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A Decade of Orexin/Hypocretin and Addiction: Where Are We Now?

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Behavioral Neuroscience of Orexin/Hypocretin

Part of the book series: Current Topics in Behavioral Neurosciences ((CTBN,volume 33))

Abstract

One decade ago, our laboratory provided the first direct evidence linking orexin/hypocretin signaling with drug seeking by showing that activation of these neurons promotes conditioned morphine-seeking behavior. In the years since, contributions from many investigators have revealed roles for orexins in addiction for all drugs of abuse tested, but only under select circumstances. We recently proposed that orexins play a fundamentally unified role in coordinating “motivational activation” under numerous behavioral conditions, and here we unpack this hypothesis as it applies to drug addiction. We describe evidence collected over the past 10 years that elaborates the role of orexin in drug seeking under circumstances where high levels of effort are required to obtain the drug, or when motivation for drug reward is augmented by the presence of external stimuli like drug-associated cues/contexts or stressors. Evidence from studies using traditional self-administration and reinstatement models, as well as behavioral economic analyses of drug demand elasticity, clearly delineates a role for orexin in modulating motivational, rather than the primary reinforcing aspects of drug reward. We also discuss the anatomical interconnectedness of the orexin system with wider motivation and reward circuits, with a particular focus on how orexin modulates prefrontal and other glutamatergic inputs onto ventral tegmental area dopamine neurons. Last, we look ahead to the next decade of the research in this area, highlighting the recent FDA approval of the dual orexin receptor antagonist suvorexant (Belsomra®) for the treatment of insomnia as a promising sign of the potential clinical utility of orexin-based therapies for the treatment of addiction.

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References

  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(1):322–327

    Google Scholar 

  2. 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(4):573–585

    CAS  PubMed  Google Scholar 

  3. Sweet DC, Levine AS, Billington CJ, Kotz CM (1999) Feeding response to central orexins. Brain Res 821(2):535–538

    CAS  PubMed  Google Scholar 

  4. Haynes AC, Jackson B, Chapman H, Tadayyon M, Johns A, Porter RA, Arch JR (2000) A selective orexin-1 receptor antagonist reduces food consumption in male and female rats. Regul Pept 96(1–2):45–51

    CAS  PubMed  Google Scholar 

  5. 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 Res 1314:74–90

    CAS  PubMed  Google Scholar 

  6. Baimel C, Bartlett SE, Chiou LC, Lawrence AJ, Muschamp JW, Patkar O, Tung LW, Borgland SL (2014) Orexin/hypocretin role in reward: implications for opioid and other addictions. Br J Pharmacol 172:334–348

    PubMed  PubMed Central  Google Scholar 

  7. Boutrel B, Cannella N, de Lecea L (2010) The role of hypocretin in driving arousal and goal-oriented behaviors. Brain Res 1314:103–111

    CAS  PubMed  Google Scholar 

  8. Harris GC, Aston-Jones G (2006) Arousal and reward: a dichotomy in orexin function. Trends Neurosci 29(10):571–577

    CAS  PubMed  Google Scholar 

  9. 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 S4:008

    Google Scholar 

  10. Khoo SY, Brown RM (2014) Orexin/hypocretin based pharmacotherapies for the treatment of addiction: DORA or SORA? CNS Drugs 28(8):713–730

    CAS  PubMed  Google Scholar 

  11. Mahler SV, Moorman DE, Smith RJ, James MH, Aston-Jones G (2014) Motivational activation: a unifying hypothesis of orexin/hypocretin function. Nat Neurosci 17(10):1298–1303

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Mahler SV, Smith RJ, Moorman DE, Sartor GC, Aston-Jones G (2012) Multiple roles for orexin/hypocretin in addiction. Prog Brain Res 198:79–121

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E (2000) Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355(9197):39–40

    CAS  PubMed  Google Scholar 

  14. Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, Nevsimalova S, Aldrich M, Reynolds D, Albin R, Li R, Hungs M, Pedrazzoli M, Padigaru M, Kucherlapati M, Fan J, Maki R, Lammers GJ, Bouras C, Kucherlapati R, Nishino S, Mignot E (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):991–997

    CAS  PubMed  Google Scholar 

  15. Akimoto H, Honda Y, Takahashi Y (1960) Pharmacotherapy in narcolepsy. Dis Nerv Syst 21:704–706

    CAS  PubMed  Google Scholar 

  16. Nishino S, Mignot E (1997) Pharmacological aspects of human and canine narcolepsy. Prog Neurobiol 52(1):27–78

    CAS  PubMed  Google Scholar 

  17. 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. J Neurosci 23(8):3106–3111

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Harris GC, Wimmer M, Aston-Jones G (2005) A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437(7058):556–559

    CAS  PubMed  Google Scholar 

  19. 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(52):19168–19173

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 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. J Neurosci 29(36):11215–11225

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Bentzley BS, Aston-Jones G (2015) Orexin-1 receptor signaling increases motivation for cocaine-associated cues. Eur J Neurosci 41(9):1149–1156

    PubMed  PubMed Central  Google Scholar 

  22. Walker LC, Lawrence AJ (2016) The role of orexins/hypocretins in alcohol use and abuse. Curr Top Behav Neurosci. doi:10.1007/7854_2016_55

    Google Scholar 

  23. Koob GF (1992) Neural mechanisms of drug reinforcement. Ann N Y Acad Sci 654:171–191

    CAS  PubMed  Google Scholar 

  24. Wise RA (1987) Intravenous drug self-administration: a special case of positive reinforcement. In: Bozarth MA (ed) Methods of assessing the reinforcing properties of abused drugs. Springer, New York, pp 117–141

