CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 8, Issue 4, 2009

Since their discovery in 1998, it has been shown that the orexin (hypocretin) peptides are involved in almost all of the functions historically associated with the lateral hypothalamus. These peptides are produced by only some thousand neurons restricted to the posterolateral hypothalamus. A decade later, the orexin neurons have emerged as an important mode of signalling in the hypothalamus. Orexins were recognized as regulators of feeding behaviour. The subsequent finding that an orexin deficiency causes narcolepsy in humans and animals indicates that these hypothalamic neuropeptides also have a crucial role in regulating sleep and wakefulness. Recent studies of orexin-producing neurons and their efferent and afferent systems, as well as phenotypic characterizations of mice with genetic alterations in the orexin system, have suggested further roles for orexin in the coordination of emotion, energy homeostasis, reward, drug addiction and arousal. In this special issue, we will discuss the role of orexins in sleep-wake regulation and its involvement in narcolepsy.

Kuniomi Ishimori and Henri Piéron were the first researchers to introduce the concept and experimental evidence for a chemical factor that would presumably accumulate in the brain during waking and eventually induce sleep. This substance was named hypnotoxin. Currently, the variety of substances which have been shown to alter sleep includes peptides, cytokines, neurotransmitters and some substances of lipidic nature, many of which are well known for their involvement in other biological activities. In this chapter, we describe the sleep-inducing properties of the vasoactive intestinal peptide, prolactin, adenosine and anandamide.

Regulation of the sleep-waking cycle is complex, involving multiple neurological circuits and diverse endogenous molecules. Interplay among assorted neuroanatomical and neurochemical systems such as acetylcholine, dopamine, noradrenaline, serotonin, histamine, and hypocretin maintain the waking (W) state. The sleep-onset is governed by the interacting forces of the sleep drive, which steadily increases with duration of W, and circadian fluctuations. Sleeppromoting neurons located in the anterior hypothalamus release GABA and inhibit wake-promoting regions in the hypothalamus and brainstem and participate in the generation of slow wave sleep (SWS). During rapid eye movement (REM) sleep, brainstem regions typically inhibited during W and SWS become active. In this regard, ascending projections from cholinergic neurons in the brainstem activate the thalamus which in turn increases the firing of the neurons in the cortex. Finally, sleep-promoting substances that accumulate in the brain during natural or prolonged W implicate a further complexity in the mechanism of modulation of the sleep-wake cycle. This review provides a broad understanding of our present knowledge in the field of sleep research.

Neuroimaging techniques have refined the characterization of neural structures involved in the regulation of normal sleep-wake cycle in healthy humans. Yet brain imaging studies in patients with sleep disorders still remain scarce. In narcoleptic patients, structural and functional brain imaging studies have suggested the involvement of the hypothalamus in the pathophysiology of narcolepsy, plausibly consistent with an impairment of the hypocretin-orexin system. Some recent studies have further suggested that cataplexy, a key feature of the narcoleptic syndrome, might result from a dysfunction of the hypothalamus and its interactions with limbic structures. Other neuroimaging studies have focused on the assessment of neurotransmission and the effects of pharmacological treatment in narcoleptic patients. However, the neural correlates of some main symptoms of narcolepsy, such as sleep attacks, hypnagogic/hypnopompic hallucinations and sleep paralysis, are still unknown. In addition, the description of brain activity patterns during sleep in narcoleptic patients needs further investigation. Neuroimaging has proven to be a valuable tool for the study of sleep regulation and sleep disorders; its future developments will undoubtedly improve our understanding of the neural mechanisms underlying narcolepsy with cataplexy.

