The Orexin/Hypocretin System provides an overview of all the recent exciting discoveries in the field as well as new findings such as ligand replacement and gene therapies in the animal models of narcolepsy. Several contributions cover sleep and the multiple systems involved in its regulation.

Includes supplementary material: sn.pub/extras

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Orexin/hypocretin research began in 1998, as a result of the discovery of a new hypothalamic neuropeptide. In 1999, it was found that mutations in the orexin/ hypocretin-related genes caused a sleep disorder (narcolepsy) in dogs and mice. These findings were soon followed by the discoveries of orexin/hypocretin ligand deficiency in human narcolepsy. The finding of the major pathophysiological mechanisms of human narcolepsy resulted in its reclassification as a neurological, not a psychiatric, disorder. The - portance of early diagnosis and initiation of treatment for human narcolepsy has been repeatedly emphasized because the disease typically starts around puberty (when social and school influences become important). Orexin/hypocretin de- ciency in narcolepsy subjects can be detected clinically in cerebrospinal fluid (CSF) orexin/hypocretin measures (low CSF orexin/hypocretin levels are strongly asso- ated with narcolepsy cataplexy among various neurologic and sleep disorders). Thus, the CSF orexin/hypocretin measurements are expected to be included as a diagnostic test for narcolepsy cataplexy in the second revision of international di- nostic criteria (ICSD). This positive diagnostic test is very useful for establishing an early diagnosis for narcolepsy cataplexy, and many patients will likely receive im- diate benefits. Cerebrospinal orexin/hypocretin measurements are also informative for the nosological classification of hypersomnia. Because orexin/hypocretin de- ciency is observed in most human narcolepsy cataplexy, orexin/hypocretin repla- ment therapy is now a promising new choice for the treatment of human narcolepsy, and research in this area is actively in progress.

Inhalt
History.- History and Overview of Orexin/Hypocretin Research.- Overview of the Orexin/Hypocretin Neuronal System.- Orexin and Orexin Receptors.- Orexin Projections and Localization of Orexin Receptors.- Neuronal Responses to Hypocretin/Orexin.- Afferent System of Orexin Neurons.- Assessment of Orexin/Hypocretin Functions in Tissue and Biological Fluids.- Hypocretin Measurements in the CSF, and Blood and Brain Tissue.- Hypocretin Receptor-Activated G Proteins Revealed by [35S]GTP?S Autoradiography.- Physiology.- Orexin System and Feeding Behavior.- Orexins and the Autonomic Nervous System.- Neuroendocrine Role of the Orexins (Hypocretins).- The Orexin/Hypocretin System and Stress and Emotion.- Physiology.- Hypocretin as a Wakefulness Regulatory Peptide.- Hypocretin/Orexin Tonus and Vigilance Control.- Hypocretin System and Aminergic and Cholinergic Systems in the Control of Vigilance.- Orexin and Hypothalamic Control of Sleep and Waking.- Hypocretin/Orexin and Motor Function.- Pathophysiology: Narcolepsy and Orexin/Hypocretin Deficiency.- Overview of Human Narcolepsy.- Canine Models of Narcolepsy.- Rodent Models of Human Narcolepsy-Cataplexy.- Pathophysiology: Narcolepsy and Orexin/Hypocretin Deficiency.- Hypocretin Deficiency in Human Narcolepsy.- Hypocretin Status in Neurological Disorders in Relation to Excessive Sleepiness and Cataplexy.- Hypocretin Measures in Psychiatric Disorders.- Neuroendocrinology of Human Narcolepsy.- Narcolepsy and Autoimmunity.- Pathophysiology: Narcolepsy and Orexin/Hypocretin Deficiency.- Pharmacology of Hypocretin/Orexin Peptides and Small Molecules.- Rescue of Narcoleptic Orexin Neuron-Ablated Mice by Ectopic Overexpression of Orexin Peptides.- Hypocretin/Orexin Replacement Therapy in Hypocretin/Orexin-Deficient Narcolepsy.