    Google Scholar 

  25. Wise RA (1997) Drug self-administration viewed as ingestive behaviour. Appetite 28(1):1–5

    CAS  PubMed  Google Scholar 

  26. Espana RA, Oleson EB, Locke JL, Brookshire BR, Roberts DC, Jones SR (2010) The hypocretin-orexin system regulates cocaine self-administration via actions on the mesolimbic dopamine system. Eur J Neurosci 31(2):336–348

    PubMed  Google Scholar 

  27. Hutcheson DM, Quarta D, Halbout B, Rigal A, Valerio E, Heidbreder C (2011) Orexin-1 receptor antagonist SB-334867 reduces the acquisition and expression of cocaine-conditioned reinforcement and the expression of amphetamine-conditioned reward. Behav Pharmacol 22(2):173–181

    CAS  PubMed  Google Scholar 

  28. Smith RJ, See RE, Aston-Jones G (2009) Orexin/hypocretin signaling at the orexin 1 receptor regulates cue-elicited cocaine-seeking. Eur J Neurosci 30(3):493–503

    PubMed  PubMed Central  Google Scholar 

  29. 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. Front Behav Neurosci 6:47

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 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 (Berl) 214(2):415–426

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  32. Riday TT, Fish EW, Robinson JE, Jarrett TM, McGuigan MM, Malanga CJ (2012) Orexin-1 receptor antagonism does not reduce the rewarding potency of cocaine in Swiss–Webster mice. Brain Res 1431:53–61

    CAS  PubMed  Google Scholar 

  33. 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 Res 1391:54–59

    CAS  PubMed  Google Scholar 

  34. 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(4):880–889

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Lawrence AJ, Cowen MS, Yang HJ, Chen F, Oldfield B (2006) The orexin system regulates alcohol-seeking in rats. Br J Pharmacol 148(6):752–759

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 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(49):19480–19485

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Smith RJ, Aston-Jones G (2012) Orexin/hypocretin 1 receptor antagonist reduces heroin self-administration and cue-induced heroin seeking. Eur J Neurosci 35(5):798–804

    PubMed  PubMed Central  Google Scholar 

  38. LeSage MG, Perry JL, Kotz CM, Shelley D, Corrigall WA (2010) Nicotine self-administration in the rat: effects of hypocretin antagonists and changes in hypocretin mRNA. Psychopharmacology (Berl) 209(2):203–212

    CAS  PubMed  Google Scholar 

  39. Steiner MA, Lecourt H, Jenck F (2013) The dual orexin receptor antagonist almorexant, alone and in combination with morphine, cocaine and amphetamine, on conditioned place preference and locomotor sensitization in the rat. Int J Neuropsychopharmacol 16(2):417–432

    CAS  PubMed  Google Scholar 

  40. Sartor GC, Aston-Jones GS (2012) A septal-hypothalamic pathway drives orexin neurons, which is necessary for conditioned cocaine preference. J Neurosci 32(13):4623–4631

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Rao Y, Mineur YS, Gan G, Wang AH, Liu ZW, Wu X, Suyama S, de Lecea L, Horvath TL, Picciotto MR, Gao XB (2013) Repeated in vivo exposure of cocaine induces long-lasting synaptic plasticity in hypocretin/orexin-producing neurons in the lateral hypothalamus in mice. J Physiol 591(Pt 7):1951–1966

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Marchant NJ, Li X, Shaham Y (2013) Recent developments in animal models of drug relapse. Curr Opin Neurobiol 23(4):675–683

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhou L, Ghee SM, Chan C, Lin L, Cameron MD, Kenny PJ, See RE (2012) Orexin-1 receptor mediation of cocaine seeking in male and female rats. J Pharmacol Exp Ther 340(3):801–809

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Martin-Fardon R, Weiss F (2014a) Blockade of hypocretin receptor-1 preferentially prevents cocaine seeking: comparison with natural reward seeking. Neuroreport 25(7):485–488

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Smith RJ, Tahsili-Fahadan P, Aston-Jones G (2010) Orexin/hypocretin is necessary for context-driven cocaine-seeking. Neuropharmacology 58(1):179–184

    CAS  PubMed  Google Scholar 

  46. Martin-Fardon R, Weiss F (2014b) 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. Addict Biol 19(2):233–236

    CAS  PubMed  Google Scholar 

  47. Moorman DE, James MH, Kilroy EA, Aston-Jones G (2016) Orexin/hypocretin-1 receptor antagonism reduces ethanol self-administration and reinstatement selectively in highly-motivated rats. Brain Res 1654:34–42. doi:10.1016/j.brainres.2016.10.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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(6):2300–2310

    PubMed  PubMed Central  Google Scholar 

  49. Porter-Stransky KA, Bentzley BS, Aston-Jones G (2015) Individual differences in orexin-I receptor modulation of motivation for the opioid remifentanil. Addict Biol. doi:10.1111/adb.12323

    Google Scholar 

  50. Uslaner JM, Winrow CJ, Gotter AL, Roecker AJ, Coleman PJ, Hutson PH, Le AD, Renger JJ (2014) Selective orexin 2 receptor antagonism blocks cue-induced reinstatement, but not nicotine self-administration or nicotine-induced reinstatement. Behav Brain Res 269:61–65

