The hypocretin/orexin system as a target for excessive motivation in alcohol use disorders

Abstract

The hypocretin/orexin (ORX) system has been repeatedly demonstrated to regulate motivation for drugs of abuse, including alcohol. In particular, ORX seems to be critically involved in highly motivated behaviors, as is observed in high-seeking individuals in a population, in the seeking of highly palatable substances, and in models of dependence. It seems logical that this system could be considered as a potential target for treatment for addiction, particularly alcohol addiction, as ORX pharmacological manipulations significantly reduce drinking. However, the ORX system also plays a role in a wide range of other behaviors, emotions, and physiological functions and is disrupted in a number of non-dependence-associated disorders. It is therefore important to consider how the ORX system might be optimally targeted for potential treatment for alcohol use disorders either in combination with or separate from its role in other functions or diseases. This review will focus on the role of ORX in alcohol-associated behaviors and whether and how this system could be targeted to treat alcohol use disorders while avoiding impacts on other ORX-relevant functions. A brief overview of the ORX system will be followed by a discussion of some of the factors that makes it particularly intriguing as a target for alcohol addiction treatment, a consideration of some potential challenges associated with targeting this system and, finally, some future directions to optimize new treatments.

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

References

  1. Adamantidis AR, Zhang F, Aravanis AM, Deisseroth K, de Lecea L (2007) Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 450:420–424

    CAS  PubMed  Article  Google Scholar 

  2. Aitta-Aho T, Pappa E, Burdakov D, Apergis-Schoute J (2016) Cellular activation of hypothalamic hypocretin/orexin neurons facilitates short-term spatial memory in mice. Neurobiology of learning and memory 136:183–188

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. Akbari E, Naghdi N, Motamedi F (2006) Functional inactivation of orexin 1 receptors in CA1 region impairs acquisition, consolidation and retrieval in Morris water maze task. Behavioural brain research 173:47–52

    CAS  PubMed  Article  Google Scholar 

  4. Akbari E, Naghdi N, Motamedi F (2007) The selective orexin 1 receptor antagonist SB-334867-A impairs acquisition and consolidation but not retrieval of spatial memory in Morris water maze. Peptides 28:650–656

    CAS  PubMed  Article  Google Scholar 

  5. Alcaraz-Iborra M, Carvajal F, Lerma-Cabrera JM, Valor LM, Cubero I (2014) Binge-like consumption of caloric and non-caloric palatable substances in ad libitum-fed C57BL/6J mice: pharmacological and molecular evidence of orexin involvement. Behavioural brain research 272:93–99

    CAS  PubMed  Article  Google Scholar 

  6. Alcaraz-Iborra M, Navarrete F, Rodriguez-Ortega E, de la Fuente L, Manzanares J, Cubero I (2017) Different molecular/behavioral endophenotypes in C57BL/6J mice predict the impact of OX1 receptor blockade on binge-like ethanol intake. Frontiers in behavioral neuroscience 11:186

    PubMed  PubMed Central  Article  Google Scholar 

  7. Alizamini MM, Farzinpour Z, Ezzatpanah S, Haghparast A (2017) Role of intra-accumbal orexin receptors in the acquisition of morphine-induced conditioned place preference in the rats. Neuroscience letters 660:1–5

    CAS  PubMed  Article  Google Scholar 

  8. Anderson RI, Becker HC (2017) Role of the dynorphin/kappa opioid receptor system in the motivational effects of ethanol. Alcohol Clin Exp Res 41:1402–1418

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. Anderson RI, Becker HC, Adams BL, Jesudason CD, Rorick-Kehn LM (2014) Orexin-1 and orexin-2 receptor antagonists reduce ethanol self-administration in high-drinking rodent models. Frontiers in neuroscience 8:33

    PubMed  PubMed Central  Google Scholar 

  10. Aou S, Li XL, Li AJ, Oomura Y, Shiraishi T, Sasaki K, Imamura T, Wayner MJ (2003) Orexin-A (hypocretin-1) impairs Morris water maze performance and CA1-Schaffer collateral long-term potentiation in rats. Neuroscience 119:1221–1228

    CAS  PubMed  Article  Google Scholar 

  11. Ardeshiri MR, Hosseinmardi N, Akbari E (2017) The effect of orexin 1 and orexin 2 receptors antagonisms in the basolateral amygdala on memory processing in a passive avoidance task. Physiol Behav 174:42–48

    CAS  PubMed  Article  Google Scholar 

  12. Aston-Jones G, Smith RJ, Moorman DE, Richardson KA (2009) Role of lateral hypothalamic orexin neurons in reward processing and addiction. Neuropharmacology 56(Suppl 1):112–121

    CAS  PubMed  Article  Google Scholar 

  13. Aston-Jones G, Smith RJ, Sartor GC, Moorman DE, Massi L, Tahsili-Fahadan P, Richardson KA (2010) Lateral hypothalamic orexin/hypocretin neurons: a role in reward-seeking and addiction. Brain research 1314:74–90

    CAS  PubMed  Article  Google Scholar 

  14. Baimel C, Bartlett SE, Chiou LC, Lawrence AJ, Muschamp JW, Patkar O, Tung LW, Borgland SL (2015) Orexin/hypocretin role in reward: implications for opioid and other addictions. Br J Pharmacol 172:334–348

    CAS  PubMed  Article  Google Scholar 

  15. Baimel C, Borgland SL (2017) Hypocretin/orexin and plastic adaptations associated with drug abuse. Current topics in behavioral neurosciences 33:283–304

    PubMed  Article  CAS  Google Scholar 

  16. Baimel C, Lau BK, Qiao M, Borgland SL (2017) Projection-target-defined effects of orexin and dynorphin on VTA dopamine neurons. Cell reports 18:1346–1355

    CAS  PubMed  Article  Google Scholar 

  17. Barson JR, Ho HT, Leibowitz SF (2015) Anterior thalamic paraventricular nucleus is involved in intermittent access ethanol drinking: role of orexin receptor 2. Addiction biology 20:469–481

    CAS  PubMed  Article  Google Scholar 

  18. Barson JR, Leibowitz SF (2016) Hypothalamic neuropeptide signaling in alcohol addiction. Prog Neuropsychopharmacol Biol Psychiatry 65:321–329

    CAS  PubMed  Article  Google Scholar 

  19. Barson JR, Poon K, Ho HT, Alam MI, Sanzalone L, Leibowitz SF (2017) Substance P in the anterior thalamic paraventricular nucleus: promotion of ethanol drinking in response to orexin from the hypothalamus. Addiction biology 22:58–69

    CAS  PubMed  Article  Google Scholar 

  20. Bayerlein K, Kraus T, Leinonen I, Pilniok D, Rotter A, Hofner B, Schwitulla J, Sperling W, Kornhuber J, Biermann T (2011) Orexin A expression and promoter methylation in patients with alcohol dependence comparing acute and protracted withdrawal. Alcohol 45:541–547

    CAS  PubMed  Article  Google Scholar 

  21. Becker HC (2017) Influence of stress associated with chronic alcohol exposure on drinking. Neuropharmacology 122:115–126

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. Becker HC, Lopez MF, Doremus-Fitzwater TL (2011) Effects of stress on alcohol drinking: a review of animal studies. Psychopharmacology 218:131–156

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Bentzley BS, Aston-Jones G (2015) Orexin-1 receptor signaling increases motivation for cocaine-associated cues. The European journal of neuroscience 41:1149–1156

