Hypocretin/Orexin and Plastic Adaptations Associated with Drug Abuse

  • Corey Baimel
  • Stephanie L. BorglandEmail author
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 33)


Dopamine neurons in the ventral tegmental area (VTA) are a critical part of the neural circuits that underlie reward learning and motivation. Dopamine neurons send dense projections throughout the brain and recent observations suggest that both the intrinsic properties and the functional output of dopamine neurons are dependent on projection target and are subject to neuromodulatory influences. Lateral hypothalamic hypocretin (also termed orexin) neurons project to the VTA and contain both hypocretin and dynorphin peptides in the same dense core vesicles suggesting they may be co-released. Hypocretin peptides act at excitatory Gαq protein-coupled receptors and dynorphin acts at inhibitory Gαi/o protein-coupled receptors, which are both expressed on subpopulations of dopamine neurons. This review describes a role for neuromodulation of dopamine neurons and the influence on motivated behaviour in response to natural and drug rewards.


AMPA Dopamine Hypocretin Morphine NMDA Ventral tegmental area 


  1. 1.
    Deroche-Gamonet V, Piazza PV (2014) Psychobiology of cocaine addiction: contribution of a multi-symptomatic animal model of loss of control. Neuropharmacology 76(Pt B):437–449PubMedGoogle Scholar
  2. 2.
    Koob GF, Volkow ND (2010) Neurocircuitry of addiction. Neuropsychopharmacology 35:217–238Google Scholar
  3. 3.
    Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A 85:5274–5278PubMedPubMedCentralGoogle Scholar
  4. 4.
    Lüscher C, Ungless MA (2006) The mechanistic classification of addictive drugs. PLoS Med 3:e437PubMedPubMedCentralGoogle Scholar
  5. 5.
    Wang H, Treadway T, Covey DP, Cheer JF, Lupica CR (2015) Cocaine-induced endocannabinoid mobilization in the ventral tegmental area. Cell Rep 12:1997–2008PubMedPubMedCentralGoogle Scholar
  6. 6.
    Lüscher C, Pascoli V, Creed M (2015) Optogenetic dissection of neural circuitry: from synaptic causalities to blue prints for novel treatments of behavioral diseases. Curr Opin Neurobiol 35:95–100PubMedGoogle Scholar
  7. 7.
    Hyman SE, Malenka RC, Nestler EJ (2006) Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci 29:565–598PubMedGoogle Scholar
  8. 8.
    Kalivas PW, Volkow ND (2005) The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 162:1403–1413Google Scholar
  9. 9.
    Kauer JA, Malenka RC (2007) Synaptic plasticity and addiction. Nat Rev Neurosci 8:844–858PubMedGoogle Scholar
  10. 10.
    Kelley AE (2004) Memory and addiction: shared neural circuitry and molecular mechanisms. Neuron 44:161–179PubMedGoogle Scholar
  11. 11.
    Brown MTC, Bellone C, Mameli M, Labouèbe G, Bocklisch C, Balland B, Dahan L, Luján R, Deisseroth K, Lüscher C (2010) Drug-driven AMPA receptor redistribution mimicked by selective dopamine neuron stimulation. PLoS One 5:e15870PubMedPubMedCentralGoogle Scholar
  12. 12.
    Saal D, Dong Y, Bonci A, Malenka RC (2003) Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37:577–582Google Scholar
  13. 13.
    Ungless MA, Whistler JL, Malenka RC, Bonci A (2001) Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411:583–587Google Scholar
  14. 14.
    Chen BT, Bowers MS, Martin M, Hopf FW, Guillory AM, Carelli RM, Chou JK, Bonci A (2008) Cocaine but not natural reward self-administration nor passive cocaine infusion produces persistent LTP in the VTA. Neuron 59:288–297PubMedPubMedCentralGoogle Scholar
  15. 15.
    Faleiro LJ, Jones S, Kauer JA (2003) Rapid AMPAR/NMDAR response to amphetamine: a detectable increase in AMPAR/NMDAR ratios in the ventral tegmental area is detectable after amphetamine injection. Ann N Y Acad Sci 1003:391–394PubMedGoogle Scholar
  16. 16.
    Heikkinen AE, Möykkynen TP, Korpi ER (2009) Long-lasting modulation of glutamatergic transmission in VTA dopamine neurons after a single dose of benzodiazepine agonists. Neuropsychopharmacology 34:290–298PubMedGoogle Scholar
  17. 17.
    Good CH, Lupica CR (2010) Afferent-specific AMPA receptor subunit composition and regulation of synaptic plasticity in midbrain dopamine neurons by abused drugs. J Neurosci 30:7900–7909PubMedPubMedCentralGoogle Scholar
  18. 18.
