Glutamate (Glu) is the main excitatory neurotransmitter in vertebrate brain and GABA is the main inhibitory neurotransmitter. Brain excitability and arousal level therefore depend on the dynamic interplay between Glu and GABA activity: excitability can be lowered by increasing GABA or by decreasing Glu tone. Despite a vast literature on the reduction of arousal and the induction of sleep by GABAergic drugs, Glu has remained relatively neglected. The reason for this unequal treatment is obvious. Drugs that depress brain excitability by stimulating the GABA–benzodiazepine receptor have been extraordinarily useful as hypnotics and short-term anesthetics, and new ones are being constantly developed. However, diminishing returns have now begun to affect the hegemony of the GABAergic hypnotics. Their well recognized limitations include tachyphyllaxis, addiction, and withdrawal syndromes with life-threatening convulsions. Moreover, they induce a sleep pattern with a non-physiological electroencephalogram (EEG) that is typically experienced as non-refreshing. It may thus now be a propitious time to manipulate the other side of the excitation–inhibition equation and examine Glu in more detail. Altering brain excitability by enhancing or depressing Glu transmission could lead to the development of drugs with unique and perhaps more favorable clinical profiles. The discussion in this chapter illustrates the basic science and the clinical potential of this alternative approach.

Introduction

The functional states of the central nervous system are determined not only by the inputs received from the external world but also by internally generated electrical and chemical signals. These internally generated signals are responsible for the generation of the states we call sleep and wakefulness and for the transition between states. Neurons generate electrical signals as a result of the uneven distribution of ions across their cell membranes and the passage of ions through pores (ion channels) in these membranes. Neurotransmitters (chemical signaling molecules) are released from the processes of neurons and affect the electrical signaling of target neurons (or muscles) by opening ion channels themselves or by modulating ion channels via second messenger systems. The electrical properties of neurons involved in the control of rapid eye movement (REM) sleep and wakefulness will be described separately. Here we focus on the localization and neurochemistry of neurotransmitters involved in the control of these states.

A variety of different methodologies has been employed to investigate the neurotransmitter systems involved in control of behavioral states. Biochemical experiments have elucidated the pathways and enzymes involved in the synthesis, degradation, release and reuptake of different neurotransmitters. Immunohistochemical techniques have allowed the visualization of their cellular and subcellular distribution throughout the nervous system as well as the distribution of their receptors and uptake systems.

Dopamine is the most abundant of monoamines in the central nervous system (CNS). It modulates diverse behaviors including movement, motivation/reward, cognition, and feeding that share one notable attribute in common: they all play out on a backdrop of wakefulness (Bjorklund and Lindvall 1984; Marin et al. 1998; Durstewitz et al. 1999; Williams and Goldman-Rakic 1998). Dopamine's influence(s) upon normal and pathologic wake–sleep has unfortunately only recently begun to receive more widespread attention. The rebirth of interest in dopamine's participation in wake–sleep behaviors comes straight from the clinical arena. Here, sleepiness has been noted to be a common and disabling feature attending midbrain dopamine cell loss in Parkinson's disease (PD), as well as with dopamine agonist treatment of PD and additional disorders that interfere with normal sleep such as restless legs syndrome, and periodic leg movement and rapid eye movement sleep disorders (Rye 2004a,b; Rye and Jankovic 2002). Although this clinical experience argues that dopamine signaling is integral to maintaining wakefulness, a complete understanding is only beginning to emerge from recent scientific inquiries. What follows is a comprehensive account of the current state of knowledge of the brain's dopamine pathways as it pertains to their modulation of normal and pathologic wake–sleep state(s).

