It is now well known that modern-day children and adolescents get less sleep than the kids in the previous generations (Dollman et al., 2007). The American Academy of Sleep Medicine recommended that adolescents should sleep 8–10 h per night to promote optimum health (Paruthi et al., 2016), but large survey studies conducted by the Youth Risk Behavior Surveys (YRBSs) reported that around 72% of adolescents sleep less than the recommended sleep duration (Wheaton et al., 2018). Excessive use of electronic devices, extended use of screen time at night, early school time, and large school workload have largely contributed to shorter duration of sleep in today’s youth (Hale and Guan, 2015; Woods and Scott, 2016; Gariepy et al., 2020). The reduced weekday sleep time and oversleep over the weekend, to make up for lost sleep during the weekday, are postulated to result in chronic sleep deprivation or “social jetlag” (Seton and Fitzgerald, 2021). The consequences of chronic sleep deprivation on stress response, mood, anxiety, and cognition have been investigated in preclinical (Pires et al., 2012, 2016; Abel et al., 2013; Hirotsu et al., 2015; Villafuerte et al., 2015; Atrooz et al., 2019) and epidemiological settings (Goel et al., 2013; Minkel et al., 2014). Lately, insufficient sleep in adolescent and young adults has been associated with risk behavior and substance use including alcohol, marijuana, and cigarettes (Wong et al., 2010, 2015; Hasler et al., 2012; Kenney et al., 2012; Logan et al., 2018; Kwon et al., 2019, 2020; Hasler and Pedersen, 2020). Sleep deprivation, especially in adolescents, negatively impacts normal behavior, emotion, and attention (Dahl and Lewin, 2002). This seems reasonable as adolescence is a sensitive developmental period and often highly susceptible to anxiety and depression (Costello et al., 2003; Barker et al., 2019), as well as risky behavior such as substance use and abuse (Young et al., 2002; Peiper et al., 2016). The prevalence of adolescent substance use has rapidly increased particularly in the past three decades (Chassin et al., 2004). Alcohol is one of the most commonly used substances among adolescents, followed by marijuana (Gray and Squeglia, 2018).

The adolescence phase is characterized by increased reward-seeking behavior. The brain undergoes significant neurodevelopmental changes occurring between the childhood phase and young adulthood period, which continues until the age of 25 (Pfefferbaum et al., 1994; Giedd, 2004). Human and animal studies both have suggested differential developmental trajectories of limbic reward systems relative to top-down prefrontal control systems during adolescence, with limbic systems developing earlier than prefrontal control regions. According to this model, in emotionally salient situations, the limbic system predominates the prefrontal control systems, thus increasing the engagement in risky behavior during adolescence (Casey et al., 2008). A growing body of evidence suggests that poor sleep may exaggerate the normative maturation imbalance between affective and cognitive control systems, leading to greater risk-taking behaviors in adolescents (Kenney et al., 2012; Telzer et al., 2013), including substance use (McKnight-Eily et al., 2011), yet the underlying mechanism(s) affording such behaviors are not fully understood. Therefore, examining the neurobiological underpinnings which may connect sleep deprivation and substance use during adolescence will be critical for appropriate intervention.

In this study, utilizing our previously established model (Atrooz et al., 2019), we examined the impact of early-life sleep deprivation on alcohol consumption in adolescent rats. We hypothesize that early-life sleep deprivation will increase the reward-seeking behavior in adolescent rats indicated by enhanced voluntary alcohol intake. Male Sprague-Dawley rats at postnatal day (PND) 19 served as either the control (CON) or sleep-deprived (SD) group. Sleep deprivation was induced using a Pinnacle automated sleep deprivation apparatus. The SD group of rats was sleep deprived for 6–8 h/day for 14 days from PND19 to PND32. This developmental period in rats represents childhood and early adolescence stages, which is considered comparable to 2–11 years in human age (Semple et al., 2013). We observed that alcohol consumption increased in rats that were exposed to early-life sleep deprivation as compared to control rats. This study forms the premise for future studies designed to explore the structural and functional determinants of the reward centers of the brain, which may reveal biochemical triggers that connect early-life sleep deprivation with increased reward-seeking behavior and enhanced alcohol consumption in adolescents.

Rats in the SD group exhibited a normal-weight-gain pattern during the sleep deprivation protocol. Weight gain pattern in SD rats was comparable to CON group suggesting that sleep deprivation protocol did not affect body weight-gain and growth in rats, (see Figure 1A).