    PubMed  PubMed Central  Article  Google Scholar 

  24. Berridge CW, Espana RA, Vittoz NM (2010) Hypocretin/orexin in arousal and stress. Brain research 1314:91–102

    CAS  PubMed  Article  Google Scholar 

  25. Bonaventure P, Yun S, Johnson PL, Shekhar A, Fitz SD, Shireman BT, Lebold TP, Nepomuceno D, Lord B, Wennerholm M, Shelton J, Carruthers N, Lovenberg T, Dugovic C (2015) A selective orexin-1 receptor antagonist attenuates stress-induced hyperarousal without hypnotic effects. J Pharmacol Exp Ther 352:590–601

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  26. Bonnavion P, Jackson AC, Carter ME, de Lecea L (2015) Antagonistic interplay between hypocretin and leptin in the lateral hypothalamus regulates stress responses. Nature communications 6:6266

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. Borgland SL, Chang SJ, Bowers MS, Thompson JL, Vittoz N, Floresco SB, Chou J, Chen BT, Bonci A (2009) Orexin A/hypocretin-1 selectively promotes motivation for positive reinforcers. The Journal of neuroscience : the official journal of the Society for Neuroscience 29:11215–11225

    CAS  Article  Google Scholar 

  28. Borgland SL, Taha SA, Sarti F, Fields HL, Bonci A (2006) Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Neuron 49:589–601

    CAS  PubMed  Article  Google Scholar 

  29. Boschen KE, Fadel JR, Burk JA (2009) Systemic and intrabasalis administration of the orexin-1 receptor antagonist, SB-334867, disrupts attentional performance in rats. Psychopharmacology 206:205–213

    CAS  PubMed  Article  Google Scholar 

  30. Boutrel B, de Lecea L (2008) Addiction and arousal: the hypocretin connection. Physiol Behav 93:947–951

    CAS  PubMed  Article  Google Scholar 

  31. Boutrel B, Kenny PJ, Specio SE, Martin-Fardon R, Markou A, Koob GF, de Lecea L (2005) Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proc Natl Acad Sci U S A 102:19168–19173

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Brisbare-Roch C, Dingemanse J, Koberstein R, Hoever P, Aissaoui H, Flores S, Mueller C, Nayler O, van Gerven J, de Haas SL, Hess P, Qiu C, Buchmann S, Scherz M, Weller T, Fischli W, Clozel M, Jenck F (2007) Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nature medicine 13:150

    CAS  PubMed  Article  Google Scholar 

  33. Brower KJ, Aldrich MS, Robinson EA, Zucker RA, Greden JF (2001) Insomnia, self-medication, and relapse to alcoholism. Am J Psychiatry 158:399–404

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Brower KJ, Perron BE (2010) Prevalence and correlates of withdrawal-related insomnia among adults with alcohol dependence: results from a national survey. The American journal on addictions 19:238–244

    PubMed  PubMed Central  Article  Google Scholar 

  35. Brown RM, Khoo SY, Lawrence AJ (2013) Central orexin (hypocretin) 2 receptor antagonism reduces ethanol self-administration, but not cue-conditioned ethanol-seeking, in ethanol-preferring rats. The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum 16: 2067-2079.

  36. Brown RM, Kim AK, Khoo SY, Kim JH, Jupp B, Lawrence AJ (2016) Orexin-1 receptor signalling in the prelimbic cortex and ventral tegmental area regulates cue-induced reinstatement of ethanol-seeking in iP rats. Addiction biology 21:603–612

    CAS  PubMed  Article  Google Scholar 

  37. Brown RM, Lawrence AJ (2013) Ascending orexinergic pathways and alcohol-seeking. Current opinion in neurobiology 23:467–472

    CAS  PubMed  Article  Google Scholar 

  38. Brundin L, Björkqvist M, Petersén Å, Träskman-Bendz L (2007) Reduced orexin levels in the cerebrospinal fluid of suicidal patients with major depressive disorder. European Neuropsychopharmacology 17:573–579

    CAS  PubMed  Article  Google Scholar 

  39. Calipari ES, Espana RA (2012) Hypocretin/orexin regulation of dopamine signaling: implications for reward and reinforcement mechanisms. Frontiers in behavioral neuroscience 6:54

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Cannella N, Economidou D, Kallupi M, Stopponi S, Heilig M, Massi M, Ciccocioppo R (2009) Persistent increase of alcohol-seeking evoked by neuropeptide S: an effect mediated by the hypothalamic hypocretin system. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 34:2125–2134

    CAS  Article  Google Scholar 

  41. Carrive P, Kuwaki T (2017) Orexin and central modulation of cardiovascular and respiratory function. Current topics in behavioral neurosciences 33:157–196

    PubMed  Article  CAS  Google Scholar 

  42. Carvajal F, Alcaraz-Iborra M, Lerma-Cabrera JM, Valor LM, de la Fuente L, Sanchez-Amate Mdel C, Cubero I (2015) Orexin receptor 1 signaling contributes to ethanol binge-like drinking: pharmacological and molecular evidence. Behavioural brain research 287:230–237

    CAS  PubMed  Article  Google Scholar 

  43. Cason AM, Aston-Jones G (2013) Attenuation of saccharin-seeking in rats by orexin/hypocretin receptor 1 antagonist. Psychopharmacology 228:499–507

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Cason AM, Smith RJ, Tahsili-Fahadan P, Moorman DE, Sartor GC, Aston-Jones G (2010) Role of orexin/hypocretin in reward-seeking and addiction: implications for obesity. Physiol Behav 100:419–428

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Center for Behavioral Health Statistics and Quality (2016) Key substance use and mental health indicators in the United States: Results from the 2015 National Survey on Drug Use and Health HHS Publication No SMA 16-4984, NSDUH Series H-51, Rockville, MD

  46. Chen Q, de Lecea L, Hu Z, Gao D (2015) The hypocretin/orexin system: an increasingly important role in neuropsychiatry. Medicinal research reviews 35:152–197

    CAS  PubMed  Article  Google Scholar 

  47. Chen X, Li S, Kirouac GJ (2014a) 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 120:1–6

    PubMed  Article  CAS  Google Scholar 

  48. Chen YW, Barson JR, Chen A, Hoebel BG, Leibowitz SF (2014b) Hypothalamic peptides controlling alcohol intake: differential effects on microstructure of drinking bouts. Alcohol 48:657–664

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Chieffi S, Carotenuto M, Monda V, Valenzano A, Villano I, Precenzano F, Tafuri D, Salerno M, Filippi N, Nuccio F, Ruberto M, De Luca V, Cipolloni L, Cibelli G, Mollica MP, Iacono D, Nigro E, Monda M, Messina G, Messina A (2017) Orexin system: the key for a healthy life. Frontiers in physiology 8:357

    PubMed  PubMed Central  Article  Google Scholar 

  50. Choi DL, Davis JF, Fitzgerald ME, Benoit SC (2010) The role of orexin-A in food motivation, reward-based feeding behavior and food-induced neuronal activation in rats. Neuroscience 167:11–20

    CAS  PubMed  Article  Google Scholar 

  51. 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. Regulatory peptides 194-195:16–22

    CAS  PubMed  Article  Google Scholar 

  52. Clegg DJ, Air EL, Woods SC, Seeley RJ (2002) Eating elicited by orexin-a, but not melanin-concentrating hormone, is opioid mediated. Endocrinology 143:2995–3000

    CAS  PubMed  Article  Google Scholar 

  53. Cluderay JE, Harrison DC, Hervieu GJ (2002) Protein distribution of the orexin-2 receptor in the rat central nervous system. Regulatory peptides 104:131–144

