Narcolepsy pp 241-251 | Cite as

Effects of Orexin/Hypocretin on Ventral Tegmental Area Dopamine Neurons: An Emerging Role in Addiction



Addiction poses a significant threat to the health, social, and economic fabric of families, communities, and nations. The extent of worldwide psychoactive drug use is estimated at 2 billion alcohol users, 1.3 billion smokers, and 185 million drug users (UNDCP Statistics, 2002). Currently, there is no effective treatment for craving related to substance abuse. Several medications used clinically to counteract the effects of craving and relapse targeting different receptors have so far shown little efficacy. For example, drug-free retention rates with the use of opioid receptor antagonist, naltrexone, is often less that 20% in heroin addicts [1] and 30–40% in alcoholics [2]. Tricyclic antidepressants and serotonin reuptake inhibitors have been widely used in the treatment of cocaine addicts, but have not been efficacious [1]. Finally, trials using the GABAB receptor agonist, baclofen, have shown reductions in cocaine craving, but long-term outcome studies looking at craving and ­continued cocaine use are needed [3]. Taken together, novel targets are needed for the development of new medications for chronically relapsing forms of addiction. Interestingly, patients with narcolepsy are often treated with highly addictive amphetamine-like drugs such as methylphenidate, amphetamine, and γ-hydroxybutyrate [4], but they rarely become addicted to these drugs [5, 6]. Because narcolepsy results from a deficient orexin/hypocretin (ox/hcrt) system, the absence of addiction in narcoleptic patients treated with psychostimulants suggests the possibility of this system’s involvement in the reinforcing aspect of addictive drugs. This chapter will discuss evidence for the interaction of these peptides in the neural circuits mediating drug-seeking behaviors.


Addiction Reward Ventral tegmental area Orexin Hypocretin Motivation 


  1. 1.
    Kreek MJ, Bart G, Lilly C, Laforge S, Nielsen DA. Pharmacogenetics and human molecular genetics of opiate and cocaine addictions and their treatments. Pharmacol Rev. 2005;57:1–26.PubMedCrossRefGoogle Scholar
  2. 2.
    Johnson BA. Update on neuropharmacological treatments for alcoholism: scientific basis and clinical findings. Biochem Pharmacol. 2008;75:34–56.PubMedCrossRefGoogle Scholar
  3. 3.
    Shoptaw S, Yang X, Rotheram-Fuller EJ, Hsieh YC, Kintaudi PC, Charuvastra VC, et al. Randomized placebo-controlled trial of baclofen for cocaine dependence: preliminary effects for individuals with chronic patterns of cocaine use. J Clin Psychiatry. 2003;64:1440–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Nishino S, Mignot E. Pharmacological aspects of human and canine narcolepsy. Prog Neurobiol. 1997;52:27–78.PubMedCrossRefGoogle Scholar
  5. 5.
    Akimoto H, Honda Y, Takahashi Y. Pharmacotherapy in narcolepsy. Dis Nerv Syst. 1960;21:704–6.PubMedGoogle Scholar
  6. 6.
    Guilleminault C, Carskadon M, Dement WC. On the treatment of rapid eye movement narcolepsy. Arch Neurol. 1974;30:90–3.PubMedCrossRefGoogle Scholar
  7. 7.
    Robinson TE, Berridge KC. The neural basis of drug craving; an incentive-sensitization theory of addiction. Brain Res Rev. 1993;18:247–91.PubMedCrossRefGoogle Scholar
  8. 8.
    Nestler EJ. Molecular mechanisms of drug addiction. Annu Rev Med. 2004;55:113–32.PubMedCrossRefGoogle Scholar
  9. 9.
    Thomas MJ, Kalivas PW, Shaham Y. Neuroplasticity in the mesolimbic dopamine system and cocaine addiction. Br J Pharmacol. 2008;154:327–42.PubMedCrossRefGoogle Scholar
  10. 10.
    Weiss F, Parsons LH, Schulteis G, Hyytiä P, Lorang MT, Bloom FE, et al. Ethanol self-administration restores withdrawal-associated deficiencies in accumbal dopamine and 5-hydroxytryptamine release in dependent rats. J Neurosci. 1996;16:3474–85.PubMedGoogle Scholar
  11. 11.
