Skip to main content
Log in

Role of Orexin in the Pathophysiology of Depression: Potential for Pharmacological Intervention

CNS Drugs Aims and scope Submit manuscript

Abstract

Depression is a devastating mental disorder with an increasing impact throughout the world, whereas the efficacy of currently available pharmacological treatment is still limited. Growing evidence from preclinical and clinical studies suggests that orexins (neuropeptides that are also known as hypocretins) and their receptors are involved in the physiopathology of depression. Indeed, the orexinergic system regulates functions that are disturbed in depressive states such as sleep, reward system, feeding behavior, the stress response and monoaminergic neurotransmission. Nevertheless, the precise role of orexins in behavioral and neurophysiological impairments observed in depression is still unclear. Both hypoactivity and hyperactivity of orexin signaling pathways have been found to be associated with depression. These discrepancies in the literature prompted the necessity for additional investigations, as the orexinergic system appears to be a promising target to treat the symptoms of depression. This assumption is underlined by recent data suggesting that pharmacological blockade of orexin receptors induces a robust antidepressant-like effect in an animal model of depression. Further preclinical and clinical studies are needed to progress the overall understanding of the orexinergic alterations in depression, which will eventually translate preliminary observations into real therapeutic potential. The aim of this paper is to provide an overview of human and animal research dedicated to the study of the specific involvement of orexins in depression, and to propose a framework in which disturbances of the orexinergic system are regarded as an integral component of the etiology of depression.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

References

  1. Bromet E, Andrade LH, Hwang I, et al. Cross-national epidemiology of DSM-IV major depressive episode. BMC Med. 2011;9:90.

    PubMed Central  PubMed  Google Scholar 

  2. Nestler EJ, Barrot M, DiLeone RJ, et al. Neurobiology of depression. Neuron. 2002;34(1):13–25.

    CAS  PubMed  Google Scholar 

  3. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006;3(11):e442.

    PubMed Central  PubMed  Google Scholar 

  4. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet. 1997;349(9064):1498–504.

    CAS  PubMed  Google Scholar 

  5. Kessler RC. The costs of depression. Psychiatr Clin N Am. 2012;35(1):1–14.

    Google Scholar 

  6. Sobocki P, Jonsson B, Angst J, et al. Cost of depression in Europe. J Ment Health Policy Econ. 2006;9(2):87–98.

    PubMed  Google Scholar 

  7. Fava GA, Offidani E. The mechanisms of tolerance in antidepressant action. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(7):1593–602.

    CAS  PubMed  Google Scholar 

  8. Ginsberg LD. Impact of drug tolerability on the selection of antidepressant treatment in patients with major depressive disorder. CNS Spectr. 2009;14(12 Suppl 12):8–14.

    Google Scholar 

  9. Kirsch I, Deacon BJ, Huedo-Medina TB, et al. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 2008;5(2):e45.

    PubMed Central  PubMed  Google Scholar 

  10. Naudet F, Maria AS, Falissard B. Antidepressant response in major depressive disorder: a meta-regression comparison of randomized controlled trials and observational studies. PLoS One. 2011;6(6):e20811.

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Belzung C, Yalcin I, Griebel G, et al. Neuropeptides in psychiatric diseases: an overview with a particular focus on depression and anxiety disorders. CNS Neurol Disord Drug Targets. 2006;5(2):135–45.

    CAS  PubMed  Google Scholar 

  12. Rotzinger S, Lovejoy DA, Tan LA. Behavioral effects of neuropeptides in rodent models of depression and anxiety. Peptides. 2010;31(4):736–56.

    CAS  PubMed  Google Scholar 

  13. Hokfelt T, Broberger C, Xu ZQ, et al. Neuropeptides: an overview. Neuropharmacology. 2000;39(8):1337–56.

    CAS  PubMed  Google Scholar 

  14. de Lecea L, Kilduff TS, Peyron C, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA. 1998;95(1):322–7.

    PubMed  Google Scholar 

  15. Sakurai T, Amemiya A, Ishii M, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 1998;92(4):573–85.

    CAS  PubMed  Google Scholar 

  16. Peyron C, Tighe DK, van den Pol AN, et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci. 1998;18(23):9996–10015.

