A commentary on the neurobiology
of the hypocretin/orexin system

Mignot E.
Stanford Center for Narcolepsy,
Department of Psychiatry and Behavioral Sciences,
1201 Welch Road, P-114, 94305-5485,
Palo Alto, CA, USA
Neuropsychopharmacology 2001 Nov; 25(5 Suppl 1):S5-S13


Hypocretins/orexins are rapidly emerging as functionally important neurotransmitters. Two related neuropeptides (Hcrt-1/OXA, Hcrt-2/OXB) encoded by the same precursor gene and two G-protein coupled receptors (Hcrtr1/OXR1, Hcrtr2/OXR2) are currently known. Hypocretin-containing cells are discretely localized within the perifornical hypothalamus but have widespread projections, with generally excitatory postsynaptic effects. Dense excitatory projections to all monoaminergic cell groups have been reported. A major emerging function for this system is likely to be the regulation of sleep. Alterations in hypocretin neurotransmission causes the sleep disorder narcolepsy in mice, dogs and humans. Effects on appetite, neuroendocrine and energy metabolism regulation are also suggested by other studies. Hypocretins are uniquely positioned to link sleep, appetite and neuroendocrine control, three behaviors of major importance in psychiatry. The potential role of this system in regulating the sleep cycle, modulating wakefulness at selected circadian times and in mediating the deleterious effects of sleep deprivation is discussed.

Orexin A
The sleep-switch
Modafinil: structure
Modafinil and serotonin
Modafinil and the aviator
Modafinil and the marmoset
Modafinil: pharmacokinetics
Orexins to treat narcolepsy
Modafinil as an antidepressant
Orexins and forebrain cholinergic neurons
Modafinil, narcolepsy-catalepsy and orexin neuropeptides
Mood-lifting effect of caloric restriction is mediated by orexin