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A role for lateral hypothalamic orexin neurons in reward seeking

Nature volume 437, pages 556–559 (2005)Cite this article

Abstract

The lateral hypothalamus is a brain region historically implicated in reward and motivation1,2,3,4, but the identity of the neurotransmitters involved are unknown. The orexins (or hypocretins) are neuropeptides recently identified as neurotransmitters in lateral hypothalamus neurons5,6. Although knockout and transgenic overexpression studies have implicated orexin neurons in arousal and sleep7, these cells also project to reward-associated brain regions, including the nucleus accumbens and ventral tegmental area8,9. This indicates a possible role for these neurons in reward function and motivation3,10, consistent with previous studies implicating these neurons in feeding6. Here we show that activation of lateral hypothalamus orexin neurons is strongly linked to preferences for cues associated with drug and food reward. In addition, we show that chemical activation of lateral hypothalamus orexin neurons reinstates an extinguished drug-seeking behaviour. This reinstatement effect was completely blocked by prior administration of an orexin A antagonist. Moreover, administration of the orexin A peptide directly into the ventral tegmental area also reinstated drug-seeking. These data reveal a new role for lateral hypothalamus orexin neurons in reward-seeking, drug relapse and addiction.

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Figure 1: Morphine conditioned animals had significantly greater place preferences and Fos activated orexin neurons in the lateral hypothalamus than non-conditioned animals.
Figure 2: Activation of lateral hypothalamus orexin neurons by rPP reinstated an extinguished preference for morphine.
Figure 3: Orexin administration into the VTA reinstated an extinguished preference for morphine.

References

  1. Anand, B. K. & Brobeck, J. R. Hypothalamic control of food intake in rats and cats. Yale J. Biol. Med. 24, 123–140 (1951)

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Olds, J. & Milner, P. Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. J. Comp. Physiol. Psychol. 47, 419–427 (1954)

    Article  CAS  Google Scholar 

  3. DiLeone, R. J., Georgescu, D. & Nestler, E. J. Lateral hypothalmic neuropeptides in reward and drug addiction. Life Sci. 73, 759–768 (2003)

    Article  CAS  Google Scholar 

  4. Petrovich, G. D. & Gallagher, M. Amygdala subsystems and control of feeding behaviour by learned cues. Ann NY Acad. Sci. 985, 251–262 (2003)

    Article  ADS  Google Scholar 

  5. de Lecea, L. et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl Acad. Sci. USA 95, 322–327 (1998)

    Article  ADS  CAS  Google Scholar 

  6. Sakurai, T. et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behaviour. Cell 92, 573–585 (1998)

    Article  CAS  Google Scholar 

  7. Chemelli, R. M. et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437–451 (1999)

    Article  CAS  Google Scholar 

  8. Peyron, C. et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J. Neurosci. 18, 9996–10015 (1998)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Baldo, B. A., Daniel, R. A., Berridge, C. W. & Kelley, A. E. Overlapping distributions of orexin/hypocretin- and dopamine-beta-hydroxylase immunoreactive fibers in rat brain regions mediating arousal, motivation, and stress. J. Comp. Neurol. 464, 220–237 (2003)

    Article  Google Scholar 

  11. Harris, G. C. & Aston-Jones, G. Enhanced morphine preference following prolonged abstinence: association with increased Fos expression in the extended amygdala. Neuropsychopharmacology 28, 292–299 (2003)

    Article  CAS  Google Scholar 

  12. Harris, G. C. & Aston-Jones, G. Critical role for ventral tegmental glutamate in preference for a cocaine-conditioned environment. Neuropsychopharmacology 28, 73–76 (2003)

    Article  CAS  Google Scholar 

  13. Harris, G. C. & Aston-Jones, G. Altered motivation and learning following opiate withdrawal: evidence for prolonged dysregulation of reward processing. Neuropsychopharmacology 28, 865–871 (2003)

    Article  CAS  Google Scholar 

  14. Siegel, J. M. Hypocretin (orexin): role in normal behaviour and neuropathology. Annu. Rev. Psychol. 55, 125–148 (2004)

    Article  Google Scholar 

  15. Herrera, D. G. & Robertson, H. A. Activation of c-fos in the brain. Prog. Neurobiol. 50, 83–107 (1996)

    Article  CAS  Google Scholar 

  16. Espana, R. A., Valentino, R. J. & Berridge, C. W. 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, 201–217 (2003)