REM (rapid eye movement) sleep behavior disorder (RBD) is a well known parasomnia [1]. Its first description in humans dates back to 1985, and its first description in narcoleptic patients to 1992. Although the precise pathophysiology of RBD remains unclear, it is likely, in the case of RBD associated with narcolepsy, that the altered function of hypocretin pathways projecting from the lateral hypothalamus to the ventrolateral part of the periaqueductal grey matter and the lateral pontine tegmentum has a consistent role. The percentage of narcoleptic patients complaining of clinical RBD lies somewhere between 10 and 15% of the narcoleptic population. The age of onset is younger than in the other forms of chronic RBD. Clinical features are the same as in the other forms of chronic RBD, but the frequency of the episodes is less marked. Associated features include other parasomnias, periodic limb movements in sleep (PLMs) and olfactory dysfunction. Polysomnographic tracings are remarkable for elevated submental electromyographic (EMG) tone and/or excessive phasic submental EMG twitching. Data on human leukocyte antigen (HLA) association and on cerebrospinal fluid (CSF) hypocretin/orexin levels are limited. Clinical variants include RBD induced or worsened by pharmacological agents, most of them being used to treat cataplexy, RBD in narcoleptic children and RBD in the context of symptomatic narcolepsy. Several treatments of RBD are available including clonazepam, melatonin and more recently pramipexole. However, in the absence of any pharmacological trials of these drugs on RBD in narcoleptic patients, it is difficult to provide guidance other than to recommend conventional treatments of RBD.

A series of discoveries spanning the last decade have uncovered a new neurotransmitter - hypocretin - and its role in energy metabolism, arousal, and addiction. Also, notably, a lack of hypocretin function has been unequivocally associated with the sleep disorder narcolepsy. Here we review these findings and discuss how they will influence future treatments of narcolepsy and other arousal and hyperarousal disorders. We introduce the concept of the hypocretin peptides and receptors and discuss the neuroanatomy and neurophysiology of the hypocretin system. A gain of function through pharmacolological and optogenetic means is also addressed in the following text, as is the loss of function: specifically narcolepsy in dogs, mice and humans and the challenges currently faced in treatment.

Recent studies have established that the orexin system is a critical regulator of sleep/wake states. Deficiency of orexin signaling results in the sleep disorder narcolepsy-cataplexy in humans, dogs, and rodents. These findings have brought about the possibility of novel therapies for sleep disorders including narcolepsy-cataplexy. Furthermore, accumulating evidence has indicated that the orexin system regulates sleep and wakefulness through interactions with neuronal systems that regulate emotion, reward, and energy homeostasis. This review presents and discusses the current understanding of the integrative physiology of the orexin system.

Narcolepsy is a debilitating sleep disorder with excessive daytime sleepiness and cataplexy as its two major symptoms. Although this disease was first described about one century ago, an animal model was not available until the 1970s. With the establishment of the Stanford canine narcolepsy colony, researchers were able to conduct multiple neurochemical studies to explore the pathophysiology of this disease. It was concluded that there was an imbalance between monoaminergic and cholinergic systems in canine narcolepsy. In 1999, two independent studies revealed that orexin neurotransmission deficiency was pivotal to the development of narcolepsy with cataplexy. This scientific leap fueled the generation of several genetically engineered mouse and rat models of narcolepsy. To facilitate further research, it is imperative that researchers reach a consensus concerning the evaluation of narcoleptic behavioral and EEG phenomenology in these models.

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep-onset rapid eye movement (REM) sleep periods. Narcolepsy is now identified to be a neurodegenerative disease, as there is a massive loss of neurons containing the neuropeptide, hypocretin/orexin. Orexin neurons are solely located in the hypothalamus, particularly in its perifornical, dorsomedial and lateral portions. Orexin fibers widely project throughout the brain and generally have excitatory effects on their postsynaptic cells. Patients with narcolepsy have a severe reduction in the levels of orexins in the cerebrospinal fluid, a finding consistent with orexin neuronal loss. Experimental models have been generated in order to study the physiology of the orexin system and narcolepsy. The discovery of orexin deficiency in narcolepsy is redefining the clinical entity of narcolepsy and offering novel diagnostic procedures. This article reviews the current understanding of narcolepsy and discusses the opportunity to explore the potential use of transplants as a therapeutical tool in order to treat narcolepsy.