    Bellone C, Lüscher C (2006) Cocaine triggered AMPA receptor redistribution is reversed in vivo by mGluR-dependent long-term depression. Nat Neurosci 9:636–641PubMedGoogle Scholar
  19. 19.
    Mameli M, Bellone C, Brown MTC, Lüscher C (2011) Cocaine inverts rules for synaptic plasticity of glutamate transmission in the ventral tegmental area. Nat Neurosci 14:414–416PubMedGoogle Scholar
  20. 20.
    Yuan T, Mameli M, O’ Connor EC, Dey PN, Verpelli C, Sala C, Perez-Otano I, Lüscher C, Bellone C (2013) Expression of cocaine-evoked synaptic plasticity by GluN3A-containing NMDA receptors. Neuron 80:1025–1038PubMedGoogle Scholar
  21. 21.
    Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, Kilduff TS (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18:9996–10015PubMedGoogle Scholar
  22. 22.
    Mahler SV, Moorman DE, Smith RJ, James MH, Aston-Jones G (2014) Motivational activation: a unifying hypothesis of orexin/hypocretin function. Nat Neurosci 17:1298–1303PubMedPubMedCentralGoogle Scholar
  23. 23.
    Valenstein ES, Cox VC, Kakolewski JW (1970) Reexamination of the role of the hypothalamus in motivation. Psychol Rev 77:16–31PubMedGoogle Scholar
  24. 24.
    Heath RG (1963) Electrical self-stimulation of the brain in man. Am J Psychiatry 120:571–577PubMedGoogle Scholar
  25. 25.
    Olds J, Milner P (1954) Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. J Comp Physiol Psychol 47:419–427PubMedGoogle Scholar
  26. 26.
    Adams WJ, Lorens SA, Mitchell CL (1972) Morphine enhances lateral hypothalamic self-stimulation in the rat. Proc Soc Exp Biol Med 140:770–771PubMedGoogle Scholar
  27. 27.
    Carey RJ, Goodal E (1975) Differential effects of amphetamine and food deprivation of self-stimulation of the lateral hypothalamus and medial frontal cortex. J Comp Physiol Psychol 88:224–230PubMedGoogle Scholar
  28. 28.
    Cazala P, Darracq C, Saint-Marc M (1987) Self-administration of morphine into the lateral hypothalamus in the mouse. Brain Res 416:283–288PubMedGoogle Scholar
  29. 29.
    de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 95:322–327PubMedPubMedCentralGoogle Scholar
  30. 30.
    Sakurai T et al (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92:573–585PubMedGoogle Scholar
  31. 31.
    Hollander JA, Lu Q, Cameron MD, Kamenecka TM, Kenny PJ (2008) Insular hypocretin transmission regulates nicotine reward. Proc Natl Acad Sci U S A 105:19480–19485PubMedPubMedCentralGoogle Scholar
  32. 32.
    Dube MG, Kalra SP, Kalra PS (1999) Food intake elicited by central administration of orexins/hypocretins: identification of hypothalamic sites of action. Brain Res 842:473–477PubMedGoogle Scholar
  33. 33.
    Haynes AC, Jackson B, Overend P, Buckingham RE, Wilson S, Tadayyon M, Arch JR (1999) Effects of single and chronic intracerebroventricular administration of the orexins on feeding in the rat. Peptides 20:1099–1105PubMedGoogle Scholar
  34. 34.
    Kunii K, Yamanaka A, Nambu T, Matsuzaki I, Goto K, Sakurai T (1999) Orexins/hypocretins regulate drinking behaviour. Brain Res 842:256–261PubMedGoogle Scholar
  35. 35.
    Gulia KK, Mallick HN, Kumar VM (2003) Orexin A (hypocretin-1) application at the medial preoptic area potentiates male sexual behavior in rats. Neuroscience 116:921–923PubMedGoogle Scholar
  36. 36.
    Kotz CM, Teske JA, Levine JA, Wang C (2002) Feeding and activity induced by orexin A in the lateral hypothalamus in rats. Regul Pept 104:27–32PubMedGoogle Scholar
  37. 37.
    Baimel C, Bartlett SE, Chiou L-C, Lawrence AJ, Muschamp JW, Patkar O, Tung L-W, Borgland SL (2015) Orexin/hypocretin role in reward: implications for opioid and other addictions. Br J Pharmacol 172:334–348PubMedGoogle Scholar
  38. 38.
    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 503:668–684PubMedGoogle Scholar
  39. 39.
    Fadel J, Deutch AY (2002) Anatomical substrates of orexin-dopamine interactions: lateral hypothalamic projections to the ventral tegmental area. Neuroscience 111:379–387PubMedGoogle Scholar
  40. 40.
