The orexin/hypocretin system in neuropsychiatric disorders: Relation to signs and symptoms

Hypocretin-1 and 2 (or orexin A and B) are neuropeptides exclusively produced by a group of neurons in the lateral and dorsomedial hypothalamus that project throughout the brain. In accordance with this, the two different hypocretin receptors are also found throughout the brain. The hypocretin system is mainly involved in sleep–wake regulation, but also in reward mechanisms, food intake and metabolism, autonomic regulation including thermoregulation, and pain. The disorder most strongly linked to the hypocretin system is the primary sleep disorder narcolepsy type 1 caused by a lack of hypocretin signaling, which is most likely due to an autoimmune process targeting the hypocretin-producing neurons. However, the hypocretin system may also be affected, but to a lesser extent and less specifically, in various other neurological disorders. Examples are neurodegenerative diseases such as Alzheimer’s, Huntington's and Parkinson's disease, immune-mediated disorders such as multiple sclerosis, neuromyelitis optica, and anti-Ma2 encephalitis, and genetic disorders such as type 1 diabetus mellitus and Prader–Willi Syndrome. A partial hypocretin deficiency may contribute to the sleep features of these disorders.