    CAS  PubMed  Google Scholar 

  17. Marcus JN, Aschkenasi CJ, Lee CE, et al. Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol. 2001;435(1):6–25.

    CAS  PubMed  Google Scholar 

  18. Trivedi P, Yu H, MacNeil DJ, et al. Distribution of orexin receptor mRNA in the rat brain. FEBS Lett. 1998;438(1–2):71–5.

    CAS  PubMed  Google Scholar 

  19. Armitage R. Sleep and circadian rhythms in mood disorders. Acta Psychiatr Scand Suppl. 2007;433:104–15.

    PubMed  Google Scholar 

  20. Steiger A, Kimura M. Wake and sleep EEG provide biomarkers in depression. J Psychiatr Res. 2010;44(4):242–52.

    PubMed  Google Scholar 

  21. Gorwood P. Neurobiological mechanisms of anhedonia. Dialogues Clin Neurosci. 2008;10(3):291–9.

    PubMed Central  PubMed  Google Scholar 

  22. Treadway MT, Zald DH. Reconsidering anhedonia in depression: lessons from translational neuroscience. Neurosci Biobehav Rev. 2011;35(3):537–55.

    PubMed Central  PubMed  Google Scholar 

  23. Luppino FS, de Wit LM, Bouvy PF, et al. Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies. Arch Gen Psychiatry. 2010;67(3):220–9.

    PubMed  Google Scholar 

  24. Stunkard AJ, Faith MS, Allison KC. Depression and obesity. Biol Psychiatry. 2003;54(3):330–7.

    PubMed  Google Scholar 

  25. Atlantis E, Sullivan T. Bidirectional association between depression and sexual dysfunction: a systematic review and meta-analysis. J Sex Med. 2012;9(6):1497–507.

    PubMed  Google Scholar 

  26. Laurent SM, Simons AD. Sexual dysfunction in depression and anxiety: conceptualizing sexual dysfunction as part of an internalizing dimension. Clin Psychol Rev. 2009;29(7):573–85.

    PubMed  Google Scholar 

  27. Marazziti D, Consoli G, Picchetti M, et al. Cognitive impairment in major depression. Eur J Pharmacol. 2010;626(1):83–6.

    CAS  PubMed  Google Scholar 

  28. Murrough JW, Iacoviello B, Neumeister A, et al. Cognitive dysfunction in depression: neurocircuitry and new therapeutic strategies. Neurobiol Learn Mem. 2011;96(4):553–63.

    CAS  PubMed  Google Scholar 

  29. Anacker C, Zunszain PA, Carvalho LA, et al. The glucocorticoid receptor: pivot of depression and of antidepressant treatment? Psychoneuroendocrinology. 2011;36(3):415–25.

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Bao AM, Meynen G, Swaab DF. The stress system in depression and neurodegeneration: focus on the human hypothalamus. Brain Res Rev. 2008;57(2):531–53.

    CAS  PubMed  Google Scholar 

  31. Elhwuegi AS. Central monoamines and their role in major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28(3):435–51.

    CAS  PubMed  Google Scholar 

  32. Jabbi M, Korf J, Ormel J, et al. Investigating the molecular basis of major depressive disorder etiology: a functional convergent genetic approach. Ann N Y Acad Sci. 2008;1148:42–56.

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Sakurai T, Mieda M. Connectomics of orexin-producing neurons: interface of systems of emotion, energy homeostasis and arousal. Trends Pharmacol Sci. 2011;32(8):451–62.

    CAS  PubMed  Google Scholar 

  34. Aston-Jones G, Smith RJ, Moorman DE, et al. Role of lateral hypothalamic orexin neurons in reward processing and addiction. Neuropharmacology. 2009;56(Suppl 1):112–21.

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Aston-Jones G, Smith RJ, Sartor GC, et al. Lateral hypothalamic orexin/hypocretin neurons: a role in reward-seeking and addiction. Brain Res. 2010;1314:74–90.

    CAS  PubMed  Google Scholar 

  36. Thompson JL, Borgland SL. A role for hypocretin/orexin in motivation. Behav Brain Res. 2011;217(2):446–53.

    CAS  PubMed  Google Scholar 

  37. Di Sebastiano AR, Coolen LM. Orexin and natural reward: feeding, maternal, and male sexual behavior. Prog Brain Res. 2012;198:65–77.