    CAS  PubMed  Article  Google Scholar 

  54. Coleman PJ, Gotter AL, Herring WJ, Winrow CJ, Renger JJ (2017) The discovery of suvorexant, the first orexin receptor drug for insomnia. Annu Rev Pharmacol Toxicol 57:509–533

    CAS  PubMed  Article  Google Scholar 

  55. Colrain IM, Nicholas CL, Baker FC (2014) Alcohol and the sleeping brain. Handbook of clinical neurology 125:415–431

    PubMed  PubMed Central  Article  Google Scholar 

  56. Colrain IM, Turlington S, Baker FC (2009) Impact of alcoholism on sleep architecture and EEG power spectra in men and women. Sleep 32:1341–1352

    PubMed  PubMed Central  Article  Google Scholar 

  57. Conrad KL, Davis AR, Silberman Y, Sheffler DJ, Shields AD, Saleh SA, Sen N, Matthies HJ, Javitch JA, Lindsley CW, Winder DG (2012) Yohimbine depresses excitatory transmission in BNST and impairs extinction of cocaine place preference through orexin-dependent, norepinephrine-independent processes. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 37:2253–2266

    CAS  Article  Google Scholar 

  58. Cortese S, Konofal E, Lecendreux M (2008) Alertness and feeding behaviors in ADHD: does the hypocretin/orexin system play a role? Medical hypotheses 71(5):770

    CAS  PubMed  Article  Google Scholar 

  59. Crocker A, Espana RA, Papadopoulou M, Saper CB, Faraco J, Sakurai T, Honda M, Mignot E, Scammell TE (2005) Concomitant loss of dynorphin, NARP, and orexin in narcolepsy. Neurology 65(8):1184

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Dang R, Chen Q, Song J, He C, Zhang J, Xia J, Hu Z (2018) Orexin knockout mice exhibit impaired spatial working memory. Neuroscience letters 668:92–97

    CAS  PubMed  Article  Google Scholar 

  61. Date Y, Ueta Y, Yamashita H, Yamaguchi H, Matsukura S, Kangawa K, Sakurai T, Yanagisawa M, Nakazato M (1999) Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc Natl Acad Sci U S A 96:748–753

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Dayas CV, McGranahan TM, Martin-Fardon R, Weiss F (2008) Stimuli linked to ethanol availability activate hypothalamic CART and orexin neurons in a reinstatement model of relapse. Biological psychiatry 63:152–157

    CAS  PubMed  Article  Google Scholar 

  63. 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 95:322–327

    PubMed  PubMed Central  Article  Google Scholar 

  64. Deadwyler SA, Porrino L, Siegel JM, Hampson RE (2007) Systemic and nasal delivery of orexin-A (hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates. The Journal of Neuroscience 27:14239

    CAS  PubMed  Article  Google Scholar 

  65. Dhaher R, Hauser SR, Getachew B, Bell RL, McBride WJ, McKinzie DL, Rodd ZA (2010) The orexin-1 receptor antagonist SB-334867 reduces alcohol relapse drinking, but not alcohol-seeking, in alcohol-preferring (P) rats. Journal of addiction medicine 4:153–159

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. Drummond SP, Gillin JC, Smith TL, DeModena A (1998) The sleep of abstinent pure primary alcoholic patients: natural course and relationship to relapse. Alcohol Clin Exp Res 22:1796–1802

    CAS  PubMed  Google Scholar 

  67. Ebrahim IO, Shapiro CM, Williams AJ, Fenwick PB (2013) Alcohol and sleep I: effects on normal sleep. Alcohol Clin Exp Res 37:539–549

    CAS  PubMed  Article  Google Scholar 

  68. Espana RA, Baldo BA, Kelley AE, Berridge CW (2001) Wake-promoting and sleep-suppressing actions of hypocretin (orexin): basal forebrain sites of action. Neuroscience 106:699–715

    CAS  PubMed  Article  Google Scholar 

  69. Espana RA, Melchior JR, Roberts DC, Jones SR (2011) Hypocretin 1/orexin A in the ventral tegmental area enhances dopamine responses to cocaine and promotes cocaine self-administration. Psychopharmacology 214:415–426

    CAS  PubMed  Article  Google Scholar 

  70. Espana RA, Oleson EB, Locke JL, Brookshire BR, Roberts DCS, Jones SR (2010) The hypocretin-orexin system regulates cocaine self-administration via actions on the mesolimbic dopamine system. European Journal of Neuroscience 31:336–348

    PubMed  Article  Google Scholar 

  71. Fadel J, Burk JA (2010) Orexin/hypocretin modulation of the basal forebrain cholinergic system: role in attention. Brain research 1314:112–123

    CAS  PubMed  Article  Google Scholar 

  72. Farahimanesh S, Zarrabian S, Haghparast A (2017) Role of orexin receptors in the ventral tegmental area on acquisition and expression of morphine-induced conditioned place preference in the rats. Neuropeptides.

  73. Flores A, Herry C, Maldonado R, Berrendero F (2017) Facilitation of contextual fear extinction by orexin-1 receptor antagonism is associated with the activation of specific amygdala cell subpopulations. The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum 20:654–659

    Article  Google Scholar 

  74. Flores A, Saravia R, Maldonado R, Berrendero F (2015) Orexins and fear: implications for the treatment of anxiety disorders. Trends Neurosci 38(9):550

    CAS  PubMed  Article  Google Scholar 

  75. Flores A, Valls-Comamala V, Costa G, Saravia R, Maldonado R, Berrendero F (2014) The hypocretin/orexin system mediates the extinction of fear memories. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 39:2732–2741

    CAS  Article  Google Scholar 

  76. Furutani N, Hondo M, Kageyama H, Tsujino N, Mieda M, Yanagisawa M, Shioda S, Sakurai T (2013) Neurotensin co-expressed in orexin-producing neurons in the lateral hypothalamus plays an important role in regulation of sleep/wakefulness states. PloS one 8:e62391

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. Georgescu D, Zachariou V, Barrot M, Mieda M, Willie JT, Eisch AJ, Yanagisawa M, Nestler EJ, DiLeone RJ (2003) Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal. The Journal of neuroscience : the official journal of the Society for Neuroscience 23:3106–3111

    CAS  Article  Google Scholar 

  78. Giardino WJ, de Lecea L (2014) Hypocretin (orexin) neuromodulation of stress and reward pathways. Current opinion in neurobiology 29:103–108

    CAS  PubMed  Article  Google Scholar 

  79. Gonzalez JA, Jensen LT, Fugger L, Burdakov D (2012) Convergent inputs from electrically and topographically distinct orexin cells to locus coeruleus and ventral tegmental area. The European journal of neuroscience 35:1426–1432

    PubMed  PubMed Central  Article  Google Scholar 

  80. Graebner AK, Iyer M, Carter ME (2015) Understanding how discrete populations of hypothalamic neurons orchestrate complicated behavioral states. Frontiers in systems neuroscience 9:111

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  81. Hagan JJ, Leslie RA, Patel S, Evans ML, Wattam TA, Holmes S, Benham CD, Taylor SG, Routledge C, Hemmati P, Munton RP, Ashmeade TE, Shah AS, Hatcher JP, Hatcher PD, Jones DN, Smith MI, Piper DC, Hunter AJ, Porter RA, Upton N (1999) Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc Natl Acad Sci U S A 96:10911–10916

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. Hakansson M, de Lecea L, Sutcliffe JG, Yanagisawa M, Meister B (1999) Leptin receptor- and STAT3-immunoreactivities in hypocretin/orexin neurones of the lateral hypothalamus. Journal of neuroendocrinology 11: 653-663.

