Advertisement

The Role of Orexins/Hypocretins in Alcohol Use and Abuse

  • Leigh C. Walker
  • Andrew J. Lawrence
Chapter
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 33)

Abstract

Addiction is a chronic relapsing disorder characterized by compulsive drug seeking and drug taking despite negative consequences. Alcohol abuse and addiction have major social and economic consequences and cause significant morbidity and mortality worldwide. Currently available therapeutics are inadequate, outlining the need for alternative treatments. Detailed knowledge of the neurocircuitry and brain chemistry responsible for aberrant behavior patterns should enable the development of novel pharmacotherapies to treat addiction. Therefore it is important to expand our knowledge and understanding of the neural pathways and mechanisms involved in alcohol seeking and abuse. The orexin (hypocretin) neuropeptide system is an attractive target, given the recent FDA and PMDA approval of suvorexant for the treatment of insomnia. Orexin is synthesized exclusively in neurons located in the lateral (LH), perifornical (PEF), and dorsal medial (DMH) hypothalamus. These neurons project widely throughout the neuraxis with regulatory roles in a wide range of behavioral and physiological responses, including sleep–wake cycle neuroendocrine regulation, anxiety, feeding behavior, and reward seeking. Here we summarize the literature to date, which have evaluated the interplay between alcohol and the orexin system.