    PubMed  Google Scholar 

  38. Cason AM, Smith RJ, Tahsili-Fahadan P, et al. Role of orexin/hypocretin in reward-seeking and addiction: implications for obesity. Physiol Behav. 2010;100(5):419–28.

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Karnani M, Burdakov D. Multiple hypothalamic circuits sense and regulate glucose levels. Am J Physiol Regul Integr Comp Physiol. 2011;300(1):R47–55.

    CAS  PubMed  Google Scholar 

  40. Di Sebastiano AR, Yong-Yow S, Wagner L, et al. Orexin mediates initiation of sexual behavior in sexually naive male rats, but is not critical for sexual performance. Horm Behav. 2010;58(3):397–404.

    PubMed Central  PubMed  Google Scholar 

  41. Di Sebastiano AR, Wilson-Perez HE, Lehman MN, et al. Lesions of orexin neurons block conditioned place preference for sexual behavior in male rats. Horm Behav. 2011;59(1):1–8.

    PubMed  Google Scholar 

  42. Akbari E, Naghdi N, Motamedi F. The selective orexin 1 receptor antagonist SB-334867-A impairs acquisition and consolidation but not retrieval of spatial memory in Morris water maze. Peptides. 2007;28(3):650–6.

    CAS  PubMed  Google Scholar 

  43. Deadwyler SA, Porrino L, Siegel JM, et al. Systemic and nasal delivery of orexin-A (hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates. J Neurosci. 2007;27(52):14239–47.

    CAS  PubMed  Google Scholar 

  44. Winsky-Sommerer R, Yamanaka A, Diano S, et al. Interaction between the corticotropin-releasing factor system and hypocretins (orexins): a novel circuit mediating stress response. J Neurosci. 2004;24(50):11439–48.

    CAS  PubMed  Google Scholar 

  45. Lopez M, Tena-Sempere M, Dieguez C. Cross-talk between orexins (hypocretins) and the neuroendocrine axes (hypothalamic–pituitary axes). Front Neuroendocrinol. 2010;31(2):113–27.

    CAS  PubMed  Google Scholar 

  46. Spinazzi R, Andreis PG, Rossi GP, et al. Orexins in the regulation of the hypothalamic–pituitary–adrenal axis. Pharmacol Rev. 2006;58(1):46–57.

    CAS  PubMed  Google Scholar 

  47. Harris GC, Aston-Jones G. Arousal and reward: a dichotomy in orexin function. Trends Neurosci. 2006;29(10):571–7.

    CAS  PubMed  Google Scholar 

  48. Estabrooke IV, McCarthy MT, Ko E, et al. Fos expression in orexin neurons varies with behavioral state. J Neurosci. 2001;21(5):1656–62.

    CAS  PubMed  Google Scholar 

  49. Johnson PL, Truitt W, Fitz SD, et al. A key role for orexin in panic anxiety. Nat Med. 2010;16(1):111–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Johnson PL, Samuels BC, Fitz SD, et al. Orexin 1 receptors are a novel target to modulate panic responses and the panic brain network. Physiol Behav. 2012;107(5):733–42.

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Salomon RM, Ripley B, Kennedy JS, et al. Diurnal variation of cerebrospinal fluid hypocretin-1 (orexin-A) levels in control and depressed subjects. Biol Psychiatry. 2003;54(2):96–104.

    CAS  PubMed  Google Scholar 

  52. Grady SP, Nishino S, Czeisler CA, et al. Diurnal variation in CSF orexin-A in healthy male subjects. Sleep. 2006;29(3):295–7.

    PubMed  Google Scholar 

  53. Brundin L, Petersen A, Bjorkqvist M, et al. Orexin and psychiatric symptoms in suicide attempters. J Affect Disord. 2007;100(1–3):259–63.

    CAS  PubMed  Google Scholar 

  54. Brundin L, Bjorkqvist M, Petersen A, et al. Reduced orexin levels in the cerebrospinal fluid of suicidal patients with major depressive disorder. Eur Neuropsychopharmacol. 2007;17(9):573–9.

