Role of the Orexin/Hypocretin System in Stress-Related Psychiatric Disorders

  • Morgan H. James
  • Erin J. Campbell
  • Christopher V. DayasEmail author
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 33)


Orexins (hypocretins) are critically involved in coordinating appropriate physiological and behavioral responses to aversive and threatening stimuli. Acute stressors engage orexin neurons via direct projections from stress-sensitive brain regions. Orexin neurons, in turn, facilitate adaptive behavior via reciprocal connections as well as via direct projections to the hypophysiotropic neurons that coordinate the hypothalamic-pituitary-adrenal (HPA) axis response to stress. Consequently, hyperactivity of the orexin system is associated with increased motivated arousal and anxiety, and is emerging as a key feature of panic disorder. Accordingly, there has been significant interest in the therapeutic potential of pharmacological agents that antagonize orexin signaling at their receptors for the treatment of anxiety disorders. In contrast, disorders characterized by inappropriately low levels of motivated arousal, such as depression, generally appear to be associated with hypoactivity of the orexin system. This includes narcolepsy with cataplexy, a disorder characterized by the progressive loss of orexin neurons and increased rates of moderate/severe depression symptomology. Here, we provide a comprehensive overview of both clinical and preclinical evidence highlighting the role of orexin signaling in stress reactivity, as well as how perturbations to this system can result in dysregulated behavioral phenotypes.


Anxiety Corticosterone Depression Dual orexin receptor antagonists (DORAs) HPA axis Panic Single orexin receptor antagonists (SORAs) Stress 



This chapter was supported by project grant 510778 from the National Health and Medical Research Council (NHMRC) of Australia and NHMRC CJ Martin Fellowship (Australia) 1072706 to M.H.J.


  1. 1.
    de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS 2nd, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 95:322–327PubMedPubMedCentralGoogle Scholar
  2. 2.
    Sakurai T et al (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92:573–585Google Scholar
  3. 3.
    Carrive P, Kuwaki P (2016) Orexin and central modulation of cardiovascular and respiratory function. Curr Top Behav Neurosci. doi: 10.1007/7854_2016_46CrossRefGoogle Scholar
  4. 4.
    Walker LC, Lawrence AJ (2016) The role of orexins/hypocretins in alcohol use and abuse. Curr Top Behav Neurosci. doi: 10.1007/7854_2016_55CrossRefGoogle Scholar
  5. 5.
    James MH et al (2016) Role of the orexin/hypocretin system in stress-related psychiatric disorders. Curr Top Behav Neurosci.  10.1007/7854_2016_56
  6. 6.
    Mahler SV, Moorman DE, Smith RJ, James MH, Aston-Jones G (2014) Motivational activation: a unifying hypothesis of orexin/hypocretin function. Nat Neurosci 17:1298–1303PubMedPubMedCentralGoogle Scholar
  7. 7.
    Bonnavion P, Jackson AC, Carter ME, de Lecea L (2015) Antagonistic interplay between hypocretin and leptin in the lateral hypothalamus regulates stress responses. Nat Commun 6:6266PubMedPubMedCentralGoogle Scholar
  8. 8.
    Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, Elmquist JK (2001) Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435:6–25Google Scholar
  9. 9.
    Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, Kilduff TS (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18:9996–10015Google Scholar
  10. 10.
    Johnson PL, Molosh A, Fitz SD, Truitt WA, Shekhar A (2012) Orexin, stress, and anxiety/panic states. Prog Brain Res 198:133–161PubMedPubMedCentralGoogle Scholar
  11. 11.
    Horvath TL, Peyron C, Diano S, Ivanov A, Aston-Jones G, Kilduff TS, van Den Pol AN (1999) Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system. J Comp Neurol 415:145–159PubMedGoogle Scholar
  12. 12.
    Hagan JJ et al (1999) Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc Natl Acad Sci U S A 96:10911–10916PubMedPubMedCentralGoogle Scholar
  13. 13.
    Walling SG, Nutt DJ, Lalies MD, Harley CW (2004) Orexin-A infusion in the locus ceruleus triggers norepinephrine (NE) release and NE-induced long-term potentiation in the dentate gyrus. J Neurosci 24:7421–7426PubMedGoogle Scholar
  14. 14.
    Brown RE, Sergeeva OA, Eriksson KS, Haas HL (2002) Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine and noradrenaline). J Neurosci 22:8850–8859PubMedPubMedCentralGoogle Scholar
  15. 15.
    Trivedi P, Yu H, MacNeil DJ, Van der Ploeg LH, Guan XM (1998) Distribution of orexin receptor mRNA in the rat brain. FEBS Lett 438:71–75PubMedPubMedCentralGoogle Scholar
  16. 16.
    Tsujino N, Sakurai T (2013) Role of orexin in modulating arousal, feeding, and motivation. Front Behav Neurosci 7:28PubMedPubMedCentralGoogle Scholar
  17. 17.
    Blasiak A, Siwiec M, Grabowiecka A, Blasiak T, Czerw A, Blasiak E, Kania A, Rajfur Z, Lewandowski MH, Gundlach AL (2015) Excitatory orexinergic innervation of rat nucleus incertus – implications for ascending arousal, motivation and feeding control. Neuropharmacology 99:432–447Google Scholar
  18. 18.
    Kastman HE, Blasiak A, Walker L, Siwiec M, Krstew EV, Gundlach AL, Lawrence AJ (2016) Nucleus incertus Orexin2 receptors mediate alcohol seeking in rats. Neuropharmacology 110(Part A):82–91Google Scholar
  19. 19.
