Skip to main content
SpringerLink
Log in

Hypocretin in Neuropsychiatric Disorders

  • Chapter
Hypocretins

  • 358 Accesses

10. Conclusion

In summary, deficient hypocretin-1 transmission is highly specific and sensitive for sporadic narcolepsy with typical excessive daytime somnolence, cataplexy and HLA DQB1*0602 allele. Hypocretin ligand deficiency appears not to be the major cause for other hypersomnias but a pathophysiological continuum between narcolepsy without cataplexy and idiopathic hypersomnia could be hypothesized. Undetectable CSF hcrt-1 levels are highly sensitive and specific for narcolepsy and are a useful diagnostic tool for pediatric and atypical cases. A decreased level however should not systematically suggest the diagnosis of narcolepsy. Indeed, low levels can be observed in various neurological conditions: neuroimmune disorders such as Guillain Barré syndrome and Miller Fisher syndrome; neurological conditions associated with lesion or dysfunction of the lateral hypothalamus; advanced forms of Parkinson disease. Finally, exploring the hypocretins in neuropsychiatric disorders is a growing field that requires further investigation to understand the role of hypocretins in pathology. The evaluation methods of the hypocretinergic system needs also to be improved with other techniques in order to evaluate the functioning of hypocretin-1 or 2 receptors as well as the consequences of partial lesions of hypocretin cells without low CSF hypocretin-1. Measurement and interpretation of intermediate and high levels of hypocretin, as reported in restless legs syndrome for example, requires more study.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

11. References

  1. L. Lin, M. Hungs, and E. Mignot, Narcolepsy and the HLA region, J. Neuroimmunol. 117, 9–20 (2001).

    Article  PubMed  CAS  Google Scholar 

  2. L. Lin, J. Faraco, R. Li, H. Kadotani, W. Rogers, X. Lin, X. Qiu, P. J. de Jong, S. Nishino, and E. Mignot, The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene, Cell 98, 365–376 (1999).

    Article  PubMed  CAS  Google Scholar 

  3. R. M. Chemelli, J. T. Willie, C. M. Sinton, J. K. Elmquist, T. Scammell, C. Lee, J. A. Richardson, S. C. Williams, Y. Xiong, Y. Kisanuki, T. E. Fitch, M. Nakazato, R. E. Hammer, C. B. Saper, and M. Yanagisawa, Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation, Cell 98, 437–451 (1999).

    Article  PubMed  CAS  Google Scholar 

  4. C. Peyron, J. Faraco, W. Rogers, B. Ripley, S. Overeem, Y. Charnay, S. Nevsimalova, M. Aldrich, D. Reynolds, R. Albin, R. Li, M. Hungs, M. Pedrazzoli, M. Padigaru, M. Kucherlapati, J. Fan, R. Maki, G. J. Lammers, C. Bouras, R. Kucherlapati, S. Nishino, and E. Mignot, A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains, Nat. Med. 6, 991–997 (2000).

    Article  PubMed  CAS  Google Scholar 

  5. T. C. Thannickal, R. Y. Moore, R. Nienhuis, L. Ramanathan, S. Gulyani, M. Aldrich, M. Cornford, and J. M. Siegel, Reduced number of hypocretin neurons in human narcolepsy, Neuron 27, 469–474 (2000).

    Article  PubMed  CAS  Google Scholar 

  6. S. Nishino, B. Ripley, S. Overeem, G. J. Lammers, and E. Mignot, Hypocretin (orexin) deficiency in human narcolepsy, Lancet 355, 39–40 (2000).

    Article  PubMed  CAS  Google Scholar 

  7. B. Ripley, S. Overeem, N. Fujiki, S. Nevsimalova, M. Uchino, J. Yesavage, D. Di Monte, K. Dohi, A. Melberg, G. J. Lammers, Y. Nishida, F. W. Roelandse, M. Hungs, E. Mignot, and S. Nishino, CSF hypocretin/orexin levels in narcolepsy and other neurological conditions, Neurology 57, 2253–2258 (2001).

    PubMed  CAS  Google Scholar 

  8. A. Melberg, B. Ripley, L. Lin, J. Hetta, E. Mignot, and S. Nishino, Hypocretin deficiency in familial symptomatic narcolepsy, Ann. Neurol. 49, 136–137 (2001).

    Article  PubMed  CAS  Google Scholar 

  9. G. Hartwig, J. Harsh, B. Ripley, S. Nishino, and E. Mignot, Low cerebrospinal fluid hypocretin levels found in familial narcolepsy, Sleep Med. 2, 451–453 (2001).

