Wake-promoting and sleep-suppressing actions of hypocretin (orexin): basal forebrain sites of action

Neuroscience. 2001;106(4):699-715. doi: 10.1016/s0306-4522(01)00319-0.


The hypocretins (orexins) are a newly identified peptide family comprised of two peptides, hypocretin-1 and hypocretin-2. Recent observations suggest an involvement of these peptides in the regulation of behavioral state. For example, these peptides are found in a variety of brain regions associated with the regulation of forebrain neuronal and behavioral activity states. Furthermore, when infused into the lateral ventricles in awake animals, hypocretin-1 elicits increased duration of waking beyond that observed in vehicle-treated animals. Previous studies have been limited to an examination of the sleep-wake effects of hypocretin-1 in awake animals. Currently, the sleep-wake effects of hypocretin-2 and the extent to which hypocretins can initiate waking in the sleeping animal remain unclear. To better characterize the wake-promoting actions of the hypocretins, the current studies examined the sleep-wake effects of varying doses (0.007, 0.07 and 0.7 nmol) of hypocretin-1 and hypocretin-2 when administered into sleeping rats (e.g. remote-controlled infusions). Infusions of hypocretin-1 and hypocretin-2 into the lateral ventricles elicited a short latency (0.7 nmol hypocretin-1; 93+/-30 s from the start of the 120-s infusion) increase in electroencephalographic, electromyographic, and behavioral indices of waking. These infusions also produced substantial decreases in slow-wave and rapid-eye movement sleep. Hypocretin-1 was more potent than hypocretin-2 in these actions. Interestingly, hypocretin-1 infused into the fourth ventricle elicited less robust waking which occurred with a longer latency than infusions into the lateral ventricles. These latter observations suggest a forebrain site of action participates in hypocretin-1-induced waking. Within the forebrain, a variety of basal forebrain structures, including the medial preoptic area, the medial septal area and the substantia innominata, receive a moderate hypocretin innervation. Therefore, additional studies examined the sleep-wake effects of bilateral hypocretin-1 infusions into these basal forebrain structures. Robust increases in waking were observed following infusions into, but not outside, the medial septal area, the medial preoptic area and the substantia innominata. These results indicate a potentially prominent role of hypocretins in sleep-wake regulation via actions within certain basal forebrain structures and are consistent with studies indicating a prominent role of hypocretins in sleep/arousal disorders.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology
  • Carrier Proteins / pharmacology*
  • Dose-Response Relationship, Drug
  • Electroencephalography / drug effects
  • Electromyography / drug effects
  • Fourth Ventricle / drug effects
  • Fourth Ventricle / physiology
  • Immunohistochemistry
  • Injections, Intraventricular
  • Intracellular Signaling Peptides and Proteins*
  • Lateral Ventricles / drug effects
  • Lateral Ventricles / physiology
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Muscle Contraction / drug effects
  • Muscle Contraction / physiology
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neuropeptides / pharmacology*
  • Orexins
  • Preoptic Area / cytology
  • Preoptic Area / drug effects
  • Preoptic Area / metabolism
  • Prosencephalon / cytology
  • Prosencephalon / drug effects*
  • Prosencephalon / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Septal Nuclei / cytology
  • Septal Nuclei / drug effects
  • Septal Nuclei / metabolism
  • Sleep / drug effects*
  • Sleep / physiology
  • Substantia Innominata / cytology
  • Substantia Innominata / drug effects
  • Substantia Innominata / metabolism
  • Wakefulness / drug effects*
  • Wakefulness / physiology


  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Neuropeptides
  • Orexins