Central Nervous System mechanisms involved in the sleep-wake cycle.

1. Introduction
Antihistamines are inverse agonists of histaminergic receptors and are commonly used to treat allergic reactions. Histamines are potent inflammatory mediators, which are released from mast cells and basophils upon exposure to allergens. By administering an antihistamine such as chlorphenamine, the binding of histamines to histamine receptors is prevented. As a result, inflammatory signalling pathways mediated by histamines are terminated. However, it was observed that one of the clinical side effects of first generation chlorphenamine was sleepiness (Montoro et al., 2006). Sleep is controlled by the brain and studies have shown that some antihistamines are lipophilictic and can cross the blood brain barrier.

The presence of histamines in the brain was discovered in the 1940s (Haas et al., 2008). The sedative effects of antihistamines and the role of histamines in promoting wakefulness were established at the same time. Most over-the-counter sleeping pills now contain antihistaminergic components such as diphenhydramine and doxylamine. Data from electroencephalography (EEG) has shown that chlorphenamine reduces electrical activity that corresponds to wakefulness whilst enhancing characteristics of deep sleep in rats and dogs (Lin et al., 1996). Despite extensive applications of antihistamines, the precise role of histamine in the sleep-wake cycle controlled by the central nervous system is yet to be fully unveiled. It is now widely believed that histaminergic neurons in the central nervous system have a significant influence on sleep regulation, memory and learning (Passan et al., 2007). Some characteristics of sleep can be observed during the loss of consciousness induced by general anaesthetics. The molecular mechanism of general anaesthetics is believed to involve γ-aminobutyric acid receptor type A (GABAA), which mediates most of the inhibitory pathways in the central nervous system (Franks, 2008). It has been shown that antagonists of non-histaminergic receptors such as serotonergic, orexinergic and dopaminergic receptors can induce sleep, which suggests that wakefulness requires stimulation from various neuromodulators.

The fact that so many substances are implicated in the regulation of sleep and wakefulness indicates the complexity of this regulatory network. Extensive studies have been conducted to investigate the significance and functions of different neuromodulators in controlling the sleep-wake cycle. This review discusses current opinions of the roles of histaminergic neurons in maintaining wakefulness and also the mechanisms responsible for the transition between wakefulness and sleep. Once the interactions between histaminergic neurons and other brain nuclei implicated in the sleep-wake cycle are understood, more effective treatments can be developed for sleeping disorders such as insomnia and narcolepsy.

2. Wakefulness and Sleep
Sleep is a physiological state of rest observed in all mammals. It can be identified by changes in the electrical activities of the brain, recorded by EEG. During a typical night’s sleep, the brain undergoes several cycles of sleep stages that can be broadly divided into rapid-eye movement sleep (REMS) and non-rapid-eye movement sleep (NREMS) (see Figure 1). REMS is characterised by high frequency, low amplitude oscillations, similar to that of the waking stage. Muscle atonia and rapid eye movements are evident during REMS (Purves et al., 2008).

NREMS can be subdivided into four stages (I-IV) according to the frequencies of activity as recorded by EEG. Stage I is the transition state from wakefulness to sleep, when drowsiness or light sleep occurs. The EEG activity at this stage exhibits lower frequency (4-8Hz) but higher amplitude (50-100µV) oscillations. Stage II NREMS is characterised by the presence of spindle activity in the brain. Spindles are higher amplitude bursts of activity (10-12Hz) and are probably due to the synchronization of neurons in the cortex and the thalamus. Stages III and IV represent deep sleep during which EEG frequency is further reduced whilst the amplitude is increased, leading to slow-wave sleep (SWS), characterized by delta waves (0.5-4Hz). It has been suggested that the intense firing of sleep spindles is important for long term plasticity that underlies memory consolidation (Wafford, et al., 2008).

Histamine concentration in the brain has been shown to correlate with different stages of sleep (Takahashi, et al., 2006). The level of histamine in the hypothalamus is the highest when the person is awake and gradually declines as the brain enters deeper sleep states (Strecker et al., 2002). During REMS, histamine is at its lowest level in the brain and, thus, histaminergic neurons are also known as ‘REM-off’ neurons, like other aminergic neurons in the brain. Conversely, ’REM-on’ neurons, such as cholinergic neurons, tend to fire more frequently during REMS, (Rosenwasser, 2009). Studies have shown that histaminergic firing leads to the desynchronization of the cortical EEG observed during the waking period (Luo et al., 2009). However, exactly how histamines cause arousal has not been fully elucidated. It has been postulated that histamines induce wakefulness by prompting the firing of other neurons such as noradrenergic and serotonergic neurons, and it is through the neurotransmission of an orchestra of neurons that the cortex becomes desynchronized (Saper et al.).