    Article  PubMed  CAS  Google Scholar 

  10. L. E. Krahn, V. S. Pankratz, L. Oliver, B. F. Boeve, and M. H. Silber, Hypocretin (orexin) levels in cerebrospinal fluid of patients with narcolepsy: relationship to cataplexy and HLA DQB1*0602 status, Sleep 25, 733–736 (2002).

    PubMed  Google Scholar 

  11. E. Mignot, G. J. Lammers, B. Ripley, M. Okun, S. Nevsimalova, S. Overeem, J. Vankova, J. Black, J. Harsh, C. Bassetti, H. Schrader, and S. Nishino, The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias, Arch. Neurol. 59, 1553–1562 (2002).

    Article  PubMed  Google Scholar 

  12. T. Kanbayashi, Y. Inoue, S. Chiba, R. Aizawa, Y. Saito, H. Tsukamoto, Y. Fujii, S. Nishino, and T. Shimizu, CSF hypocretin-1 (orexin-A) concentrations in narcolepsy with and without cataplexy and idiopathic hypersomnia, J Sleep Res 11, 91–93 (2002).

    Article  PubMed  Google Scholar 

  13. C. Bassetti, M. Gugger, M. Bischof, J. Mathis, C. Sturzenegger, E. Werth, B. Radanov, B. Ripley, S. Nishino, and E. Mignot, The narcoleptic borderland: a multimodal diagnostic approach including cerebrospinal fluid levels of hypocretin-1 (orexin A), Sleep Med. 4, 7–12 (2003).

    Article  PubMed  Google Scholar 

  14. Y. Dauvilliers, C. R. Baumann, B. Carlander, M. Bischof, T. Blatter, M. Lecendreux, F. Maly, A. Besset, J. Touchon, M. Billiard, M. Tafti, and C. L. Bassetti, CSF hypocretin-1 levels in narcolepsy, Kleine-Levin syndrome, and other hypersomnias and neurological conditions, J. Neurol. Neurosurg. Psychiatry 74, 1667–1673 (2003).

    Article  PubMed  CAS  Google Scholar 

  15. Y. Dauvilliers, S. Maret, C. Bassetti, B. Carlander, M. Billiard, J. Touchon, and M. Tafti, A monozygotic twin pair discordant for narcolepsy and CSF hypocretin-1, Neurology 62, 2137–2138 (2004).

    PubMed  CAS  Google Scholar 

  16. T. Kanbayashi, Y. Inoue, K. Kawanishi, H. Takasaki, R. Aizawa, K. Takahashi, Y. Ogawa, M. Abe, Y. Hishikawa, and T. Shimizu, CSF hypocretin measures in patients with obstructive sleep apnea, J. Sleep Res. 12, 339–341 (2003).

    PubMed  CAS  Google Scholar 

  17. M. Lecendreux, S. Maret, C. Bassetti, M. C. Mouren, and M. Tafti, Clinical efficacy of high-dose intravenous immunoglobulins near the onset of narcolepsy in a 10-year-old boy, J. Sleep Res. 12, 347–348 (2003).

    PubMed  Google Scholar 

  18. S. Nishino, T. Kanbayashi, N. Fujiki, M. Uchino, B. Ripley, M. Watanabe, G. J. Lammers, H. Ishiguro, S. Shoji, Y. Nishida, S. Overeem, I. Toyoshima, Y. Yoshida, T. Shimizu, S. Taheri, and E. Mignot, CSF hypocretin levels in Guillain-Barre syndrome and other inflammatory neuropathies, Neurology 61, 823–825 (2003).

    PubMed  CAS  Google Scholar 

  19. T. Kanbayashi, H. Ishiguro, R. Aizawa, Y. Saito, Y. Ogawa, M. Abe, K. Hirota, S. Nishino, and T. Shimizu, Hypocretin-1 (orexin-A) concentrations in cerebrospinal fluid are low in patients with Guillain-Barre syndrome, Psychiatry Clin. Neurosci. 56, 273–274 (2002).

    Article  PubMed  CAS  Google Scholar 

  20. C. R. Baumann, Y. Dauvilliers, E. Mignot, and C. L. Bassetti, Normal CSF Hypocretin-1 (Orexin A) Levels in Dementia with Lewy Bodies Associated with Excessive Daytime Sleepiness, Eur. Neurol. 52, 73–76 (2004).