    Kalivas PW, Duffy P. Time course of extracellular ­dopamine and behavioral sensitization to cocaine. I. Dopamine axon terminals. J Neurosci. 1993;13:266–75.PubMedGoogle Scholar
  12. 12.
    Kalivas PW, Duffy P. Time course of extracellular dopamine and behavioral sensitization to cocaine. II. Dopamine perikarya. J Neurosci. 1993;13:276–84.PubMedGoogle Scholar
  13. 13.
    Post RM, Rose H. Increasing effects of repetitive cocaine administration in the rat. Nature. 1976;260:731–2.PubMedCrossRefGoogle Scholar
  14. 14.
    Boileau I, Dagher A, Leyton M, Gunn RN, Baker GB, Diksic M, et al. Modeling sensitization to stimulants in humans: an [11C]raclopride/positron emission tomography study in healthy men. Arch Gen Psychiatry. 2006;63:1386–95.PubMedCrossRefGoogle Scholar
  15. 15.
    Redgrave P, Gurney K. The short-latency dopamine signal: a role in discovering novel actions? Nat Rev Neurosci. 2006;7:967–75.PubMedCrossRefGoogle Scholar
  16. 16.
    Berridge KC. The debate over dopamine’s role in reward: the case for incentive salience. Psychopharmacol. 2007;191:391–431.CrossRefGoogle Scholar
  17. 17.
    Wise RA. Dopamine, learning and motivation. Nat Rev Neurosci. 2004;5:483–94.PubMedCrossRefGoogle Scholar
  18. 18.
    Roitman MF, Stuber GD, Phillips PE, Wightman RM, Carelli RM. Dopamine operates as a subsecond modulator of food seeking. J Neurosci. 2004;24:1265–71.PubMedCrossRefGoogle Scholar
  19. 19.
    Phillips PE, Stuber GD, Heien ML, Wightman RM, Carelli RM. Subsecond dopamine release promotes cocaine seeking. Nature. 2003;422:614–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Grace AA, Bunney BS. The control of firing pattern in nigral dopamine neurons: burst firing. J Neurosci. 1984;4:2877–90.PubMedGoogle Scholar
  21. 21.
    Grace AA, Bunney BS. The control of firing pattern in nigral dopamine neurons: single spike firing. J Neurosci. 1984;4:2866–76.PubMedGoogle Scholar
  22. 22.
    Temper JM, Martin LM, Anderson DR. GABAA receptor-mediated inhibition of rat substantia nigra dopaminergic neurons by pars reticulata projection neurons. J Neurosci. 1995;15:3092–103.Google Scholar
  23. 23.
    Overton PG, Clark D. Burst firing in midbrain dopaminergic neurons. Brain Res Brain Res Rev. 1997;25:312–34.PubMedCrossRefGoogle Scholar
  24. 24.
    Schultz W. Getting formal with dopamine reward. Neuron. 2002;36:241–63.PubMedCrossRefGoogle Scholar
  25. 25.
    Wightman RM, Zimmerman JB. Control of dopamine extracellular concentration in rat striatum by impulse flow and uptake. Brain Res Rev. 1990;15:135–44.PubMedCrossRefGoogle Scholar
  26. 26.
    Suaud-Chagny MF, Chergui K, Chouvet G, Gonon F. Relationship between dopamine release in the rat nucleus accumbens and the discharge activity of dopaminergic neurons during local in vivo application of amino acids in the ventral tegmental area. Neuroscience. 1992;49:63–72.PubMedCrossRefGoogle Scholar
  27. 27.
    Murase S, Grenhoff J, Chouvet G, Gonon FG, Svensson TH. Prefrontal cortex regulates burst firing and transmitter release in rat mesolimbic dopamine neurons studied in vivo. Neurosci Lett. 1993;157:53–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Johnson SW, Seutin V, North RA. Burst firing in dopamine neurons induced by N-methyl-D-aspartate: role of electrogenic sodium pump. Science. 1992;258:665–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Overton PG, Clark D. Iontophroetically administered drugs acting at the N-methyl-D-aspartate receptor modulate burst firing in A9 dopamine neurons in the rat. Synapse. 1992;10:131–40.PubMedCrossRefGoogle Scholar
  30. 30.