3. The Significance of Histamines in the Arousal-Promoting System
Histaminergic neurons are not the sole determinant for the initiation and maintenance of wakefulness. One of the many nuclei that have been implicated in arousal is the noradrenergic nucleus in the locus coeruleus (see Figure 4). Lesions in this area result in reduced wakefulness (Berridge, 2008). As with histaminergic neurons, noradrenergic neurons fire at higher rate during the waking period (Aston-Jones et al., 1981). The activity decreases during NREMS and becomes almost non-existent during REMS. The arousal effects of noradrenaline are mediated by α1- and β- receptors, which are found in several regions of the brain, including the cortex. Noradrenalines are believed to modulate the state of wakefulness by affecting both sleep- and arousal-promoting neurons (Szabadi, 2006). Noradrenergic neurons are reciprocally connected with GABAergic neurons, and are thought to inhibit the inhibitory action of GABA on histaminergic neurons (Mitchel et al., 2010).

Serotonergic neurons located in the dorsal raphe exhibit similar firing pattern to histaminergic neurons (Ursin, 2002) (see Figure 4). When the role of serotonin in the sleep-wake cycle was first identified, it was suggested that serotonergic neurons are sleep-promoting. Lesions in the dorsal raphe of cats resulted in decreased serotonin levels in the brain, and a reduction in sleep was observed. In addition, administration of serotonin receptor 5-HT2B antagonists reduced sleep, demonstrating that serotonins are involved in the induction of sleep (Borbely et al., 1989). However, single unit recordings showed contradicting results; it was demonstrated that serotonergic firing leads to arousal. The waking effect of serotonin is thought to be mediated by 5-HT2A receptors, as increased sleep can be observed when 5-HT2A antagonists are administered (Szabadi, 2006). Although serotonins seem to affect the sleep-wake cycle in different ways, serotonergic neurons, like histaminergic neurons, are characterized as REM-off neurons. The amount of REMS is enhanced in 5-HT1 receptor knockout mice (Fort et al., 2009).

Midbrain dopaminergic nuclei, located in the ventral tegmental area (VTA), have also been implicated in wakefulness (see Figure 4). The alertness effect of amphetamine is believed to be mediated by dopamine release in the brain (Isaac et al., 2006). Also, lesions in the VTA resulted in decreased wakefulness (Miller et al., 2006). However, the firing pattern of dopaminergic neurons is different to that observed in histaminergic, noradrenergic and serotonergic neurons. The activity of dopaminergic neurons does not alter much between wakefulness and sleep. It has thus been suggested that dopamine exerts its arousal effect via the stimulation of other nuclei such as noradrenergic neurons in the LC, which are subsequently connected with histaminergic neurons.

The release of acetylcholine has been shown to be higher during waking and REMS than NREMS. Cholinergic neurons from the basal forebrain project extensively to the cortex (see Figure 4), and have been shown to affect cortical EEG. A high density of histaminergic receptors can be located on these neurons, suggesting that histamines regulate cholinergic release into the cortex. Evidence has shown that the stimulation of histaminergic neurons in the TMN can result in cholinergic release in the hippocampus (Mochizuki et al., 1994). Apart from its contribution to arousal, acetylcholine release has also been shown to induce REMS (Vazquez et al., 2001). Cholinergic neurons from the laterodorsal tegmental nuclei (LDT) and pedunculopontine nuclei (PPT) project into the thalamus. Lesions in the LDT and PPT resulted in reduced REMS in cats, suggesting that these regions are important for the REM-on action of acetylcholine.

The neuromodulators discussed so far – histamine, noradrenaline, serotonin and acetylcholine – are part of the ascending arousal system that also includes a further neuropeptide; orexin. Orexinergic neurons from the lateral hypothalamus innervate all the other neurons in the ascending arousal system (see Figure 4), and some argue that orexins play as important a role as histamines in maintaining wakefulness (de Lecea, 2010). The firing of orexinergic neurons is the highest during periods of wakefulness and decreases in REMS and NREMS (Takahashi et al., 2008). Some functional overlap has been observed between orexinergic neurons and histaminergic neurons, as both seem to coordinate other neurotransmitters in the ascending arousal system. However, recent studies using knockout mice demonstrated the functional difference between orexins and histamines. When orexin was studied in KO mice, the mice exhibited a wake-sleep pattern that is the same as in wild mice, but they had decreased locomotion. Conversely, when HDC was studied, KO mice showed an impaired EEG pattern, but no change in locomotion was observed (Anaclet et al., 2009). It has thus been hypothesized that histaminergic neurons are responsible for cortical activation during wakefulness, whereas orexin mediates the behaviours associated with arousal. This may explain the loss of muscle tone during narcolepsy caused by orexin deficiency. More importantly, orexinergic neurons possess the ability to activate histaminergic neurons in the TMN directly (Eriksson et al., 2001), as orexin 1 (ORX1) and orexin 2 (ORX2) receptors are expressed on histaminergic neurons (Eriksson et al., 2010). The two nuclei appear to regulate each other via H1 and OXR2 signalling pathways (Tsujino et al., 2009). The level of orexin is lowered in H1 KO mice, whilst the level of histamine is reduced in OXR2 KO dogs.