    Article  PubMed  CAS  Google Scholar 

  21. J. Dalmau, F. Graus, A. Villarejo, J. B. Posner, D. Blumenthal, B. Thiessen, A. Saiz, P. Meneses, and M. R. Rosenfeld, Clinical analysis of anti-Ma2-associated encephalitis, Brain 127, 1831–1844 (2004).

    Article  PubMed  Google Scholar 

  22. S. Overeem, J. Dalmau, L. Bataller, S. Nishino, E. Mignot, J. Verschuuren, and G. J. Lammers, Hypocretin-1 CSF levels in anti-Ma2 associated encephalitis, Neurology 62, 138–140 (2004).

    PubMed  CAS  Google Scholar 

  23. I. O. Ebrahim, Y. K. Semra, S. De Lacy, R. S. Howard, M. D. Kopelman, A. Williams, and M. K. Sharief, CSF hypocretin (Orexin) in neurological and psychiatric conditions, J. Sleep Res. 12, 83–84 (2003).

    Article  PubMed  CAS  Google Scholar 

  24. E. G. Celius, H. F. Harbo, T. Egeland, F. Vartdal, B. Vandvik, and A. Spurkiand, Sex and age at diagnosis are correlated with the HLA-DR2, DQ6 haplotype in multiple sclerosis, J. Neurol. Sci. 178, 132–135 (2000).

    Article  PubMed  CAS  Google Scholar 

  25. T. Kato, T. Kanbayashi, K. Yamamoto, T. Nakano, T. Shimizu, T. Hashimoto, and S. Ikeda, Hypersomnia and low CSF hypocretin-1 (orexin-A) concentration in a patient with multiple sclerosis showing bilateral hypothalamic lesions, Intern. Med. 42, 743–745 (2003).

    PubMed  Google Scholar 

  26. H. Kubota, T. Kanbayashi, Y. Tanabe, J. Takanashi, and Y. Kohno, A case of acute disseminated encephalomyelitis presenting hypersomnia with decreased hypocretin level in cerebrospinal fluid, J. Child Neurol. 17, 537–539 (2002).

    PubMed  Google Scholar 

  27. R. F. Gledhill, P. R. Bartel, Y. Yoshida, S. Nishino, and T. E. Scammell, Narcolepsy caused by acute disseminated encephalomyelitis, Arch. Neurol. 61, 758–760 (2004).

    Article  PubMed  Google Scholar 

  28. J. D. Katz, and A. H. Ropper, Familial Kleine-Levin syndrome: two siblings with unusually long hypersomnic spells, Arch. Neurol. 59, 1959–1961 (2002).

    Article  PubMed  Google Scholar 

  29. J. Vankova, I. Stepanova, R. Jech, M. Elleder, L. Ling, E. Mignot, S. Nishino, and S. Nevsimalova, Sleep disturbances and hypocretin deficiency in Niemann-Pick disease type C, Sleep 26, 427–430 (2003).

    PubMed  Google Scholar 

  30. J. E. Martinez-Rodriguez, L. Lin, A. Iranzo, D. Genis, M. J. Marti, J. Santamaria, and E. Mignot, Decreased hypocretin-1 (Orexin-A) levels in the cerebrospinal fluid of patients with myotonic dystrophy and excessive daytime sleepiness, Sleep 26, 287–290 (2003).

    PubMed  Google Scholar 

  31. J. Arii, T. Kanbayashi, Y. Tanabe, J. Ono, S. Nishino, and Y. Kohno, A hypersomnolent girl with decreased CSF hypocretin level after removal of a hypothalamic tumor, Neurology 56, 1775–1776 (2001).

    PubMed  CAS  Google Scholar 

  32. T. E. Scammell, S. Nishino, E. Mignot, and C. B. Saper, Narcolepsy and low CSF orexin (hypocretin) concentration after a diencephalic stroke, Neurology 56, 1751–1753 (2001).

    PubMed  CAS  Google Scholar 

  33. O. J. Dempsey, P. McGeoch, R. N. de Silva, and N. J. Douglas, Acquired narcolepsy in an acromegalic patient who underwent pituitary irradiation, Neurology 61, 537–540 (2003).

    PubMed  Google Scholar 

  34. D. B. Rye, and J. Jankovic, Emerging views of dopamine in modulating sleep/wake state from an unlikely source: PD, Neurology 58, 341–346 (2002).