    Borgland SL, Storm E, Bonci A (2008) Orexin B/hypocretin 2 increases glutamatergic transmission to ventral tegmental area neurons. Eur J Neurosci 28:1545–1556PubMedGoogle Scholar
  41. 41.
    Borgland SL, Taha SA, Sarti F, Fields HL, Bonci A (2006) Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Neuron 49:589–601PubMedGoogle Scholar
  42. 42.
    Uramura K, Funahashi H, Muroya S, Shioda S, Takigawa M, Yada T (2001) Orexin-a activates phospholipase C- and protein kinase C-mediated Ca2+ signaling in dopamine neurons of the ventral tegmental area. Neuroreport 12:1885–1889PubMedGoogle Scholar
  43. 43.
    Yang B, Samson WK, Ferguson AV (2003) Excitatory effects of orexin-A on nucleus tractus solitarius neurons are mediated by phospholipase C and protein kinase C. J Neurosci 23:6215–6222PubMedGoogle Scholar
  44. 44.
    Kukkonen JP, Leonard CS (2014) Orexin/hypocretin receptor signalling cascades. Br J Pharmacol 171:314–331Google Scholar
  45. 45.
    Baldo BA, Daniel RA, Berridge CW, Kelley AE (2003) Overlapping distributions of orexin/hypocretin- and dopamine-beta-hydroxylase immunoreactive fibers in rat brain regions mediating arousal, motivation, and stress. J Comp Neurol 464:220–237PubMedGoogle Scholar
  46. 46.
    Trivedi P, Yu H, MacNeil DJ, Van der Ploeg LH, Guan XM (1998) Distribution of orexin receptor mRNA in the rat brain. FEBS Lett 438:71–75PubMedGoogle Scholar
  47. 47.
    Adamantidis AR, Zhang F, Aravanis AM, Deisseroth K, de Lecea L (2007) Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 450:420–424PubMedGoogle Scholar
  48. 48.
    Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y, Fitch TE, Nakazato M, Hammer RE, Saper CB, Yanagisawa M (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98:437–451Google Scholar
  49. 49.
    Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, Qiu X, de Jong PJ, Nishino S, Mignot E (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98:365–376Google Scholar
  50. 50.
    Peyron C et al (2000) A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 6:991–997PubMedGoogle Scholar
  51. 51.
    Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M, Cornford M, Siegel JM (2000) Reduced number of hypocretin neurons in human narcolepsy. Neuron 27:469–474Google Scholar
  52. 52.
    Burgess CR, Scammell TE (2012) Narcolepsy: neural mechanisms of sleepiness and cataplexy. J Neurosci 32:12305–12311PubMedPubMedCentralGoogle Scholar
  53. 53.
    Akimoto H, Honda Y, Takahashi Y (1960) Pharmacotherapy in narcolepsy. Dis Nerv Syst 21:704–706PubMedGoogle Scholar
  54. 54.
    Guilleminault C, Carskadon M, Dement WC (1974) On the treatment of rapid eye movement narcolepsy. Arch Neurol 30:90–93PubMedGoogle Scholar
  55. 55.
    Nishino S, Mignot E (1997) Pharmacological aspects of human and canine narcolepsy. Prog Neurobiol 52:27–78PubMedGoogle Scholar
  56. 56.
    Dimitrova A, Fronczek R, Van der Ploeg J, Scammell T, Gautam S, Pascual-Leone A, Lammers GJ (2011) Reward-seeking behavior in human narcolepsy. J Clin Sleep Med 7:293–300PubMedPubMedCentralGoogle Scholar
  57. 57.
    Blouin AM, Fried I, Wilson CL, Staba RJ, Behnke EJ, Lam HA, Maidment NT, Karlsson KÆ, Lapierre JL, Siegel JM (2013) Human hypocretin and melanin-concentrating hormone levels are linked to emotion and social interaction. Nat Commun 4:1547PubMedPubMedCentralGoogle Scholar
  58. 58.
    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 21:1656–1662PubMedGoogle Scholar
  59. 59.
    Lee MG, Hassani OK, Jones BE (2005) Discharge of identified orexin/hypocretin neurons across the sleep-waking cycle. J Neurosci 25:6716–6720PubMedGoogle Scholar
  60. 60.
    Mileykovskiy BY, Kiyashchenko LI, Siegel JM (2005) Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron 46:787–798PubMedGoogle Scholar
  61. 61.
    Chou TC, Lee CE, Lu J, Elmquist JK, Hara J, Willie JT, Beuckmann CT, Chemelli RM, Sakurai T, Yanagisawa M, Saper CB, Scammell TE (2001) Orexin (hypocretin) neurons contain dynorphin. J Neurosci 21:RC168PubMedGoogle Scholar
  62. 62.