    Bayer L, Eggermann E, Serafin M, Saint-Mleux B, Machard D, Jones B, Muhlethaler M (2001) Orexins (hypocretins) directly excite tuberomammillary neurons. Eur J Neurosci 14:1571–1575PubMedGoogle Scholar
  20. 20.
    Eriksson KS, Sergeeva O, Brown RE, Haas HL (2001) Orexin/hypocretin excites the histaminergic neurons of the tuberomammillary nucleus. J Neurosci 21:9273–9279Google Scholar
  21. 21.
    Huang ZL, Qu WM, Li WD, Mochizuki T, Eguchi N, Watanabe T, Urade Y, Hayaishi O (2001) Arousal effect of orexin A depends on activation of the histaminergic system. Proc Natl Acad Sci U S A 98:9965–9970PubMedPubMedCentralGoogle Scholar
  22. 22.
    Henny P, Jones BE (2008) Projections from basal forebrain to prefrontal cortex comprise cholinergic, GABAergic and glutamatergic inputs to pyramidal cells or interneurons. Eur J Neurosci 27:654–670PubMedPubMedCentralGoogle Scholar
  23. 23.
    Rye DB, Wainer BH, Mesulam MM, Mufson EJ, Saper CB (1984) Cortical projections arising from the basal forebrain: a study of cholinergic and noncholinergic components employing combined retrograde tracing and immunohistochemical localization of choline acetyltransferase. Neuroscience 13:627–643PubMedGoogle Scholar
  24. 24.
    Arrigoni E, Mochizuki T, Scammell TE (2010) Activation of the basal forebrain by the orexin/hypocretin neurones. Acta Physiol 198:223–235Google Scholar
  25. 25.
    Fadel J, Frederick-Duus D (2008) Orexin/hypocretin modulation of the basal forebrain cholinergic system: insights from in vivo microdialysis studies. Pharmacol Biochem Behav 90:156–162PubMedGoogle Scholar
  26. 26.
    Alexandre C, Andermann ML, Scammell TE (2013) Control of arousal by the orexin neurons. Curr Opin Neurobiol 23:752–759PubMedPubMedCentralGoogle Scholar
  27. 27.
    de Lecea L (2015) Optogenetic control of hypocretin (orexin) neurons and arousal circuits. Curr Top Behav Neurosci 25:367–378PubMedPubMedCentralGoogle Scholar
  28. 28.
    Luong LN, Carrive P (2012) Orexin microinjection in the medullary raphe increases heart rate and arterial pressure but does not reduce tail skin blood flow in the awake rat. Neuroscience 202:209–217PubMedGoogle Scholar
  29. 29.
    Lazarenko RM, Stornetta RL, Bayliss DA, Guyenet PG (2011) Orexin A activates retrotrapezoid neurons in mice. Respir Physiol Neurobiol 175:283–287PubMedGoogle Scholar
  30. 30.
    Zheng H, Patterson LM, Berthoud HR (2005) Orexin-A projections to the caudal medulla and orexin-induced c-Fos expression, food intake, and autonomic function. J Comp Neurol 485:127–142PubMedGoogle Scholar
  31. 31.
    Yang B, Samson WK, Ferguson AV (2003) Excitatory effects of orexin-A on nucleus tractus solitarius neurons are mediated by phospholipase C and protein kinase C. J Neurosci 23:6215–6222Google Scholar
  32. 32.
    de Oliveira CV, Rosas-Arellano MP, Solano-Flores LP, Ciriello J (2003) Cardiovascular effects of hypocretin-1 in nucleus of the solitary tract. Am J Physiol Heart Circ Physiol 284:H1369–H1377PubMedGoogle Scholar
  33. 33.
    de Oliveira CV, Rosas-Arellano MP, Solano-Flores LP, Babic T, Li Z, Ciriello J (2003) Estrogen alters the bradycardia response to hypocretin-1 in the nucleus tractus solitarius of the ovariectomized female. Brain Res 978:14–23PubMedGoogle Scholar
  34. 34.
    Shih CD, Chuang YC (2007) Nitric oxide and GABA mediate bi-directional cardiovascular effects of orexin in the nucleus tractus solitarii of rats. Neuroscience 149:625–635PubMedGoogle Scholar
  35. 35.
    Ho YC, Lee HJ, Tung LW, Liao YY, Fu SY, Teng SF, Liao HT, Mackie K, Chiou LC (2011) Activation of orexin 1 receptors in the periaqueductal gray of male rats leads to antinociception via retrograde endocannabinoid (2-arachidonoylglycerol)-induced disinhibition. J Neurosci 31:14600–14610PubMedPubMedCentralGoogle Scholar
  36. 36.
    Azhdari Zarmehri H, Semnanian S, Fathollahi Y, Erami E, Khakpay R, Azizi H, Rohampour K (2011) Intra-periaqueductal gray matter microinjection of orexin-A decreases formalin-induced nociceptive behaviors in adult male rats. J Pain 12:280–287PubMedGoogle Scholar
  37. 37.
    Dayas CV, Buller KM, Crane JW, Xu Y, Day TA (2001) Stressor categorization: acute physical and psychological stressors elicit distinctive recruitment patterns in the amygdala and in medullary noradrenergic cell groups. Eur J Neurosci 14:1143–1152PubMedGoogle Scholar
  38. 38.
    Cluderay JE, Harrison DC, Hervieu GJ (2002) Protein distribution of the orexin-2 receptor in the rat central nervous system. Regul Pept 104:131–144PubMedGoogle Scholar
  39. 39.
