The primary source of NE (also known as noradrenaline) in the brain is the LC in the pons of the brainstem. There is a linear relationship between neuronal firing in the LC and NE release (Berridge, & Abercrombie, 1999). LC neurons fire at the highest rate during wake, to a lesser extent during NREM, and are essentially inactive throughout REM sleep (Aston-Jones, & Bloom, 1981; Foote, Aston-Jones, & Bloom, 1980). A considerable body of animal experiments has demonstrated the NE action of the LC in promoting behavioral and EEG indices of wakefulness and arousal (Berridge, & Arnsten, 2013). Infusion of NE or NE agonists into the forebrain increases wakefulness (Berridge, Isaac, & Espana, 2003). There are three major receptor types, α₁, α₂, and β, that mediate the actions of NE. Blocking α2 receptors increases activity in the LC and promotes wakefulness (Berridge, & Foote, 1991; De Sarro, Ascioti, Froio, Libri, & Nisticò, 1987), whereas α1 and β antagonists increases NREM sleep (Berridge, & Espana, 2000). It is thought that anomalies with the NE system may contribute to the inability to fall or stay asleep associated with insomnia (Reyes, Carvalho, Vakharia, & Van Bockstaele, 2011).

Further to the involvement of NE in sleep/wake, it is also associated with the level of arousal during wake, and appears to be most prominent for highly salient stimuli and stress-related arousal. A precise level of NE is essential for optimal prefrontal cortex functioning, in a similar manner to dopamine. NE levels exhibit an inverted U-shaped dose response on arousal whereby low levels lead to sleepy and inattentive behavior, where levels that are too high generate anxious and distractible behaviors (Stahl, 2013). This has led to the proposal that the LC may stimulate arousal in a manner that optimizes attention and task performance (Aston-Jones, & Cohen, 2005). For example, experiments in monkeys show that LC neurons fire in a particular pattern for stimuli that represent a reward but not to irrelevant stimuli (Aston-Jones, Rajkowski, Kubiak, & Alexinsky, 1994), and a lesion in the LC in rats leads to lower behavioral signs of arousal and less cortical activation to novel stimuli (Gompf et al., 2010). NE dysregulation is thought to play a critical role in ADHD, in particular with the high-level cognitive deficits. Stimulant ADHD medication, such as methylphenidate (MPH), increases dopamine signaling through multiple actions and also increases NE availability (Wilens, 2008). While some nonstimulants like atomoxetine also impact both dopamine and NE neurotransmission, others such as the guanfacine, increase NE neurotransmission with no impact on dopaminergic signaling. Alpha_2A agonists, including guanfacine and clonidine, are also effective treatments for ADHD, and have a more specific mechanism of action than stimulants. The effects of NE-modulating pharmacotherapies on ADHD symptoms are thought to possibly stem from intermediary effects on cognition (Chamberlain, Robbins, & Sahakian, 2007).

Dopamine plays a role in the regulation of a variety of behavioral and physiological processes including motor function, reward, and cognition. Dopaminergic neurons pertinent to the arousal in the brainstem are found primarily in the SN and VTA. These nuclei have many interconnections with other nuclei in the brainstem as well as the LH, thalamus, and basal forebrain. Compared to most other nuclei in the ascending arousal system, the firing activity of dopaminergic neurons does not dramatically alter between states of wake and sleep, rather their firing has a temporal pattern associated with different actions including reward, locomotion, and cognition (Le Moal, & Simon, 1991; Schultz, 2007). Despite the firing rate, extracellular levels of dopamine are highest during wake and lower during NREM sleep (Trulson, 1985). How exactly dopamine neurons foster arousal in unclear, although the wake-promoting action of dopamine is apparent. It is clear that stimulant drugs promote wakefulness by increasing dopamine release and minimizing its reuptake by that dopamine transporter (Wisor et al., 2001). Deficiencies in DA, such as in Parkinson’s disease and via drugs that block dopamine receptors, leads to sleepiness (Rye, 2004).