    Malenka RC, Bear MF. LTP and LTD: an embarrassment of riches. Neuron. 2004;44:5–21.PubMedCrossRefGoogle Scholar
  31. 31.
    Bonci A, Malenka RC. Properties and plasticity of excitatory synapses on dopaminergic and GABAergic cells in the ventral tegmental area. J Neurosci. 1999;19:3723–30.PubMedGoogle Scholar
  32. 32.
    Overton PG, Richards CD, Berry MS, Clark D. Long-term potentiation at excitatory amino acid synapses on midbrain dopamine neurons. Neuroreport. 1999;10:221–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Jones S, Kornblum JL, Kauer JA. Amphetamine blocks long term synaptic depression in the ventral tegmental area. J Neurosci. 2000;20:5575–80.PubMedGoogle Scholar
  34. 34.
    Thomas MT, Malenka RC, Bonci A. Modulation of long-term depression by dopamine in the mesolimbic system. J Neurosci. 2000;20:5581–6.PubMedGoogle Scholar
  35. 35.
    Bellone C, Lüscher C. mGluRs induce a long-term depression in the ventral tegmental area that involves a switch of the subunit composition of AMPA receptors. Eur J Neurosci. 2005;21:1280–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Stuber GD, Klanker M, de Ridder B, Bowers MS, Joosten RN, Feenstra MG, et al. Reward predictive cues enhance excitatory synaptic strength onto midbrain dopamine neurons. Science. 2008;321:1690–2.PubMedCrossRefGoogle Scholar
  37. 37.
    Ungless MA, Whistler JL, Malenka RC, Bonci A. A single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature. 2001;411:583–7.PubMedCrossRefGoogle Scholar
  38. 38.
    Borgland SL, Malenka R, Bonci A. Acute and chronic cocaine-induced potentiation of synaptic strength in the VTA: electrophysiological and behavioral correlates in individual rats. J Neurosci. 2004;24:7482–90.PubMedCrossRefGoogle Scholar
  39. 39.
    Saal D, Dong Y, Bonci A, Malenka RC. Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron. 2003;37:577–82.PubMedCrossRefGoogle Scholar
  40. 40.
    Chen BT, Bowers MS, Martin M, Hopf FW, Guillory AM, Carelli RM, et al. Cocaine but not natural reward self-administration nor passive cocaine infusion produces persistent LTP in the VTA. Neuron. 2008;59:288–97.PubMedCrossRefGoogle Scholar
  41. 41.
    Fadel J, Deutch AY. Anatomical substrates of orexin-dopamine interactions: lateral hypothalamic projections to the ventral tegmental area. Neuroscience. 2002;111:379–87.PubMedCrossRefGoogle Scholar
  42. 42.
    Narita M, Nagumo Y, Hashimoto S, Narita M, Khotib J, Miyatake M, et al. Direct involvement of orexinergic systems in the activation of the mesolimbic dopamine pathway and related behaviors induced by morphine. J Neurosci. 2006;26:398–405.PubMedCrossRefGoogle Scholar
  43. 43.
    Korotkova TM, Sergeeva OA, Eriksson KS, Haas HL, Brown RE. Excitation of ventral tegmental area dopaminergic and non-dopaminergic neurons by orexin/hypocretins. J Neurosci. 2003;23:7–11.PubMedGoogle Scholar
  44. 44.
    Adamantidis A, de Lecea L. The hypocretins as sensors for metabolism and arousal. J Physiol. 2009;587:33–40.PubMedCrossRefGoogle Scholar
  45. 45.
    Siegel JM. Hypocretin (orexin): role in normal behavior and neuropathology. Annu Rev Psychol. 2004;55:125–48.PubMedCrossRefGoogle Scholar
  46. 46.
    Boutrel B, Kenny PJ, Specio SE, Martin-Fardon R, Markou A, Koob GF, et al. Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proc Natl Acad Sci U S A. 2005;102:19168–91.PubMedCrossRefGoogle Scholar
  47. 47.
