A role for lateral hypothalamic orexin neurons in reward seeking

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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.