    PubMed  Google Scholar 

  35. P. Bourgin, S. Huitron-Resendiz, A. D. Spier, V. Fabre, B. Morte, J. R. Criado, J. G. Sutcliffe, S. J. Henriksen, and L. de Lecea, Hypocretin-1 modulates rapid eye movement sleep through activation of locus coeruleus neurons, J. Neurosci. 20, 7760–7765 (2000).

    PubMed  CAS  Google Scholar 

  36. T. Mochizuki, and T. E. Scammell, Orexin/hypocretin: wired for wakefulness, Curr. Biol. 13, R563–564 (2003).

    Article  PubMed  CAS  Google Scholar 

  37. B. A. Baldo, R. A. Daniel, C. W. Berridge, and A. E. Kelley, Overlapping distributions of orexin/hypocretin-and dopamine-beta-hydroxylase immunoreactive fibers in rat brain regions mediating arousal, motivation, and stress, J. Comp. Neurol. 464, 220–237 (2003).

    Article  PubMed  Google Scholar 

  38. S. Overeem, J. J. van Hilten, B. Ripley, E. Mignot, S. Nishino, and G. J. Lammers, Normal hypocretin-1 levels in Parkinson’s disease patients with excessive daytime sleepiness, Neurology 58, 498–499 (2002).

    PubMed  CAS  Google Scholar 

  39. X. Drouot, S. Moutereau, J. P. Nguyen, J. P. Lefaucheur, A. Creange, P. Remy, F. Goldenberg, and M. P. d’Ortho, Low levels of ventricular CSF orexin/hypocretin in advanced PD, Neurology 61, 540–543 (2003).

    PubMed  CAS  Google Scholar 

  40. I. Arnulf, E. Konofal, M. Merino-Andreu, J. L. Houeto, V. Mesnage, M. L. Welter, L. Lacomblez, J. L. Golmard, J. P. Derenne, and Y. Agid, Parkinson’s disease and sleepiness: an integral part of PD, Neurology 58, 1019–1024 (2002).

    PubMed  CAS  Google Scholar 

  41. R. P. Allen, E. Mignot, B. Ripley, S. Nishino, and C. J. Earley, Increased CSF hypocretin-1 (orexin-A) in restless legs syndrome, Neurology 59, 639–641 (2002).

    PubMed  CAS  Google Scholar 

  42. K. Stiasny-Kolster, E. Mignot, L. Ling, J. C. Moller, W. Cassel, and W. H. Oertel, CSF hypocretin-1 levels in restless legs syndrome, Neurology 61, 1426–1429 (2003).

    PubMed  CAS  Google Scholar 

  43. J. E. Martinez-Rodriguez, R. Sanchez-Valle, A. Saiz, L. Lin, A. Iranzo, E. Mignot, and J. Santamaria, Normal hypocretin-1 levels in the cerebrospinal fluid of patients with fatal familial insomnia, Sleep 26, 1068 (2003).

    PubMed  Google Scholar 

  44. D. Georgescu, V. Zachariou, M. Barrot, M. Mieda, J. T. Willie, A. J. Eisch, M. Yanagisawa, E. J. Nestler, and R. J. DiLeone, Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal, J. Neurosci. 23, 3106–3111 (2003).

    PubMed  CAS  Google Scholar 

  45. M. Pedrazzoli, V. D’Almeida, P. J. Martins, R. B. Machado, L. Ling, S. Nishino, S. Tufik, and E. Mignot, Increased hypocretin-1 levels in cerebrospinal fluid after REM sleep deprivation, Brain Res. 995, 1–6 (2004).

    Article  PubMed  CAS  Google Scholar 

  46. C. Peyron, D. K. Tighe, A. N. van den Pol, L. de Lecea, H. C. Heller, J. G. Sutcliffe, and T. S. Kilduff, Neurons containing hypocretin (orexin) project to multiple neuronal systems, J. Neurosci. 18, 9996–10015 (1998).

    PubMed  CAS  Google Scholar 

  47. K. S. Eriksson, O. Sergeeva, R. E. Brown, and H. L. Haas, Orexin/hypocretin excites the histaminergic neurons of the tuberomammillary nucleus, J. Neurosci. 21, 9273–9279 (2001).

    PubMed  CAS  Google Scholar 

  48. S. Taheri, J. Gardiner, S. Hafizi, K. Murphy, C. Dakin, L. Seal, C. Small, M. Ghatei, and S. Bloom, Orexin A immunoreactivity and preproorexin mRNA in the brain of Zucker and WKY rats, Neuroreport 12, 459–464 (2001).