In this study, we observed that early-life sleep deprivation enhanced alcohol consumption in adolescent rats. This was accompanied with anxiety- and depression-like behaviors in adolescent rats. To our knowledge, our study is the first preclinical model to report the enhancement effect of early-life sleep deprivation on alcohol consumption in adolescent rats. Only one group studied the impact of chronic partial sleep deprivation on alcohol consumption in adolescent rats. The authors reported enhancement of alcohol consumption following sleep deprivation. However, control conditions were also associated with increased alcohol consumption. Hence, the authors could not conclude that there is a causal relationship between sleep deprivation and alcohol consumption (Sequeira, 2015; Khan, 2021). On the other hand, several rodent studies have examined the relationship between sleep deprivation, alcohol consumption, and behavior in adult animals (Aalto and Kiianmaa, 1984; Cowan, 2017). One study conducted in adult rats showed that sleep restriction (4 h/day for 7 days) stimulated alcohol consumption and induced a significant increase in the number of delta FosB-positive cells in the NAc and VTA brain regions, suggesting the increased activity of reward-related circuitry of the brain following prolonged sleep restriction (García-García et al., 2021). Another study conducted in adult rats suggested that REM-sleep deprivation increases alcohol intake and alcohol consumption, which further intensifies REM-sleep deprivation (Aalto and Kiianmaa, 1984). This is not surprising as alcohol is believed to alter sleep homeostasis, inducing insomnia and sleep disruption. Six weeks of ethanol exposure in rats produced persistent diminution in cortical slow-wave power (Ehlers and Slawecki, 2000). Acute sleep deprivation in mice induced a sustained impairment in adenosine-regulated sleep homeostasis, which lasted for 4 weeks and altered the sensitivity to the motor-impairing effects of alcohol (Clasadonte et al., 2014). The results suggested that chronic sleep restriction induced a sustained impairment in adenosine-regulated sleep homeostasis and consequentially impacted the response to alcohol.

Our data suggesting that early-life sleep deprivation leads to anxiety-like and depression-like behaviors in adolescent rats are significant and translationally relevant, as the relationship between affective problems and substance use has been established in several human studies (Valentiner et al., 2004; Wu et al., 2010). Affective problems, such as depression and anxiety, which often emerge during adolescence, are reported to be associated with greater rates of substance use. In fact, chronic sleep deprivation in children and adolescents is believed to increase the risk for mood and behavioral problems such us drug and alcohol use (Johnson and Breslau, 2001; Smaldone et al., 2007; Wong et al., 2010, 2015; Logan et al., 2018). Poor sleep during early life prospectively predicted alcohol-related problems and illicit drug use in adolescents and young adults (Wong et al., 2010, 2015). In a sample of South Korean middle- and high-school students aged 13–18 years, self-rated stress levels and depression were inversely proportional to nocturnal sleep duration. Health risk behaviors such as smoking and alcohol consumption were more common in sleep-deprived students (Lee et al., 2013). Adolescents’ preference for later activity and sleep is associated with greater alcohol involvement (Pieters et al., 2010; Urbán et al., 2011). Furthermore, delayed sleep time was associated with negative outcomes such as lower average school grades, smoking, alcohol use, and elevated anxiety and depression scores in Norwegian adolescents (Saxvig et al., 2012).

Finally, our data are important as they imply that sleep deprivation during developmental stages of early life may be a risk factor for alcohol use in adolescents. A growing body of evidence suggests that exposure to alcohol at early age increases the risk of alcohol dependence and drug addiction in adolescent and young adults (Grant et al., 2006; Hingson et al., 2006). In a 6-year cohort study, alcohol dependence in young adults was preceded by higher persisting teenage rates of frequent drinking (Bonomo et al., 2004). In adolescent rats, intermittent ethanol treatment induced short- and long-lasting cognitive and behavioral deficits and caused prefrontal cortex and hippocampal damage by inflammatory processes (Pascual et al., 2007). The sensitivity of adolescent brain to ethanol exposure involved dopaminergic and glutamatergic neurotransmission, leading to long-lasting abnormal plasticity in reward-related brain regions that could contribute to alcohol addiction (Pascual et al., 2009).

This study is a brief report in which we have established a preclinical model for studying the impact of sleep deprivation on alcohol consumption in adolescent rats. Several aspects are considered for future studies. First, we are interested in examining sex-based differential behavioral responses to early-life sleep deprivation in adolescent rats. Second, understanding resilience and susceptibility to developing dependence, reward-seeking behavior, and behavioral impairments using correlation analysis is a future aim of this project. Third, clarifying brain region selectivity and changes in brain circuitry which controls reward-seeking behavior and associated with enhancement of alcohol consumption is a future aim of this study. This will be conducted using imaging, molecular, and electrophysiological methodologies.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

The animal study was reviewed and approved by Institutional Animal Care and Use Committee (IACUC), University of Houston.

FA and GA conducted the sleep deprivation protocol and the behavior assessment experiments. AH and GA conducted the data analysis. FA wrote the first draft of the manuscript. SS finalized the draft after several layers of edits and iterations by all authors.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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