Tobacco use is a major cause of disease and premature death in the United States. Nicotine is considered the key component of tobacco responsible for addiction in human smokers. Accumulating evidence supports an important role for the hypocretin (orexin) neuropeptide system in regulating the reinforcing properties of most major drugs of abuse, including nicotine. Here, data showing that nicotine activates hypocretin-producing neurons in the lateral hypothalamus, and that disruption of hypocretin transmission decreases nicotine self-administration behavior in rats will be reviewed. Recent findings suggesting that plasma hypocretin levels may be related to the magnitude of cigarette craving in abstinent smokers will be discussed. Finally, the data suggesting that hypocretin transmission in the insular cortex may play an important role in regulating nicotine self-administration behavior in rats will be reviewed. This latter finding may provide mechanistic insight into the apparent disruption of tobacco addiction reported in human smokers with stroke-associated damage to the insular cortex.
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