Keywords

Addiction Alcohol Hypocretin Orexin 

References

  1. 1.
    Rehm J, Mathers C, Popova S et al (2009) Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders. Lancet 373:2223–2233. doi: 10.1016/S0140-6736(09)60746-7CrossRefPubMedGoogle Scholar
  2. 2.
    Wagner F (2002) From first drug use to drug dependence; developmental periods of risk for dependence upon marijuana, cocaine, and alcohol. Neuropsychopharmacology 26:479–488. doi: 10.1016/S0893-133X(01)00367-0CrossRefPubMedGoogle Scholar
  3. 3.
    Anton RF (2001) Carbohydrate-deficient transferrin for detection and monitoring of sustained heavy drinking. Alcohol 25:185–188. doi: 10.1016/S0741-8329(01)00165-3CrossRefPubMedGoogle Scholar
  4. 4.
    Jupp B, Lawrence AJ (2010) New horizons for therapeutics in drug and alcohol abuse. Pharmacol Ther 125:138–168. doi: 10.1016/j.pharmthera.2009.11.002CrossRefPubMedGoogle Scholar
  5. 5.
    Cowen MS, Chen F, Lawrence AJ (2004) Neuropeptides: implications for alcoholism. J Neurochem 89:273–285. doi: 10.1111/j.1471-4159.2004.02394.xCrossRefPubMedGoogle Scholar
  6. 6.
    Boss C, Roch C (2015) Recent trends in orexin research – 2010 to 2015. Bioorg Med Chem Lett 25:2875–2887. doi: 10.1016/j.bmcl.2015.05.012CrossRefPubMedGoogle Scholar
  7. 7.
    Wayner MJ, Greenberg I, Carey RJ, Nolley D (1971) Ethanol drinking elicited during electrical stimulation of the lateral hypothalamus. Physiol Behav 7:793–795. doi: 10.1016/0031-9384(71)90152-1CrossRefPubMedGoogle Scholar
  8. 8.
    Lestang I, Cardo B, Roy MT, Velley L (1985) Electrical self-stimulation deficits in the anterior and posterior parts of the medial forebrain bundle after ibotenic acid lesion of the middle lateral hypothalamus. Neuroscience 15:379–388. doi: 10.1016/0306-4522(85)90220-9CrossRefPubMedGoogle Scholar
  9. 9.
    de Lecea L, Kilduff TS, Peyron C et al (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci 95:322–327. doi: 10.1073/pnas.95.1.322CrossRefPubMedGoogle Scholar
  10. 10.
    Sakurai T, Amemiya A, Ishii M et al (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92:573–585. doi: 10.1016/S0092-8674(00)80949-6CrossRefPubMedGoogle Scholar
  11. 11.
    Chemelli RM, Willie JT, Sinton CM et al (1999) Narcolepsy in orexin knockout mice. Cell 98:437–451. doi: 10.1016/S0092-8674(00)81973-XCrossRefPubMedGoogle Scholar
  12. 12.
    Lin L, Faraco J, Li R et al (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98:365–376. doi: 10.1016/S0092-8674(00)81965-0CrossRefPubMedGoogle Scholar
  13. 13.
    Nishino S, Ripley B, Overeem S et al (2000) Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355:39–40. doi: 10.1016/S0140-6736(99)05582-8CrossRefPubMedGoogle Scholar
  14. 14.
    Nishino S (2007) The hypocretin/orexin receptor: therapeutic prospective in sleep disorders. Expert Opin Investig Drugs 16(11):1785–1797CrossRefGoogle Scholar
  15. 15.
    Sakurai T (2007) The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci 8:171–181. doi: 10.1038/nrn2092CrossRefPubMedGoogle Scholar
  16. 16.
    Peyron C, Tighe DK, van den Pol AN et al (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18:9996–10015CrossRefGoogle Scholar
  17. 17.
    Fadel J, Deutch A (2002) Anatomical substrates of orexin–dopamine interactions: lateral hypothalamic projections to the ventral tegmental area. Neuroscience 111(2):379–387CrossRefGoogle Scholar
  18. 18.
    Winsky-Sommerer R, Boutrel B, De Lecea L (2003) The role of the hypocretinergic system in the integration of networks that dictate the states of arousal. Drug News Perspect 16:504–512CrossRefGoogle Scholar
  19. 19.
    Harris GC, Wimmer M, Aston-Jones G (2005) A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437:556–559. doi: 10.1038/nature04071CrossRefPubMedGoogle Scholar
  20. 20.
    Boutrel B, Kenny PJ, Specio SE et al (2005) Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proc Natl Acad Sci 102:19168–19173. doi: 10.1073/pnas.0507480102CrossRefPubMedGoogle Scholar
  21. 21.
    Lawrence AJ, Cowen MS, Yang H-J et al (2006) The orexin system regulates alcohol-seeking in rats. Br J Pharmacol 148:752–759. doi: 10.1038/sj.bjp.0706789CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    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 20:469–481CrossRefGoogle Scholar
  23. 23.