    CAS  PubMed  Google Scholar 

  55. Brundin L, Bjorkqvist M, Traskman-Bendz L, et al. Increased orexin levels in the cerebrospinal fluid the first year after a suicide attempt. J Affect Disord. 2009;113(1–2):179–82.

    CAS  PubMed  Google Scholar 

  56. Fronczek R, Overeem S, Lee SY, et al. Hypocretin (orexin) loss and sleep disturbances in Parkinson’s disease. Brain. 2008;131(Pt 1):e88.

    PubMed  Google Scholar 

  57. Thannickal TC, Lai YY, Siegel JM. Hypocretin (orexin) and melanin concentrating hormone loss and the symptoms of Parkinson’s disease. Brain. 2008;131(Pt 1):e87.

    PubMed  Google Scholar 

  58. Palhagen S, Qi H, Martensson B, et al. Monoamines, BDNF, IL-6 and corticosterone in CSF in patients with Parkinson’s disease and major depression. J Neurol. 2010;257(4):524–32.

    CAS  PubMed  Google Scholar 

  59. Rainero I, Ostacoli L, Rubino E, et al. Association between major mood disorders and the hypocretin receptor 1 gene. J Affect Disord. 2011;130(3):487–91.

    CAS  PubMed  Google Scholar 

  60. Rotter A, Asemann R, Decker A, et al. Orexin expression and promoter-methylation in peripheral blood of patients suffering from major depressive disorder. J Affect Disord. 2011;131(1–3):186–92.

    CAS  PubMed  Google Scholar 

  61. von der Goltz C, Koopmann A, Dinter C, et al. Involvement of orexin in the regulation of stress, depression and reward in alcohol dependence. Horm Behav. 2011;60(5):644–50.

    PubMed  Google Scholar 

  62. Schmidt FM, Brugel M, Kratzsch J, et al. Cerebrospinal fluid hypocretin-1 (orexin A) levels in mania compared to unipolar depression and healthy controls. Neurosci Lett. 2010;483(1):20–2.

    CAS  PubMed  Google Scholar 

  63. Schmidt FM, Arendt E, Steinmetzer A, et al. CSF-hypocretin-1 levels in patients with major depressive disorder compared to healthy controls. Psychiatry Res. 2011;190(2–3):240–3.

    CAS  PubMed  Google Scholar 

  64. Allard JS, Tizabi Y, Shaffery JP, et al. Stereological analysis of the hypothalamic hypocretin/orexin neurons in an animal model of depression. Neuropeptides. 2004;38(5):311–5.

    CAS  PubMed  Google Scholar 

  65. Taheri S, Gardiner J, Hafizi S, et al. Orexin A immunoreactivity and preproorexin mRNA in the brain of Zucker and WKY rats. Neuroreport. 2001;12(3):459–64.

    CAS  PubMed  Google Scholar 

  66. Mikrouli E, Wortwein G, Soylu R, et al. Increased numbers of orexin/hypocretin neurons in a genetic rat depression model. Neuropeptides. 2011;45(6):401–6.

    CAS  PubMed  Google Scholar 

  67. Hemmeter UM, Hemmeter-Spernal J, Krieg JC. Sleep deprivation in depression. Expert Rev Neurother. 2010;10(7):1101–15.

    PubMed  Google Scholar 

  68. Allard JS, Tizabi Y, Shaffery JP, et al. Effects of rapid eye movement sleep deprivation on hypocretin neurons in the hypothalamus of a rat model of depression. Neuropeptides. 2007;41(5):329–37.

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Feng P, Vurbic D, Wu Z, et al. Brain orexins and wake regulation in rats exposed to maternal deprivation. Brain Res. 2007;1154:163–72.

    CAS  PubMed  Google Scholar 

  70. Feng P, Vurbic D, Wu Z, et al. Changes in brain orexin levels in a rat model of depression induced by neonatal administration of clomipramine. J Psychopharmacol. 2008;22(7):784–91.

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Mori T, Ito S, Kuwaki T, et al. Monoaminergic neuronal changes in orexin deficient mice. Neuropharmacology. 2010;58(4–5):826–32.