  83. Hamlin AS, Newby J, McNally GP (2007) The neural correlates and role of D1 dopamine receptors in renewal of extinguished alcohol-seeking. Neuroscience 146:525–536

    CAS  PubMed  Article  Google Scholar 

  84. Harris GC, Aston-Jones G (2006) Arousal and reward: a dichotomy in orexin function. Trends Neurosci 29:571–577

    CAS  PubMed  Article  Google Scholar 

  85. Harris GC, Wimmer M, Aston-Jones G (2005) A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437:556–559

    CAS  PubMed  Article  Google Scholar 

  86. Harris GC, Wimmer M, Randall-Thompson JF, Aston-Jones G (2007) Lateral hypothalamic orexin neurons are critically involved in learning to associate an environment with morphine reward. Behavioural brain research 183:43–51

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. Harthoorn LF, Sane A, Nethe M, Van Heerikhuize JJ (2005) Multi-transcriptional profiling of melanin-concentrating hormone and orexin-containing neurons. Cellular and molecular neurobiology 25:1209–1223

    PubMed  Article  Google Scholar 

  88. Henny P, Brischoux F, Mainville L, Stroh T, Jones BE (2010) Immunohistochemical evidence for synaptic release of glutamate from orexin terminals in the locus coeruleus. Neuroscience 169:1150–1157

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 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 103:777–797

    CAS  PubMed  Article  Google Scholar 

  90. Hollander JA, Lu Q, Cameron MD, Kamenecka TM, Kenny PJ (2008) Insular hypocretin transmission regulates nicotine reward. Proc Natl Acad Sci U S A 105:19480–19485

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. Hollander JA, Pham D, Fowler CD, Kenny PJ (2012) Hypocretin-1 receptors regulate the reinforcing and reward-enhancing effects of cocaine: pharmacological and behavioral genetics evidence. Frontiers in behavioral neuroscience 6:47

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. Hoyer D, Jacobson LH (2013) Orexin in sleep, addiction and more: is the perfect insomnia drug at hand? Neuropeptides 47:477–488

    CAS  PubMed  Article  Google Scholar 

  93. Jacobson LH, Chen S, Mir S, Hoyer D (2017) Orexin OX2 receptor antagonists as sleep aids. Current topics in behavioral neurosciences 33:105–136

    PubMed  Article  CAS  Google Scholar 

  94. Jaeger LB, Farr SA, Banks WA, Morley JE (2002) Effects of orexin-A on memory processing. Peptides 23:1683–1688

    CAS  PubMed  Article  Google Scholar 

  95. James MH, Campbell EJ, Dayas CV (2017a) Role of the orexin/hypocretin system in stress-related psychiatric disorders. Current topics in behavioral neurosciences 33:197–219

    PubMed  Article  CAS  Google Scholar 

  96. 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. The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP) 14:684–690

    CAS  Article  Google Scholar 

  97. James MH, Dayas CV (2013) What about me...? The PVT: a role for the paraventricular thalamus (PVT) in drug-seeking behavior. Frontiers in behavioral neuroscience 7:18

    PubMed  PubMed Central  Article  Google Scholar 

  98. James MH, Mahler SV, Moorman DE, Aston-Jones G (2017b) A decade of orexin/hypocretin and addiction: where are we now? Current topics in behavioral neurosciences 33:247–281

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  99. Johnson PL, Molosh A, Fitz SD, Truitt WA, Shekhar A (2012) Orexin, stress, and anxiety/panic states. Progress in brain research 198:133–161

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. 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. Nature medicine 16:111–115

    CAS  PubMed  Article  Google Scholar 

  101. Jupp B, Krivdic B, Krstew E, Lawrence AJ (2011a) The orexin(1) receptor antagonist SB-334867 dissociates the motivational properties of alcohol and sucrose in rats. Brain research 1391:54–59

    CAS  PubMed  Article  Google Scholar 

  102. Jupp B, Krstew E, Dezsi G, Lawrence AJ (2011b) Discrete cue-conditioned alcohol-seeking after protracted abstinence: pattern of neural activation and involvement of orexin(1) receptors. Br J Pharmacol 162:880–889

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. 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 110:82–91

    CAS  PubMed  Article  Google Scholar 

  104. Kay K, Parise EM, Lilly N, Williams DL (2014) Hindbrain orexin 1 receptors influence palatable food intake, operant responding for food, and food-conditioned place preference in rats. Psychopharmacology 231:419–427

    CAS  PubMed  Article  Google Scholar 

  105. Khoo SY, Brown RM (2014) Orexin/hypocretin based pharmacotherapies for the treatment of addiction: DORA or SORA? CNS drugs 28:713–730

    CAS  PubMed  Article  Google Scholar 

  106. Kiyashchenko LI, Mileykovskiy BY, Lai YY, Siegel JM (2001) Increased and decreased muscle tone with orexin (hypocretin) microinjections in the locus coeruleus and pontine inhibitory area. Journal of neurophysiology 85:2008–2016

    CAS  PubMed  Article  Google Scholar 

  107. Koob GF (2008) A role for brain stress systems in addiction. Neuron 59:11–34

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. Koob GF (2009) Brain stress systems in the amygdala and addiction. Brain research 1293:61–75

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. Koob GF (2014) Neurocircuitry of alcohol addiction: synthesis from animal models. Handbook of clinical neurology 125:33–54

    PubMed  Article  Google Scholar 

  110. Koob GF (2015) The dark side of emotion: the addiction perspective. European journal of pharmacology.

    Google Scholar 

  111. Koob GF, Buck CL, Cohen A, Edwards S, Park PE, Schlosburg JE, Schmeichel B, Vendruscolo LF, Wade CL, Whitfield TW, Jr., George O (2014) Addiction as a stress surfeit disorder. Neuropharmacology 76 Pt B: 370-82.

  112. Koob GF, Volkow ND (2016) Neurobiology of addiction: a neurocircuitry analysis. The lancet Psychiatry 3:760–773

    PubMed  Article  PubMed Central  Google Scholar 

  113. Kummangal BA, Kumar D, Mallick HN (2013) Intracerebroventricular injection of orexin-2 receptor antagonist promotes REM sleep. Behavioural brain research 237:59–62

    CAS  PubMed  Article  Google Scholar 

  114. Kuwaki T (2015) Thermoregulation under pressure: a role for orexin neurons. Temperature 2:379–391

    Article  Google Scholar 

  115. Kuwaki T, Zhang W (2012) Orexin neurons and emotional stress. Vitamins and hormones 89:135–158

    CAS  PubMed  Article  Google Scholar 

  116. Lawrence AJ (2010) Regulation of alcohol-seeking by orexin (hypocretin) neurons. Brain research 1314:124–129

    CAS  PubMed  Article  Google Scholar 

  117. Lawrence AJ, Cowen MS, Yang HJ, Chen F, Oldfield B (2006) The orexin system regulates alcohol-seeking in rats. Br J Pharmacol 148:752–759

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. Le Berre AP, Fama R, Sullivan EV (2017) Executive functions, memory, and social cognitive deficits and recovery in chronic alcoholism: a critical review to inform future research. Alcohol Clin Exp Res 41:1432–1443

    PubMed  Article  PubMed Central  Google Scholar 

  119. Lei K, Wegner SA, Yu JH, Hopf FW (2016a) Orexin-1 receptor blockade suppresses compulsive-like alcohol drinking in mice. Neuropharmacology 110:431–437

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. Lei K, Wegner SA, Yu JH, Mototake A, Hu B, Hopf FW (2016b) Nucleus accumbens shell and mPFC but not insula orexin-1 receptors promote excessive alcohol drinking. Frontiers in neuroscience 10:400