    Sterling ME, Karatayev O, Chang G-Q et al (2015) Model of voluntary ethanol intake in zebrafish: effect on behavior and hypothalamic orexigenic peptides. Behav Brain Res 278:29–39. doi: 10.1016/j.bbr.2014.09.024CrossRefPubMedGoogle Scholar
  24. 24.
    Morganstern I, Chang G-Q, Barson JR et al (2010) Differential effects of acute and chronic ethanol exposure on orexin expression in the perifornical lateral hypothalamus. Alcohol Clin Exp Res 34:886–896. doi: 10.1111/j.1530-0277.2010.01161.xCrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    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. doi: 10.1111/acer.12591CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Holtz NA, Zlebnik NE, Carroll ME (2012) Differential orexin/hypocretin expression in addiction-prone and -resistant rats selectively bred for high (HiS) and low (LoS) saccharin intake. Neurosci Lett 522:12–15. doi: 10.1016/j.neulet.2012.05.066CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Dess NK, Badia-Elder NE, Thiele TE et al (1998) Ethanol consumption in rats selectively bred for differential saccharin intake. Alcohol 16:275–278CrossRefGoogle Scholar
  28. 28.
    Perry JL, Morgan AD, Anker JJ et al (2006) Escalation of i.v. cocaine self-administration and reinstatement of cocaine-seeking behavior in rats bred for high and low saccharin intake. Psychopharmacology (Berl) 186:235–245. doi: 10.1007/s00213-006-0371-xCrossRefGoogle Scholar
  29. 29.
    Dess NK, Chapman CD, Monroe D (2009) Consumption of SC45647 and sucralose by rats selectively bred for high and low saccharin intake. Chem Senses 34:211–220. doi: 10.1093/chemse/bjn078CrossRefPubMedGoogle Scholar
  30. 30.
    Barson JR, Karatayev O, Gaysinskaya V et al (2012) Effect of dietary fatty acid composition on food intake, triglycerides, and hypothalamic peptides. Regul Pept 173:13–20. doi: 10.1016/j.regpep.2011.08.012CrossRefPubMedGoogle Scholar
  31. 31.
    Carvajal F, Alcaraz-Iborra M, Lerma-Cabrera JM et al (2015) Orexin receptor 1 signaling contributes to ethanol binge-like drinking: pharmacological and molecular evidence. Behav Brain Res 287:230–237. doi: 10.1016/j.bbr.2015.03.046CrossRefPubMedGoogle Scholar
  32. 32.
    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. doi: 10.1111/ejn.13170CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Richards JK, Simms JA, Steensland P et al (2008) Inhibition of orexin-1/hypocretin-1 receptors inhibits yohimbine-induced reinstatement of ethanol and sucrose seeking in Long-Evans rats. Psychopharmacology (Berl) 199:109–117. doi: 10.1007/s00213-008-1136-5CrossRefGoogle Scholar
  34. 34.
    Shoblock JR, Welty N, Aluisio L et al (2011) Selective blockade of the orexin-2 receptor attenuates ethanol self-administration, place preference, and reinstatement. Psychopharmacology (Berl) 215:191–203. doi: 10.1007/s00213-010-2127-xCrossRefGoogle Scholar
  35. 35.
    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. doi: 10.1016/j.alcohol.2009.07.002CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Srinivasan S, Simms JA, Nielsen CK et al (2012) The dual orexin/hypocretin receptor antagonist, almorexant, in the ventral tegmental area attenuates ethanol self-administration. PLoS One 7:e44726. doi: 10.1371/journal.pone.0044726CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Anderson RI, Becker HC, Adams BL et al (2014) Orexin-1 and orexin-2 receptor antagonists reduce ethanol self-administration in high-drinking rodent models. Front Neurosci 8:33. doi: 10.3389/fnins.2014.00033CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Cason AM, Smith RJ, Tahsili-Fahadan P et al (2010) Role of orexin/hypocretin in reward-seeking and addiction: implications for obesity. Physiol Behav 100:419–428. doi: 10.1016/j.physbeh.2010.03.009CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Jupp B, Krstew E, Dezsi G, Lawrence AJ (2011) Discrete cue-conditioned alcohol-seeking after protracted abstinence: pattern of neural activation and involvement of orexin1 receptors. Br J Pharmacol 162:880–889. doi: 10.1111/j.1476-5381.2010.01088.xCrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Thiele TE, Navarro M (2014) “Drinking in the dark” (DID) procedures: a model of binge-like ethanol drinking in non-dependent mice. Alcohol 48:235–241CrossRefGoogle Scholar
  41. 41.
