Hypocretin/Orexin System

Abstract

The hypocretins (also called the orexins) are excitatory neurotransmitters produced in a few thousand neurons of the lateral hypothalamus. Two G protein‐coupled receptors for the hypocretins have different distributions within the CNS and differential affinities for the two hypocretin peptides. Hypocretins efferents project to areas within the posterior hypothalamus that are implicated in feeding behaviors and hormone secretion. Hypocretin fibers also project to diverse targets in other brain regions and the spinal cord, including several areas implicated in cardiovascular function and sleep‐wake regulation. Administration of the hypocretins stimulates food intake, affects blood pressure, hormone secretion and locomotor activity, and increases wakefulness while suppressing rapid eye movement (REM) sleep. Narcolepsy is a disorder of the hypocretin system. One aspect of hypocretin activity is the direct excitation of cholinergic forebrain neurons, brainstem monoaminergic REM‐off neurons in the locus coeruleus and dorsal raphe nucleus, and histaminergic tuberomammillary nucleus, which together suppress slow‐wave sleep. The hypocretins also modulate the activity of cholinergic REM‐on neurons in the brainstem, which gate REM entry.