    PubMed  PubMed Central  Article  Google Scholar 

  121. Li Y, van den Pol AN (2006) Differential target-dependent actions of coexpressed inhibitory dynorphin and excitatory hypocretin/orexin neuropeptides. The Journal of neuroscience : the official journal of the Society for Neuroscience 26:13037–13047

    CAS  Article  Google Scholar 

  122. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, Amann M, Anderson HR, Andrews KG, Aryee M, Atkinson C, Bacchus LJ, Bahalim AN, Balakrishnan K, Balmes J, Barker-Collo S, Baxter A, Bell ML, Blore JD, Blyth F, Bonner C, Borges G, Bourne R, Boussinesq M, Brauer M, Brooks P, Bruce NG, Brunekreef B, Bryan-Hancock C, Bucello C, Buchbinder R, Bull F, Burnett RT, Byers TE, Calabria B, Carapetis J, Carnahan E, Chafe Z, Charlson F, Chen H, Chen JS, Cheng AT, Child JC, Cohen A, Colson KE, Cowie BC, Darby S, Darling S, Davis A, Degenhardt L, Dentener F, Des Jarlais DC, Devries K, Dherani M, Ding EL, Dorsey ER, Driscoll T, Edmond K, Ali SE, Engell RE, Erwin PJ, Fahimi S, Falder G, Farzadfar F, Ferrari A, Finucane MM, Flaxman S, Fowkes FG, Freedman G, Freeman MK, Gakidou E, Ghosh S, Giovannucci E, Gmel G, Graham K, Grainger R, Grant B, Gunnell D, Gutierrez HR, Hall W, Hoek HW, Hogan A, Hosgood HD, 3rd, Hoy D, Hu H, Hubbell BJ, Hutchings SJ, Ibeanusi SE, Jacklyn GL, Jasrasaria R, Jonas JB, Kan H, Kanis JA, Kassebaum N, Kawakami N, Khang YH, Khatibzadeh S, Khoo JP, Kok C, Laden F, Lalloo R, Lan Q, Lathlean T, Leasher JL, Leigh J, Li Y, Lin JK, Lipshultz SE, London S, Lozano R, Lu Y, Mak J, Malekzadeh R, Mallinger L, Marcenes W, March L, Marks R, Martin R, McGale P, McGrath J, Mehta S, Mensah GA, Merriman TR, Micha R, Michaud C, Mishra V, Mohd Hanafiah K, Mokdad AA, Morawska L, Mozaffarian D, Murphy T, Naghavi M, Neal B, Nelson PK, Nolla JM, Norman R, Olives C, Omer SB, Orchard J, Osborne R, Ostro B, Page A, Pandey KD, Parry CD, Passmore E, Patra J, Pearce N, Pelizzari PM, Petzold M, Phillips MR, Pope D, Pope CA, 3rd, Powles J, Rao M, Razavi H, Rehfuess EA, Rehm JT, Ritz B, Rivara FP, Roberts T, Robinson C, Rodriguez-Portales JA, Romieu I, Room R, Rosenfeld LC, Roy A, Rushton L, Salomon JA, Sampson U, Sanchez-Riera L, Sanman E, Sapkota A, Seedat S, Shi P, Shield K, Shivakoti R, Singh GM, Sleet DA, Smith E, Smith KR, Stapelberg NJ, Steenland K, Stockl H, Stovner LJ, Straif K, Straney L, Thurston GD, Tran JH, Van Dingenen R, van Donkelaar A, Veerman JL, Vijayakumar L, Weintraub R, Weissman MM, White RA, Whiteford H, Wiersma ST, Wilkinson JD, Williams HC, Williams W, Wilson N, Woolf AD, Yip P, Zielinski JM, Lopez AD, Murray CJ, Ezzati M, AlMazroa MA, Memish ZA (2012) A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380: 2224-2260.

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

    CAS  PubMed  Article  Google Scholar 

  124. Litten RZ, Falk DE, Ryan ML, Fertig JB (2016) Discovery, development, and adoption of medications to treat alcohol use disorder: goals for the phases of medications development. Alcohol Clin Exp Res 40:1368–1379

    PubMed  PubMed Central  Article  Google Scholar 

  125. Lopez MF, Moorman DE, Aston-Jones G, Becker HC (2016) The highly selective orexin/hypocretin 1 receptor antagonist GSK1059865 potently reduces ethanol drinking in ethanol dependent mice. Brain research.

  126. Lutter M, Krishnan V, Russo SJ, Jung S, McClung CA, Nestler EJ (2008) Orexin signaling mediates the antidepressant-like effect of calorie restriction. The Journal of neuroscience : the official journal of the Society for Neuroscience 28:3071–3075

    CAS  Article  Google Scholar 

  127. Macedo GC, Kawakami SE, Vignoli T, Sinigaglia-Coimbra R, Suchecki D (2013) The influence of orexins on ethanol-induced behavioral sensitization in male mice. Neuroscience letters 551:84–88

    CAS  PubMed  Article  Google Scholar 

  128. Madden CJ, Tupone D, Morrison SF (2012) Orexin modulates brown adipose tissue thermogenesis. Biomolecular concepts 3:381–386

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. Mahler SV, Moorman DE, Smith RJ, James MH, Aston-Jones G (2014) Motivational activation: a unifying hypothesis of orexin/hypocretin function. Nature neuroscience 17:1298–1303

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. Mahler SV, Smith RJ, Aston-Jones G (2012a) Interactions between VTA orexin and glutamate in cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology.

  131. Mahler SV, Smith RJ, Moorman DE, Sartor GC, Aston-Jones G (2012b) Multiple roles for orexin/hypocretin in addiction. Progress in brain research 198:79–121

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 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. The Journal of comparative neurology 435:6–25

    CAS  PubMed  Article  Google Scholar 

  133. Martin-Fardon R, Boutrel B (2012) Orexin/hypocretin (Orx/Hcrt) transmission and drug-seeking behavior: is the paraventricular nucleus of the thalamus (PVT) part of the drug seeking circuitry? Frontiers in behavioral neuroscience 6:75

    PubMed  PubMed Central  Article  Google Scholar 

  134. Martin-Fardon R, Weiss F (2014) N-(2-methyl-6-benzoxazolyl)-N'-1,5-naphthyridin-4-yl urea (SB334867), a hypocretin receptor-1 antagonist, preferentially prevents ethanol seeking: comparison with natural reward seeking. Addiction biology 19:233–236

    CAS  PubMed  Article  Google Scholar 

  135. Matzeu A, Kallupi M, George O, Schweitzer P, Martin-Fardon R (2017) Dynorphin counteracts orexin in the paraventricular nucleus of the thalamus: cellular and behavioral evidence. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology.