    Muschamp JW, Hollander JA, Thompson JL, Voren G, Hassinger LC, Onvani S, Kamenecka TM, Borgland SL, Kenny PJ, Carlezon WA (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–E1655PubMedPubMedCentralGoogle Scholar
  63. 63.
    Rosin DL, Weston MC, Sevigny CP, Stornetta RL, Guyenet PG (2003) Hypothalamic orexin (hypocretin) neurons express vesicular glutamate transporters VGLUT1 or VGLUT2. J Comp Neurol 465:593–603PubMedGoogle Scholar
  64. 64.
    Schöne C, Apergis-Schoute J, Sakurai T, Adamantidis A, Burdakov D (2014) Coreleased orexin and glutamate evoke nonredundant spike outputs and computations in histamine neurons. Cell Rep 7:697–704PubMedPubMedCentralGoogle Scholar
  65. 65.
    Schöne C, Cao ZFH, Apergis-Schoute J, Adamantidis A, Sakurai T, Burdakov D (2012) Optogenetic probing of fast glutamatergic transmission from hypocretin/orexin to histamine neurons in situ. J Neurosci 32:12437–12443PubMedGoogle Scholar
  66. 66.
    Apergis-Schoute J, Iordanidou P, Faure C, Jego S, Schöne C, Aitta-Aho T, Adamantidis A, Burdakov D (2015) Optogenetic evidence for inhibitory signaling from orexin to MCH neurons via local microcircuits. J Neurosci 35:5435–5441PubMedPubMedCentralGoogle Scholar
  67. 67.
    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 32:3809–3817PubMedPubMedCentralGoogle Scholar
  68. 68.
    Harris GC, Wimmer M, Aston-Jones G (2005) A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437:556–559Google Scholar
  69. 69.
    Huang H, Xu Y, van den Pol AN (2011) Nicotine excites hypothalamic arcuate anorexigenic proopiomelanocortin neurons and orexigenic neuropeptide Y neurons: similarities and differences. J Neurophysiol 106:1191–1202PubMedPubMedCentralGoogle Scholar
  70. 70.
    Pasumarthi RK, Fadel J (2008) Activation of orexin/hypocretin projections to basal forebrain and paraventricular thalamus by acute nicotine. Brain Res Bull 77:367–373PubMedPubMedCentralGoogle Scholar
  71. 71.
    Plaza-Zabala A, Martín-García E, de Lecea L, Maldonado R, Berrendero F (2010) Hypocretins regulate the anxiogenic-like effects of nicotine and induce reinstatement of nicotine-seeking behavior. J Neurosci 30:2300–2310PubMedPubMedCentralGoogle Scholar
  72. 72.
    Fadel J, Bubser M, Deutch AY (2002) Differential activation of orexin neurons by antipsychotic drugs associated with weight gain. J Neurosci 22:6742–6746PubMedGoogle Scholar
  73. 73.
    Moorman DE, James MH, Kilroy EA, Aston-Jones G (2016) Orexin/hypocretin neuron activation is correlated with alcohol seeking and preference in a topographically specific manner. Eur J Neurosci 43:710–720PubMedPubMedCentralGoogle Scholar
  74. 74.
    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 63:152–157PubMedGoogle Scholar
  75. 75.
    Harris GC, Aston-Jones G (2006) Arousal and reward: a dichotomy in orexin function. Trends Neurosci 29:571–577PubMedGoogle Scholar
  76. 76.
    Willie JT, Chemelli RM, Sinton CM, Tokita S, Williams SC, Kisanuki YY, Marcus JN, Lee C, Elmquist JK, Kohlmeier KA, Leonard CS, Richardson JA, Hammer RE, Yanagisawa M (2003) Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes. Neuron 38:715–730PubMedGoogle Scholar
  77. 77.
    González 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 35:1426–1432PubMedPubMedCentralGoogle Scholar
  78. 78.
    McPherson CS, Featherby T, Krstew E, Lawrence AJ (2007) Quantification of phosphorylated cAMP-response element-binding protein expression throughout the brain of amphetamine-sensitized rats: activation of hypothalamic orexin A-containing neurons. J Pharmacol Exp Ther 323:805–812PubMedGoogle Scholar
  79. 79.
    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 23:3106–3111PubMedGoogle Scholar
  80. 80.
    Laorden ML, Ferenczi S, Pintér-Kübler B, González-Martín LL, Lasheras MC, Kovács KJ, Milanés MV, Núñez C (2012) Hypothalamic orexin – a neurons are involved in the response of the brain stress system to morphine withdrawal. PLoS One 7:e36871PubMedPubMedCentralGoogle Scholar
  81. 81.
