The brain hypocretins and their receptors: mediators of allostatic arousal

Current Opinion in Pharmacology

Volumn 9, Issue 1, 2009, Pages 39-45

  Carter, Matthew E ^a   Borg, Jana Schaich ^a   de Lecea, Luis ^a  

^a STANFORD UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 (2 METHYL 6 BENZOXAZOLYL) 3 (1,5 NAPHTHYRIDIN 4 YL)UREA; ACT 078573; ALMOREXANT; HORMONE RECEPTOR BLOCKING AGENT; MODAFINIL; NEUROPEPTIDE; OREXIN 1 RECEPTOR; OREXIN 2 RECEPTOR; OREXIN A; OREXIN B; UNCLASSIFIED DRUG;

ADDICTION; ALLOSTASIS; BRAIN REGION; CELL NUCLEUS; CELL POPULATION; COGNITION; DRUG APPROVAL; DRUG TARGETING; FOOD AND DRUG ADMINISTRATION; FOOD INTAKE; HUMAN; HYPOTHALAMUS; INSOMNIA; NARCOLEPSY; NERVE CELL; NONHUMAN; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN SECRETION; RECEPTOR BINDING; REVIEW; REWARD; SATIETY; SLEEP WAKING CYCLE; STRESS; WAKEFULNESS;

ALLOSTASIS; ANIMALS; AROUSAL; HOMEOSTASIS; HUMANS; HYPOTHALAMUS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; NEUROPEPTIDES; RECEPTORS, G-PROTEIN-COUPLED; RECEPTORS, NEUROPEPTIDE; STRESS, PHYSIOLOGICAL; WAKEFULNESS;

EID: 59349089712     PISSN: 14714892     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.coph.2008.12.018     Document Type: Review

References (54)