    CAS  PubMed  Google Scholar 

  72. Muraki Y, Yamanaka A, Tsujino N, et al. Serotonergic regulation of the orexin/hypocretin neurons through the 5-HT1A receptor. J Neurosci. 2004;24(32):7159–66.

    CAS  PubMed  Google Scholar 

  73. Yamanaka A, Muraki Y, Ichiki K, et al. Orexin neurons are directly and indirectly regulated by catecholamines in a complex manner. J Neurophysiol. 2006;96(1):284–98.

    CAS  PubMed  Google Scholar 

  74. Feng P, Hu Y, Li D, et al. The effect of clomipramine on wake/sleep and orexinergic expression in rats. J Psychopharmacol. 2009;23(5):559–66.

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Nocjar C, Zhang J, Feng P, et al. The social defeat animal model of depression shows diminished levels of orexin in mesocortical regions of the dopamine system, and of dynorphin and orexin in the hypothalamus. Neuroscience. 2012;218:138–53.

    CAS  PubMed  Google Scholar 

  76. Lutter M, Krishnan V, Russo SJ, et al. Orexin signaling mediates the antidepressant-like effect of calorie restriction. J Neurosci. 2008;28(12):3071–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Mahler SV, Smith RJ, Moorman DE, et al. Multiple roles for orexin/hypocretin in addiction. Prog Brain Res. 2012;198:79–121.

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Santarelli L, Saxe M, Gross C, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301(5634):805–9.

    CAS  PubMed  Google Scholar 

  79. Surget A, Tanti A, Leonardo ED, et al. Antidepressants recruit new neurons to improve stress response regulation. Mol Psychiatry. 2011;16(12):1177–88.

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Ito N, Yabe T, Gamo Y, et al. I.c.v. administration of orexin-A induces an antidepressive-like effect through hippocampal cell proliferation. Neuroscience. 2008;157(4):720–32.

    CAS  PubMed  Google Scholar 

  81. Howell OW, Doyle K, Goodman JH, et al. Neuropeptide Y stimulates neuronal precursor proliferation in the post-natal and adult dentate gyrus. J Neurochem. 2005;93(3):560–70.

    CAS  PubMed  Google Scholar 

  82. Ito N, Yabe T, Nagai T, et al. A possible mechanism underlying an antidepressive-like effect of Kososan, a Kampo medicine, via the hypothalamic orexinergic system in the stress-induced depression-like model mice. Biol Pharm Bull. 2009;32(10):1716–22.

    CAS  PubMed  Google Scholar 

  83. Adidharma W, Leach G, Yan L. Orexinergic signaling mediates light-induced neuronal activation in the dorsal raphe nucleus. Neuroscience. 2012;220:201–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Pail G, Huf W, Pjrek E, et al. Bright-light therapy in the treatment of mood disorders. Neuropsychobiology. 2011;64(3):152–62.

    CAS  PubMed  Google Scholar 

  85. Surget A, Belzung C. Unpredictable chronic mild stress in mice. In: Kalueff AV, LaPorte JL, editors. Experimental animal models in neurobehavioral research. New York: Nova Science Publishers; 2009. p. 79–112.

    Google Scholar 

  86. Nollet M, Gaillard P, Minier F, et al. Activation of orexin neurons in dorsomedial/perifornical hypothalamus and antidepressant reversal in a rodent model of depression. Neuropharmacology. 2011;61(1–2):336–46.

    CAS  PubMed  Google Scholar 

  87. Nollet M, Gaillard P, Tanti A, et al. Neurogenesis-independent antidepressant-like effects on behavior and stress axis response of a dual orexin receptor antagonist in a rodent model of depression. Neuropsychopharmacology. 2012;37(10):2210–21.

    CAS  PubMed  Google Scholar 

  88. Fanselow MS, Dong HW. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron. 2010;65(1):7–19.

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Harald B, Gordon P. Meta-review of depressive subtyping models. J Affect Disord. 2012;139(2):126–40.

    PubMed  Google Scholar 

  90. Pae CU, Tharwani H, Marks DM, et al. Atypical depression: a comprehensive review. CNS Drugs. 2009;23(12):1023–37.

    CAS  PubMed  Google Scholar 

  91. Yoshida Y, Fujiki N, Nakajima T, et al. Fluctuation of extracellular hypocretin-1 (orexin A) levels in the rat in relation to the light-dark cycle and sleep-wake activities. Eur J Neurosci. 2001;14(7):1075–81.

