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

Correspondence to: Glenda C. Harris¹ Correspondence and requests for materials should be addressed to G.C.H. (Email: glenda@dolphin.upenn.edu).

The lateral hypothalamus is a brain region historically implicated in reward and motivation^{1, 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 neurons^{5, 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 area^{8, 9}. This indicates a possible role for these neurons in reward function and motivation^{3, 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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