Skip to main content
SpringerLink
Log in

Neurobiological Role of Hypocretin in Regulation of Psychiatric Disorders

  • Review
  • Published:
Sleep and Vigilance Aims and scope Submit manuscript

Abstract

Hypocretins are hypothalamic neuropeptides acting on the regulation of several physiological functions, the most important being the control of arousal. Hypocretin 1 and hypocretin 2 are derived from the same precursor and both bind to the orexin receptors. The hypocretinergic system has been a target of several studies that try to understand its function on the regulation of mood and behavior. The hypocretinergic system has a direct relationship with the pathways related to emotions and reward system, besides the interaction with the stress circuit. This article aims to analyze the relationship of hypocretins with anxiety, stress and depression, through a review of the existing literature.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Song J, Kim E, Kim C, Song H, Lee J. The role of orexin in post-stroke inflammation, cognitive decline, and depression. Mol Brain. 2015;8:16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Arendt D, Hassell J, Li H, Achua J, Guarnieri D, DiLeone R, Ronan PJ, Summers CH. Anxiolytic function of the orexin 2/hypocretin. A receptor in the basolateral amygdala. Psychoneuroendocrinology. 2014;40:17–26.

    Article  PubMed  CAS  Google Scholar 

  3. Boss C, Roch C. Recent trends in orexin research—2010 to 2015. Bioorg Med Chem Lett. 2015;25:2875–87.

    Article  PubMed  CAS  Google Scholar 

  4. Yeoh J, Campbell E, James M, Graham B, Dayas C. Orexins antagonists for neuropsychiatric disease: progress and potential pitfalls. Front Neurosci. 2014;8:36.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Abbas G, Shoji H, Soya S, Hondo M, Miyakawa T, Sakurai T. Comprehensive behavioral analysis of male OX1R−/− mice showed implication of orexin receptor 1 in mood, anxiety and social behavior. Front Behav Neurosci. 2015;9:324.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Sakurai T. The role of orexin in motivated behaviours. Nat Rev. 2014;15:719–31.

    Article  CAS  Google Scholar 

  7. Sakurai T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Ver Neurosc. 2007;8:171–81.

    Article  CAS  Google Scholar 

  8. Scott M, Marcus J, Pettersen A, Bimbaum S, Mochizuki T, Scammell T, Nestler E, Elmquist J, Lutter M. Hcrtr1 and 2 signaling differentially regulates depression-like behaviors. Behav Brain Res. 2011;222:289–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Li J, Hu Z, De Lecea L. The hypocretins/orexins: integrators of multiple physiological functions. Brit J Pharmacol. 2013;171:332–50.

    Article  CAS  Google Scholar 

  10. Pich E, Melotto S. Orexin 1 receptor antagonists in compulsive behavior and anxiety: possible therapeutic use. Front Neurosci. 2014;8:26.

    Google Scholar 

  11. Johnson P, Truitt W, Fitz S, Minick P, Dietrich A, Sanghani S, Bendz L, Goddard A, Brundin L, Shekhar A. A key role for orexin in panic anxiety. Nat Med. 2010;16:111–5.

    Article  PubMed  CAS  Google Scholar 

  12. Brown R, Basheer R, McKenna J, Strecker R, McCarley R. Control of sleep and wakefulness. Physiol Rev. 2012;92:1087–187.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Fisher S, Foster R, Peirson S. The circadian control of sleep. Handb Exp Pharmacol. 2013;217:157–83.

    Article  CAS  Google Scholar 

  14. Verwey M, Amir S. From genes to chronotypes: the influence of circadian clock genes on our daily patterns of sleep and wakefulness. Ann Transl Med. 2016;4(9):184.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Boucetta S, Cissé Y, Mainville L, Morales M, Jones B. Discharge profiles across the sleep-waking cycle of identified cholinergic, GABAergic, and glutamatergic neurons in the pontomesencephalic tegmentum of the rat. J Neurosci. 2014;34:4708–27.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Nakazawa S, Nakamichi K, Imai H, Ichihara J. Effect of dopamine D4 receptor agonists on sleep architecture in rats. Prog Neuropsychopharmacol Biol Psychiatry. 2015;63:6–13.

    Article  PubMed  CAS  Google Scholar 

  17. Monti J, Jantos H. The effects of systemic administration and local microinjection into the central nervous system of the selective serotonin 5-HT2C receptor agonist RO-600175 on sleep and wakefulness in the rat. Behav Pharmacol. 2015;26:418–26.