Abstract

Aserinsky & Kleitman (1953) identified within sleep a physiological state that expresses several signs apparently similar to those that occur during wakefulness. This state was termed rapid eye movement (REM) sleep. REM sleep may play a significant role in maintaining normal physiological functions, as its loss has serious detrimental psychopathological effects. The mechanism of REM sleep regulation is still unknown. The pontine cholinergic and noradrenergic transmissions in the brain undergo reciprocal variations in activity associated with the transformation from non-REM sleep to a REM sleep state and vice versa. The cessation of noradrenergic neuronal firing in the locus coeruleus (LC) plays a crucial role in the regulation of REM sleep. Disinhibition of the LC neurons may result in increased levels of noradrenaline (NA) in the brain, and this increased brain NA is likely to be responsible for the pathophysiological effects associated with REM sleep deprivation. Based on recent findings, we discuss the modulation as well as the role of LC neurons and NA in the modulation of REM sleep and the pathophysiological conditions associated with its deprivation. We propose that LC NA neurons are negative executive neurons for the regulation of REM sleep.

Introduction

One of the important characteristics of living beings is to alternate between active and rest phases, but the underlying mechanism/s and functions are not yet known.

Introduction

Sleep substances

The humoral theory of sleep regulation, the concept that sleep and wakefulness are induced and regulated by a hormone-like chemical substance rather than by a neural network, was initially proposed by Kuniomi Ishimori of Nagoya, Japan, and independently and concurrently by the French neuroscientist Henri Piéron of Paris, in the first decade of the twentieth century. They took samples of cerebrospinal fluid (CSF) from sleep-deprived dogs and infused them into the brains of normal dogs. The recipient dogs soon fell asleep. Thus these researchers became the first to demonstrate the existence of endogenous sleep-promoting substances. However, the chemical nature of these sleep substance(s) was not identified. During the following 90 years, more than 30 so-called endogenous sleep and wake substances were reported by numerous investigators to exist in the brain, CSF, urine, and other organs and tissues of animals. For example, delta-sleep-inducing peptide, muramyl peptides, uridine, oxidized glutathione, and vitamin B12 have been proposed as endogenous somnogenic substances. The detailed account of these substances is described in an excellent treatise by Inoué (1989). During the early 1980s, Professor Jouvet and his colleagues in Lyon also found a sleep-inducing factor produced by the periventricular structures including the choroid plexus in the central nervous system (CNS) of cats (Bobillier et al., 1982; Jouvet et al., 1983).

Introduction

The importance of peptide transmitters in the modulation of sleep and wakefulness has become apparent in recent years. Previous work had focused on the role of monoamines in the circuitry that regulates the transitions between states of vigilance. Histaminergic neurons in the tuberomammillary nucleus are known to be key players in the activation of subcortical afferents during wakefulness (Wada et al., 1991). Activity of noradrenergic neurons in the locus coeruleus correlates with the state of vigilance (Jones, 1991). The role of serotonergic neurons in rapid eye movement (REM) sleep has also been established (Lydic et al., 1987; Monti & Jantos, 1992; Fabre et al., 2000).

In spite of major advances in our understanding of the neuronal circuits that govern the sleep–wakefulness cycle (Pace-Schott & Hobson, 2002), the cell groups involved in the coordination of the different stages of sleep and in the control of the boundaries between sleep states are poorly understood. The development of molecular markers that define neuronal cell groups with distinct physiological properties is expected to enhance our understanding of the regulation of the states of vigilance.

With this in mind, the search for molecular markers that define populations of neurons in areas important for arousal is clearly warranted.

Paradoxical sleep: the early years

In 1959, Michel Jouvet and François Michel discovered in cats a phase of sleep characterized by a complete disappearance of the muscle tone, and paradoxically associated with a cortical activation and rapid eye movements (REM) (Jouvet & Michel, 1959). In view of its singularity, they proposed to call this state paradoxical sleep (PS). It corresponded to REM sleep, the state described in 1953 by Aserinsky and Kleitman and that correlates with dream activity in humans (Aserinsky & Kleitman, 1953; Dement & Kleitman, 1957). In view of the occurrence of muscle atonia, Jouvet proposed that PS was a distinct sleep state and a true vigilance state independent of slow wave sleep (SWS) and waking (W). Over the 40 years following its discovery, Jouvet and co-workers pursued the study of PS. Supporting the theory of the duality of sleep, they showed that PS, in contrast to SWS, was present in mammals and birds but absent from amphibians and reptiles. Jouvet also demonstrated that PS onset and maintenance depended upon structures different from those regulating SWS and W. He first showed that PS persists after decortication, after cerebellar ablation or transections of the brainstem rostral to the pons. In contrast, transections at the posterior limit of the pons suppressed PS (Jouvet, 1962a).