    Harris GC, Wimmer W, Aston Jones G. A role for lateral hypothalamic orexin neurons in reward seeking. Nature. 2005;437:556–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Borgland SL, Taha S, Sarti F, Fields HL, Bonci A. Orexin A signaling in dopamine neurons is critical for cocaine induced synaptic plasticity and behavioral sensitization. Neuron. 2006;49:589–601.PubMedCrossRefGoogle Scholar
  49. 49.
    Lawrence AJ, Cowen MS, Yang H-J, Chen F, Oldfield B. The orexin system regulates alcohol-seeking in rats. Br J Pharmacol. 2006;148:752–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Harris GC, Wimmer M, Randall-Thompson JF, Aston-Jones G. Lateral hypothalamic orexin neurons are criti­cally involved in learning to associate an environment with morphine reward. Behav Brain Res. 2007;183:43–51.PubMedCrossRefGoogle Scholar
  51. 51.
    Hollander JA, Lu Q, Cameron MD, Kamenecka TM, Kenny PJ. Insular hypocretin transmission regulates nicotine reward. Proc Natl Acad Sci U S A. 2008;105:19480–5.PubMedCrossRefGoogle Scholar
  52. 52.
    Peyron C, Tighe DK, van den Pol A, de Lecea L, Heller HC, Sutcliffe JG, et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci. 1998;18:9996–10015.PubMedGoogle Scholar
  53. 53.
    Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. Orexin and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 1998;92:573–85.PubMedCrossRefGoogle Scholar
  54. 54.
    Balcita-Pedicino JJ, Sesack SR. Orexin axons in the rat ventral tegmental area synapse infrequently onto dopamine and gamma-aminobutyric acid neurons. J Comp Neurol. 2007;503:668–85.PubMedCrossRefGoogle Scholar
  55. 55.
    Zhu Y, Miwa Y, Yamanaka A, Yada T, Shibahara M, Abe Y, et al. Orexin receptor type-1 couples exclusively to pertussis toxin-insensitive G-proteins, while orexin receptor type-2 couples to both pertussis toxin-sensitive and -insensitive G-proteins. J Pharmacol Sci. 2003;92:259–66.PubMedCrossRefGoogle Scholar
  56. 56.
    Muschamp JW, Dominguez JM, Sato SM, Shen RY, Hull EM. A role for hypocretin (orexin) in male sexual behavior. J Neurosci. 2007;27:2837–45.PubMedCrossRefGoogle Scholar
  57. 57.
    Vittoz NM, Berridge CW. Hypocretin/orexin selectively increases dopamine efflux within the prefrontal cortex: involvement of the ventral tegmental area. Neuropsychopharmacology. 2006;31:384–95.PubMedCrossRefGoogle Scholar
  58. 58.
    Vittoz NM, Schmeichel B, Berridge CW. Hypocretin /orexin preferentially activates caudomedial ventral tegmental area dopamine neurons. Eur J Neurosci. 2008;28:1629–40.PubMedCrossRefGoogle Scholar
  59. 59.
    Borgland SL, Storm E, Bonci A. Orexin B/hypocretin-2 increases glutamatergic synaptic transmission to ventral tegmental area neurons. Eur J Neurosci. 2008;29:1–12.Google Scholar
  60. 60.
    Georgescu D, Zachariou V, Barrot M, Mieda M, Willie JT, Eisch AJ, et al. Involvement of lateral hypothalamic peptide orexin in morphine dependence and withdrawal. J Neurosci. 2003;23:3106–11.PubMedGoogle Scholar
  61. 61.
    Cazala P, Darracq C, Saint-Marc M. Self-administration of morphine into the lateral hypothalamus in the mouse. Brain Res. 1987;416:283–8.PubMedCrossRefGoogle Scholar
  62. 62.
    Li Y, van den Pol AN. Mu-opioid receptor-mediated depression of the hypothalamic hypocretin/orexin arousal system. J Neurosci. 2008;28:2814–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Huang H, Acuna-Goycolea C, Li Y, Cheng HM, Obrietan K, van den Pol AN. Cannabinoids excite hypothalamic melanin-concentrating hormone but inhibit hypocretin/orexin neurons: implications for cannabinoid actions on food intake and cognitive arousal. J Neurosci. 2007;27:4870–81.PubMedCrossRefGoogle Scholar
  64. 64.