    Article  PubMed  CAS  Google Scholar 

  18. Schwartz M, Kilduff T. The neurobiology of sleep and wakefulness. Psychiatr Clin North Am. 2015;38:615–44.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Yu X, Ye Z, Houston C, Zecharia A, Ma Y, Zhang Z, Uygun DS, Parker S, Vyssotski AL, Yustos R, Franks NP, Brickley SG, Wisden W. Wakefulness is governed by GABA and histamine cotransmission. Neuron. 2015;87:164–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Bellesi M, Tononi G, Cirelli C, Serra P. Region-specific dissociation between cortical noradrenaline levels and the sleep/wake cycle. Sleep. 2016;39:143–54.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Branch A, Navidi W, Tabuchi S, Terao A, Yamanaka A, Scammell T, Diniz Behn C. Progressive loss of the orexin neurons reveals dual effects on wakefulness. Sleep. 2016;39:369–77.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Parmentier R, Zhao Y, Perier M, Akaoka H, Lintunen M, Hou Y, Panula P, Watanabe T, Franco P, Lin J. Role of histamine H1-receptor on behavioral states and wake maintenance during deficiency of a brain activating system: a study using a knockout mouse model. Neuropharmacol. 2016;106:20–34.

    Article  CAS  Google Scholar 

  23. Schöne C, Burdakov D. Orexin/hypocretin and organizing principles for a diversity of wake-promoting neurons in the brain. Curr Top Behav Neurosci. 2016.

  24. Zant JC, Kim T, Prokai L, Szarka S, McNally J, McKenna JT, Shukla C, Yang C, Kalinchuk AV, McCarley RW, Brown RE, Basheer R. Cholinergic neurons in the basal forebrain promote wakefulness by actions on neighboring non-cholinergic neurons: an opto-dialysis study. J Neurosci. 2016;36:2057–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Nambu T, Sakurai T, Mizukami K, Hosoya Y, Yanagisawa M, Goto K. Distribution of orexin neurons in the adult rat brain. Brain Res. 1999;827:243–60.

    Article  PubMed  CAS  Google Scholar 

  26. Date Y, Mondal MS, Matsukura S, Nakazato M. Distribution of orexin-A and orexin-B (hypocretins) in the rat spinal cord. Neurosci Lett. 2000;288:87–90.

    Article  PubMed  CAS  Google Scholar 

  27. Stoyanova II, Rutten WL, le Feber J. Orexin-A and orexin-B during the postnatal development of the rat brain. Cell Mol Neurobiol. 2010;30:81–9.

    Article  PubMed  CAS  Google Scholar 

  28. Deutch AY, Bubser M. The orexins/hypocretins and schizophrenia. Schizophr Bull. 2007;33:1277–83.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Plaza-Zabala A, Maldonado R, Berrendero F. The hypocretin/orexin system: implications for drug reward and relapse. Mol Neurobiol. 2012;45:424–39.

    Article  PubMed  CAS  Google Scholar 

  30. Hu B, Yang N, Qiao QC, Hu ZA, Zhang J. Roles of the orexin system in central motor control. Neurosci Biobehav Rev. 2015;49:43–54.

    Article  PubMed  CAS  Google Scholar 

  31. Peyron C, Tighe DK, Van den Pol NA, de Lecea L, Heller HC, Sutcliffe JG, Kilduff TS. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci. 1998;18:9996–10015.

    Article  PubMed  CAS  Google Scholar 

  32. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richarson JÁ, Kozlowski GP, Wilson S, Buckingham JR, Haynes AC, Carr AS, Annan RS, McNulty DE, Liu WS, Terrett JÁ, Elshourbagy NA, Bergsma DJ, Yanagisawa M. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 1998;92:573–85.

    Article  PubMed  CAS  Google Scholar 

  33. 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. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell. 1999;98:437–51.

    Article  PubMed  CAS  Google Scholar 

  34. Mieda M, Sakurai T. Overview of orexin/hypocretin system. Prog Brain Res. 2012;198:5–14.

    Article  PubMed  CAS  Google Scholar 

  35. Chow M, Cao M. The hypocretin/orexin system in sleep disorders: preclinical insights and clinical progress. Nat Sci Sleep. 2016;8:81–6.

    Article  PubMed  PubMed Central  Google Scholar 

  36. LaCrosse AL. Olive MF Neuropeptide systems and schizophrenia. CNS Neurol Disord: Drug Targets. 2013;12:619–32.

    Article  CAS  Google Scholar 

  37. Huang YS, Guilleminault C, Chen CH, Lai PC, Hwang FM. Narcolepsy-cataplexy and schizophrenia in adolescents. Sleep Med. 2014;15:15–22.

    Article  PubMed  Google Scholar 

  38. Zawilska J. A new face of orexins action—neuroprotection. Springerplus. 2015;4(1):L59.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Sansa G, Gavaldà A, Gaig C, Monreal J, Ercilla G, Casamitjana R, Ribera G, Iranzo A, Santamaria J. Exploring the presence of narcolepsy in patients with schizophrenia. BMC Psychiatry. 2016;16:177.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Feng P, Vurbic D, Wu Z, Strohl KP. Brain orexin and wake regulation in rats exposed to maternal deprivation. Brain Res. 2007;1154:163–72.

    Article  PubMed  CAS  Google Scholar 

  41. Sakurai H, Suzuki T, Bies RR, Pollock BG, Mimura M, Kapur S, Uchida H. Increasing versus maintaining the dose of olanzapine or risperidone in schizophrenia patients who did not respond to a modest dosage: a double-blind randomized controlled trial. J Clin Psychiatry. 2016;77:1381–90.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  43. Schmidt F, Arendt E, Steinmetzer A, Bruegel M, Kratzsch J, Straub M, Baum P, Hegerl U, Schonknecht P. CSF-hypocretin-1 levels in patients with major depressive disorder compared to healthy controls. Psychiatry Res. 2011;190:240–3.

