Introduction

Although the past decade has witnessed many advances in the basic science and clinical practice of sleep medicine, perhaps none has been more significant than the discovery of the orexin (also called hypocretin) neuropeptides that are produced in the lateral hypothalamus (LH). Failure of orexin signaling causes narcolepsy–cataplexy in humans and animals. In this chapter, we briefly review current knowledge about orexins and the symptoms of narcolepsy–cataplexy in humans. We discuss the molecular genetic analysis of the narcolepsy–cataplexy syndrome through phenotypic characterization of rodents genetically modified to be deficient in orexins or orexin receptors. These studies point to the mechanisms by which orexins promote arousal and gate sleep in normal animals; they thus have important therapeutic implications for disorders of sleep and wakefulness. We conclude with recent data implicating melanin-concentrating hormone (MCH), a related hypothalamic neuropeptide system, in the modulation of arousal. Orexin and MCH may act in concert to stabilize vigilance states, suggesting a more significant role for the LH in sleep–wakefulness regulation than previously appreciated.

The orexin neuropeptide system

Orexins are two hypothalamically expressed neuropeptide sequences, the gene for which was described concurrently and independently by two groups using different biochemical and genetic approaches (de Lecea, This volume, de Lecea et al., 1998; Sakurai et al., 1998).

Neurochemistry of Sleep and Wakefulness focuses on the actions and interactions of neurotransmitters involved in the control and modulation of the behavioral states that we know as waking and sleeping. It presents results and emerging concepts that in recent years have challenged our understanding about the basic brain systems that are involved in sleep and wakefulness. As might be expected, these new findings are also having an effect on the practice of sleep medicine. In fact, once considered a minor sub-specialty, sleep medicine is developing into a significant and growing area of medicine; and much of this growth can be attributed to improved knowledge about brain neurochemistry and the drugs that have been developed as a result.

Thus, inevitably, the relationship between sleep and the chemistry of neurotransmission has become an area of intense medical, biological, and scientific interest. It seemingly affects all facets of our health and well-being. But this relationship is also complex because it involves fundamental, yet still incompletely understood mechanisms and functions in the brain, most notably the essential difference between sleep and wakefulness. Although this field of research in its current form began with the identification of specific chemical neurotransmitter systems in the brain some forty years ago, we can actually date the beginning of research into sleep neurochemistry to the onset of the twentieth century.