    McElhinny CJ, Lewin AH, Mascarella SW et al (2012) Hydrolytic instability of the important orexin 1 receptor antagonist SB-334867: possible confounding effects on in vivo and in vitro studies. Bioorg Med Chem Lett 22:6661–6664. doi: 10.1016/j.bmcl.2012.08.109CrossRefPubMedGoogle Scholar
  42. 42.
    Brown R, Khoo S, Lawrence A (2013) Central orexin (hypocretin) 2 receptor antagonism reduces ethanol self-administration, but not cue-conditioned ethanol-seeking, in ethanol-preferring rats. Int J Neuropsychopharmacol 16:2067–2079. doi: 10.1017/S1461145713000333CrossRefPubMedGoogle Scholar
  43. 43.
    Sterling ME, Chang G-Q, Karatayev O et al (2016) Effects of embryonic ethanol exposure at low doses on neuronal development, voluntary ethanol consumption and related behaviors in larval and adult zebrafish: role of hypothalamic orexigenic peptides. Behav Brain Res. doi: 10.1016/j.bbr.2016.01.013CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Steiner MA, Lecourt H, Strasser DS et al (2011) Differential effects of the dual orexin receptor antagonist almorexant and the GABA(A)-α1 receptor modulator zolpidem, alone or combined with ethanol, on motor performance in the rat. Neuropsychopharmacology 36:848–856. doi: 10.1038/npp.2010.224CrossRefPubMedGoogle Scholar
  45. 45.
    Brisbare-Roch C, Dingemanse J, Koberstein R et al (2007) Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med 13:150–155. doi: 10.1038/nm1544CrossRefPubMedGoogle Scholar
  46. 46.
    Schneider ER, Rada P, Darby RD et al (2007) Orexigenic peptides and alcohol intake: differential effects of orexin, galanin, and ghrelin. Alcohol Clin Exp Res 31:1858–1865. doi: 10.1111/j.1530-0277.2007.00510.xCrossRefPubMedGoogle Scholar
  47. 47.
    Chen Y-W, Barson JR, Chen A, Hoebel BG, Leibowitz SF (2014) Hypothalamic peptides controlling alcohol intake: differential effects on microstructure of drinking bouts. Alcohol 48:657–664CrossRefGoogle Scholar
  48. 48.
    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. Addict Biol 19:233–236. doi: 10.1111/j.1369-1600.2012.00480.xCrossRefPubMedGoogle Scholar
  49. 49.
    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 32:13309–13326. doi: 10.1523/JNEUROSCI.2277-12.2012CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Mayannavar S, Rashmi KS, Rao YD, Yadav S, Ganaraja B (2016) Effect of Orexin A antagonist (SB-334867) infusion into the nucleus accumbens on consummatory behavior and alcohol preference in Wistar rats. Indian J Pharm 48:53CrossRefGoogle Scholar
  51. 51.
    Dhaher R, Hauser SR, Getachew B et al (2010) The orexin-1 receptor antagonist SB-334867 reduces alcohol relapse drinking, but not alcohol-seeking, in alcohol-preferring (P) rats. J Addict Med 4:153–159. doi: 10.1097/ADM.0b013e3181bd893fCrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    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 63:152–157. doi: 10.1016/j.biopsych.2007.02.002CrossRefPubMedGoogle Scholar
  53. 53.
    Brown RM, Kim AK, Khoo SY-S et al (2015) Orexin-1 receptor signalling in the prelimbic cortex and ventral tegmental area regulates cue-induced reinstatement of ethanol-seeking in iP rats. Addict Biol. doi: 10.1111/adb.12251CrossRefPubMedGoogle Scholar
  54. 54.
    Millan EZ, Furlong TM, McNally GP (2010) Accumbens shell-hypothalamus interactions mediate extinction of alcohol seeking. J Neurosci 30:4626–4635. doi: 10.1523/JNEUROSCI.4933-09.2010CrossRefPubMedGoogle Scholar
  55. 55.
    Schacht JP, Anton RF, Myrick H (2013) Functional neuroimaging studies of alcohol cue reactivity: a quantitative meta-analysis and systematic review. Addict Biol 18:121–133. doi: 10.1111/j.1369-1600.2012.00464.xCrossRefPubMedGoogle Scholar
  56. 56.
    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. doi: 10.1016/j.neuroscience.2007.01.063CrossRefPubMedGoogle Scholar
  57. 57.
    Prasad AA, McNally GP (2014) Effects of vivo morpholino knockdown of lateral hypothalamus orexin/hypocretin on renewal of alcohol seeking. PLoS One 9:e110385. doi: 10.1371/journal.pone.0110385CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Marchant NJ, Hamlin AS, McNally GP (2009) Lateral hypothalamus is required for context-induced reinstatement of extinguished reward seeking. J Neurosci 29:1331–1342. doi: 10.1523/JNEUROSCI.5194-08.2009CrossRefPubMedGoogle Scholar
  59. 59.
