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Wakefulness benefits of Hypocretin (Orexin)


Below is a great abstract from a study that looked at the specific actions of hypocretin (orexin) in relation to wakefulness and the suppression of sleep.  The two key findings of the study were that hypocretin-1 and hypocretin-2 increase wakefulness in awake rats as well as increasing the vital signs associated with becoming awake in sleeping rats.  For the more science-inclined, the study also found that frontal brain structures played a part in the mechanisms of wakefulness.



What this means for the bigger picture


The positive links drawn between hypocretin and wakefulness are in keeping with current research and will add to a body of knowledge that can potentially combat sleep disorders such as narcolepsy.  The study will also likely lead to further research into the role of frontal brain structures in wakefulness and arousal.




The study was limited in scope and only involved rats, meaning there are dozens of variables to consider before parallels can be drawn between this study and human application.


So what does this have to do with Modafinil?


Although there is no current consensus as to the mechanisms through which Modafinil acts, a prevailing theory is that it “induces expression in orexinergic neurons.”[i] In other words, Modafinil may work by enhancing orexin (hypocretin) function.  Since this study shows that orexin is linked to wakefulness, it goes a long way to suggesting that orexin expression is a significant method through which Modafinil acts.


Lastly, since narcolepsy has been linked to the autoimmune destruction of orexingeric neurons in dog[ii] and mice[iii] studies, Modafinil could potentially offer a treatment for narcolepsy through countering this effect.


Further Reading


For more info, check out this study regarding how hypocretins could potentially provide a “novel therapeutic approach to the treatment of narcolepsy.


As well as this mice-based study by the University of Texas Midwestern.


See below for the complete abstract.



Wake-promoting and sleep-suppressing actions of hypocretin (orexin): basal forebrain sites of action
Espana RA, Baldo BA, Kelley AE, Berridge CW.
Neuroscience 2001;106(4):699-715


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.


[i] Scammell TE, Estabrooke IV, Mccarthy MT, et al. “Hypothalamic arousal regions are activated during modafinil-induced wakefulness.” J Neurosci. 2000;20(22):8620-8.

[ii]  Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, Qiu X, de Jong PJ, Nishino S, Mignot E (Aug 1999). "The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene". Cell 98 (3): 365–76. doi:10.1016/S0092-8674(00)81965-0PMID 10458611.

[iii] Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y, Fitch TE, Nakazato M, Hammer RE, Saper CB, Yanagisawa M (Aug 1999). "Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation". Cell 98 (4): 437–51. doi:10.1016/S0092-8674(00)81973-X.PMID 10481909.