Trends in Neurosciences
Volume 23, Issue 8, 1 August 2000, Pages 359-365
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Review
The hypocretin/orexin ligand–receptor system: implications for sleep and sleep disorders

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Abstract

The molecules originally described as the hypocretins and subsequently as the orexins were initially implicated in the control of food intake. Recent observations implicate this newly-described neurotransmitter system in the sleep disorder narcolepsy and, potentially, in the regulation of normal sleep processes. This article reviews the research that led to the isolation of the hypocretin/orexin peptides, their receptors and the activity of these molecules as we currently understand them. A model is proposed in which the cells that make these peptides might be involved in arousal state control.

Section snippets

Anatomy of the hypocretin/orexin system

The distribution of Hcrt/orexin-containing cells has been described both by in situ hybridization1, 7 and immunohistochemistry, using antibodies against prepro-hypocretin21, Hcrt1/orexin A (22, 23, 24, 25) and Hcrt2/orexin B (23, 26). Hcrt/orexin-containing cells are restricted to the tuberal region of the hypothalamus, specifically within the PFH and dorsomedial hypothalamic nuclei, and the dorsal and lateral hypothalamic areas, which encompass about 1 mm rostrocaudally in the rat brain (Fig. 2

Cellular effects of hypocretin/orexin

The effects of the Hcrt/orexin peptides have been uniformly reported as excitatory to date. The initial paper on the hypocretins demonstrated an excitatory effect of Hcrt2/orexin B on cultured hypothalamic cells using whole-cell patch recordings1. Subsequent studies have shown that, in addition to excitatory effects, Hcrt1/orexin A and Hcrt2/orexin B have neuromodulatory effects at nanomolar concentrations on both GABA- and glutamate-mediated neurotransmission in medial and lateral hypothalamic

Hypocretin/orexin and sleep

The widespread anatomical projections of the Hcrt/orexin neurons suggest that they might be involved in multiple functions. In addition to food intake regulation, the hypocretin/orexin system has been implicated in neuroendocrine40, 45, 46, 47, 48, cardiovascular12, 49 and gastrointestinal50 control, and in water balance51. However, two landmark papers52, 53 strongly indicate that dysfunction of the Hcrt/orexin system can result in the sleep disorder narcolepsy.

Narcolepsy is characterized by

Concluding remarks

Characterization of the discharge pattern of the Hcrt/orexin-containing cells across arousal states will be essential to understand the involvement of these cells in ‘normal’ sleep–wake regulation. Although the model proposed has focused on narcolepsy, it might be applicable to other pathophysiological conditions such as the disrupted sleep characteristic of aged individuals. Given the putative role of hypocretin/orexin in sleep–wakefulness, food intake regulation and other possible

Acknowledgements

The authors thank Jane Ding for preparation of Fig. 1. The authors’ research has been supported by NIH 1 R01HL/MH59658 and 1 R01MH61755.

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