    CAS  PubMed  Google Scholar 

  51. Brown RM, Khoo SY-S, Lawrence AJ (2013) Central orexin (hypocretin) 2 receptor antagonism reduces ethanol self-administration, but not cue-conditioned ethanol-seeking, in ethanol-preferring rats. Int J Neuropsychopharmacol 16(9):2067–2079

    CAS  PubMed  Google Scholar 

  52. Di Ciano P, Everitt BJ (2005) Neuropsychopharmacology of drug seeking: Insights from studies with second-order schedules of drug reinforcement. Eur J Pharmacol 526(1–3):186–198

    CAS  PubMed  Google Scholar 

  53. Schindler CW, Panlilio LV, Goldberg SR (2002) Second-order schedules of drug self-administration in animals. Psychopharmacology (Berl) 163(3–4):327–344

    CAS  PubMed  Google Scholar 

  54. James MH, Campbell EJ, Dayas CV (2016) Role of the orexin/hypocretin system in stress-related psychiatric disorders. Curr Top Behav Neurosci. doi:10.1007/7854_2016_56

    Article  Google Scholar 

  55. Chen X, Wang H, Lin Z, Li S, Li Y, Bergen HT, Vrontakis ME, Kirouac GJ (2013) Orexins (hypocretins) contribute to fear and avoidance in rats exposed to a single episode of footshocks. Brain Struct Funct 219:2103–2118

    PubMed  Google Scholar 

  56. 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(8):1603–1614

    PubMed  Google Scholar 

  57. 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 8:244

    PubMed  PubMed Central  Google Scholar 

  58. 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(3):155–158

    CAS  PubMed  Google Scholar 

  59. 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 6:6266

    CAS  PubMed  Google Scholar 

  60. Heydendael W, Sengupta A, Beck S, Bhatnagar S (2013) Optogenetic examination identifies a context-specific role for orexins/hypocretins in anxiety-related behavior. Physiol Behav 130:182–190

    PubMed  PubMed Central  Google Scholar 

  61. 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(3):462–466

    CAS  PubMed  Google Scholar 

  62. 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(1):111–115

    CAS  PubMed  Google Scholar 

  63. Shaham Y, Erb S, Stewart J (2000) Stress-induced relapse to heroin and cocaine seeking in rats: a review. Brain Res Brain Res Rev 33(1):13–33

    CAS  PubMed  Google Scholar 

  64. Shaham Y, Shalev U, Lu L, De Wit H, Stewart J (2003) The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology (Berl) 168(1–2):3–20

    CAS  PubMed  Google Scholar 

  65. Shalev U, Marinelli M, Baumann MH, Piazza PV, Shaham Y (2003) The role of corticosterone in food deprivation-induced reinstatement of cocaine seeking in the rat. Psychopharmacology (Berl) 168(1–2):170–176

    CAS  PubMed  Google Scholar 

  66. Le AD, Harding S, Juzytsch W, Funk D, Shaham Y (2005) Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats. Psychopharmacology (Berl) 179(2):366–373

    CAS  PubMed  Google Scholar 

  67. Lee B, Tiefenbacher S, Platt DM, Spealman RD (2004) Pharmacological blockade of alpha2-adrenoceptors induces reinstatement of cocaine-seeking behavior in squirrel monkeys. Neuropsychopharmacology 29(4):686–693

    CAS  PubMed  Google Scholar 

  68. Conrad KL, Davis AR, Silberman Y, Sheffler DJ, Shields AD, Saleh SA, Sen N, Matthies HJG, 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 37(10):2253–2266

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 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. Front Behav Neurosci 7:144

    PubMed  PubMed Central  Google Scholar 

  70. Ebrahimian F, Naghavi FS, Yazdi F, Sadeghzadeh F, Taslimi Z, Haghparast A (2016) Differential roles of orexin receptors within the dentate gyrus in stress- and drug priming-induced reinstatement of conditioned place preference in rats. Behav Neurosci 130(1):91–102

    CAS  PubMed  Google Scholar 

  71. Wang B, You ZB, Wise RA (2009) Reinstatement of cocaine seeking by hypocretin (orexin) in the ventral tegmental area: independence from the local corticotropin-releasing factor network. Biol Psychiatry 65(10):857–862

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Ehrman RN, Robbins SJ, Childress AR, O’Brien CP (1992) Conditioned responses to cocaine-related stimuli in cocaine abuse patients. Psychopharmacology (Berl) 107(4):523–529

    CAS  PubMed  Google Scholar 

  73. Ferguson SG, Shiffman S (2009) The relevance and treatment of cue-induced cravings in tobacco dependence. J Subst Abuse Treat 36(3):235–243

    PubMed  Google Scholar 

  74. O’Brien CP, Childress AR, McLellan AT, Ehrman R (1992) Classical conditioning in drug-dependent humans. Ann N Y Acad Sci 654:400–415

    PubMed  Google Scholar 

  75. Sinha R, Fox HC, Hong KI, Hansen J, Tuit K, Kreek MJ (2011) Effects of adrenal sensitivity, stress- and cue-induced craving, and anxiety on subsequent alcohol relapse and treatment outcomes. Arch Gen Psychiatry 68(9):942–952

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Sinha R, Li CS (2007) Imaging stress- and cue-induced drug and alcohol craving: association with relapse and clinical implications. Drug Alcohol Rev 26(1):25–31