    Estabrooke IV, McCarthy MT, Ko E, Chou TC, Chemelli RM, Yanagisawa M, et al. Fos expression in orexin neurons varies with behavioral state. J Neurosci. 2001;21:1656–62.PubMedGoogle Scholar
  65. 65.
    Pasumarthi RK, Reznikov LR, Fadel J. Activation of orexin neurons by acute nicotine. Eur J Pharmacol. 2006;535:172–6.PubMedCrossRefGoogle Scholar
  66. 66.
    Richards J, Simms J, Steesland P, Taha SA, Borgland SL, Bonci A, et al. Inhibition of orexin-1/hypocretin-1 receptors inhibits yohimbine-induced reinstatement of ethanol and sucrose seeking in long-evans rats. Psychopharmacol. 2008;199:109–17.CrossRefGoogle Scholar
  67. 67.
    Smith R, See RE, Aston-Jones G. Orexin/hypocretin signalling at the OX1 receptor regulates cue-elicited cocaine seeking. Eur J Neurosci. 2009;30:493–503.PubMedCrossRefGoogle Scholar
  68. 68.
    Nair SG, Golden SA, Shaham Y. Differential effects of the hypocretin 1 receptor antagonist SB334867 on high-fat food self-administration and reinstatement of food seeking in rats. Br J Pharmacol. 2008;154:1–11.CrossRefGoogle Scholar
  69. 69.
    Yamanaka A, Beuckmann CT, Willie JT, Hara J, Tsujino N, Mieda M, et al. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron. 2003;38:701–13.PubMedCrossRefGoogle Scholar
  70. 70.
    Wisor JP, Nishino S, Sora I, Uhl GH, Mignot E, Edgar DM. Dopaminergic role in stimulant-induced wakefulness. J Neurosci. 2001;21:1787–94.PubMedGoogle Scholar
  71. 71.
    Borgland SL, Chang SJ, Bowers MS, Thompson JL, Vittoz NM, Floresco S, et al. Orexin A/Hypocretin1 promotes motivation selectively for highly salient ­positive reinforcers. J Neurosci. 2009;29:11215–25.Google Scholar
  72. 72.
    Winsky-Sommerer R, Yamanaka A, Diano S, Borok E, Roberts AJ, Sakurai T, et al. Interaction between the corticotropin-releasing factor system and hypocretins (orexins): a novel circuit mediating stress response. J Neurosci. 2004;24:11439–48.PubMedCrossRefGoogle Scholar
  73. 73.
    Wang B, You Z, Wise RA. Reinstatement of cocaine-seeking by hypocretin (orexin) in the ventral tegmental area: independence from the local CRF network. Biol Psychiatry. 2009;65:857–62.PubMedCrossRefGoogle Scholar
  74. 74.
    Harris GC, Aston-Jones G. Arousal and reward: a dichotomy in orexin function. Trends Neurosci. 2006;29:571–7.PubMedCrossRefGoogle Scholar
  75. 75.
    Sharf R, Guarnieri DJ, Taylor JR, DiLeone RJ. Orexin mediates the expression of precipitated morphine withdrawal and concurrent activation of the nucleus accumbens shell. Biol Psych. 2008;64:175–83.CrossRefGoogle Scholar
  76. 76.
    Fadel J, Bubser M, Deutch AY. Differential activation of orexin neurons by antipsychotic drugs associated with weight gain. J Neurosci. 2002;22:6742–6.PubMedGoogle Scholar
  77. 77.
    Brisbare-Roch C, Dingemanse J, Koberstein R, Hoever P, Aissaoui H, Flores S, et al. Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med. 2007;13:150–5.PubMedCrossRefGoogle Scholar
  78. 78.
    Willie JT, Chemelli RM, Sinton CM, Tokita S, Williams SC, Kisanuki YY, et al. Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes. Neuron. 2003;8:715–30.CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Anesthesiology, Pharmacology and TherapeuticsThe University of British ColumbiaVancouverCanada

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