    Yoshida K, McCormack S, España RA, Crocker A, Scammell TE (2006) Afferents to the orexin neurons of the rat brain. J Comp Neurol 494:845–861PubMedPubMedCentralGoogle Scholar
  82. 82.
    Shoji S, Simms D, McDaniel WC, Gallagher JP (1997) Chronic cocaine enhances gamma-aminobutyric acid and glutamate release by altering presynaptic and not postsynaptic gamma-aminobutyric acidB receptors within the rat dorsolateral septal nucleus. J Pharmacol Exp Ther 280:129–137PubMedGoogle Scholar
  83. 83.
    Shoji S, Simms D, Yamada K, Gallagher JP (1998) Cocaine administered in vitro to brain slices from rats treated with cocaine chronically in vivo results in a gamma-aminobutyric acid receptor-mediated hyperpolarization recorded from the dorsolateral septum. J Pharmacol Exp Ther 286:509–518PubMedGoogle Scholar
  84. 84.
    Sartor GC, Aston-Jones GS (2012) A septal-hypothalamic pathway drives orexin neurons, which is necessary for conditioned cocaine preference. J Neurosci 32:4623–4631PubMedPubMedCentralGoogle Scholar
  85. 85.
    Gao X-B, Hermes G (2015) Neural plasticity in hypocretin neurons: the basis of hypocretinergic regulation of physiological and behavioral functions in animals. Front Syst Neurosci 9:142PubMedPubMedCentralGoogle Scholar
  86. 86.
    Douglas RJ, Martin KAC (2004) Neuronal circuits of the neocortex. Annu Rev Neurosci 27:419–451PubMedGoogle Scholar
  87. 87.
    Horvath TL, Gao X-B (2005) Input organization and plasticity of hypocretin neurons: possible clues to obesity’s association with insomnia. Cell Metab 1:279–286PubMedGoogle Scholar
  88. 88.
    Li Y, Gao XB, Sakurai T, van den Pol AN (2002) Hypocretin/orexin excites hypocretin neurons via a local glutamate neuron – a potential mechanism for orchestrating the hypothalamic arousal system. Neuron 36:1169–1181PubMedGoogle Scholar
  89. 89.
    Xie X, Crowder TL, Yamanaka A, Morairty SR, Lewinter RD, Sakurai T, Kilduff TS (2006) GABA(B) receptor-mediated modulation of hypocretin/orexin neurones in mouse hypothalamus. J Physiol 574:399–414PubMedPubMedCentralGoogle Scholar
  90. 90.
    Rao Y, Liu Z-W, Borok E, Rabenstein RL, Shanabrough M, Lu M, Picciotto MR, Horvath TL, Gao X-B (2007) Prolonged wakefulness induces experience-dependent synaptic plasticity in mouse hypocretin/orexin neurons. J Clin Invest 117:4022–4033PubMedPubMedCentralGoogle Scholar
  91. 91.
    Rao Y, Lu M, Ge F, Marsh DJ, Qian S, Wang AH, Picciotto MR, Gao X-B (2008) Regulation of synaptic efficacy in hypocretin/orexin-containing neurons by melanin concentrating hormone in the lateral hypothalamus. J Neurosci 28:9101–9110PubMedPubMedCentralGoogle Scholar
  92. 92.
    Rao Y, Mineur YS, Gan G, Wang AH, Liu Z-W, Wu X, Suyama S, de Lecea L, Horvath TL, Picciotto MR, Gao X-B (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 591:1951–1966PubMedPubMedCentralGoogle Scholar
  93. 93.
    Creed MC, Lüscher C (2013) Drug-evoked synaptic plasticity: beyond metaplasticity. Curr Opin Neurobiol 23:553–558PubMedGoogle Scholar
  94. 94.
    Yeoh JW, James MH, Jobling P, Bains JS, Graham BA, Dayas CV (2012) Cocaine potentiates excitatory drive in the perifornical/lateral hypothalamus. J Physiol 590:3677–3689PubMedPubMedCentralGoogle Scholar
  95. 95.
    Li Y, van den Pol AN (2008) Mu-opioid receptor-mediated depression of the hypothalamic hypocretin/orexin arousal system. J Neurosci 28:2814–2819PubMedGoogle Scholar
  96. 96.
    Südhof TC (2012) The presynaptic active zone. Neuron 75:11–25PubMedPubMedCentralGoogle Scholar
  97. 97.