    PubMed  Google Scholar 

  77. Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Childress AR, Jayne M, Ma Y, Wong C (2008) Dopamine increases in striatum do not elicit craving in cocaine abusers unless they are coupled with cocaine cues. Neuroimage 39(3):1266–1273

    PubMed  Google Scholar 

  78. Cason AM, Aston-Jones G (2013) Role of orexin/hypocretin in conditioned sucrose-seeking in rats. Psychopharmacology (Berl) 226(1):155–165

    CAS  PubMed  Google Scholar 

  79. Muschamp JW, Dominguez JM, Sato SM, Shen RY, Hull EM (2007) A role for hypocretin (orexin) in male sexual behavior. J Neurosci 27(11):2837–2845

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Cruz HG, Hoever P, Chakraborty B, Schoedel K, Sellers EM, Dingemanse J (2014) Assessment of the abuse liability of a dual orexin receptor antagonist: a crossover study of almorexant and zolpidem in recreational drug users. CNS Drugs 28(4):361–372

    CAS  PubMed  Google Scholar 

  81. Yeoh JW, Campbell EJ, James MH, Graham BA, Dayas CV (2014a) Orexin antagonists for neuropsychiatric disease: progress and potential pitfalls. Front Neurosci 8:36

    PubMed  PubMed Central  Google Scholar 

  82. Bentzley BS, Fender KM, Aston-Jones G (2013) The behavioral economics of drug self-administration: a review and new analytical approach for within-session procedures. Psychopharmacology (Berl) 226(1):113–125

    CAS  PubMed  Google Scholar 

  83. Oleson EB, Roberts DCS (2008) Behavioral economic assessment of price and cocaine consumption following self-administration histories that produce escalation of either final ratios or intake. Neuropsychopharmacology 34(3):796–804

    PubMed  Google Scholar 

  84. Hursh SR, Silberberg A (2008) Economic demand and essential value. Psychol Rev 115(1):186–198

    PubMed  Google Scholar 

  85. Bentzley BS, Jhou TC, Aston-Jones G (2014) Economic demand predicts addiction-like behavior and therapeutic efficacy of oxytocin in the rat. Proc Natl Acad Sci U S A 111(32):11822–11827

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Robinson TE, Yager LM, Cogan ES, Saunders BT (2014) On the motivational properties of reward cues: individual differences. Neuropharmacology 76(Pt B):450–459

    CAS  PubMed  Google Scholar 

  87. 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(1):6–25

    CAS  PubMed  Google Scholar 

  88. 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(23):9996–10015

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 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(2):297–308

    CAS  PubMed  Google Scholar 

  90. Yoshida K, McCormack S, Espana RA, Crocker A, Scammell TE (2006) Afferents to the orexin neurons of the rat brain. J Comp Neurol 494(5):845–861

    PubMed  PubMed Central  Google Scholar 

  91. Hamlin AS, Clemens KJ, McNally GP (2008) Renewal of extinguished cocaine-seeking. Neuroscience 151(3):659–670

    CAS  PubMed  Google Scholar 

  92. Marchant NJ, Hamlin AS, McNally GP (2009) Lateral hypothalamus is required for context-induced reinstatement of extinguished reward seeking. J Neurosci 29(5):1331–1342

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Millan EZ, Furlong TM, McNally GP (2010) Accumbens shell-hypothalamus interactions mediate extinction of alcohol seeking. J Neurosci 30(13):4626–4635

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Baldo BA, Gual-Bonilla L, Sijapati K, Daniel RA, Landry CF, Kelley AE (2004) Activation of a subpopulation of orexin/hypocretin-containing hypothalamic neurons by GABAA receptor-mediated inhibition of the nucleus accumbens shell, but not by exposure to a novel environment. Eur J Neurosci 19(2):376–386

    PubMed  Google Scholar 

  95. Yeoh JW, James MH, Jobling P, Bains JS, Graham BA, Dayas CV (2012) Cocaine potentiates excitatory drive in the perifornical/lateral hypothalamus. J Physiol 590(Pt 16):3677–3689

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Swanson LW (1982) The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat. Brain Res Bull 9(1–6):321–353

    CAS  PubMed  Google Scholar 

  97. Di Chiara G, Bassareo V, Fenu S, De Luca MA, Spina L, Cadoni C, Acquas E, Carboni E, Valentini V, Lecca D (2004) Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology 47(Suppl 1):227–241

    CAS  PubMed  Google Scholar 

  98. Ranaldi R, Wise RA (2001) Blockade of D1 dopamine receptors in the ventral tegmental area decreases cocaine reward: possible role for dendritically released dopamine. J Neurosci 21(15):5841–5846

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Wise RA (2008) Dopamine and reward: the anhedonia hypothesis 30 years on. Neurotox Res 14(2–3):169–183

    PubMed  PubMed Central  Google Scholar 

  100. Balcita-Pedicino JJ, Sesack SR (2007) Orexin axons in the rat ventral tegmental area synapse infrequently onto dopamine and gamma-aminobutyric acid neurons. J Comp Neurol 503(5):668–684

    PubMed  Google Scholar 

  101. Korotkova TM, Sergeeva OA, Eriksson KS, Haas HL, Brown RE (2003) Excitation of ventral tegmental area dopaminergic and nondopaminergic neurons by orexins/hypocretins. J Neurosci 23(1):7–11

    CAS  PubMed  PubMed Central  Google Scholar 

  102. James MH, Charnley JL, Levi EM, Jones E, Yeoh JW, Smith DW, Dayas CV (2011b) 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(5):684–690

