A role for lateral hypothalamic orexin neurons in reward seeking

The activation of neurons in the lateral hypothalamus of the brain that contain the novel neuropeptide orexin may be responsible for the cravings experienced by both overeaters and drug addicts. A study in rats shows that these orexin neurons are strongly stimulated in proportion to the degree of food- or drug-seeking that animals exhibit in a conditioning experiment. Direct stimulation of these orexin neurons causes a relapse of drug-seeking behaviour, and a similar relapse was induced by direct administration of orexin into a major reward centre in the brain, the ventral tegmental area. These findings reveal some of the mechanisms of motivation and reward in the brain, and have implications for understanding and treating drug addiction and overeating. 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.