Dopamine is suggested to play a key role in regulating neuronal noise (Winterer, & Weinberger, 2004). The inverted U-shaped function of dopamine is similar to that of NE whereby an ideal level must be maintained in order to optimize performance. Too low or too high a level leads to an impaired signal-to-noise ratio, resulting in inattention and impeding task performance (Stahl, 2013). An influential model of catecholamine actions suggests the prefrontal cortex is regulated by a reciprocal relationship between NE (increases signals) and dopamine (reduces noise) (Arnsten, & Rubia, 2012). Relevant salient stimuli cause increased NE stimulation of alpha_2A receptors to enhance the signal in the prefrontal cortex, while irrelevant detracting stimuli detected as noise cause dopamine to be released, bind with the D₁ receptor to gate out inappropriate inputs (Stahl, 2013).

Dopamine is probably the most obvious candidate when addressing the neurobiological overlap between sleep and ADHD, as dysregulation of dopamine is the prevailing hypothesis attributed to the behavioral and cognitive deficits seen in ADHD (Castellanos, & Tannock, 2002; Solanto, 2002; Swanson et al., 2000). MPH is a psychostimulant medication used in the primary treatment of ADHD. Despite its prominent use and efficacy, little is known about the mechanisms of action and the effect on brain function. A large body of research has examined the MPH effects on subcortical dopaminergic structures that are thought to mediate the cognitive and behavioral outcomes, with MPH increasing dopamine concentrations by blocking 60%–70% of striatal dopamine transporters (Volkow, Fowler, Ding, Wang, & Gatley, 1998).

There is some evidence that ADHD medications affecting the dopaminergic system may lead to sleep disturbances, however the finding are mixed. Some studies report that stimulants increase sleep latency and shorten sleep duration (Galland, Tripp, & Taylor, 2010; Stein, 1999). Lee et al. (2012) report that these negative effects are not related to the type of MPH preparation or dosage within the therapeutic range. However, there are studies that report that MPH does not affect negatively sleep latency or total sleep time (Ashkenasi, 2011) and may even reduce night time wakening (Kim et al., 2010).

Serotonin plays a role in a number of emotional, cognitive, and behavioral control processes (Cools, Roberts, & Robbins, 2008) including appetite, mood, anxiety, and sleep/wake behavior. Serotonin is produced by neurons in the DRN and innervate structures including the preoptic area, basal forebrain, hypothalamus, and thalamus. These neurons fire at high rates during wake, less during NREM sleep, and are lowest during REM sleep (Trulson, & Jacobs, 1979). Its exact role in arousal is not very clear as it acts via a number of mechanisms, binding to at least 15 different receptors (Espana, & Scammell, 2011).

Banerjee and Nandagopal (2015) reviews whether serotonin deficit may mediate susceptibility to ADHD. There is some suggestion of lower blood serontonin levels in hyperactive ADHD children (Coleman, 1971; Spivak et al., 1999); reduced binding capacity of serotonin transporter (Oades, 2008); and an ADHD risk polymorphism in the serotonin transporter promoter, 5HTTLPR (Gadow et al., 2013). There are behavioral and neurochemical studies the suggest that MPH has effects on the serotonergic system (Kuczenski, & Segal, 1997; Molina-Carballo et al., 2013; Volkow, Gatley, Fowler, Wang, & Swanson, 2000), and that it can modulate activity in the DR nucleus (Kharas, Whitt, Reyes-Vasquez, & Dafny, 2017). There is also some suggestion that atomoxetine not only binds to the NE transporter, but also binds to serotonin transporter with high affinity (Ding et al., 2014).

Overall, at present the evidence linking serotonin and ADHD is not strong however it is proposed that some of the effects seen may be via serotonin’s interaction with the dopaminergic system (Oades, 2008).

Although only a small nucleus, the TMN in the posterior hypothalamus is the sole source of histamine in the brain and projects all over the central nervous system. Similar to the pattern for NE and serotonin, TMN fires most and releases more histamine during wakefulness, is lower during NREM and lowest during REM (Ko, Estabrooke, McCarthy, & Scammell, 2003).