    Bisetti A, Cvetkovic V, Serafin M, Bayer L, Machard D, Jones BE, Muhlethaler M (2006) Excitatory action of hypocretin/orexin on neurons of the central medial amygdala. Neuroscience 142:999–1004PubMedGoogle Scholar
  40. 40.
    Lungwitz EA, Molosh A, Johnson PL, Harvey BP, Dirks RC, Dietrich A, Minick P, Shekhar A, Truitt WA (2012) Orexin-A induces anxiety-like behavior through interactions with glutamatergic receptors in the bed nucleus of the stria terminalis of rats. Physiol Behav 107:726–732PubMedPubMedCentralGoogle Scholar
  41. 41.
    Arendt DH, Hassell J, Li H, Achua JK, Guarnieri DJ, Dileone RJ, Ronan PJ, Summers CH (2014) Anxiolytic function of the orexin 2/hypocretin A receptor in the basolateral amygdala. Psychoneuroendocrinology 40:17–26PubMedGoogle Scholar
  42. 42.
    James MH, Yeoh JW, Graham BA, Dayas CV (2012) Insights for developing pharmacological treatments for psychostimulant relapse targeting hypothalamic peptide systems. J Addict Res Ther S4:008Google Scholar
  43. 43.
    James MH, Charnley JL, Levi EM, Jones E, Yeoh JW, Smith DW, Dayas CV (2011) Orexin-1 receptor signalling within the ventral tegmental area, but not the paraventricular thalamus, is critical to regulating cue-induced reinstatement of cocaine-seeking. Int J Neuropsychopharmacol 14:684–690Google Scholar
  44. 44.
    Li Y, Li S, Wei C, Wang H, Sui N, Kirouac GJ (2010) Orexins in the paraventricular nucleus of the thalamus mediate anxiety-like responses in rats. Psychopharmacology (Berl) 212:251–265Google Scholar
  45. 45.
    Li Y, Wang H, Qi K, Chen X, Li S, Sui N, Kirouac GJ (2011) Orexins in the midline thalamus are involved in the expression of conditioned place aversion to morphine withdrawal. Physiol Behav 102:42–50PubMedGoogle Scholar
  46. 46.
    Baffi JS, Palkovits M (2000) Fine topography of brain areas activated by cold stress. A fos immunohistochemical study in rats. Neuroendocrinology 72:102–113PubMedGoogle Scholar
  47. 47.
    James MH, Dayas CV (2013) What about me…? The PVT: a role for the paraventricular thalamus (PVT) in drug-seeking behavior. Front Behav Neurosci 7:18PubMedPubMedCentralGoogle Scholar
  48. 48.
    James MH, Campbell EJ, Walker FR, Smith DW, Richardson HN, Hodgson DM, Dayas CV (2014) Exercise reverses the effects of early life stress on orexin cell reactivity in male but not female rats. Front Behav Neurosci 8:244PubMedPubMedCentralGoogle Scholar
  49. 49.
    Senba E, Matsunaga K, Tohyama M, Noguchi K (1993) Stress-induced c-fos expression in the rat brain: activation mechanism of sympathetic pathway. Brain Res Bull 31:329–344PubMedGoogle Scholar
  50. 50.
    Yeoh JW, James MH, Graham BA, Dayas CV (2014) Electrophysiological characteristics of paraventricular thalamic (PVT) neurons in response to cocaine and cocaine- and amphetamine-regulated transcript (CART). Front Behav Neurosci 8:280PubMedPubMedCentralGoogle Scholar
  51. 51.
    Ishibashi M, Takano S, Yanagida H, Takatsuna M, Nakajima K, Oomura Y, Wayner MJ, Sasaki K (2005) Effects of orexins/hypocretins on neuronal activity in the paraventricular nucleus of the thalamus in rats in vitro. Peptides 26:471–481PubMedGoogle Scholar
  52. 52.
    Huang H, Ghosh P, van den Pol AN (2006) Prefrontal cortex-projecting glutamatergic thalamic paraventricular nucleus-excited by hypocretin: a feedforward circuit that may enhance cognitive arousal. J Neurophysiol 95:1656–1668PubMedGoogle Scholar
  53. 53.
    Date Y, Mondal MS, Matsukura S, Ueta Y, Yamashita H, Kaiya H, Kangawa K, Nakazato M (2000) Distribution of orexin/hypocretin in the rat median eminence and pituitary. Brain Res Mol Brain Res 76:1–6PubMedGoogle Scholar
  54. 54.
    Sakurai T, Nagata R, Yamanaka A, Kawamura H, Tsujino N, Muraki Y, Kageyama H, Kunita S, Takahashi S, Goto K, Koyama Y, Shioda S, Yanagisawa M (2005) Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice. Neuron 46:297–308PubMedPubMedCentralGoogle Scholar
  55. 55.
    Yoshida K, McCormack S, Espana RA, Crocker A, Scammell TE (2006) Afferents to the orexin neurons of the rat brain. J Comp Neurol 494:845–861PubMedPubMedCentralGoogle Scholar
  56. 56.
    Schone C, Burdakov D (2012) Glutamate and GABA as rapid effectors of hypothalamic “peptidergic” neurons. Front Behav Neurosci 6:81PubMedPubMedCentralGoogle Scholar
  57. 57.
    Schone C, Apergis-Schoute J, Sakurai T, Adamantidis A, Burdakov D (2014) Coreleased orexin and glutamate evoke nonredundant spike outputs and computations in histamine neurons. Cell Rep 7:697–704PubMedPubMedCentralGoogle Scholar
  58. 58.