1. Lin L., Faraco J., Li R., Kadotani H., Rogers W., Lin X., Qiu X., de Jong P.J., Nishino S., and Mignot E. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98 (1999) 365-376
2. Chemelli R.M., Willie J.T., Sinton C.M., Elmquist J.K., Scammell T., Lee C., Richardson J.A., Williams S.C., Xiong Y., Kisanuki Y., et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98 (1999) 437-451. These two studies were the first to indicate that dyregulation of the Hcrt system is sufficient to cause narcolepsy. These seminal publications greatly increased our understanding of the cause of narcolepsy and sleep disorders and also discovered a crucial role for the Hcrts in the maintenance of wakefulness and arousal.
3. Hara J., Beuckmann C.T., Nambu T., Willie J.T., Chemelli R.M., Sinton C.M., Sugiyama F., Yagami K., Goto K., Yanagisawa M., et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30 (2001) 345-354
4. Nishino S., Ripley B., Overeem S., Lammers G.J., and Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355 (2000) 39-40
5. Thannickal T.C., Moore R.Y., Nienhuis R., Ramanathan L., Gulyani S., Aldrich M., Cornford M., and Siegel J.M. Reduced number of hypocretin neurons in human narcolepsy. Neuron 27 (2000) 469-474
6. Sakurai T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci 8 (2007) 171-181. An excellent review on the Hcrt system and the important role of Hcrts in mediating sleep/wake transitions.
7. Saper C.B., Scammell T.E., and Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature 437 (2005) 1257-1263. An excellent review on the subcortical regulation of sleep and circadian rhythms by brainstem and hypothalamic nuclei. A model is proposed, the 'flip/flop' model of sleep regulation, with Hcrt neurons playing a key role in maintaining wakefulness.
8. de Lecea L., Kilduff T.S., Peyron C., Gao X.-B., Foye P.E., Danielson P.E., Fukuhara C., Battenberg E.L.F., Gautvik V.T., Bartlett II F.S., et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 95 (1998) 322-327
9. Sakurai T., Amemiya A., Ishii M., Matsuzaki I., Chemelli R.M., Tanaka H., Williams S.C., Richardson J.A., Kozlowski G.P., Wilson S., et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and g protein-coupled receptors that regulate feeding behavior. Cell 92 (1998) 573-585. These two studies were the first to discover the Hcrt system, identifying the peptides, their expression in the lateral hypothalamus, their receptors, and their neuroexcitatory activity.
10. Heinonen M.V., Purhonen A.K., Mäkelä K.A., and Herzig K.H. Functions of orexins in peripheral tissues. Acta Physiol 192 (2008) 471-485
11. Yoshida K., McCormack S., Espana R.A., Crocker A., and Scammell T.E. Afferents to the orexin neurons of the rat brain. J Comp Neurol 494 (2006) 845-861
12. Henny P., and Jones B.E. Innervation of orexin/hypocretin neurons by GABAergic, glutamatergic or cholinergic basal forebrain terminals evidenced by immunostaining for presynaptic vesicular transporter and postsynaptic scaffolding proteins. J Comp Neurol 499 (2006) 645-661
13. Ohno K., and Sakurait T. Orexin neuronal circuitry: role in the rgulation of sleep and wakefulness. Front Neurodendocrinol 29 (2008) 70-87
14. Peyron C., Tighe D.K., van den Pol A.N., de Lecea L., Heller H.C., Sutcliffe J.G., and Kilduff T.S. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18 (1998) 9996-10015. This study used immunohistochemistry to map the efferent projections of Hcrt-expressing neurons. Based on the diffuse projections to many different nuclei, the authors speculate that Hcrts must be involved in many physiological functions, especially a role in the sleep/wake cycle.
15. Lang M., Bufe B., De Pol S., Reiser O., Meyerhof W., and Beck-Sickinger A.G. Structural properties of orexins for activation of their receptors. J Peptide Sci 12 (2006) 258-266
16. Kelz M.B., Sun Y., Chen J., Cheng Meng Q., Moore J.T., Veasey S.C., Dixon S., Thornton M., Funato H., and Yanagisawa M. An essential role for orexins in emergence from general anesthesia. Proc Natl Acad Sci U S A 105 (2008) 1309-1314. This study demonstrates that Hcrts are necessary for the normal emergence from unconsciousness after administration of the common anesthetics isofluorane and sevofluorane. This demonstrates that emergence from anesthesia depends on sleep/wake circuitry and that the Hcrt system is a key player.
17. Espana R.A., Baldo B.A., Kelley A.E., and Berridge C.W. Wake-promoting and sleep-suppressing actions of hypocretin (orexin): basal forebrain sites of action. Neuroscience 106 (2001) 699-715
18. Piper D.C., Upton N., Smith M.I., and Hunter A.J. The novel brain neuropeptide, orexin-A, modulates the sleep-wake cycle of rats. Eur J Neurosci 12 (2000) 726-730