    Sinha R (2001) How does stress increase risk of drug abuse and relapse? Psychopharmacology (Berl) 158:343–359. doi: 10.1007/s002130100917CrossRefGoogle Scholar
  60. 60.
    Samson WK, Taylor MM, Follwell M, Ferguson AV (2002) Orexin actions in hypothalamic paraventricular nucleus: physiological consequences and cellular correlates. Regul Pept 104:97–103. doi: 10.1016/S0167-0115(01)00353-6CrossRefPubMedGoogle Scholar
  61. 61.
    Kuru M, Ueta Y, Serino R et al (2000) Centrally administered orexin/hypocretin activates HPA axis in rats. Neuroreport 11:1977–1980. doi: 10.1097/00001756-200006260-00034CrossRefPubMedGoogle Scholar
  62. 62.
    Winsky-Sommerer R, Yamanaka A, Diano S et al (2004) Interaction between the corticotropin-releasing factor system and hypocretins (orexins): a novel circuit mediating stress response. J Neurosci 24:11439–11448. doi: 10.1523/JNEUROSCI.3459-04.2004CrossRefPubMedGoogle Scholar
  63. 63.
    Wang B, You Z-B, 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 65:857–862. doi: 10.1016/j.biopsych.2009.01.018CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Plaza-Zabala A, Martín-García E, de Lecea L et al (2010) Hypocretins regulate the anxiogenic-like effects of nicotine and induce reinstatement of nicotine-seeking behavior. J Neurosci 30:2300–2310. doi: 10.1523/JNEUROSCI.5724-09.2010CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Blasiak A, Siwiec M, Grabowiecka A et al (2015) Excitatory orexinergic innervation of rat nucleus incertus – implications for ascending arousal, motivation and feeding control. Neuropharmacology 99:432–447. doi: 10.1016/j.neuropharm.2015.08.014CrossRefPubMedGoogle Scholar
  66. 66.
    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 110:82–91CrossRefGoogle Scholar
  67. 67.
    Ryan PJ, Kastman HE, Krstew EV et al (2013) Relaxin-3/RXFP3 system regulates alcohol-seeking. Proc Natl Acad Sci U S A 110:20789–20794. doi: 10.1073/pnas.1317807110CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Walker AW, Smith CM, Chua BE et al (2015) Relaxin-3 receptor (RXFP3) signalling mediates stress-related alcohol preference in mice. PLoS One 10:e0122504. doi: 10.1371/journal.pone.0122504CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Chen Y-W, Fiscella KA, Bacharach SZ et al (2015) Effect of yohimbine on reinstatement of operant responding in rats is dependent on cue contingency but not food reward history. Addict Biol 20:690–700. doi: 10.1111/adb.12164CrossRefPubMedGoogle Scholar
  70. 70.
    McDougle CJ, Price LH, Heninger GR et al (1995) Noradrenergic response to acute ethanol administration in heathly subjects: comparison with intravenous yohimbine. Psychopharmacology (Berl) 118:127–135. doi: 10.1007/BF02245830CrossRefGoogle Scholar
  71. 71.
    Umhau JC, Schwandt ML, Usala J et al (2011) Pharmacologically induced alcohol craving in treatment seeking alcoholics correlates with alcoholism severity, but is insensitive to acamprosate. Neuropsychopharmacology 36:1178–1186. doi: 10.1038/npp.2010.253CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    See RE, Waters RP (2010) Pharmacologically-induced stress: a cross-species probe for translational research in drug addiction and relapse. Am J Transl Res 3:81–89PubMedPubMedCentralGoogle Scholar
  73. 73.
    Mantsch JR, Baker DA, Funk D et al (2016) Stress-induced reinstatement of drug seeking: 20 years of progress. Neuropsychopharmacology 41:335–356. doi: 10.1038/npp.2015.142CrossRefPubMedGoogle Scholar
  74. 74.
    Lê AD, Harding S, Juzytsch W et al (2000) The role of corticotrophin-releasing factor in stress-induced relapse to alcohol-seeking behavior in rats. Psychopharmacology (Berl) 150:317–324. doi: 10.1007/s002130000411CrossRefGoogle Scholar
  75. 75.
    Funk D, Li Z, Lê AD (2006) Effects of environmental and pharmacological stressors on c-fos and corticotropin-releasing factor mRNA in rat brain: relationship to the reinstatement of alcohol seeking. Neuroscience 138:235–243. doi: 10.1016/j.neuroscience.2005.10.062CrossRefPubMedGoogle Scholar
  76. 76.
    Marinelli PW, Funk D, Juzytsch W et al (2007) The CRF1 receptor antagonist antalarmin attenuates yohimbine-induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats. Psychopharmacology (Berl) 195:345–355. doi: 10.1007/s00213-007-0905-xCrossRefGoogle Scholar
  77. 77.