    Schone C, Cao ZF, Apergis-Schoute J, Adamantidis A, Sakurai T, Burdakov D (2012) Optogenetic probing of fast glutamatergic transmission from hypocretin/orexin to histamine neurons in situ. J Neurosci 32:12437–12443PubMedGoogle Scholar
  59. 59.
    Chou TC, Lee CE, Lu J, Elmquist JK, Hara J, Willie JT, Beuckmann CT, Chemelli RM, Sakurai T, Yanagisawa M, Saper CB, Scammell TE (2001) Orexin (hypocretin) neurons contain dynorphin. J Neurosci 21:RC168PubMedGoogle Scholar
  60. 60.
    Sartor GC, Aston-Jones GS (2012) A septal-hypothalamic pathway drives orexin neurons, which is necessary for conditioned cocaine preference. J Neurosci 32:4623–4631PubMedPubMedCentralGoogle Scholar
  61. 61.
    Johnson PL, Samuels BC, Fitz SD, Federici LM, Hammes N, Early MC, Truitt W, Lowry CA, Shekhar A (2012) Orexin 1 receptors are a novel target to modulate panic responses and the panic brain network. Physiol Behav 107:733–742PubMedPubMedCentralGoogle Scholar
  62. 62.
    Herman JP, Figueiredo H, Mueller NK, Ulrich-Lai Y, Ostrander MM, Choi DC, Cullinan WE (2003) Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical responsiveness. Front Neuroendocr 24:151–180Google Scholar
  63. 63.
    Hervieu GJ, Cluderay JE, Harrison DC, Roberts JC, Leslie RA (2001) Gene expression and protein distribution of the orexin-1 receptor in the rat brain and spinal cord. Neuroscience 103:777–797PubMedGoogle Scholar
  64. 64.
    Russell SH, Small CJ, Dakin CL, Abbott CR, Morgan DG, Ghatei MA, Bloom SR (2001) The central effects of orexin-A in the hypothalamic-pituitary-adrenal axis in vivo and in vitro in male rats. J Neuroendocrinol 13:561–566PubMedGoogle Scholar
  65. 65.
    Samson WK, Taylor MM, Follwell M, Ferguson AV (2002) Orexin actions in hypothalamic paraventricular nucleus: physiological consequences and cellular correlates. Regul Pept 104:97–103Google Scholar
  66. 66.
    Lopez M, Seoane L, Senaris RM, Dieguez C (2001) Prepro-orexin mRNA levels in the rat hypothalamus, and orexin receptors mRNA levels in the rat hypothalamus and adrenal gland are not influenced by the thyroid status. Neurosci Lett 300:171–175PubMedGoogle Scholar
  67. 67.
    Lopez M, Senaris R, Gallego R, Garcia-Caballero T, Lago F, Seoane L, Casanueva F, Dieguez C (1999) Orexin receptors are expressed in the adrenal medulla of the rat. Endocrinology 140:5991–5994PubMedGoogle Scholar
  68. 68.
    Malendowicz LK, Jedrzejczak N, Belloni AS, Trejter M, Hochol A, Nussdorfer GG (2001) Effects of orexins A and B on the secretory and proliferative activity of immature and regenerating rat adrenal glands. Histol Histopathol 16:713–717PubMedGoogle Scholar
  69. 69.
    Ziolkowska A, Spinazzi R, Albertin G, Nowak M, Malendowicz LK, Tortorella C, Nussdorfer GG (2005) Orexins stimulate glucocorticoid secretion from cultured rat and human adrenocortical cells, exclusively acting via the OX1 receptor. J Steroid Biochem Mol Biol 96:423–429PubMedGoogle Scholar
  70. 70.
    Johren O, Bruggemann N, Dendorfer A, Dominiak P (2003) Gonadal steroids differentially regulate the messenger ribonucleic acid expression of pituitary orexin type 1 receptors and adrenal orexin type 2 receptors. Endocrinology 144:1219–1225PubMedGoogle Scholar
  71. 71.
    Johren O, Neidert SJ, Kummer M, Dendorfer A, Dominiak P (2001) Prepro-orexin and orexin receptor mRNAs are differentially expressed in peripheral tissues of male and female rats. Endocrinology 142:3324–3331PubMedGoogle Scholar
  72. 72.
    Kummer M, Neidert SJ, Johren O, Dominiak P (2001) Orexin (hypocretin) gene expression in rat ependymal cells. Neuroreport 12:2117–2120PubMedGoogle Scholar
  73. 73.
    Nanmoku T, Isobe K, Sakurai T, Yamanaka A, Takekoshi K, Kawakami Y, Ishii K, Goto K, Nakai T (2000) Orexins suppress catecholamine synthesis and secretion in cultured PC12 cells. Biochem Biophys Res Commun 274:310–315PubMedGoogle Scholar
  74. 74.
    Spinazzi R, Ziolkowska A, Neri G, Nowak M, Rebuffat P, Nussdorfer GG, Andreis PG, Malendowicz LK (2005) Orexins modulate the growth of cultured rat adrenocortical cells, acting through type 1 and type 2 receptors coupled to the MAPK p42/p44- and p38-dependent cascades. Int J Mol Med 15:847–852PubMedGoogle Scholar
  75. 75.
    Mazzocchi G, Malendowicz LK, Gottardo L, Aragona F, Nussdorfer GG (2001) Orexin A stimulates cortisol secretion from human adrenocortical cells through activation of the adenylate cyclase-dependent signaling cascade. J Clin Endocrinol Metab 86:778–782PubMedGoogle Scholar
  76. 76.