    CAS  PubMed  Google Scholar 

  103. Mahler SV, Smith RJ, Aston-Jones G (2013) Interactions between VTA orexin and glutamate in cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology (Berl) 226(4):687–698

    CAS  PubMed  Google Scholar 

  104. 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. Addict Biol 21(3):603–612

    CAS  PubMed  Google Scholar 

  105. Berridge KC, Robinson TE (1998) What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res Rev 28(3):309–369

    CAS  PubMed  Google Scholar 

  106. Cheer JF, Aragona BJ, Heien ML, Seipel AT, Carelli RM, Wightman RM (2007) Coordinated accumbal dopamine release and neural activity drive goal-directed behavior. Neuron 54(2):237–244

    CAS  PubMed  Google Scholar 

  107. Fiorillo CD, Tobler PN, Schultz W (2003) Discrete coding of reward probability and uncertainty by dopamine neurons. Science 299(5614):1898–1902

    CAS  PubMed  Google Scholar 

  108. Ikemoto S, Panksepp J (1999) The role of nucleus accumbens dopamine in motivated behavior: a unifying interpretation with special reference to reward-seeking. Brain Res Brain Res Rev 31(1):6–41

    CAS  PubMed  Google Scholar 

  109. Phillips PE, Stuber GD, Heien ML, Wightman RM, Carelli RM (2003) Subsecond dopamine release promotes cocaine seeking. Nature 422(6932):614–618

    CAS  PubMed  Google Scholar 

  110. Salamone JD, Correa M, Farrar A, Mingote SM (2007) Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits. Psychopharmacology (Berl) 191(3):461–482

    CAS  PubMed  Google Scholar 

  111. Satoh T, Nakai S, Sato T, Kimura M (2003) Correlated coding of motivation and outcome of decision by dopamine neurons. J Neurosci 23(30):9913–9923

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Stuber GD, Roitman MF, Phillips PE, Carelli RM, Wightman RM (2005) Rapid dopamine signaling in the nucleus accumbens during contingent and noncontingent cocaine administration. Neuropsychopharmacology 30(5):853–863

    CAS  PubMed  Google Scholar 

  113. Vittoz NM, Schmeichel B, Berridge CW (2008) Hypocretin/orexin preferentially activates caudomedial ventral tegmental area dopamine neurons. Eur J Neurosci 28(8):1629–1640

    PubMed  PubMed Central  Google Scholar 

  114. Chergui K, Charlety PJ, Akaoka H, Saunier CF, Brunet JL, Buda M, Svensson TH, Chouvet G (1993) Tonic activation of NMDA receptors causes spontaneous burst discharge of rat midbrain dopamine neurons in vivo. Eur J Neurosci 5(2):137–144

    CAS  PubMed  Google Scholar 

  115. Harris GC, Aston-Jones G (2003) Critical role for ventral tegmental glutamate in preference for a cocaine-conditioned environment. Neuropsychopharmacology 28(1):73–76

    CAS  PubMed  Google Scholar 

  116. Wang T, O’Connor WT, Ungerstedt U, French ED (1994) N-methyl-d-aspartic acid biphasically regulates the biochemical and electrophysiological response of A10 dopamine neurons in the ventral tegmental area: in vivo microdialysis and in vitro electrophysiological studies. Brain Res 666(2):255–262

    CAS  PubMed  Google Scholar 

  117. Zellner MR, Ranaldi R (2010) How conditioned stimuli acquire the ability to activate VTA dopamine cells: a proposed neurobiological component of reward-related learning. Neurosci Biobehav Rev 34(5):769–780

    CAS  PubMed  Google Scholar 

  118. 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(4):589–601

    CAS  PubMed  Google Scholar 

  119. Borgland SL, Storm E, Bonci A (2008) Orexin B/hypocretin 2 increases glutamatergic transmission to ventral tegmental area neurons. Eur J Neurosci 28(8):1545–1556

    CAS  PubMed  Google Scholar 

  120. Geisler S, Marinelli M, Degarmo B, Becker ML, Freiman AJ, Beales M, Meredith GE, Zahm DS (2008) Prominent activation of brainstem and pallidal afferents of the ventral tegmental area by cocaine. Neuropsychopharmacology 33(11):2688–2700

    CAS  PubMed  Google Scholar 

  121. Moorman DE, James MH, McGlinchey EM, Aston-Jones G (2015) Differential roles of medial prefrontal subregions in the regulation of drug seeking. Brain Res 1628(Pt A):130–146

    CAS  PubMed  Google Scholar 

  122. Gariano RF, Groves PM (1988) Burst firing induced in midbrain dopamine neurons by stimulation of the medial prefrontal and anterior cingulate cortices. Brain Res 462(1):194–198

    CAS  PubMed  Google Scholar 

  123. Tong ZY, Overton PG, Clark D (1996) Stimulation of the prefrontal cortex in the rat induces patterns of activity in midbrain dopaminergic neurons which resemble natural burst events. Synapse 22(3):195–208

    CAS  PubMed  Google Scholar 

  124. Moorman DE, Aston-Jones G (2010) Orexin/hypocretin modulates response of ventral tegmental dopamine neurons to prefrontal activation: diurnal influences. J Neurosci 30(46):15585–15599

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Mahler SV, Aston-Jones GS (2012) Fos activation of selective afferents to ventral tegmental area during cue-induced reinstatement of cocaine seeking in rats. J Neurosci 32(38):13309–13326

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 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(3):471–481