  136. Matzeu A, Kerr TM, Weiss F, Martin-Fardon R (2016) Orexin-A/hypocretin-1 mediates cocaine-seeking behavior in the posterior paraventricular nucleus of the thalamus via orexin/hypocretin receptor-2. J Pharmacol Exp Ther 359:273–279

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. Matzeu A, Zamora-Martinez ER, Martin-Fardon R (2014) The paraventricular nucleus of the thalamus is recruited by both natural rewards and drugs of abuse: recent evidence of a pivotal role for orexin/hypocretin signaling in this thalamic nucleus in drug-seeking behavior. Frontiers in behavioral neuroscience 8:117

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  138. Mavanji V, Butterick TA, Duffy CM, Nixon JP, Billington CJ, Kotz CM (2017) Orexin/hypocretin treatment restores hippocampal-dependent memory in orexin-deficient mice. Neurobiology of learning and memory 146:21–30

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. McGregor R, Wu MF, Barber G, Ramanathan L, Siegel JM (2011) Highly specific role of hypocretin (orexin) neurons: differential activation as a function of diurnal phase, operant reinforcement versus operant avoidance and light level. The Journal of neuroscience : the official journal of the Society for Neuroscience 31:15455–15467

    CAS  Article  Google Scholar 

  140. Mileykovskiy BY, Kiyashchenko LI, Siegel JM (2002) Muscle tone facilitation and inhibition after orexin-a (hypocretin-1) microinjections into the medial medulla. Journal of neurophysiology 87:2480–2489

    CAS  PubMed  Article  Google Scholar 

  141. Millan EZ, Furlong TM, McNally GP (2010) Accumbens shell-hypothalamus interactions mediate extinction of alcohol seeking. The Journal of neuroscience : the official journal of the Society for Neuroscience 30:4626–4635

    CAS  Article  Google Scholar 

  142. Moore MW, Akladious A, Hu Y, Azzam S, Feng P, Strohl KP (2014) Effects of orexin 2 receptor activation on apnea in the C57BL/6J mouse. Respiratory physiology & neurobiology 200:118–125

    CAS  Article  Google Scholar 

  143. Moorman DE, Aston-Jones G (2009) Orexin-1 receptor antagonism decreases ethanol consumption and preference selectively in high-ethanol-preferring Sprague-Dawley rats. Alcohol 43:379–386

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. 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. The European journal of neuroscience 43:710–720

    PubMed  PubMed Central  Article  Google Scholar 

  145. Moorman DE, James MH, Kilroy EA, Aston-Jones G (2017) Orexin/hypocretin-1 receptor antagonism reduces ethanol self-administration and reinstatement selectively in highly-motivated rats. Brain research 1654:34–42

    CAS  PubMed  Article  Google Scholar 

  146. Morganstern I, Chang GQ, Barson JR, Ye Z, Karatayev O, Leibowitz SF (2010) Differential effects of acute and chronic ethanol exposure on orexin expression in the perifornical lateral hypothalamus. Alcohol Clin Exp Res 34:886–896

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. Muschamp JW, Hollander JA, Thompson JL, Voren G, Hassinger LC, Onvani S, Kamenecka TM, Borgland SL, Kenny PJ, Carlezon WA Jr (2014) Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area. Proc Natl Acad Sci U S A 111:E1648–E1655

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. Nair SG, Golden SA, Shaham Y (2008) Differential effects of the hypocretin 1 receptor antagonist SB 334867 on high-fat food self-administration and reinstatement of food seeking in rats. Br J Pharmacol 154:406–416

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  149. Nambu T, Sakurai T, Mizukami K, Hosoya Y, Yanagisawa M, Goto K (1999) Distribution of orexin neurons in the adult rat brain. Brain research 827:243–260

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  151. Nixon JP, Smale L (2007) A comparative analysis of the distribution of immunoreactive orexin A and B in the brains of nocturnal and diurnal rodents. Behavioral and brain functions : BBF 3:28

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  152. 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 218:138–153

    CAS  PubMed  Article  Google Scholar 

  153. 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 61:336–346

    CAS  PubMed  Article  Google Scholar 

  154. Nollet M, Leman S (2013) Role of orexin in the pathophysiology of depression: potential for pharmacological intervention. CNS drugs 27:411–422

    CAS  PubMed  Article  Google Scholar 

  155. Oldfield BJ, Giles ME, Watson A, Anderson C, Colvill LM, McKinley MJ (2002) The neurochemical characterisation of hypothalamic pathways projecting polysynaptically to brown adipose tissue in the rat. Neuroscience 110:515–526

    CAS  PubMed  Article  Google Scholar 

  156. Olney JJ, Navarro M, Thiele TE (2015) Binge-like consumption of ethanol and other salient reinforcers is blocked by orexin-1 receptor inhibition and leads to a reduction of hypothalamic orexin immunoreactivity. Alcohol Clin Exp Res 39:21–29

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  157. Olney JJ, Navarro M, Thiele TE (2017) The role of orexin signaling in the ventral tegmental area and central amygdala in modulating binge-like ethanol drinking behavior. Alcohol Clin Exp Res 41:551–561

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. Oscar-Berman M, Marinkovic K (2007) Alcohol: effects on neurobehavioral functions and the brain. Neuropsychology review 17:239–257

    PubMed  PubMed Central  Article  Google Scholar 

  159. Palotai M, Telegdy G, Ekwerike A, Jaszberenyi M (2014) The action of orexin B on passive avoidance learning. Involvement of neurotransmitters. Behavioural brain research 272:1–7

    CAS  PubMed  Article  Google Scholar 

  160. Palpacuer C, Duprez R, Huneau A, Locher C, Boussageon R, Laviolle B, Naudet F (2017) Pharmacologically controlled drinking in the treatment of alcohol dependence or alcohol use disorders: a systematic review with direct and network meta-analyses on nalmefene, naltrexone, acamprosate, baclofen and topiramate. Addiction.

  161. 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. The Journal of neuroscience : the official journal of the Society for Neuroscience 18:9996–10015

    CAS  Article  Google Scholar 

  162. Piantadosi PT, Holmes A, Roberts BM, Bailey AM (2015) Orexin receptor activity in the basal forebrain alters performance on an olfactory discrimination task. Brain research 1594:215–222

    CAS  PubMed  Article  Google Scholar 

  163. Piccoli L, Micioni Di Bonaventura MV, Cifani C, Costantini VJ, Massagrande M, Montanari D, Martinelli P, Antolini M, Ciccocioppo R, Massi M, Merlo-Pich E, Di Fabio R, Corsi M (2012) Role of orexin-1 receptor mechanisms on compulsive food consumption in a model of binge eating in female rats. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 37: 1999-2011.

  164. Plaza-Zabala A, Flores A, Martin-Garcia E, Saravia R, Maldonado R, Berrendero F (2013a) A role for hypocretin/orexin receptor-1 in cue-induced reinstatement of nicotine-seeking behavior. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 38:1724–1736

    CAS  Article  Google Scholar 

  165. Plaza-Zabala A, Li X, Milovanovic M, Loweth JA, Maldonado R, Berrendero F, Wolf ME (2013b) An investigation of interactions between hypocretin/orexin signaling and glutamate receptor surface expression in the rat nucleus accumbens under basal conditions and after cocaine exposure. Neuroscience letters 557 Pt B: 101-6.

  166. Plaza-Zabala A, Maldonado R, Berrendero F (2012) The hypocretin/orexin system: implications for drug reward and relapse. Molecular neurobiology 45:424–439

    CAS  PubMed  Article  Google Scholar 

  167. Porter-Stransky KA, Bentzley BS, Aston-Jones G (2015) Individual differences in orexin-I receptor modulation of motivation for the opioid remifentanil. Addiction biology.