    Mazzocchi G, Malendowicz LK, Aragona F, Rebuffat P, Gottardo L, Nussdorfer GG (2001) Human pheochromocytomas express orexin receptor type 2 gene and display an in vitro secretory response to orexins A and B. J Clin Endocrinol Metab 86:4818–4821PubMedGoogle Scholar
  77. 77.
    Chang H, Saito T, Ohiwa N, Tateoka M, Deocaris CC, Fujikawa T, Soya H (2007) Inhibitory effects of an orexin-2 receptor antagonist on orexin A- and stress-induced ACTH responses in conscious rats. Neurosci Res 57:462–466PubMedGoogle Scholar
  78. 78.
    Girault EM, Foppen E, Ackermans MT, Fliers E, Kalsbeek A (2013) Central administration of an orexin receptor 1 antagonist prevents the stimulatory effect of Olanzapine on endogenous glucose production. Brain Res 1527:238–245PubMedGoogle Scholar
  79. 79.
    Steiner MA, Sciarretta C, Brisbare-Roch C, Strasser DS, Studer R, Jenck F (2013) Examining the role of endogenous orexins in hypothalamus-pituitary-adrenal axis endocrine function using transient dual orexin receptor antagonism in the rat. Psychoneuroendocrinology 38:560–571PubMedGoogle Scholar
  80. 80.
    Flores A, Saravia R, Maldonado R, Berrendero F (2015) Orexins and fear: implications for the treatment of anxiety disorders. Trends Neurosci 38:550–559PubMedGoogle Scholar
  81. 81.
    Furlong TM, Vianna DM, Liu L, Carrive P (2009) Hypocretin/orexin contributes to the expression of some but not all forms of stress and arousal. Eur J Neurosci 30:1603–1614PubMedGoogle Scholar
  82. 82.
    Chen X, Li S, Kirouac GJ (2014) Blocking of corticotrophin releasing factor receptor-1 during footshock attenuates context fear but not the upregulation of prepro-orexin mRNA in rats. Pharmacol Biochem Behav 120:1–6PubMedGoogle Scholar
  83. 83.
    Chen X, Wang H, Lin Z, Li S, Li Y, Bergen HT, Vrontakis ME, Kirouac GJ (2014) Orexins (hypocretins) contribute to fear and avoidance in rats exposed to a single episode of footshocks. Brain Struct Funct 219:2103–2118PubMedGoogle Scholar
  84. 84.
    Harris GC, Aston-Jones G (2006) Arousal and reward: a dichotomy in orexin function. Trends Neurosci 29:571–577PubMedGoogle Scholar
  85. 85.
    Martins PJ, D’Almeida V, Pedrazzoli M, Lin L, Mignot E, Tufik S (2004) Increased hypocretin-1 (orexin-a) levels in cerebrospinal fluid of rats after short-term forced activity. Regul Pept 117:155–158PubMedGoogle Scholar
  86. 86.
    Morgan JI, Curran T (1991) Stimulus-transcription coupling in the nervous system: involvement of the inducible proto-oncogenes fos and jun. Annu Rev Neurosci 14:421–451Google Scholar
  87. 87.
    Panhelainen AE, Korpi ER (2012) Evidence for a role of inhibition of orexinergic neurons in the anxiolytic and sedative effects of diazepam: a c-Fos study. Pharmacol Biochem Behav 101:115–124PubMedGoogle Scholar
  88. 88.
    Laorden ML, Ferenczi S, Pinter-Kubler B, Gonzalez-Martin LL, Lasheras MC, Kovacs KJ, Milanes MV, Nunez C (2012) Hypothalamic orexin-a neurons are involved in the response of the brain stress system to morphine withdrawal. PLoS One 7:e36871PubMedPubMedCentralGoogle Scholar
  89. 89.
    Johnson PL, Federici LM, Fitz SD, Renger JJ, Shireman B, Winrow CJ, Bonaventure P, Shekhar A (2015) Orexin 1 and 2 receptor involvement in Co2-induced panic-associated behavior and autonomic responses. Depress Anxiety 32:671–683PubMedPubMedCentralGoogle Scholar
  90. 90.
    Arthaud S, Varin C, Gay N, Libourel PA, Chauveau F, Fort P, Luppi PH, Peyron C (2015) Paradoxical (REM) sleep deprivation in mice using the small-platforms-over-water method: polysomnographic analyses and melanin-concentrating hormone and hypocretin/orexin neuronal activation before, during and after deprivation. J Sleep Res 24:309–319PubMedGoogle Scholar
  91. 91.
    Kurose T, Ueta Y, Yamamoto Y, Serino R, Ozaki Y, Saito J, Nagata S, Yamashita H (2002) Effects of restricted feeding on the activity of hypothalamic Orexin (OX)-A containing neurons and OX2 receptor mRNA level in the paraventricular nucleus of rats. Regul Pept 104:145–151PubMedGoogle Scholar
  92. 92.
    Johnson PL, Truitt W, Fitz SD, Minick PE, Dietrich A, Sanghani S, Traskman-Bendz L, Goddard AW, Brundin L, Shekhar A (2010) A key role for orexin in panic anxiety. Nat Med 16:111–115Google Scholar
  93. 93.