    CAS  PubMed  Google Scholar 

  127. James MH, Charnley JL, Flynn JR, Smith DW, Dayas CV (2011a) Propensity to ‘relapse’ following exposure to cocaine cues is associated with the recruitment of specific thalamic and epithalamic nuclei. Neuroscience 199:235–242

    CAS  PubMed  Google Scholar 

  128. Barson JR, Ho HT, Leibowitz SF (2015) Anterior thalamic paraventricular nucleus is involved in intermittent access ethanol drinking: role of orexin receptor 2. Addict Biol 20(3):469–481

    CAS  PubMed  Google Scholar 

  129. 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. Biol Psychiatry 63(2):152–157

    CAS  PubMed  Google Scholar 

  130. James MH, Charnley JL, Jones E, Levi EM, Yeoh JW, Flynn JR, Smith DW, Dayas CV (2010) Cocaine- and amphetamine-regulated transcript (CART) signaling within the paraventricular thalamus modulates cocaine-seeking behaviour. PLoS One 5(9):e12980

    PubMed  PubMed Central  Google Scholar 

  131. James MH, Dayas CV (2013) What about me…? The PVT: a role for the paraventricular thalamus (PVT) in drug-seeking behavior. Front Behav Neurosci 7:18

    PubMed  PubMed Central  Google Scholar 

  132. 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? Front Behav Neurosci 6:75

    PubMed  PubMed Central  Google Scholar 

  133. Yeoh JW, James MH, Graham BA, Dayas CV (2014b) Electrophysiological characteristics of paraventricular thalamic (PVT) neurons in response to cocaine and cocaine- and amphetamine-regulated transcript (CART). Front Behav Neurosci 8:280

    PubMed  PubMed Central  Google Scholar 

  134. 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. doi:10.1124/jpet.116.235945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. 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(1–2):71–75

    CAS  PubMed  Google Scholar 

  136. Mori K, Kim J, Sasaki K (2011) Electrophysiological effects of orexin-B and dopamine on rat nucleus accumbens shell neurons in vitro. Peptides 32(2):246–252

    CAS  PubMed  Google Scholar 

  137. Mukai K, Kim J, Nakajima K, Oomura Y, Wayner MJ, Sasaki K (2009) Electrophysiological effects of orexin/hypocretin on nucleus accumbens shell neurons in rats: an in vitro study. Peptides 30(8):1487–1496

    CAS  PubMed  Google Scholar 

  138. Castro DC, Terry RA, Berridge KC (2016) Orexin in rostral hotspot of nucleus accumbens enhances sucrose ‘liking’ and intake but scopolamine in caudal shell shifts ‘liking’ toward ‘disgust’ and ‘fear’. Neuropsychopharmacology 41:2101–2111

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Ho CY, Berridge KC (2013) An orexin hotspot in ventral pallidum amplifies hedonic 'liking' for sweetness. Neuropsychopharmacology 38(9):1655–1664

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 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. Biol Psychiatry 79(6):452–462

    CAS  PubMed  Google Scholar 

  141. 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):82–91

    CAS  PubMed  Google Scholar 

  142. 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(9):e44726

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Li J, Hu Z, de Lecea L (2014) The hypocretins/orexins: integrators of multiple physiological functions. Br J Pharmacol 171(2):332–350

    CAS  PubMed  Google Scholar 

  144. Sakurai T (2014) The role of orexin in motivated behaviours. Nat Rev Neurosci 15(11):719–731

    CAS  PubMed  Google Scholar 

  145. Fadel J, Bubser M, Deutch AY (2002) Differential activation of orexin neurons by antipsychotic drugs associated with weight gain. J Neurosci 22(15):6742–6746

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Estabrooke IV, McCarthy MT, Ko E, Chou TC, Chemelli RM, Yanagisawa M, Saper CB, Scammell TE (2001) Fos expression in orexin neurons varies with behavioral state. J Neurosci 21(5):1656–1662

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Murphy JA, Deurveilher S, Semba K (2003) Stimulant doses of caffeine induce c-FOS activation in orexin/hypocretin-containing neurons in rat. Neuroscience 121(2):269–275

    CAS  PubMed  Google Scholar 

  148. Sakamoto F, Yamada S, Ueta Y (2004) Centrally administered orexin-A activates corticotropin-releasing factor-containing neurons in the hypothalamic paraventricular nucleus and central amygdaloid nucleus of rats: possible involvement of central orexins on stress-activated central CRF neurons. Regul Pept 118(3):183–191

    CAS  PubMed  Google Scholar 

  149. Winsky-Sommerer R, Yamanaka A, Diano S, Borok E, Roberts AJ, Sakurai T, Kilduff TS, Horvath TL, de Lecea L (2004) Interaction between the corticotropin-releasing factor system and hypocretins (orexins): a novel circuit mediating stress response. J Neurosci 24(50):11439–11448

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 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. Behav Brain Res 183(1):43–51

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 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 43:710–720

    PubMed  PubMed Central  Google Scholar 

  152. Richardson KA, Aston-Jones G (2012) Lateral hypothalamic orexin/hypocretin neurons that project to ventral tegmental area are differentially activated with morphine preference. J Neurosci 32(11):3809–3817

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Gompf HS, Aston-Jones G (2008) Role of orexin input in the diurnal rhythm of locus coeruleus impulse activity. Brain Res 1224:43–52

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Hamlin AS, Newby J, McNally GP (2007) The neural correlates and role of D1 dopamine receptors in renewal of extinguished alcohol-seeking. Neuroscience 146(2):525–536