    Article  PubMed  CAS  Google Scholar 

  49. R. M. Salomon, B. Ripley, J. S. Kennedy, B. Johnson, D. Schmidt, J. M. Zeitzer, S. Nishino, and E. Mignot, Diurnal variation of cerebrospinal fluid hypocretin-1 (Orexin-A) levels in control and depressed subjects, Biol. Psychiatry 54, 96–104 (2003).

    Article  PubMed  CAS  Google Scholar 

  50. C. Cajochen, D. P. Brunner, K. Krauchi, P. Graw, and A. Wirz-Justice, EEG and subjective sleepiness during extended wakefulness in seasonal affective disorder: circadian and homeostatic influences, Biol. Psychiatry 47, 610–617 (2000).

    Article  PubMed  CAS  Google Scholar 

  51. T. C. Chou, T. E. Scammell, J. J. Gooley, S. E. Gaus, C. B. Saper, and J. Lu, Critical role of dorsomedial hypothalamic nucleus in a wide range of behavioral circadian rhythms, J. Neurosci. 23, 10691–10702 (2003).

    PubMed  CAS  Google Scholar 

  52. T. Nakamura, K. Uramura, T. Nambu, T. Yada, K. Goto, M. Yanagisawa, and T. Sakurai, Orexin-induced hyperlocomotion and stereotypy are mediated by the dopaminergic system, Brain Res. 873, 181–187 (2000).

    Article  PubMed  CAS  Google Scholar 

  53. M. Kuru, Y. Ueta, R. Serino, M. Nakazato, Y. Yamamoto, I. Shibuya, and H. Yamashita, Centrally administered orexin/hypocretin activates HPA axis in rats, Neuroreport 11, 1977–1980 (2000).

    Article  PubMed  CAS  Google Scholar 

  54. M. Jaszberenyi, E. Bujdoso, I. Pataki, and G. Telegdy, Effects of orexins on the hypothalamic-pituitaryadrenal system, J Neuroendocrinol 12, 1174–1178 (2000).

    Article  PubMed  CAS  Google Scholar 

  55. S. Nishino, B. Ripley, E. Mignot, K. L. Benson, and V. P. Zarcone, CSF hypocretin-1 levels in schizophrenics and controls: relationship to sleep architecture, Psychiatry Res 110, 1–7 (2002).

    Article  PubMed  CAS  Google Scholar 

  56. M. A. Dalal, A. Schuld, and T. Pollmacher, Lower CSF orexin A (hypocretin-1) levels in patients with schizophrenia treated with haloperidol compared to unmedicated subjects, Mol. Psychiatry 8, 836–837 (2003).

    Article  PubMed  CAS  Google Scholar 

  57. T. Kanbayashi, T. Yano, H. Ishiguro, K. Kawanishi, S. Chiba, R. Aizawa, Y. Sawaishi, K. Hirota, S. Nishino, and T. Shimizu, Hypocretin-1 (orexin-A) levels in human lumbar CSF in different age groups: infants to elderly persons, Sleep 25, 337–339 (2002).

    PubMed  Google Scholar 

  58. D. Gerashchenko, E. Murillo-Rodriguez, L. Lin, M. Xu, L. Hallett, S. Nishino, E. Mignot, and P. J. Shiromani, Relationship between CSF hypocretin levels and hypocretin neuronal loss, Exp. Neurol. 184, 1010–1016 (2003).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Narcolepsy Research, Stanford University, Palo Alto, California, 94304

    Patrice Bourgin

  2. Hôpital Gui de Chauliac, Montpellier, INSERM, E0361, Montpellier, France

    Yves Dauvilliers

Authors
  1. Patrice Bourgin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yves Dauvilliers
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. The Scripps Research Institute, La Jolla, CA, 92037, USA

    Luis de Lecea  & J. Gregor Sutcliffe  & 

Rights and permissions

Reprints and permissions

Copyright information

© 2005 Springer Science+Business Media, Inc.

About this chapter

Cite this chapter

Bourgin, P., Dauvilliers, Y. (2005). Hypocretin in Neuropsychiatric Disorders. In: de Lecea, L., Sutcliffe, J.G. (eds) Hypocretins. Springer, Boston, MA. https://doi.org/10.1007/0-387-25446-3_17

Download citation

Publish with us

Policies and ethics

Search

Navigation