    Campbell EJ, Watters SM, Zouikr I, Hodgson DM, Dayas CV (2015) Recruitment of hypothalamic orexin neurons after formalin injections in adult male rats exposed to a neonatal immune challenge. Front Neurosci 9:65PubMedPubMedCentralGoogle Scholar
  94. 94.
    Berridge CW, Espana RA, Vittoz NM (2010) Hypocretin/orexin in arousal and stress. Brain Res 1314:91–102PubMedGoogle Scholar
  95. 95.
    Moorman DE, James MH, Kilroy EA, Aston-Jones G (2016) Orexin/hypocretin neuron activation is correlated with alcohol seeking and preference in a topographically specific manner. Eur J Neurosci 43:710–720PubMedPubMedCentralGoogle Scholar
  96. 96.
    Ida T, Nakahara K, Katayama T, Murakami N, Nakazato M (1999) Effect of lateral cerebroventricular injection of the appetite-stimulating neuropeptide, orexin and neuropeptide Y, on the various behavioral activities of rats. Brain Res 821:526–529PubMedGoogle Scholar
  97. 97.
    Ida T, Nakahara K, Murakami T, Hanada R, Nakazato M, Murakami N (2000) Possible involvement of orexin in the stress reaction in rats. Biochem Biophys Res Commun 270:318–323PubMedGoogle Scholar
  98. 98.
    Suzuki M, Beuckmann CT, Shikata K, Ogura H, Sawai T (2005) Orexin-A (hypocretin-1) is possibly involved in generation of anxiety-like behavior. Brain Res 1044:116–121PubMedGoogle Scholar
  99. 99.
    Chung HS, Kim JG, Kim JW, Kim HW, Yoon BJ (2014) Orexin administration to mice that underwent chronic stress produces bimodal effects on emotion-related behaviors. Regul Pept 194–195:16–22PubMedGoogle Scholar
  100. 100.
    Palotai M, Telegdy G, Jászberényi M (2014) Orexin A-induced anxiety-like behavior is mediated through GABA-ergic, α- and β-adrenergic neurotransmissions in mice. Peptides 57:129–134PubMedGoogle Scholar
  101. 101.
    Li Y, Li S, Wei C, Wang H, Sui N, Kirouac GJ (2010) Changes in emotional behavior produced by orexin microinjections in the paraventricular nucleus of the thalamus. Pharmacol Biochem Behav 95:121–128PubMedGoogle Scholar
  102. 102.
    Heydendael W, Sengupta A, Beck S, Bhatnagar S (2014) Optogenetic examination identifies a context-specific role for orexins/hypocretins in anxiety-related behavior. Physiol Behav 130:182–190PubMedGoogle Scholar
  103. 103.
    Brundin L, Bjorkqvist M, Traskman-Bendz L, Petersen A (2009) Increased orexin levels in the cerebrospinal fluid the first year after a suicide attempt. J Affect Disord 113:179–182PubMedGoogle Scholar
  104. 104.
    Brundin L, Bjorkqvist M, Petersen A, Traskman-Bendz L (2007) Reduced orexin levels in the cerebrospinal fluid of suicidal patients with major depressive disorder. Eur Neuropsychopharmacol 17(9):573–579PubMedGoogle Scholar
  105. 105.
    Brundin L, Petersen A, Bjorkqvist M, Traskman-Bendz L (2007) Orexin and psychiatric symptoms in suicide attempters. J Affect Disord 100(1–3):259–263PubMedGoogle Scholar
  106. 106.
    Salomon RM, Ripley B, Kennedy JS, Johnson B, Schmidt D, Zeitzer JM, Nishino S, Mignot E (2003) Diurnal variation of cerebrospinal fluid hypocretin-1 (Orexin-A) levels in control and depressed subjects. Biol Psychiatry 54:96–104PubMedGoogle Scholar
  107. 107.
    Rotter A, Asemann R, Decker A, Kornhuber J, Biermann T (2011) Orexin expression and promoter-methylation in peripheral blood of patients suffering from major depressive disorder. J Affect Disord 131:186–192Google Scholar
  108. 108.
    Blouin AM, Fried I, Wilson CL, Staba RJ, Behnke EJ, Lam HA, Maidment NT, Karlsson KAE, Lapierre JL, Siegel JM (2013) Human hypocretin and melanin-concentrating hormone levels are linked to emotion and social interaction. Nat Commun 4:1547PubMedPubMedCentralGoogle Scholar
  109. 109.
    Gozzi A, Lepore S, Vicentini E, Merlo-Pich E, Bifone A (2013) Differential effect of orexin-1 and CRF-1 antagonism on stress circuits: a fMRI study in the rat with the pharmacological stressor Yohimbine. Neuropsychopharmacology 38:2120–2130PubMedPubMedCentralGoogle Scholar
  110. 110.
    Heydendael W, Sharma K, Iyer V, Luz S, Piel D, Beck S, Bhatnagar S (2011) Orexins/hypocretins act in the posterior paraventricular thalamic nucleus during repeated stress to regulate facilitation to novel stress. Endocrinology 152:4738–4752PubMedPubMedCentralGoogle Scholar
  111. 111.
    Plaza-Zabala A, Martin-Garcia E, de Lecea L, Maldonado R, Berrendero F (2010) Hypocretins regulate the anxiogenic-like effects of nicotine and induce reinstatement of nicotine-seeking behavior. J Neurosci 30:2300–2310PubMedPubMedCentralGoogle Scholar
  112. 112.
    Staples LG, Cornish JL (2014) The orexin-1 receptor antagonist SB-334867 attenuates anxiety in rats exposed to cat odor but not the elevated plus maze: an investigation of Trial 1 and Trial 2 effects. Horm Behav 65:294–300PubMedGoogle Scholar
  113. 113.