    CAS  PubMed  Google Scholar 

  155. Kallupi M, Cannella N, Economidou D, Ubaldi M, Ruggeri B, Weiss F, Massi M, Marugan J, Heilig M, Bonnavion P, de Lecea L, Ciccocioppo R (2010) Neuropeptide S facilitates cue-induced relapse to cocaine seeking through activation of the hypothalamic hypocretin system. Proc Natl Acad Sci U S A 107(45):19567–19572

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Lasheras MC, Laorden ML, Milanes MV, Nunez C (2015) Corticotropin-releasing factor 1 receptor mediates the activity of the reward system evoked by morphine-induced conditioned place preference. Neuropharmacology 95:168–180

    CAS  PubMed  Google Scholar 

  157. Hassani OK, Krause MR, Mainville L, Cordova CA, Jones BE (2016) Orexin neurons respond differentially to auditory cues associated with appetitive versus aversive outcomes. J Neurosci 36(5):1747–1757

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Lee MG, Hassani OK, Jones BE (2005) Discharge of identified orexin/hypocretin neurons across the sleep-waking cycle. J Neurosci 25(28):6716–6720

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 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):336–346

    CAS  PubMed  Google Scholar 

  160. Sharf R, Sarhan M, Dileone RJ (2008) Orexin mediates the expression of precipitated morphine withdrawal and concurrent activation of the nucleus accumbens shell. Biol Psychiatry 64(3):175–183

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Plaza-Zabala A, Flores A, Maldonado R, Berrendero F (2012) Hypocretin/orexin signaling in the hypothalamic paraventricular nucleus is essential for the expression of nicotine withdrawal. Biol Psychiatry 71(3):214–223

    CAS  PubMed  Google Scholar 

  162. Johnson PL, Molosh A, Fitz SD, Truitt WA, Shekhar A (2012a) Orexin, stress, and anxiety/panic states. Prog Brain Res 198:133–161

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Johnson PL, Samuels BC, Fitz SD, Federici LM, Hammes N, Early MC, Truitt W, Lowry CA, Shekhar A (2012b) Orexin 1 receptors are a novel target to modulate panic responses and the panic brain network. Physiol Behav 107(5):733–742

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Sunanaga J, Deng BS, Zhang W, Kanmura Y, Kuwaki T (2009) CO2 activates orexin-containing neurons in mice. Respir Physiol Neurobiol 166(3):184–186

    CAS  PubMed  Google Scholar 

  165. 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 9:65

    PubMed  PubMed Central  Google Scholar 

  166. Tung LW, Lu GL, Lee YH, Yu L, Lee HJ, Leishman E, Bradshaw H, Hwang LL, Hung MS, Mackie K, Zimmer A, Chiou LC (2016) Orexins contribute to restraint stress-induced cocaine relapse by endocannabinoid-mediated disinhibition of dopaminergic neurons. Nat Commun 7:12199

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Johnson PL et al. (2011) Induction of c-Fos in ‘panic/defence’-related brain circuits following brief hypercarbic gas exposure. J Psychopharmacol 25:26–36. doi:10.1177/0269881109353464

    Article  CAS  PubMed  Google Scholar 

  168. Webb IC, Patton DF, Hamson DK, Mistlberger RE (2008) Neural correlates of arousal-induced circadian clock resetting: hypocretin/orexin and the intergeniculate leaflet. Eur J Neurosci 27:828–835. doi:10.1111/j.1460-9568.2008.06074

    Article  PubMed  Google Scholar 

  169. Chemelli RM et al. (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 20:437–451

    Google Scholar 

  170. Plaza-Zabala A et al. (2013) A role for hypocretin/orexin receptor-1 in cue-induced reinstatement of nicotine-seeking behavior. Neuropsychopharmacology 38:1724–1736

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Cornish JL et al. (2012) Regional c-Fos and FosB/ΔFosB expression associated with chronic methamphetamine self-administration and methamphetamine-seeking behavior in rat. Neuroscience 206:100–114. doi:10.1016/j.neuroscience.2012.01.004

    Article  CAS  PubMed  Google Scholar 

  172. Espana RA, Valentino RJ, Berridge CW (2003) Fos immunoreactivity in hypocretin-synthesizing and hypocretin-1 receptor-expressing neurons: effects of diurnal and nocturnal spontaneous waking, stress and hypocretin-1 administration. Neuroscience 121(1):201–217

    CAS  PubMed  Google Scholar 

  173. 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. J Neurosci 31(43):15455–15467

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Cole S, Hobin MP, Petrovich GD (2015) Appetitive associative learning recruits a distinct network with cortical, striatal, and hypothalamic regions. Neuroscience 286:187–202

    CAS  PubMed  Google Scholar 

  175. Petrovich GD, Hobin MP, Reppucci CJ (2012) Selective Fos induction in hypothalamic orexin/hypocretin, but not melanin-concentrating hormone neurons, by a learned food-cue that stimulates feeding in sated rats. Neuroscience 224:70–80

    CAS  PubMed  Google Scholar 

  176. 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(1):11–20

    CAS  PubMed  Google Scholar 

  177. Mena JD, Selleck RA, Baldo BA (2013) Mu-opioid stimulation in rat prefrontal cortex engages hypothalamic orexin/hypocretin-containing neurons, and reveals dissociable roles of nucleus accumbens and hypothalamus in cortically driven feeding. J Neurosci 33(47):18540–18552