19. Adamantidis A.R., Zhang F., Aravanis A.M., Deisseroth K., and de Lecea L. Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 450 (2007) 420-424. Optogenetic technology is applied to the Hcrt system, showing that stimulation of Hcrt neurons is sufficient to increase the probability of an awakening event during slow-wave-sleep or REM sleep. This effect is blocked in Hcrt KO mice and in the presence of a Hcrtr-1 antagonist, demonstrating that Hcrt peptides, and not other neurotransmitters, are necessary for the wake-promoting effects of Hcrt neurons.
20. 2+ signaling in a reciprocal manner to leptin: orexigenic neuronal pathways in the mediobasal hypothalamus. Eur J Neurosci 19 (2004) 1524-1534
21. Harris G.C., Wimmer M., and Aston-Jones G. A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437 (2005) 556-559
22. Boutrel B., Kenny P.J., Specio S.E., Martin-Fardon R., Markou A., Koob G.F., and de Lecea L. Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proc Natl Acad Sci 102 (2005) 19168-19173. These studies were first to demonstrate an important role for the Hcrt system in reward seeking behavior, an active area of current addiction research.
23. Aston-Jones G., Smith R.J., Moorman D.E., and Richardson K.A. Role of lateral hypothalamic orexin neurons in reward processing and addiction. Neuropharmacology 56 (2009) 112-121. An excellent review on the recent research on the role of Hcrts in reward seeking behaviors.
24. Winsky-Sommerer R., Boutrel B., and de Lecea L. Stress and arousal: the corticotrophin-releasing factor/hypocretin circuitry. Mol Neurobiol 32 (2005) 285-294. A review that surveys evidence that Hcrts play an important role in regulating the increased arousal associated with the response to environmental stressors.
25. Chen C.T., Hwang L.L., Chang J.K., and Dun N.J. Pressor effects of orexins injected intracisternally and to rostral ventrolateral medulla of anesthetized rats. Am J Physiol - Regul, Integr Comp Physiol 278 (2000) R692-697
26. Samson W.K., Gosnell B., Chang J.K., Resch Z.T., and Murphy T.C. Cardiovascular regulatory actions of the hypocretins in brain. Brain Res 831 (1999) 248-253
27. Shirasaka T., Nakazato M., Matsukura S., Takasaki M., and Kannan H. Sympathetic and cardiovascular actions of orexins in conscious rats. Am J Physiol 277 (1999) R1780-R1785
28. Winsky-Sommerer R., Yamanaka A., Diano S., Borok E., Roberts A.J., Sakurai T., Kilduff T.S., Horvath T.L., and de Lecea L. Interaction between the corticotropin-releasing factor system and hypocretins (orexins): a novel circuit mediating stress response. J Neurosci 24 (2004) 11439-11448. This study presents anatomical and electrophysiological evidence that Hcrt neurons receive excitatory input from CRF-containing neurons and that this circuit may mediate the increase in arousal associated with the stress response.
29. Samson W., Taylor M., and Ferguson A. The hypocretins/orexins and the hypothalamo-pituitary-adrenal axis. In: de Lecea L., and Sutcliffe J. (Eds). Hypocretins: Integrators of Physiological Functions (2005), Springer 369-382
30. Lambe E.K., Olausson P., Horst N.K., Taylor J.R., and Aghajanian G.K. Hypocretin and nicotine excite the same thalamocortical synapses in prefrontal cortex: correlation with improved attention in rat. J Neurosci 25 (2005) 5225-5229
31. Muschamp J.W., Dominguez J.M., Sato S.M., Shen R.-Y., and Hull E.M. A role for hypocretin (orexin) in male sexual behavior. J Neurosci 27 (2007) 2837-2845. This interesting study demonstrates that Hcrts are necessary for the normal increase in arousal associated with male sexual behavior. Furthermore, electrophysiological evidence suggests that Hcrts activate the mesolimbic dopaminergic system, and that this circuitry may facilitate the arousal for natural rewards, such as sex.
32. Fronczek R., Overeem S., Lee S.Y.Y., Hegeman I.M., van Pelt J., van Duinen S.G., Lammers G.J., and Swaab D.F. Hypocretin (orexin) loss in Parkinson's disease. Brain 130 (2007) 1577-1585
33. Salomon R.M. Hypocretin measures in psychiatric disorders. In: Nishino S., and Sakurai T. (Eds). The Orexin/Hypocretin System (2005), Humana Press 317-327. This chapter outlines evidence suggesting the Hcrt system might facilitate some symptoms of psychiatric disease, focusing on schizophrenia, depression and substance abuse. It also proposes methods for using the Hcrt system to identify other brain systems responsible for psychiatric dysfunction.
34. Deutch A.Y., and Bubser M. The orexins/hypocretins and schizophrenia. Schizophrenia Bull 33 (2007) 1277-1283
35. Brundin L., Björkqvist M., Petersén A., and Träskman-Bendz L. Reduced orexin levels in the cerebrospinal fluid of suicidal patients with major depressive disorder. Eur Neuropsychopharmacol 17 (2007) 573-579
36. Feng P., Vurbic D., Wu Z., Hu Y., and Strohl K. Changes in brain orexin levels in a rat model of depression induced by neonatal administration of clomipramine. J Psychopharmacol 22 (2008) 784-791