  168. Prince CD, Rau AR, Yorgason JT, Espana RA (2015) Hypocretin/orexin regulation of dopamine signaling and cocaine self-administration is mediated predominantly by hypocretin receptor 1. ACS chemical neuroscience 6:138–146

    CAS  PubMed  Article  Google Scholar 

  169. Qi K, Wei C, Li Y, Sui N (2013) Orexin receptors within the nucleus accumbens shell mediate the stress but not drug priming-induced reinstatement of morphine conditioned place preference. Frontiers in behavioral neuroscience 7:144

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  170. Reti IM, Reddy R, Worley PF, Baraban JM (2002) Selective expression of Narp, a secreted neuronal pentraxin, in orexin neurons. J Neurochem 82:1561–1565

    CAS  PubMed  Article  Google Scholar 

  171. Riahi E, Khodagholi F, Haghparast A (2013) Role of dorsal hippocampal orexin-1 receptors in associating morphine reward with contextual stimuli. Behavioural pharmacology 24:237–248

    CAS  PubMed  Article  Google Scholar 

  172. Richards JK, Simms JA, Steensland P, Taha SA, Borgland SL, Bonci A, Bartlett SE (2008) Inhibition of orexin-1/hypocretin-1 receptors inhibits yohimbine-induced reinstatement of ethanol and sucrose seeking in Long-Evans rats. Psychopharmacology 199:109–117

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  173. Richardson KA, Aston-Jones G (2012) Lateral hypothalamic orexin/hypocretin neurons that project to ventral tegmental area are differentially activated with morphine preference. Journal of Neuroscience 32:3809–3817

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  174. Risold PY, Griffond B, Kilduff TS, Sutcliffe JG, Fellmann D (1999) Preprohypocretin (orexin) and prolactin-like immunoreactivity are coexpressed by neurons of the rat lateral hypothalamic area. Neuroscience letters 259:153–156

    CAS  PubMed  Article  Google Scholar 

  175. Roehrs T, Roth T (2001) Sleep, sleepiness, and alcohol use. Alcohol research & health : the journal of the National Institute on Alcohol Abuse and Alcoholism 25: 101-109.

  176. Rosin DL, Weston MC, Sevigny CP, Stornetta RL, Guyenet PG (2003) Hypothalamic orexin (hypocretin) neurons express vesicular glutamate transporters VGLUT1 or VGLUT2. The Journal of comparative neurology 465:593–603

    CAS  PubMed  Article  Google Scholar 

  177. Sadeghi B, Ezzatpanah S, Haghparast A (2016) Effects of dorsal hippocampal orexin-2 receptor antagonism on the acquisition, expression, and extinction of morphine-induced place preference in rats. Psychopharmacology 233:2329–2341

    CAS  PubMed  Article  Google Scholar 

  178. Sadeghzadeh F, Namvar P, Naghavi FS, Haghparast A (2016) Differential effects of intra-accumbal orexin-1 and -2 receptor antagonists on the expression and extinction of morphine-induced conditioned place preference in rats. Pharmacol Biochem Behav 142:8–14

    CAS  PubMed  Article  Google Scholar 

  179. Sakurai T (2007) The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nature reviews Neuroscience 8:171–181

    CAS  PubMed  Article  Google Scholar 

  180. Sakurai T (2014) The role of orexin in motivated behaviours. Nature reviews Neuroscience 15:719–731

    CAS  PubMed  Article  Google Scholar 

  181. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92:573–585

    CAS  PubMed  Article  Google Scholar 

  182. Schmeichel BE, Herman MA, Roberto M, Koob GF (2017) Hypocretin neurotransmission within the central amygdala mediates escalated cocaine self-administration and stress-induced reinstatement in Rats. Biological psychiatry 81:606–615

    CAS  PubMed  Article  Google Scholar 

  183. Schneider ER, Rada P, Darby RD, Leibowitz SF, Hoebel BG (2007) Orexigenic peptides and alcohol intake: differential effects of orexin, galanin, and ghrelin. Alcohol Clin Exp Res 31:1858–1865

    CAS  PubMed  Article  Google Scholar 

  184. 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 reports 7:697–704

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  185. Schone C, Burdakov D (2012) Glutamate and GABA as rapid effectors of hypothalamic “peptidergic” neurons. Frontiers in behavioral neuroscience 6:81

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  186. Schone C, Burdakov D (2017) Orexin/hypocretin and organizing principles for a diversity of wake-promoting neurons in the brain. Current topics in behavioral neurosciences 33:51–74

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  187. 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. The Journal of neuroscience : the official journal of the Society for Neuroscience 32:12437–12443

    CAS  Article  Google Scholar 

  188. 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. Behavioural brain research 222:289–294

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  189. Sears RM, Fink AE, Wigestrand MB, Farb CR, de Lecea L, Ledoux JE (2013) Orexin/hypocretin system modulates amygdala-dependent threat learning through the locus coeruleus. Proc Natl Acad Sci U S A 110:20260–20265

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  190. Selbach O, Bohla C, Barbara A, Doreulee N, Eriksson KS, Sergeeva OA, Haas HL (2010) Orexins/hypocretins control bistability of hippocampal long-term synaptic plasticity through co-activation of multiple kinases. Acta physiologica 198:277–285

    CAS  PubMed  Article  Google Scholar 

  191. Sharf R, Sarhan M, Brayton CE, Guarnieri DJ, Taylor JR, DiLeone RJ (2010) Orexin signaling via the orexin 1 receptor mediates operant responding for food reinforcement. Biological psychiatry 67:753–760

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  192. Sharma R, Bradshaw K, Sahota P, Thakkar MM (2014) Acute binge alcohol administration reverses sleep-wake cycle in Sprague Dawley rats. Alcohol Clin Exp Res 38:1941–1946

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  193. Shirasaka T, Nakazato M, Matsukura S, Takasaki M, Kannan H (1999) Sympathetic and cardiovascular actions of orexins in conscious rats. Am J Physiol 277:R1780–R1785

    CAS  PubMed  Google Scholar 

  194. Shoblock JR, Welty N, Aluisio L, Fraser I, Motley ST, Morton K, Palmer J, Bonaventure P, Carruthers NI, Lovenberg TW, Boggs J, Galici R (2011) Selective blockade of the orexin-2 receptor attenuates ethanol self-administration, place preference, and reinstatement. Psychopharmacology 215:191–203

    CAS  PubMed  Article  Google Scholar 

  195. Siegel JM (2004) Hypocretin (orexin): role in normal behavior and neuropathology. Annual review of psychology 55:125–148

    PubMed  Article  Google Scholar 

  196. Smith RJ, Aston-Jones G (2012) Orexin / hypocretin 1 receptor antagonist reduces heroin self-administration and cue-induced heroin seeking. The European journal of neuroscience 35:798–804

    PubMed  PubMed Central  Article  Google Scholar 

  197. Srinivasan S, Simms JA, Nielsen CK, Lieske SP, Bito-Onon JJ, Yi H, Hopf FW, Bonci A, Bartlett SE (2012) The dual orexin/hypocretin receptor antagonist, almorexant, in the ventral tegmental area attenuates ethanol self-administration. PloS one 7:e44726

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  198. Sterling ME, Karatayev O, Chang GQ, Algava DB, Leibowitz SF (2015) Model of voluntary ethanol intake in zebrafish: effect on behavior and hypothalamic orexigenic peptides. Behavioural brain research 278:29–39

    CAS  PubMed  Article  Google Scholar 

  199. Sunanaga J, Deng BS, Zhang W, Kanmura Y, Kuwaki T (2009) CO2 activates orexin-containing neurons in mice. Respiratory physiology & neurobiology 166:184–186

    CAS  Article  Google Scholar 

  200. Sutcliffe JG, de Lecea L (2002) The hypocretins: setting the arousal threshold. Nature reviews Neuroscience 3:339–349

    CAS  PubMed  Article  Google Scholar 

  201. 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 research 1044:116–121

    CAS  PubMed  Article  Google Scholar 

  202. Telegdy G, Adamik A (2002) The action of orexin A on passive avoidance learning. Involvement of transmitters. Regulatory peptides 104:105–110

    CAS  PubMed  Article  Google Scholar 

  203. Thakkar MM, Sharma R, Sahota P (2015) Alcohol disrupts sleep homeostasis. Alcohol 49:299–310

    CAS  PubMed  Article  Google Scholar 

  204. Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M, Cornford M, Siegel JM (2000) Reduced number of hypocretin neurons in human narcolepsy. Neuron 27:469–474