    Steiner MA, Lecourt H, Jenck F (2012) The brain orexin system and almorexant in fear-conditioned startle reactions in the rat. Psychopharmacology (Berl) 223:465–475Google Scholar
  114. 114.
    Vanderhaven MW, Cornish JL, Staples LG (2015) The orexin-1 receptor antagonist SB-334867 decreases anxiety-like behavior and c-Fos expression in the hypothalamus of rats exposed to cat odor. Behav Brain Res 278:563–568PubMedGoogle Scholar
  115. 115.
    Rodgers RJ, Wright FL, Snow NF, Taylor LJ (2013) Orexin-1 receptor antagonism fails to reduce anxiety-like behaviour in either plus-maze-naive or plus-maze-experienced mice. Behav Brain Res 243:213–219PubMedGoogle Scholar
  116. 116.
    Abbas MG, Shoji H, Soya S, Hondo M, Miyakawa T, Sakurai T (2015) Comprehensive behavioral analysis of male Ox1r (-/-) mice showed implication of orexin receptor-1 in mood, anxiety, and social behavior. Front Behav Neurosci 9:324PubMedPubMedCentralGoogle Scholar
  117. 117.
    Allard JS, Tizabi Y, Shaffery JP, Trouth CO, Manaye K (2004) Stereological analysis of the hypothalamic hypocretin/orexin neurons in an animal model of depression. Neuropeptides 38:311–315PubMedGoogle Scholar
  118. 118.
    Jalewa J, Wong-Lin K, McGinnity TM, Prasad G, Holscher C (2014) Increased number of orexin/hypocretin neurons with high and prolonged external stress-induced depression. Behav Brain Res 272:196–204PubMedGoogle Scholar
  119. 119.
    Kim TK, Kim JE, Park JY, Lee JE, Choi J, Kim H, Lee EH, Kim SW, Lee JK, Kang HS, Han PL (2015) Antidepressant effects of exercise are produced via suppression of hypocretin/orexin and melanin-concentrating hormone in the basolateral amygdala. Neurobiol Dis 79:59–69PubMedGoogle Scholar
  120. 120.
    Lutter M, Krishnan V, Russo SJ, Jung S, McClung CA, Nestler EJ (2008) Orexin signaling mediates the antidepressant-like effect of calorie restriction. J Neurosci 28:3071–3075PubMedPubMedCentralGoogle Scholar
  121. 121.
    Mikrouli E, Wortwein G, Soylu R, Mathe AA, Petersen A (2011) Increased numbers of orexin/hypocretin neurons in a genetic rat depression model. Neuropeptides 45:401–406PubMedGoogle Scholar
  122. 122.
    Nocjar C, Zhang J, Feng P, Panksepp J (2012) 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 218:138–153PubMedGoogle Scholar
  123. 123.
    Scott MM, Marcus JN, Pettersen A, Birnbaum SG, Mochizuki T, Scammell TE, Nestler EJ, Elmquist JK, Lutter M (2011) Hcrtr1 and 2 signaling differentially regulates depression-like behaviors. Behav Brain Res 222:289–294PubMedPubMedCentralGoogle Scholar
  124. 124.
    Taheri S, Gardiner J, Hafizi S, Murphy K, Dakin C, Seal L, Small C, Ghatei M, Bloom S (2001) Orexin A immunoreactivity and preproorexin mRNA in the brain of Zucker and WKY rats. Neuroreport 12:459–464PubMedGoogle Scholar
  125. 125.
    Feng P, Vurbic D, Wu Z, Strohl KP (2007) Brain orexins and wake regulation in rats exposed to maternal deprivation. Brain Res 1154:163–172PubMedGoogle Scholar
  126. 126.
    Nollet M, Gaillard P, Minier F, Tanti A, Belzung C, Leman S (2011) Activation of orexin neurons in dorsomedial/perifornical hypothalamus and antidepressant reversal in a rodent model of depression. Neuropharmacology 61(1–2):336–346PubMedGoogle Scholar
  127. 127.
    Nollet M, Gaillard P, Tanti A, Girault V, Belzung C, Leman S (2012) Neurogenesis-independent antidepressant-like effects on behavior and stress axis response of a dual orexin receptor antagonist in a rodent model of depression. Neuropsychopharmacology 37(10):2210–2221PubMedPubMedCentralGoogle Scholar
  128. 128.
    Arendt DH, Ronan PJ, Oliver KD, Callahan LB, Summers TR, Summers CH (2013) Depressive behavior and activation of the orexin/hypocretin system. Behav Neurosci 127(1):86–94PubMedGoogle Scholar
  129. 129.
    Deats SP, Adidharma W, Lonstein JS, Yan L (2014) Attenuated orexinergic signaling underlies depression-like responses induced by daytime light deficiency. Neuroscience 272:252–260PubMedPubMedCentralGoogle Scholar
  130. 130.
    Murgatroyd CA, Pena CJ, Podda G, Nestler EJ, Nephew BC (2015) Early life social stress induced changes in depression and anxiety associated neural pathways which are correlated with impaired maternal care. Neuropeptides 52:103–111PubMedPubMedCentralGoogle Scholar
  131. 131.
    Peyron C et al (2000) A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 6(9):991–997PubMedGoogle Scholar
  132. 132.
    Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E (2000) Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355(9197):39–40Google Scholar
  133. 133.