    Zhou L, Smith RJ, Do PH et al (2012) Repeated orexin 1 receptor antagonism effects on cocaine seeking in rats. Neuropharmacology 63:1201–1207. doi: 10.1016/j.neuropharm.2012.07.044CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Ziółkowski M, Czarnecki D, Budzyński J et al (2015) Orexin in patients with alcohol dependence treated for relapse prevention: a pilot study. Alcohol Alcohol. doi: 10.1093/alcalc/agv129CrossRefPubMedGoogle Scholar
  79. 79.
    Voorhees CM, Cunningham CL (2011) Involvement of the orexin/hypocretin system in ethanol conditioned place preference. Psychopharmacology (Berl) 214:805–818. doi: 10.1007/s00213-010-2082-6CrossRefGoogle Scholar
  80. 80.
    Becker H (1999) Alcohol withdrawal: neuroadaptation and sensitization. CNS Spectr 4:38–40, 57–65CrossRefGoogle Scholar
  81. 81.
    Littleton J (1999) Neurochemical mechanisms underlying alcohol withdrawal. Alcohol Res Health 22:13Google Scholar
  82. 82.
    Georgescu D, Zachariou V, Barrot M et al (2003) Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal. J Neurosci 23:3106–3111CrossRefGoogle Scholar
  83. 83.
    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 64:175–183. doi: 10.1016/j.biopsych.2008.03.006CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    von der Goltz C, Koopmann A, Dinter C et al (2011) Involvement of orexin in the regulation of stress, depression and reward in alcohol dependence. Horm Behav 60:644–650. doi: 10.1016/j.yhbeh.2011.08.017CrossRefPubMedGoogle Scholar
  85. 85.
    Bayerlein K, Kraus T, Leinonen I et al (2011) Orexin A expression and promoter methylation in patients with alcohol dependence comparing acute and protracted withdrawal. Alcohol 45:541–547. doi: 10.1016/j.alcohol.2011.02.306CrossRefPubMedGoogle Scholar
  86. 86.
    Narita M, Nagumo Y, Hashimoto S et al (2006) Direct involvement of orexinergic systems in the activation of the mesolimbic dopamine pathway and related behaviors induced by morphine. J Neurosci 26:398–405. doi: 10.1523/JNEUROSCI.2761-05.2006CrossRefPubMedGoogle Scholar
  87. 87.
    Mang GM, Dürst T, Bürki H et al (2012) The dual orexin receptor antagonist almorexant induces sleep and decreases orexin-induced locomotion by blocking orexin 2 receptors. Sleep 35:1625–1635. doi: 10.5665/sleep.2232CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Rodgers RJ, Halford JCG, Nunes de Souza RL et al (2001) SB-334867, a selective orexin-1 receptor antagonist, enhances behavioural satiety and blocks the hyperphagic effect of orexin-A in rats. Eur J Neurosci 13:1444–1452. doi: 10.1046/j.0953-816x.2001.01518.xCrossRefPubMedGoogle Scholar
  89. 89.
    Hoch M, Hay JL, Hoever P et al (2013) Dual orexin receptor antagonism by almorexant does not potentiate impairing effects of alcohol in humans. Eur Neuropsychopharmacol 23:107–117. doi: 10.1016/j.euroneuro.2012.04.012CrossRefPubMedGoogle Scholar
  90. 90.
    Robinson TE, Berridge KC (2008) Review. The incentive sensitization theory of addiction: some current issues. Philos Trans R Soc Lond B Biol Sci 363:3137–3146. doi: 10.1098/rstb.2008.0093CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Macedo GC, Kawakami SE, Vignoli T et al (2013) The influence of orexins on ethanol-induced behavioral sensitization in male mice. Neurosci Lett 551:84–88. doi: 10.1016/j.neulet.2013.07.010CrossRefPubMedGoogle Scholar
  92. 92.
    Winrow CJ, Tanis KQ, Reiss DR et al (2010) Orexin receptor antagonism prevents transcriptional and behavioral plasticity resulting from stimulant exposure. Neuropharmacology 58:185–194. doi: 10.1016/j.neuropharm.2009.07.008CrossRefPubMedGoogle Scholar
  93. 93.
    Borgland SL, Taha SA, Sarti F et al (2006) Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Neuron 49:589–601. doi: 10.1016/j.neuron.2006.01.016CrossRefPubMedGoogle Scholar
  94. 94.
    Hutcheson DM, Quarta D, Halbout B et al (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 22:173–181. doi: 10.1097/FBP.0b013e328343d761CrossRefPubMedGoogle Scholar
  95. 95.
    Thompson JL, Borgland SL (2011) A role for hypocretin/orexin in motivation. Behav Brain Res 217:446–453. doi: 10.1016/j.bbr.2010.09.028CrossRefPubMedGoogle Scholar
  96. 96.