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Zheng H, Patterson LM, Berthoud HR (2007) Orexin signaling in the ventral tegmental area is required for high-fat appetite induced by opioid stimulation of the nucleus accumbens. J Neurosci 27(41):11075–11082

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Mileykovskiy BY, Kiyashchenko LI, Siegel JM (2005) Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron 46(5):787–798

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 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(7168):420–424

    CAS  PubMed  PubMed Central  Google Scholar 

  181. 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(36):12437–12443

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Tsunematsu T, Kilduff TS, Boyden ES, Takahashi S, Tominaga M, Yamanaka A (2011) Acute optogenetic silencing of orexin/hypocretin neurons induces slow-wave sleep in mice. J Neurosci 31(29):10529–10539

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Tsunematsu T, Tabuchi S, Tanaka KF, Boyden ES, Tominaga M, Yamanaka A (2013) Long-lasting silencing of orexin/hypocretin neurons using archaerhodopsin induces slow-wave sleep in mice. Behav Brain Res 255:64–74

    CAS  PubMed  Google Scholar 

  184. Floyd NS, Price JL, Ferry AT, Keay KA, Bandler R (2001) Orbitomedial prefrontal cortical projections to hypothalamus in the rat. J Comp Neurol 432(3):307–328

    CAS  PubMed  Google Scholar 

  185. Peters J, Kalivas PW, Quirk GJ (2009) Extinction circuits for fear and addiction overlap in prefrontal cortex. Learn Mem 16(5):279–288

    PubMed  PubMed Central  Google Scholar 

  186. Giardino WJ, de Lecea L (2014) Hypocretin (orexin) neuromodulation of stress and reward pathways. Curr Opin Neurobiol 29:103–108

    CAS  PubMed  Google Scholar 

  187. Fadel J, Deutch AY (2002) Anatomical substrates of orexin-dopamine interactions: lateral hypothalamic projections to the ventral tegmental area. Neuroscience 111(2):379–387

    CAS  PubMed  Google Scholar 

  188. 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. Eur J Neurosci 35(9):1426–1432

    PubMed  PubMed Central  Google Scholar 

  189. Narita M, Nagumo Y, Hashimoto S, Narita M, Khotib J, Miyatake M, Sakurai T, Yanagisawa M, Nakamachi T, Shioda S, Suzuki T (2006) Direct involvement of orexinergic systems in the activation of the mesolimbic dopamine pathway and related behaviors induced by morphine. J Neurosci 26(2):398–405

    CAS  PubMed  PubMed Central  Google Scholar 

  190. 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(3):697–704

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Schone C, Burdakov D (2012) Glutamate and GABA as rapid effectors of hypothalamic "peptidergic" neurons. Front Behav Neurosci 6:81

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 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(4):1033–1044

    CAS  PubMed  Google Scholar 

  193. 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(19):RC168

    CAS  PubMed  PubMed Central  Google Scholar 

  194. 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(16):E1648–E1655

    Google Scholar 

  195. Williams RH, Alexopoulos H, Jensen LT, Fugger L, Burdakov D (2008) Adaptive sugar sensors in hypothalamic feeding circuits. Proc Natl Acad Sci U S A 105(33):11975–11980

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Ahmed SH (2012) The science of making drug-addicted animals. Neuroscience 211:107–125

    CAS  PubMed  Google Scholar 

  197. Ahmed SH, Walker JR, Koob GF (2000) Persistent increase in the motivation to take heroin in rats with a history of drug escalation. Neuropsychopharmacology 22(4):413–421

    CAS  PubMed  Google Scholar 

  198. Zimmer BA, Oleson EB, Roberts DCS (2012) The motivation to self-administer is increased after a history of spiking brain levels of cocaine. Neuropsychopharmacology 37(8):1901–1910

    CAS  PubMed  PubMed Central  Google Scholar 

  199. 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(5):461–471

    CAS  PubMed  Google Scholar 

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Acknowledgments

This work is supported by an NHMRC CJ Martin Fellowship (1072706) to M.H.J., and PHS grants R00 DA035251 to SVM, and R01 DA006214 to GAJ. Support for DEM: R21 DA041674.

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Authors and Affiliations

  1. Brain Health Institute, Rutgers University/Rutgers Biomedical and Health Sciences, Piscataway, NJ, 08854, USA

    Morgan H. James & Gary Aston-Jones

  2. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, 2337, Australia

    Morgan H. James

  3. Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, 92967, USA

    Stephen V. Mahler

  4. Department of Psychological and Brain Sciences & Neuroscience and Behavior Graduate Program, University of Massachusetts Amherst, Amherst, MA, 01003, USA

    David E. Moorman

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  1. Morgan H. James
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  2. Stephen V. Mahler
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  4. Gary Aston-Jones
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Correspondence to Gary Aston-Jones .

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Editors and Affiliations

  1. Florey Institute of Neuroscience & Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, VIC, Australia

    Andrew J Lawrence

  2. Dep Psychiatry & Behav Sciences, Stanford University, Stanford, CA, USA

    Luis de Lecea

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James, M.H., Mahler, S.V., Moorman, D.E., Aston-Jones, G. (2016). A Decade of Orexin/Hypocretin and Addiction: Where Are We Now?. In: Lawrence, A.J., de Lecea, L. (eds) Behavioral Neuroscience of Orexin/Hypocretin. Current Topics in Behavioral Neurosciences, vol 33. Springer, Cham. https://doi.org/10.1007/7854_2016_57

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