    Couteaux R, Pécot-Dechavassine M (1970) Synaptic vesicles and pouches at the level of “active zones” of the neuromuscular junction. C R Acad Sci Hebd Seances Acad Sci D 271:2346–2349PubMedGoogle Scholar
  98. 98.
    van den Pol AN (2012) Neuropeptide transmission in brain circuits. Neuron 76:98–115PubMedPubMedCentralGoogle Scholar
  99. 99.
    Südhof TC (2012) Calcium control of neurotransmitter release. Cold Spring Harb Perspect Biol 4:a011353PubMedPubMedCentralGoogle Scholar
  100. 100.
    Agnati LF, Fuxe K, Zoli M, Ozini I, Toffano G, Ferraguti F (1986) A correlation analysis of the regional distribution of central enkephalin and beta-endorphin immunoreactive terminals and of opiate receptors in adult and old male rats. Evidence for the existence of two main types of communication in the central nervous system: the volume transmission and the wiring transmission. Acta Physiol Scand 128:201–207PubMedGoogle Scholar
  101. 101.
    Agnati LF, Guidolin D, Guescini M, Genedani S, Fuxe K (2010) Understanding wiring and volume transmission. Brain Res Rev 64:137–159PubMedGoogle Scholar
  102. 102.
    Agnati LF, Zoli M, Strömberg I, Fuxe K (1995) Intercellular communication in the brain: wiring versus volume transmission. Neuroscience 69:711–726PubMedGoogle Scholar
  103. 103.
    Baimel C, Borgland SL (2015) Orexin signaling in the VTA gates morphine-induced synaptic plasticity. J Neurosci 35:7295–7303PubMedGoogle Scholar
  104. 104.
    Overton P, Clark D (1992) Iontophoretically administered drugs acting at the N-methyl-D-aspartate receptor modulate burst firing in A9 dopamine neurons in the rat. Synapse 10:131–140PubMedGoogle Scholar
  105. 105.
    Suaud-Chagny MF, Chergui K, Chouvet G, Gonon F (1992) 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 49:63–72PubMedGoogle Scholar
  106. 106.
    Tong ZY, Overton PG, Clark D (1996) Antagonism of NMDA receptors but not AMPA/kainate receptors blocks bursting in dopaminergic neurons induced by electrical stimulation of the prefrontal cortex. J Neural Transm (Vienna) 103:889–904Google Scholar
  107. 107.
    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 23:7–11Google Scholar
  108. 108.
    Muschamp JW, Dominguez JM, Sato SM, Shen R-Y, Hull EM (2007) A role for hypocretin (orexin) in male sexual behavior. J Neurosci 27:2837–2845PubMedGoogle Scholar
  109. 109.
    Moorman DE, Aston-Jones G (2010) Orexin/hypocretin modulates response of ventral tegmental dopamine neurons to prefrontal activation: diurnal influences. J Neurosci 30:15585–15599PubMedPubMedCentralGoogle Scholar
  110. 110.
    Vittoz NM, Berridge CW (2006) Hypocretin/orexin selectively increases dopamine efflux within the prefrontal cortex: involvement of the ventral tegmental area. Neuropsychopharmacology 31:384–395PubMedGoogle Scholar
  111. 111.
    Vittoz NM, Schmeichel B, Berridge CW (2008) Hypocretin/orexin preferentially activates caudomedial ventral tegmental area dopamine neurons. Eur J Neurosci 28:1629–1640PubMedPubMedCentralGoogle Scholar
  112. 112.
    Narita M, Nagumo Y, Miyatake M, Ikegami D, Kurahashi K, Suzuki T (2007) Implication of protein kinase C in the orexin-induced elevation of extracellular dopamine levels and its rewarding effect. Eur J Neurosci 25:1537–1545PubMedGoogle Scholar
  113. 113.
    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 6:138–146Google Scholar
  114. 114.
    Smith RJ, See RE, Aston-Jones G (2009) Orexin/hypocretin signaling at the orexin 1 receptor regulates cue-elicited cocaine-seeking. Eur J Neurosci 30:493–503PubMedPubMedCentralGoogle Scholar
  115. 115.
    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 65:857–862PubMedPubMedCentralGoogle Scholar
  116. 116.
    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 1314:74–90PubMedGoogle Scholar
  117. 117.
    Lammel S, Hetzel A, Häckel O, Jones I, Liss B, Roeper J (2008) Unique properties of mesoprefrontal neurons within a dual mesocorticolimbic dopamine system. Neuron 57:760–773PubMedGoogle Scholar
  118. 118.
    Lammel S, Ion DI, Roeper J, Malenka RC (2011) Projection-specific modulation of dopamine neuron synapses by aversive and rewarding stimuli. Neuron 70:855–862PubMedPubMedCentralGoogle Scholar
  119. 119.