4. Inhibition of Histaminergic Neurons by the Sleep-Inducing System
The state of wakefulness is induced by cortical activation by neuromodulators in the ascending arousal system. In order for the shift in physiological state to occur, further input is required to initiate sleep. It is hypothesized that sleep is the result of the inhibition of the arousal system by GABAergic (γ-aminobutyric acid) neurons (Vincent et al., 1983). As shown by the sedative effect of antihistamines, the blockage of histamines binding to receptors reduces wakefulness. Therefore, it has been postulated that the initiation of NREMS is due to the GABAergic release of histaminergic neurons. Two GABAergic nuclei in the preoptic area (POA) have been identified as sleep-promoting – the ventrolateral preoptic nucleus (VLPO) and the median preoptic nucleus (MnPO) (Uschakov et al., 2006).

Animal models have shown that lesions in the POA result in insomnia, thus establishing the significance of the preoptic area in sleep induction (Lu et al., 2000). The VLPO, which contains GABAergic neurons, has been widely accepted as being a potent sleep-promoting nucleus in the brain. EEG studies have shown that the firing rate of neurons in the VLPO increases just before the appearance of synchronized sleep waves (Sherin et al., 1996). Furthermore, increased c-fos expression is observed in the VLPO during sleep, confirming its high neuronal activity (Gong et al., 2004). The release of GABA in the brain is highly inhibitory. GABA can bind to GABAA or GABAB receptors, leading to different outputs (Purves et al., 2008). Inhibition of histaminergic neurons is believed to be mediated by GABAA receptor binding. GABAA receptors are ionotropic receptors that function as ion channels.

Upon GABA binding, the channel pore opens to allow chloride ions (Cl­-) to flow inwards. Due to the negative charge carried by Cl­- , the post-synaptic membrane potential becomes more negative, which prevents neurons from firing. Large numbers of VLPO projections towards histaminergic neurons is observed, suggesting that the VLPO has the ability to regulate histamine release (Steininger et al., 2001). General anaesthetics enhance the ability of GABAA receptors to conduct chloride ions, either by binding to allosteric sites or acting as agonists (Franks, 2008). Perhaps the mechanism by which anaesthetics exert their sedative effects is by increasing the entry of chloride ions into histaminergic neurons in the TMN, inhibiting the excitatory effects of histamine on the cortex.

As well as GABAergic neurons, studies have shown that the VLPO contains neurons that release a sleep-activating neuropeptide known as galanin (Gaus et al., 2002). There are three types of galanin receptors – GALR1, GALR2 and GALR3, which are found throughout the central nervous system. The GALR1 receptor subtype is more abundant than the other two and is found in the posterior hypothalamus, the dorsal raphe and the locus coeruleus (Mitsukawa et al., 2008). Galanin receptors are G-protein coupled receptors, which mediate different downstream signalling pathways. The binding of galanin has been related to the activation of potassium channels, which allows potassium to flow outwards, leading to decreased membrane potential (Bedecs et al., 1995). Moreover, galanin receptor activation can inhibit adenylyl cyclase and its subsequent signalling, preventing depolarisation. Research has shown that an intravenous injection of galanin enhances sleep; this effect is likely due to the hyperpolarizing action of galanin on histaminergic neurons (Sherin et al., 1998).

The projections of sleep-promoting neurons in the VLPO extend into other neurons in the ascending arousal system (see Figure 5). Results of tracer histochemistry have shown that the VLPO innervates not only the TMN, but also the locus coeruleus and the dorsal raphe, containing noradrenergic and serotonergic neurons, respectively (Xu et al., 1998). A few projections from the VLPO were also observed on orexinergic neurons located in the lateral hypothalamus (Szymusiak et al., 2007). The simultaneous release of GABA and/or galanin from the VLPO into arousal-inducing neurons interrupts the co-operativity within the ascending arousal system. It remains unclear whether the cortical synchronization observed during sleep is the direct result of VLPO activation or whether it is due to the inhibition of arousal inputs.