    Article  CAS  Google Scholar 

  17. Smart, D. et al. SB-334867-A: the first selective orexin-1 receptor antagonist. Br. J. Pharmacol. 132, 1179–1182 (2001)

    Article  CAS  Google Scholar 

  18. Bevins, R. A. et al. Novel-object place conditioning: behavioural and dopaminergic processes in expression of novelty reward. Behav. Brain Res. 129, 41–50 (2002)

    Article  CAS  Google Scholar 

  19. Wang, B., Luo, F., Zhang, W. T. & Han, J. S. Stress or drug priming induces reinstatement of extinguished conditioned place preference. Neuroreport 11, 2781–2784 (2000)

    Article  CAS  Google Scholar 

  20. Campbell, R. E. et al. Orexin neurons express a functional pancreatic polypeptide Y4 receptor. J. Neurosci. 23, 1487–1497 (2003)

    Article  CAS  Google Scholar 

  21. Shalev, U., Grimm, J. W. & Shaham, Y. Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol. Rev. 54, 1–42 (2002)

    Article  CAS  Google Scholar 

  22. Korotkova, T. M., Sergeeva, O. A., Eriksson, K. S., Haas, H. L. & Brown, R. E. Excitation of ventral tegmental area dopaminergic and nondopaminergic neurons by orexin/hypocretins. J. Neurosci. 23, 7–11 (2003)

    Article  CAS  Google Scholar 

  23. Georgescu, D. et al. Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal. J. Neurosci. 23, 3106–3111 (2003)

    Article  CAS  Google Scholar 

  24. Trivedi, P., Yu, H., MacNeil, D. J., Van der Ploeg, L. H. & Guan, X. M. Distribution of orexin receptor mRNA in the rat brain. FEBS Lett. 438, 71–75 (1998)

    Article  CAS  Google Scholar 

  25. Marcus, J. N. et al. Differential expression of orexin receptors 1 and 2 in the rat brain. J. Comp. Neurol. 435, 6–25 (2001)

    Article  CAS  Google Scholar 

  26. Carr, K. D. Augmentation of drug reward by chronic food restriction: behavioural evidence and underlying mechanisms. Physiol. Behav. 76, 353–364 (2002)

    Article  CAS  Google Scholar 

  27. Baldo, B. A. et al. 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 (2004)

    Article  Google Scholar 

  28. Estabrooke, I. V. et al. Fos expression in orexin neurons varies with behavioural state. J. Neurosci. 21, 1656–1662 (2001)

    Article  CAS  Google Scholar 

  29. Rodgers, R. J. et al. 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 (2001)

    Article  CAS  Google Scholar 

  30. Haynes, A. C. et al. A selective orexin-1 receptor antagonist reduces food consumption in male and female rats. Regul. Pept. 96, 45–51 (2000)

    Article  CAS  Google Scholar 

  31. Swanson, L. W. Brain Maps: Structure Of The Rat Brain (Elsevier, Amsterdam, 1992)

    Google Scholar 

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Acknowledgements

We thank R. Shiekhattar and R. Smith for comments on the manuscript; and Y. Zhu and S. Aston-Jones for assistance with illustrations and photography. This work was supported by NIH.

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Authors and Affiliations

  1. Laboratory of Neuromodulation and Behavior, Department of Psychiatry, University of Pennsylvania, 705 Stellar Chance/6100 422 Curie Blvd, Pennsylvania, 19104-6100, Philadelphia, USA

    Glenda C. Harris, Mathieu Wimmer & Gary Aston-Jones

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  1. Glenda C. Harris
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  2. Mathieu Wimmer
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  3. Gary Aston-Jones
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Correspondence to Glenda C. Harris.

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Supplementary information

Supplementary Figure S1

Schematic representations of frontal sections showing the locations of neurons that stained for Fos and orexin. (PDF 174 kb)

Supplementary Figure S2

Low-power photomicrographs of the lateral hypothalamus (PDF 390 kb)

Supplementary Table S1

Orexin-Fos double labelling (DOC 21 kb)

Supplementary Figure Legends

Text to accompany the above Supplementary Figures (DOC 20 kb)

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Harris, G., Wimmer, M. & Aston-Jones, G. A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437, 556–559 (2005). https://doi.org/10.1038/nature04071

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