    CAS  PubMed  Article  Google Scholar 

  205. Torrealba F, Yanagisawa M, Saper CB (2003) Colocalization of orexin a and glutamate immunoreactivity in axon terminals in the tuberomammillary nucleus in rats. Neuroscience 119:1033–1044

    CAS  PubMed  Article  Google Scholar 

  206. Trivedi P, Yu H, MacNeil DJ, Van der Ploeg LH, Guan XM (1998) Distribution of orexin receptor mRNA in the rat brain. FEBS letters 438:71–75

    CAS  PubMed  Article  Google Scholar 

  207. Tsujino N, Sakurai T (2013) Role of orexin in modulating arousal, feeding, and motivation. Frontiers in behavioral neuroscience 7:28

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  208. Tupone D, Madden CJ, Cano G, Morrison SF (2011) An orexinergic projection from perifornical hypothalamus to raphe pallidus increases rat brown adipose tissue thermogenesis. The Journal of neuroscience : the official journal of the Society for Neuroscience 31:15944–15955

    CAS  Article  Google Scholar 

  209. Ubaldi M, Giordano A, Severi I, Li H, Kallupi M, de Guglielmo G, Ruggeri B, Stopponi S, Ciccocioppo R, Cannella N (2016) Activation of hypocretin-1/orexin-A neurons projecting to the bed nucleus of the stria terminalis and paraventricular nucleus is critical for reinstatement of alcohol seeking by neuropeptide S. Biological psychiatry 79:452–462

    CAS  PubMed  Article  Google Scholar 

  210. van den Pol AN (1999) Hypothalamic hypocretin (orexin): robust innervation of the spinal cord. The Journal of neuroscience : the official journal of the Society for Neuroscience 19:3171–3182

    Article  Google Scholar 

  211. von der Goltz C, Koopmann A, Dinter C, Richter A, Grosshans M, Fink T, Wiedemann K, Kiefer F (2011) Involvement of orexin in the regulation of stress, depression and reward in alcohol dependence. Hormones and behavior 60:644–650

    PubMed  Article  CAS  Google Scholar 

  212. Voorhees CM, Cunningham CL (2011) Involvement of the orexin/hypocretin system in ethanol conditioned place preference. Psychopharmacology 214:805–818

    CAS  PubMed  Article  Google Scholar 

  213. Walker LC, Lawrence AJ (2017) The role of orexins/hypocretins in alcohol use and abuse. Current topics in behavioral neurosciences 33:221–246

    PubMed  Article  CAS  Google Scholar 

  214. Wang B, You Z, Wise R (2009) Reinstatement of cocaine seeking by hypocretin (orexin) in the ventral tegmental area: independence from the Local Corticotropin-Releasing Factor Network. Biol Psychiat 65:857–862

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  215. Warren KR, Hewitt BG (2010) NIAAA: advancing alcohol research for 40 years. Alcohol research & health : the journal of the National Institute on Alcohol Abuse and Alcoholism 33: 5-17.

  216. Wayner MJ, Armstrong DL, Phelix CF, Oomura Y (2004) Orexin-A (hypocretin-1) and leptin enhance LTP in the dentate gyrus of rats in vivo. Peptides 25:991–996

    CAS  PubMed  Article  Google Scholar 

  217. Wheeler DS, Wan S, Miller A, Angeli N, Adileh B, Hu W, Holland PC (2014) Role of lateral hypothalamus in two aspects of attention in associative learning. The European journal of neuroscience 40:2359–2377

    PubMed  PubMed Central  Article  Google Scholar 

  218. Williams RH, Burdakov D (2008) Hypothalamic orexins/hypocretins as regulators of breathing. Expert reviews in molecular medicine 10:e28

    PubMed  PubMed Central  Article  Google Scholar 

  219. Williams RH, Jensen LT, Verkhratsky A, Fugger L, Burdakov D (2007) Control of hypothalamic orexin neurons by acid and CO2. Proc Natl Acad Sci U S A 104:10685–10690

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  220. Willie JT, Chemelli RM, Sinton CM, Tokita S, Williams SC, Kisanuki YY, Marcus JN, Lee C, Elmquist JK, Kohlmeier KA, Leonard CS, Richardson JA, Hammer RE, Yanagisawa M (2003) Distinct narcolepsy syndromes in orexin receptor-2 and orexin null mice: molecular genetic dissection of non-REM and REM sleep regulatory processes. Neuron 38:715–730

    CAS  PubMed  Article  Google Scholar 

  221. Willie JT, Chemelli RM, Sinton CM, Yanagisawa M (2001) To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Annual review of neuroscience 24:429–458

    CAS  PubMed  Article  Google Scholar 

  222. Winrow CJ, Renger JJ (2014) Discovery and development of orexin receptor antagonists as therapeutics for insomnia. Br J Pharmacol 171:283–293

    CAS  PubMed  Article  Google Scholar 

  223. Wise RA (2013) Dual roles of dopamine in food and drug seeking: the drive-reward paradox. Biological psychiatry 73:819–826

    CAS  PubMed  Article  Google Scholar 

  224. Wise RA, Koob GF (2014) The development and maintenance of drug addiction. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 39:254–262

    Article  Google Scholar 

  225. World Health Organization (2014) Global status report on alcohol and health

  226. Yang L, Zou B, Xiong X, Pascual C, Xie J, Malik A, Xie J, Sakurai T, Xie XS (2013) Hypocretin/orexin neurons contribute to hippocampus-dependent social memory and synaptic plasticity in mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 33:5275–5284

    CAS  Article  Google Scholar 

  227. Yeoh JW, Campbell EJ, James MH, Graham BA, Dayas CV (2014) Orexin antagonists for neuropsychiatric disease: progress and potential pitfalls. Frontiers in neuroscience 8:36

    PubMed  PubMed Central  Article  Google Scholar 

  228. Zajo KN, Fadel JR, Burk JA (2016) Orexin A-induced enhancement of attentional processing in rats: role of basal forebrain neurons. Psychopharmacology 233:639–647

    CAS  PubMed  Article  Google Scholar 

  229. Zhang J, Li B, Yu L, He YC, Li HZ, Zhu JN, Wang JJ (2011) A role for orexin in central vestibular motor control. Neuron 69:793–804

    CAS  PubMed  Article  Google Scholar 

  230. Zhang W, Sunanaga J, Takahashi Y, Mori T, Sakurai T, Kanmura Y, Kuwaki T (2010) Orexin neurons are indispensable for stress-induced thermogenesis in mice. The Journal of physiology 588:4117–4129

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  231. Ziolkowski M, Czarnecki D, Budzynski J, Rosinska Z, Zekanowska E, Goralczyk B (2016) Orexin in patients with alcohol dependence treated for relapse prevention: a pilot study. Alcohol and alcoholism (Oxford, Oxfordshire) 51:416–421

    CAS  Article  Google Scholar 

Download references

Acknowledgments

This work was supported by PHS research grants AA024571, AA025481, and DA041674 and a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation

Author information

Affiliations

Authors

Corresponding author

Correspondence to David E. Moorman.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Moorman, D.E. The hypocretin/orexin system as a target for excessive motivation in alcohol use disorders. Psychopharmacology 235, 1663–1680 (2018). https://doi.org/10.1007/s00213-018-4871-2

Download citation

Keywords

  • Hypothalamus
  • Neuropeptide
  • Ethanol
  • Dependence
  • Alcoholism
  • Craving