consequently, a substantial need exists for the development of novel improved medications with improved safety, tolerability and efficacy (Saper and Scammell, 2013) for treating disordered sleep-wake behaviour, which will likely depend upon research into sleep physiology (Dresler et al., 2014) and potentially interrelated neural systems (e.g. the endogenous OXT system).

To the authors’ best knowledge, no review has yet been conducted examining the influence of OXT-based interventions on sleep-wake and sleep-related behaviour and neurobiology. As such, the objective of this review was to systematically assess the extant experimental preclinical and clinical literature for the impact of OXT-based interventions on sleep-wake and sleep-related outcomes. On this basis, this review aimed to answer the following research questions: (1) can oxytocin-based manipulations influence sleep-wake behaviour, and (2) what factors likely modulate any influence on sleep-wake behaviour?