Of the different types of histamine receptor, there is pharmacological support that H1 and H3 receptors (but not the H2 receptors) play an essential role in promoting wakefulness (Thakkar, 2011). Anyone who has ever taken an antihistamine for allergies will be aware that they can make you sleepy. Antihistamines, such as a histamine H1-receptor antagonist (which reduce histamine signaling) increases both NREM and REM sleep (Tasaka, Chung, Sawada, & Mio, 1989). Inversely, administration of histamine or a H1-receptor agonist increases cortical arousal and decreases both NREM and REM sleep (Lin, Sakai, & Jouvet, 1988; Monti, Pellejero, & Jantos, 1986). Individuals with narcolepsy or hypersomnia have reduced histamine levels (Kanbayashi et al., 2009), and H3 antagonists have been shown to improve their daytime sleepiness (Bonaventure et al., 2007; Ligneau et al., 2007; Lin et al., 2008). The exact features of arousal that histamines enact upon have not yet been elucidated however, evidence from mouse research suggests that histamine may play a role in initiating arousal (Parmentier et al., 2002).

Histamine also has several other functions in the brain including promoting immunity, memory and learning, cognition, feeding behavior, and locomotion (Haas, Sergeeva, & Selbach, 2008). Recently, histamine has been raised as a potential candidate to promote ADHD-like behavior. In a rat model of ADHD, hyperlocomotion, impulsivity, and attention deficits were shown to normalize with a histamine H3-receptor antagonists (Kim, Goto, & Lee, 2018). Further, there is evidence from rodent research that both MPH and atomoxetine medications used in the treatment of ADHD, may improve cognition via increases in histamine (Horner, Johnson, Schmidt, & Rollema, 2007; Liu et al., 2008).

There has been some suggestion that perhaps environmental risk factors for ADHD, such as food additives, may be mediated via histamine. Given meta-analytic evidence that artificial food colors have a small (effect size 0.2) albeit significantly adverse impact on ADHD symptoms (Schab, & Trinh, 2004), the suggestion that artificial colors result in histamine release (Murdoch, Lessof, Pollock, & Young, 1987; Supramaniam, & Warner, 1986) and that genetic polymorphisms in the histamine N-methyltransferase (HNMT) impair histamine clearance (Preuss et al., 1998), Stevenson et al. (2010) examined whether the effect of food additives on ADHD symptoms is moderated by genetic differences. In their double-blind, placebo-controlled crossover trial, they found a link between histamine and ADHD symptoms, with variations in genes influencing the action of histamine moderating behavioral responses to food additives (Stevenson et al., 2010).

Part of the arousal system that has one of the most potent effects on maintaining wakefulness is the orexin/hypocretin pathway. Orexin/hypocretin neurons fire chiefly during wake and are silent during NREM and REM sleep (Lee, Hassani, & Jones, 2005). If injected into the brain, orexin/hypocretin heightens arousal and suppresses NREM and REM sleep (Espana, Baldo, Kelley, & Berridge, 2001). Similarly, orexin/hypocretin antagonists reduce sleep latency and REM and NREM sleep time (Brisbare-Roch et al., 2007; Scammell, & Winrow, 2011). Orexin/hypocretin antagonists also reduce motor impulsivity (Gentile et al., 2018).

Orexin/hypocretin is a neuropeptide produced primarily in the hypothalamus and innervates the VTA, DRN, LC, and TMN (Peyron et al., 1998) mediating arousal, and reward processing via the monoamine transmitters (Borgland, Ungless, & Bonci, 2010; Cortese, Konofal, & Lecendreux, 2008; Harris, Wimmer, & Aston-Jones, 2005; Sakurai, 2014). The most compelling evidence for the role of orexin/hypocretin in preventing sleep is in cases on narcolepsy where people suddenly collapse into sleep. Narcoleptics have almost complete (roughly 90%) loss of their orexin/hypocretin neurons and very low levels in the cerebral spinal fluid (Peyron et al., 2000; Thannickal et al., 2000). It is therefore thought that orexin/hypocretin neurons have a critical role in stabilizing wake (Lu, & Zee, 2010), acting as an anchor for the flip-flop switch (see Fig. 13.2).

Narcoleptics with this orexin/hypocretin deficiency also exhibit deficits in sustained attention (Fronczek, Middelkoop, van Dijk, & Lammers, 2006; Ha, Yoo, Lyoo, & Jeong, 2007), the alerting attention network (Filardi et al., 2017) and slower and more variable reaction times (Bayard, Croisier Langenier, Cochen De Cock, Scholz, & Dauvilliers, 2012; Rieger, Mayer, & Gauggel, 2003), similar to cognitive deficits in ADHD. Narcoleptics also demonstrate higher levels of both inattentive and hyperactive ADHD symptoms (Filardi et al., 2017).