    Article  PubMed  CAS  Google Scholar 

  44. Scott M, Marcus J, Pettersen A, Bimbaum S, Mochizuki T, Scammell T, Nestler E, Elmquist J, Lutter M. Hcrtr1 and 2 signaling differentially regulates depression-like behaviors. Behav Brain Res. 2011;222(2):289–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Heydendael W, Sengupta A, Beck S, Bhatnagar S. Optogenetic examination identifies a context-specific role for orexin/hypocretins in anxiety-related behavior. Physiol Behav. 2014;130:182–90.

    Article  PubMed  CAS  Google Scholar 

  46. Suzuki M, Beuckmann C, Shikata K, Ogura H, Sawai T. Orexin-A (hypocretin 1) is possibly involved in generation of anxiety-like behavior. Brain Res. 2005;1044:116–21.

    Article  PubMed  CAS  Google Scholar 

  47. Devroye C, Cathala A, Haddjeri N, Rovera R, Vallée M, Drago F, Piazza PV, Spampinato U. Differential control of dopamine ascending pathways by serotonin2B receptor antagonists: new opportunities for the treatment of schizophrenia. Neuropharmacol. 2016;109:59–68.

    Article  CAS  Google Scholar 

  48. Kamińska K, Noworyta-Sokołowska K, Jurczak A, Górska A, Rogóż Z, Gołembiowska K. Risperidone and escitalopram co-administration: a potential treatment of schizophrenia symptoms with less side effects. Pharmacol Rep. 2016;69:13–21.

    Article  PubMed  CAS  Google Scholar 

  49. Keshavan MS, Lawler NA, Nasrallah HÁ, Tandon R. New drug developments in psychosis: challenges, opportunities and strategies. Prog Neurobiol. 2016;152:3–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet. 2000;355:39–40.

    Article  PubMed  CAS  Google Scholar 

  51. Chien YL, Liu CM, Shan JC, Lee HJ, Hsieh MH, Hwu HG, Chiou LC. Elevated plasma orexin A levels in a subgroup of patients with schizophrenia associated with fewer negative and disorganized symptoms. Psychoneuroendocrinol. 2015;53:1–9.

    Article  CAS  Google Scholar 

  52. Nishino S, Ripley B, Mignot E, Benson KL, Zarcone VP. CSF hypocretin-1 levels in schizophrenics and controls: relationship to sleep architecture. Psychiatry Res. 2002;110:1–7.

    Article  PubMed  CAS  Google Scholar 

  53. Pizza F, Magnani M, Indrio C, Plazzi G. The hypocretin system and psychiatric disorders. Curr Psychiatry Rep. 2014;16:433.

    Article  PubMed  Google Scholar 

  54. Norman J, Anderson S. Novel class of medications, orexin receptor antagonists, in the treatment of insomnia—critical appraisal of suvorexant. Nat Sci Sleep. 2016;8:239–47.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Jupp B, Krividic B, Krstew E, Lawrence AJ. The orexin (1) receptor antagonist SB-334867 dissociates the motivational properties of alcohol and sucrose in rats. Brain Res. 2011;1391:54–9. https://doi.org/10.1016/j.brainres.2011.03.045.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Panic and Respiration, Institute of Psychiatry of Federal University of Rio de Janeiro, Rio De Janeiro, Brazil

    Suzana Monteiro, Barbara Monteiro, Flavia Paes, Antônio Egídio Nardi & Sergio Machado

  2. Health School, Polytechnic Institute of Porto, Porto, Portugal

    Nuno Rocha

  3. Intercontinental Neuroscience Research Group, Porto, Portugal

    Nuno Rocha, Eric Murillo-Rodriguez & Sergio Machado

  4. Laboratorio de Neurociencias Moleculares e Integrativas, Escuela de Medicina, División Ciencias de la Salud, Universidad Anáhuac Mayab, Mérida, YUC, Mexico

    Eric Murillo-Rodriguez

  5. Grupo de Investigación en Envejecimiento, División Ciencias de la Salud, Universidad Anáhuac Mayab, Mérida, YUC, Mexico

    Eric Murillo-Rodriguez

Authors
  1. Suzana Monteiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Barbara Monteiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Flavia Paes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Antônio Egídio Nardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nuno Rocha
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eric Murillo-Rodriguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sergio Machado
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sergio Machado.

Ethics declarations

Ethical Standards

All data reported in this paper are from public repositories.

Conflict of interest

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Monteiro, S., Monteiro, B., Paes, F. et al. Neurobiological Role of Hypocretin in Regulation of Psychiatric Disorders. Sleep Vigilance 2, 33–38 (2018). https://doi.org/10.1007/s41782-017-0032-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s41782-017-0032-7

Keywords

Search

Navigation