    Margolis EB, Mitchell JM, Ishikawa J, Hjelmstad GO, Fields HL (2008) Midbrain dopamine neurons: projection target determines action potential duration and dopamine D(2) receptor inhibition. J Neurosci 28:8908–8913PubMedGoogle Scholar
  120. 120.
    Lammel S, Lim BK, Ran C, Huang KW, Betley MJ, Tye KM, Deisseroth K, Malenka RC (2012) Input-specific control of reward and aversion in the ventral tegmental area. Nature 491:212–217PubMedPubMedCentralGoogle Scholar
  121. 121.
    España RA, Oleson EB, Locke JL, Brookshire BR, Roberts DCS, Jones SR (2010) The hypocretin-orexin system regulates cocaine self-administration via actions on the mesolimbic dopamine system. Eur J Neurosci 31:336–348PubMedGoogle Scholar
  122. 122.
    Quarta D, Valerio E, Hutcheson DM, Hedou G, Heidbreder C (2010) The orexin-1 receptor antagonist SB-334867 reduces amphetamine-evoked dopamine outflow in the shell of the nucleus accumbens and decreases the expression of amphetamine sensitization. Neurochem Int 56:11–15PubMedGoogle Scholar
  123. 123.
    España RA, Melchior JR, Roberts DCS, Jones SR (2011) Hypocretin 1/orexin A in the ventral tegmental area enhances dopamine responses to cocaine and promotes cocaine self-administration. Psychopharmacology (Berl) 214:415–426Google Scholar
  124. 124.
    Borgland SL, Malenka RC, Bonci A (2004) Acute and chronic cocaine-induced potentiation of synaptic strength in the ventral tegmental area: electrophysiological and behavioral correlates in individual rats. J Neurosci 24:7482–7490PubMedGoogle Scholar
  125. 125.
    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 26:398–405PubMedGoogle Scholar
  126. 126.
    Borgland SL, Chang S-J, 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 29:11215–11225PubMedPubMedCentralGoogle Scholar
  127. 127.
    Jupp B, Krivdic B, Krstew E, Lawrence AJ (2011) The orexin1 receptor antagonist SB-334867 dissociates the motivational properties of alcohol and sucrose in rats. Brain Res 1391:54–59PubMedGoogle Scholar
  128. 128.
    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 6:47PubMedPubMedCentralGoogle Scholar
  129. 129.
    Smith RJ, Aston-Jones G (2012) Orexin/hypocretin 1 receptor antagonist reduces heroin self-administration and cue-induced heroin seeking. Eur J Neurosci 35:798–804PubMedPubMedCentralGoogle Scholar
  130. 130.
    Bentzley BS, Aston-Jones G (2015) Orexin-1 receptor signaling increases motivation for cocaine-associated cues. Eur J Neurosci 41:1149–1156PubMedPubMedCentralGoogle Scholar
  131. 131.
    Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 18:247–291PubMedGoogle Scholar
  132. 132.
    James MH, Charnley JL, Levi EM, Jones E, Yeoh JW, Smith DW, Dayas CV (2011) Orexin-1 receptor signalling within the ventral tegmental area, but not the paraventricular thalamus, is critical to regulating cue-induced reinstatement of cocaine-seeking. Int J Neuropsychopharmacol 14:684–690PubMedGoogle Scholar
  133. 133.
    Brown RM, Kim AK, Khoo SY-S, 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 21:603–612Google Scholar
  134. 134.
    Lawrence AJ, Cowen MS, Yang H-J, Chen F, Oldfield B (2006) The orexin system regulates alcohol-seeking in rats. Br J Pharmacol 148:752–759PubMedPubMedCentralGoogle Scholar
  135. 135.
    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) 226:687–698Google Scholar
  136. 136.
    Boutrel B, Kenny PJ, Specio SE, Martin-Fardon R, Markou A, Koob GF, de Lecea L (2005) Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proc Natl Acad Sci U S A 102:19168–19173PubMedPubMedCentralGoogle Scholar
  137. 137.
    Zhang S, Tong Y, Tian M, Dehaven RN, Cortesburgos L, Mansson E, Simonin F, Kieffer B, Yu L (1998) Dynorphin A as a potential endogenous ligand for four members of the opioid receptor gene family. J Pharmacol Exp Ther 286:136–141PubMedGoogle Scholar
  138. 138.
    Chavkin C, James IF, Goldstein A (1982) Dynorphin is a specific endogenous ligand of the kappa opioid receptor. Science 215:413–415Google Scholar
  139. 139.
    Corbett AD, Paterson SJ, McKnight AT, Magnan J, Kosterlitz HW (1982) Dynorphin and dynorphin are ligands for the kappa-subtype of opiate receptor. Nature 299:79–81PubMedGoogle Scholar
  140. 140.
