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A role for lateral hypothalamic orexin neurons in reward seeking


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.


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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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Correspondence to Glenda C. Harris.

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Reprints and permissions information is available at The authors declare no competing financial interests.

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).

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