    Nishino S et al (2001) Low cerebrospinal fluid hypocretin (Orexin) and altered energy homeostasis in human narcolepsy. Ann Neurol 50(3):381–388PubMedGoogle Scholar
  134. 134.
    Mignot E et al (2002) The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol 59(10):1553–1562PubMedGoogle Scholar
  135. 135.
    Thannickal TC et al (2000) Reduced number of hypocretin neurons in human narcolepsy. Neuron 27(3):469–474Google Scholar
  136. 136.
    Thannickal TC, Siegel JM, Nienhuis R, Moore RY (2003) Pattern of hypocretin (orexin) soma and axon loss, and gliosis, in human narcolepsy. Brain Pathol 13(3):340–351PubMedGoogle Scholar
  137. 137.
    Crocker A et al (2005) Concomitant loss of dynorphin, NARP, and orexin in narcolepsy. Neurology 65(8):1184–1188PubMedPubMedCentralGoogle Scholar
  138. 138.
    Ramos A, Kangerski AL, Basso PF, Da Silva Santos JE, Assreuy J, Vendruscolo LF, Takahashi RN (2002) Evaluation of Lewis and SHR rat strains as a genetic model for the study of anxiety and pain. Behav Brain Res 129:113–123PubMedGoogle Scholar
  139. 139.
    Sagvolden T, Russell VA, Aase H, Johansen EB, Farshbaf M (2005) Rodent models of attention-deficit/hyperactivity disorder. Biol Psychiatry 57:1239–1247PubMedGoogle Scholar
  140. 140.
    Clifford L, Dampney BW, Carrive P (2015) Spontaneously hypertensive rats have more orexin neurons in their medial hypothalamus than normotensive rats. Exp Physiol 100:388–398PubMedGoogle Scholar
  141. 141.
    Lee Y-H, Tsai M-C, Li T-L, Dai Y-WE, Huang S-C, Hwang L-L (2015) Spontaneously hypertensive rats have more orexin neurons in the hypothalamus and enhanced orexinergic input and orexin 2 receptor-associated nitric oxide signalling in the rostral ventrolateral medulla. Exp Physiol 100:993–1007PubMedGoogle Scholar
  142. 142.
    Will CC, Aird F, Redei EE (2003) Selectively bred Wistar-Kyoto rats: an animal model of depression and hyper-responsiveness to antidepressants. Mol Psychiatry 8:925–932Google Scholar
  143. 143.
    Winslow JT, Insel TR (1991) The infant rat separation paradigm: a novel test for novel anxiolytics. Trends Pharmacol Sci 12(11):402–404PubMedGoogle Scholar
  144. 144.
    Campbell EJ, Mitchell CS, Adams CA, Yeoh JW, Hodgson DM, Graham BA, Dayas CV (2016) Chemogenetic activation of the lateral hypothalamus reverses early life stress-induced deficits in motivational drive (in preparation)Google Scholar
  145. 145.
    Boss C, Roch C (2015) Recent trends in orexin research – 2010 to 2015. Bioorg Med Chem Lett 25:2875–2887PubMedGoogle Scholar
  146. 146.
    Howland RH (2014) Suvorexant: a novel therapy for the treatment of insomnia. J Psychosoc Nurs Ment Health Serv 52:23–26PubMedGoogle Scholar
  147. 147.
    Jacobson LH, Callander GE, Hoyer D (2014) Suvorexant for the treatment of insomnia. Expert Rev Clin Pharmacol 7:711–730PubMedGoogle Scholar
  148. 148.
    Khoo SY, Brown RM (2014) Orexin/hypocretin based pharmacotherapies for the treatment of addiction: DORA or SORA? CNS Drugs 28:713–730PubMedGoogle Scholar
  149. 149.
    Michelson D, Snyder E, Paradis E, Chengan-Liu M, Snavely DB, Hutzelmann J, Walsh JK, Krystal AD, Benca RM, Cohn M, Lines C, Roth T, Herring WJ (2014) Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial. Lancet Neurol 13:461–471PubMedGoogle Scholar
  150. 150.
    Beig MI, Dampney BW, Carrive P (2015) Both Ox1r and Ox2r orexin receptors contribute to the cardiovascular and locomotor components of the novelty stress response in the rat. Neuropharmacology 89:146–156PubMedGoogle Scholar
  151. 151.
    Viviani D, Haegler P, Jenck F, Steiner MA (2015) Orexin neuropeptides contribute to the development and persistence of generalized avoidance behavior in the rat. Psychopharmacology (Berl) 232:1383–1393Google Scholar
  152. 152.
    Yeoh JW, Campbell EJ, James MH, Graham BA, Dayas CV (2014) Orexin antagonists for neuropsychiatric disease: progress and potential pitfalls. Front Neurosci 8:36PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Open Access This chapter is licensed under the terms of the Creative Commons Attribution-NonCommercial 2.5 International License (, which permits any noncommercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

Authors and Affiliations

  • Morgan H. James
    • 1
    • 2
  • Erin J. Campbell
    • 3
    • 4
  • Christopher V. Dayas
    • 3
    • 4
    Email author
  1. 1.Brain Health InstituteRutgers University/Rutgers Biomedical and Health SciencesPiscatawayUSA
  2. 2.Florey Institute of Neuroscience and Mental HealthUniversity of MelbourneParkvilleAustralia
  3. 3.School of Biomedical Sciences and Pharmacy, Centre for Brain and Mental HealthUniversity of NewcastleCallaghanAustralia
  4. 4.Hunter Medical Research InstituteNew Lambton HeightsAustralia

Personalised recommendations