    CAS  PubMed  Google Scholar 

  92. Adda C, Lefevre B, Reimao R. Narcolepsy and depression. Arq Neuropsiquiatr. 1997; 55(3A):423–6.

    Google Scholar 

  93. Fortuyn HA, Lappenschaar MA, Furer JW, et al. Anxiety and mood disorders in narcolepsy: a case-control study. Gen Hosp Psychiatry. 2010;32(1):49–56.

    PubMed  Google Scholar 

  94. Reynolds CF III, Christiansen CL, Taska LS, et al. Sleep in narcolepsy and depression. Does it all look alike? J Nerv Ment Dis. 1983;171(5):290–5.

    PubMed  Google Scholar 

  95. Vourdas A, Shneerson JM, Gregory CA, et al. Narcolepsy and psychopathology: is there an association? Sleep Med. 2002;3(4):353–60.

    CAS  PubMed  Google Scholar 

  96. Kornum BR, Faraco J, Mignot E. Narcolepsy with hypocretin/orexin deficiency, infections and autoimmunity of the brain. Curr Opin Neurobiol. 2011;21(6):897–903.

    CAS  PubMed  Google Scholar 

  97. Bayard S, Abril B, Yu H, et al. Decision making in narcolepsy with cataplexy. Sleep. 2011;34(1):99–104.

    PubMed  Google Scholar 

  98. Dimitrova A, Fronczek R, Van der Ploeg J, et al. Reward-seeking behavior in human narcolepsy. J Clin Sleep Med. 2011;7(3):293–300.

    PubMed  Google Scholar 

  99. Jara CO, Popp R, Zulley J, et al. Determinants of depressive symptoms in narcoleptic patients with and without cataplexy. J Nerv Ment Dis. 2011;199(5):329–34.

    PubMed  Google Scholar 

  100. Dodel R, Peter H, Spottke A, et al. Health-related quality of life in patients with narcolepsy. Sleep Med. 2007;8(7–8):733–41.

    PubMed  Google Scholar 

  101. Fortuyn HA, Mulders PC, Renier WO, et al. Narcolepsy and psychiatry: an evolving association of increasing interest. Sleep Med. 2011;12(7):714–9.

    PubMed  Google Scholar 

  102. Scott MM, Marcus JN, Pettersen A, et al. Hcrtr1 and 2 signaling differentially regulates depression-like behaviors. Behav Brain Res. 2011;222(2):289–94.

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Johnson PL, Samuels BC, Fitz SD, et al. Activation of the orexin 1 receptor is a critical component of CO(2)-mediated anxiety and hypertension but not bradycardia. Neuropsychopharmacology. 2012;37(8):1911–22.

    CAS  PubMed  Google Scholar 

  104. Rolls A, Colas D, Adamantidis A, et al. Optogenetic disruption of sleep continuity impairs memory consolidation. Proc Natl Acad Sci USA. 2011;108(32):13305–10.

    CAS  PubMed  Google Scholar 

  105. Steiner MA, Sciarretta C, Brisbare-Roch C, et al. Examining the role of endogenous orexins in hypothalamus–pituitary–adrenal axis endocrine function using transient dual orexin receptor antagonism in the rat. Psychoneuroendocrinology. 2013;38(4):560–71.

    CAS  PubMed  Google Scholar 

  106. Guo Y, Feng P. OX2R activation induces PKC-mediated ERK and CREB phosphorylation. Exp Cell Res. 2012;318(16):2004–13.

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

Mathieu Nollet received research grants from Région Centre (France) during his Ph.D. thesis and is now an employee of Eli Lilly and Company (UK) in partnership with the University of Surrey (UK). The authors have no disclosures and have no conflicts of interest. No sources of funding were utilized for the preparation of this manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Samuel Leman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nollet, M., Leman, S. Role of Orexin in the Pathophysiology of Depression: Potential for Pharmacological Intervention. CNS Drugs 27, 411–422 (2013). https://doi.org/10.1007/s40263-013-0064-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-013-0064-z

Keywords

Navigation