    Stettner GM, Kubin L, Volgin DV (2011) Antagonism of orexin 1 receptors eliminates motor hyperactivity and improves homing response acquisition in juvenile rats exposed to alcohol during early postnatal period. Behav Brain Res 221:324–328. doi: 10.1016/j.bbr.2011.03.028CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Chang G-Q, Karatayev O, Liang SC et al (2012) Prenatal ethanol exposure stimulates neurogenesis in hypothalamic and limbic peptide systems: possible mechanism for offspring ethanol overconsumption. Neuroscience 222:417–428. doi: 10.1016/j.neuroscience.2012.05.066CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Korotkova TM, Eriksson KS, Haas HL, Brown RE (2002) Selective excitation of GABAergic neurons in the substantia nigra of the rat by orexin/hypocretin in vitro. Regul Pept 104:83–89. doi: 10.1016/S0167-0115(01)00323-8CrossRefPubMedGoogle Scholar
  99. 99.
    Martin G, Fabre V, Siggins GR, de Lecea L (2002) Interaction of the hypocretins with neurotransmitters in the nucleus accumbens. Regul Pept 104:111–117. doi: 10.1016/S0167-0115(01)00354-8CrossRefPubMedGoogle Scholar
  100. 100.
    Schmitt O, Usunoff KG, Lazarov NE et al (2012) Orexinergic innervation of the extended amygdala and basal ganglia in the rat. Brain Struct Funct 217:233–256. doi: 10.1007/s00429-011-0343-8CrossRefPubMedGoogle Scholar
  101. 101.
    Chen Y-W, Barson JR, Chen A et al (2013) Glutamatergic input to the lateral hypothalamus stimulates ethanol intake: role of orexin and melanin-concentrating hormone. Alcohol Clin Exp Res 37:123–131. doi: 10.1111/j.1530-0277.2012.01854.xCrossRefPubMedGoogle Scholar
  102. 102.
    Cannella N, Economidou D, Kallupi M et al (2009) Persistent increase of alcohol-seeking evoked by neuropeptide S: an effect mediated by the hypothalamic hypocretin system. Neuropsychopharmacology 34:2125–2134. doi: 10.1038/npp.2009.37CrossRefPubMedGoogle Scholar
  103. 103.
    Ubaldi M, Giordano A, Severi I et al (2015) 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. doi: 10.1016/j.biopsych.2015.04.021CrossRefPubMedGoogle Scholar
  104. 104.
    Barson JR, Poon K, Ho HT, Alam MI, Sanzalone L, Leibowitz SF (2015) Substance P in the anterior thalamic paraventricular nucleus: promotion of ethanol drinking in response to orexin from the hypothalamus. Addict Biol. doi: 10.1111/adb.12288CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Marcus JN, Aschkenasi CJ, Lee CE et al (2001) Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435:6–25. doi: 10.1002/cne.1190CrossRefPubMedGoogle Scholar
  106. 106.
    Zhu Y, Miwa Y, Yamanaka A et al (2003) 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 92:259–266. doi: 10.1254/jphs.92.259CrossRefPubMedGoogle Scholar
  107. 107.
    Harris GC, Aston-Jones G (2006) Arousal and reward: a dichotomy in orexin function. Trends Neurosci 29:571–577CrossRefGoogle Scholar
  108. 108.
    Baldo BA, Gual-Bonilla L, Sijapati K et al (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 19:376–386. doi: 10.1111/j.1460-9568.2004.03093.xCrossRefPubMedGoogle Scholar
  109. 109.
    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 183:43–51. doi: 10.1016/j.bbr.2007.05.025CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Lee EY, Lee HS (2016) Dual projections of single orexin- or CART-immunoreactive, lateral hypothalamic neurons to the paraventricular thalamic nucleus and nucleus accumbens shell in the rat: light microscopic study. Brain Res. doi: 10.1016/j.brainres.2015.12.062CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Barson JR, Leibowitz SF (2016) Hypothalamic neuropeptide signaling in alcohol addiction. Prog Neuropsychopharmacology Biol Psychiatry 65:321–329CrossRefGoogle Scholar
  112. 112.
    Muschamp JW, Hollander JA, Thompson JL et al (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. doi: 10.1073/pnas.1315542111CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Khoo SY-S, Brown RM (2014) Orexin/hypocretin based pharmacotherapies for the treatment of addiction: DORA or SORA? CNS Drugs 28:713–730CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2016

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

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

Authors and Affiliations

  1. 1.The Florey Institute of Neuroscience and Mental HealthParkvilleAustralia
  2. 2.Florey Department of Neuroscience and Mental HealthThe University of MelbourneParkvilleAustralia

Personalised recommendations