    Mucha RF, Herz A (1985) Motivational properties of kappa and mu opioid receptor agonists studied with place and taste preference conditioning. Psychopharmacology (Berl) 86:274–280Google Scholar
  141. 141.
    Pfeiffer A, Brantl V, Herz A, Emrich HM (1986) Psychotomimesis mediated by kappa opiate receptors. Science 233:774–776Google Scholar
  142. 142.
    Shippenberg TS, Zapata A, Chefer VI (2007) Dynorphin and the pathophysiology of drug addiction. Pharmacol Ther 116:306–321PubMedPubMedCentralGoogle Scholar
  143. 143.
    Fujiki N, Yoshida Y, Ripley B, Honda K, Mignot E, Nishino S (2001) Changes in CSF hypocretin-1 (orexin A) levels in rats across 24 hours and in response to food deprivation. Neuroreport 12:993–997PubMedGoogle Scholar
  144. 144.
    Przewłocki R, Lasón W, Konecka AM, Gramsch C, Herz A, Reid LD (1983) The opioid peptide dynorphin, circadian rhythms, and starvation. Science 219:71–73PubMedGoogle Scholar
  145. 145.
    Crocker A, España RA, Papadopoulou M, Saper CB, Faraco J, Sakurai T, Honda M, Mignot E, Scammell TE (2005) Concomitant loss of dynorphin, NARP, and orexin in narcolepsy. Neurology 65:1184–1188PubMedPubMedCentralGoogle Scholar
  146. 146.
    Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM, Sugiyama F, Yagami K, Goto K, Yanagisawa M, Sakurai T (2001) Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30:345–354PubMedGoogle Scholar
  147. 147.
    Willie JT, Chemelli RM, Sinton CM, Yanagisawa M (2001) To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Annu Rev Neurosci 24:429–458PubMedGoogle Scholar
  148. 148.
    DePaoli AM, Hurley KM, Yasada K, Reisine T, Bell G (1994) Distribution of kappa opioid receptor mRNA in adult mouse brain: an in situ hybridization histochemistry study. Mol Cell Neurosci 5:327–335PubMedGoogle Scholar
  149. 149.
    Li Y, van den Pol AN (2006) Differential target-dependent actions of coexpressed inhibitory dynorphin and excitatory hypocretin/orexin neuropeptides. J Neurosci 26:13037–13047PubMedGoogle Scholar
  150. 150.
    Eriksson KS, Sergeeva OA, Selbach O, Haas HL (2004) Orexin (hypocretin)/dynorphin neurons control GABAergic inputs to tuberomammillary neurons. Eur J Neurosci 19:1278–1284PubMedGoogle Scholar
  151. 151.
    Robinson JD, McDonald PH (2015) The orexin 1 receptor modulates kappa opioid receptor function via a JNK-dependent mechanism. Cell Signal 27:1449–1456PubMedPubMedCentralGoogle Scholar
  152. 152.
    Li X, Marchant NJ, Shaham Y (2014) Opposing roles of cotransmission of dynorphin and hypocretin on reward and motivation. Proc Natl Acad Sci U S A 111:5765–5766PubMedPubMedCentralGoogle Scholar
  153. 153.
    Graziane NM, Polter AM, Briand LA, Pierce RC, Kauer JA (2013) Kappa opioid receptors regulate stress-induced cocaine seeking and synaptic plasticity. Neuron 77:942–954PubMedPubMedCentralGoogle Scholar
  154. 154.
    Beier KT, Steinberg EE, DeLoach KE, Xie S, Miyamichi K, Schwarz L, Gao XJ, Kremer EJ, Malenka RC, Luo L (2015) Circuit architecture of VTA dopamine neurons revealed by systematic input-output mapping. Cell 162:622–634PubMedPubMedCentralGoogle Scholar
  155. 155.
    Ford CP, Mark GP, Williams JT (2006) Properties and opioid inhibition of mesolimbic dopamine neurons vary according to target location. J Neurosci 26:2788–2797PubMedPubMedCentralGoogle Scholar
  156. 156.
    Margolis EB, Lock H, Chefer VI, Shippenberg TS, Hjelmstad GO, Fields HL (2006) Kappa opioids selectively control dopaminergic neurons projecting to the prefrontal cortex. Proc Natl Acad Sci U S A 103:2938–2942PubMedPubMedCentralGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Anesthesiology, Pharmacology and TherapeuticsUniversity of British ColumbiaVancouverCanada
  2. 2.Hotchkiss Brain InstituteUniversity of CalgaryCalgaryCanada

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