37. Pfaff D., Ribeiro A., Matthews J., and Kow L.-M. Concepts and mechanisms of generalized central nervous system arousal. Ann N Y Acad Sci 1129 (2008) 11-25. This theoretical paper provides evidence for the existence of a generalized arousal system in the CNS, and then proposes an operational definition for how to monitor this system. It describes the neuroanatomical, neurophysiological, and genomic mechanisms underlying general arousal, differentiating it from specific arousal. It also raises the interesting idea that specific arousal systems can conflict, such as when hunger leads an animal to wake up during its circadian sleep cycle.
38. Garey J., Goodwillie A., Frohlich J., Morgan M., Gustafsson J.-A., Smithies O., Korach K.S., Ogawa S., and Pfaff D.W. Genetic contributions to generalized arousal of brain and behavior. Proc Natl Acad Sci U S A 100 (2003) 11019-11022
39. Levenson R.W. Autonomic nervous systems differences among emotions. Psychol Sci 3 (1992) 23-27
40. Levenson R.W. Blood, sweat, and fears. Ann N Y Acad Sci 1000 (2003) 348-366
41. Bryant R.A., Harvey A.G., Guthrie R.M., and Moulds M.L. A prospective study of psychophysiological arousal, acute stress disorder, and posttraumatic stress disorder. J Abnormal Psychol 109 (2000) 341-344
42. Kerman I. Organization of brain somatomotor-sympathetic circuits. Exp Brain Res 187 (2008) 1-16
43. Moratti S., Rubio G., Campo P., Keil A., and Ortiz T. Hypofunction of right temporoparietal cortex during emotional arousal in depression. Arch Gen Psychiatry 65 (2008) 532-541
44. McEwen B., and Wingfield J.C. The concept of allostasis in biology and biomedicine. Hormones Behav 43 (2003) 2-15. A terrific introduction to the concept of allostasis and the physiological mechanisms that allow the body to respond to allostatic pressure.
45. Roberts A.J., Heyser C.J., Cole M., Griffin P., and Koob G.F. Excessive ethanol drinking following a history of dependence: animal model of allostasis. Neuropsychopharmacology 22 (2000) 581-594. This study provides evidence to support the hypothesis that allostatic mechanisms can explain drug relapse, a behavior coincidentally instigated by Hcrt system activation.
46. Lutter M., Krishnan V., Russo S.J., Jung S., McClung C.A., and Nestler E.J. Orexin signaling mediates the antidepressant-like effect of calorie restriction. J Neurosci 28 (2008) 3071-3075. This recent study nicely illustrates how some functions of the Hcrt system might only be detectable in the presence of allostatic pressure. In the example under investigation, hunger activates the Hcrt system, which in turn counteracts the depressive effects of chronic stress.
47. Kayaba Y., Nakamura A., Kasuya Y., Ohuchi T., Yanagisawa M., Komuro I., Fukuda Y., and Kuwaki T. Attenuated defense response and low basal blood pressure in orexin knockout mice. Am J Physiol - Regul, Integr Comp Physiol 285 (2003) R581-R593
48. Akiyama M., Yuasa T., Hayasaka N., Horikawa K., Sakurai T., and Shibata S. Reduced food anticipatory activity in genetically orexin (hypocretin) neuron-ablated mice. Eur J Neurosci 20 (2004) 3054-3062. This study provides another example of how some functions of the Hcrt system can only be observed when allostatic pressure is applied, again in the form of hunger.
49. Roecker A., and Coleman P. Orexin receptor antagonists: medicinal chemistry and therapeutic potential. Curr Top Med Chem 8 (2008) 977-987. This review highlights progress by the pharmaceutical industry in pharmacologically targeting the Hcrt system for possible treatments in sleep and other psychiatric disorders.
50. Smart D., Sabido-David C., Brough S.J., Jewitt F., Johns A., Porter R.A., and Jerman J.C. SB-334867-A: the first selective orexin-1 receptor antagonist. Br J Pharmacol 132 (2001) 1179-1182
51. Brisbare-Roch C., Dingemanse J., Koberstein R., Hoever P., Aissaoui H., Flores S., Mueller C., Nayler O., van Gerven J., de Haas S.L., et al. Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med 13 (2007) 150-155. This study describes an Hcrt receptor antagonist that targets both Hcrt receptors, can be orally administered, readily crosses the blood-brain barrier, and reversibly blocks Hcrt function in vivo.
52. Zeitzer J.M., Nishino S., and Mignot E. The neurobiology of hypocretins (orexins), narcolepsy and related therapeutic interventions. Trends Pharmacol Sci 27 (2006) 368-374. This review highlights methods of stimulating arousal in patients with dysregulation of the Hcrt system, either by trying to stimulate Hcrt neurons or Hcrt levels, or by pharmacologically targeting other brain arousal systems.
53. Harris G.C., and Aston-Jones G. Arousal and reward: a dichotomy in orexin function. Trends Neurosci 29 (2006) 571-577
54. Blanco-Centurion C., Gerashchenko D., and Shiromani P.J. Effects of saporin-induced lesions of three arousal populations on daily levels of sleep and wake. J Neurosci 27 (2007) 14041-14048. Three populations of neurons that receive heavy afferent projections from Hcrt neurons are lesioned in the same animal in order to determine their necessity in the sleep/wake cycle. Daily levels of sleep and wake are relatively normal, suggesting that Hcrt's wake-promoting effects are due to additional or altogether different nuclei within the brain.