Summary

Wakefulness is a prerequisite for survival and is accompanied by an ensemble of other behaviors. Thus, the brain contains multiple and grossly redundant systems controlling wakefulness: the histaminergic system is one of them. The histaminergic system in the central nervous system (CNS) is exclusively localized within the tuberomammillary nucleus (TMN). It consists of histamine-containing neurons that innervate almost all the major regions of the CNS, including the spinal cord. Within the CNS, histamine mediates its effects via three G-protein coupled metabotropic receptors: the H1, H2, and H3 receptors. Of these three receptors, the H3 receptor functions as an autoreceptor and regulates the synthesis and release of histamine. The histaminergic system, like other monoaminergic systems, is implicated in the regulation of sleep–wakefulness. It has been suggested that TMN neurons are under inhibitory control of the sleep-inducing ventrolateral preoptic GABAergic neurons and induce wakefulness by activating the wakefulness-promoting cholinergic neurons of the basal forebrain via the H1 receptor. Although the bulk of evidence is derived from pharmacological studies, numerous electrophysiological and biochemical studies also support the role of histamine in wakefulness.

Electrophysiological evidence suggests that the histaminergic neurons, like other monoaminergic neurons, have their highest discharge during wakefulness. Biochemical evidence also suggests that histamine release in the TMN and other target regions is highest during wakefulness.

Isolation of sleep factors from animals: historical perspectives

The concept of sleep factors stemmed from the commonplace observation that prolonged wakefulness makes people more sleepy. This led to the idea that, during wakefulness, an endogenously occurring sleep-inducing substance may accumulate in the body and this, in turn, would foster sleep. The first experiments addressing this hypothesis were performed independently in Japan by Ishimori (Ishimori 1909) and in France by Legendre and Piéron (Legendre and Piéron 1910, 1912) at the beginning of the twentieth century. In both series of experiments, cerebrospinal fluid (CSF) or serum of sleep-deprived dogs induced increased sleep in recipient animals. This suggested to the French scientists the accumulation of a “hypnotoxin” during wakefulness.

The quest for a key endogenous substance, the action of which is solely or mainly responsible for sleep, continued well into the 1980s. The heroic early era of endocrinology that yielded the discovery of key hormones that regulate various aspects of homeostasis, growth, and reproductive functions, also greatly influenced sleep research. Repeated attempts were made to try to identify and isolate the key hormone that may be responsible for sleep regulation. Schnedorf and Ivy successfully replicated the experiments of Legendre and Piéron 30 years later (Schnedorf and Ivy 1939).

Introduction

The timing and amount of sleep is regulated by two main processes in order to optimize for the survival of the individual. A circadian process, driven by the internal clock in the brain, facilitates wakefulness at those times of the day when activity and foraging are possible, and facilitates sleep at those times when it is dangerous to leave the abode, or difficult to find nourishment. A homeostatic process ensures that the proper amount of sleep is acquired, according to the specific needs of the species and the individual. Insufficient sleep will cause “sleep pressure”, which is expressed in increased propensity for sleep. If sleep is delayed, e.g. by activity, the accumulating sleep pressure will eventually result in “recovery sleep”, characterized by increased duration and intensity, when sleep is again possible. To some extent the opposite is true: previous oversleeping may reduce sleep pressure to reduce sleep time. The interaction between these processes to regulate wake–sleep behavior has been formulated in Borbély's two-process theory (Borbély, 1982), the main tenet of which is still valid today. Adenosine has been shown to play a part in the homeostatic process, and this chapter will review that role.

As early as in 1909, it was recognized that some chemical factor in the brain was responsible for recovery sleep.