More recently, the MnPO has been found to contain sleep-promoting neurons that are also GABAergic. The activity of GABAergic neurons in the MnPO increases during NREMS and REMS, but gradually decreases over a long period of NREMS (Suntsova et al., 2002). Similar to the VLPO, the MnPO also projects to neurons involved in wakefulness, including noradrenergic neurons in the locus coeruleus and serotonergic neurons in the dorsal raphe (Zardetto-Smith et al., 1995). However, no direct connection between the MnPO and histaminergic neurons found in the TMN has been elucidated. GABAergic neurons in the MnPO have been shown to innervate GABAergic and galanergic neurons in the VLPO (Uschakov et al., 2007). Perhaps the MnPO functions as a sleep-inducer, preventing the GABAergic and galaninergic neurons from inhibiting the VLPO itself. The VLPO can thus fire and release GABA and galanin into arousal neurons, resulting in the down-regulation of wakefulness.

Although the inhibitory functions of the VLPO and the MnPO seem plausible for sleep induction, they are not the only sources of inhibitory neuromodulators. In 1983, the presence of GABAergic neurons was discovered in the posterior hypothalamus. Further evidence showed that GABAergic neurons are co-localized with histaminergic neurons in the TMN (Trottier et al., 2002). Additionally, a low concentration of galanin in the TMN has also been reported (Kukko-Lukjanov et al., 2003). However, it remains unclear whether the release of GABA and galanin by neurons in the TMN is for inhibiting histaminergic neurons or for regulating other arousal neurons interconnected with the TMN.
5. Treatment potential of of Antihistamine

Sleep is very important. It is thought that during sleep, memory processing, body restoration and development occurs. Stress and many other environmental and genetic factors may affect the quality of sleep and lead to chronic sleep disorders such as insomnia and hypersomnia. The busy modern lifestyle has resulted in a large proportion of the population experiencing symptoms of sleep disorders, mainly insomnia (Horne, 2010).

Insomnia is characterized by the inability to fall asleep or to maintain extended periods of sleep (Bonnet et al., 2010). It can have a significant impact on normal body functions and mental health. Benzodiazepines such as diazepam are currently the most common treatment for insomnia (Van Dort et al., 2008). Benzodiazepines are allosteric enhancers of GABAA receptors in the central nervous system (Harrison, 2007). We have seen that the two key sleep-promoting nuclei, the VLPO and the MnPO, both contain neurons that release GABA as neurotransmitters. Additionally, GABAA receptors have been found across the arousal system with particular emphasis on histaminergic neurons. In the presence of benzodiazepines, GABA can bind more effectively to GABAA receptors on histaminergic neurons, and the conductance of negative chloride ions is increased. This causes a decrease in the membrane potential of histaminergic neurons, which prevents the release of excitatory histamines to the cortex. It is postulated that treatments containing benzodiazepine have a sedative effect due to the actions of histaminergic neurons. If this is the case, perhaps more effective treatments can be developed by targeting the histaminergic system directly.

Although all current antihistamines on the market target the H1 receptor signalling pathway, the therapeutic possibilities of H2 and H3 receptor pathways should also be considered. Experimental data has shown that the H3 antagonist, ciproxifan, can enhance wakefulness in mice, and this positive effect is likely to be mediated by the action of the H1 receptor signalling pathway (Huang et al., 206). The increase in wakefulness observed when ciproxifan was administered, is eliminated in H1 knockout mice, but not in H2 knockout mice. This is possibly due ciproxifan binding to the H3 receptor, blocking feedback signalling to sustain the release of histamines. It also demonstrates that the binding of histamines to H1 receptors is essential for the induction of wakefulness. One of the H3 receptor antagonists used in clinical trials is tiprolisant, which was developed to treat another sleep disorder known as narcolepsy (Sander et al., 2008). Narcoleptic patients suffer from excessive daytime sleepiness (EDS), and may experience sudden loss of muscle tone. The symptoms of narcolepsy can severely impact patients’ quality of life. Currently, the most common treatment of narcolepsy is modafinil, which is believed to affect orexin receptors. Unlike modafinil, tiprolisant promotes wakefulness by interfering with the H3 autoreceptor and heteroreceptor. Animal studies have shown that the administration of tiprolisant can result in full cortical activation, and hence maintain arousal (Lin et al., 2008). Tiprolisant may also up-regulate other neurotransmitters regulated by the H3 heteroreceptor, such as dopamine and acetylcholine. Phase II clinical trials of tiprolisant showed a significant decrease in EDS observed in narcoleptic individuals, but without any adverse effects on locomotor activity that is apparent with the use of modafinil (Lin et al., 2008).

Many potential targets exist for the treatment of sleep disorders due to the complexity of the sleep-wake regulatory network. However, targeting a single neuromodulator may cause imbalances within the network and also influence other behaviours, as shown by the side-effects of benzodiazepines and modafinil. Although histaminergic neurons can be an attractive target for novel treatments, some pharmaceutical companies have adopted dual-targeting strategies. For example, Eli Lily is developing a compound that targets both serotonin (5HT2A) receptors and histamine H1 receptors (Wafford et al., 2008). Further evidence and assessment are required to prove the efficacy of this type of approach.

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