Since the initial discovery of the hypocretin (HCRT)/orexin peptide system, substantial information has been gained regarding the behavioral and physiological actions of this putative neurotransmitter system. The presence of HCRT within a variety of arousal-related systems and the demonstration of dysregulation of HCRT neurotransmission in narcolepsy prompted intense interest in the wake-promoting actions of this peptide system. Beyond the regulation of waking per se, emerging evidence suggests prominent actions of HCRT under high-arousal conditions, including stress. This chapter will review the arousal-enhancing (wake-promoting) actions of HCRT and recent evidence suggesting a potential role of HCRT in stress and other high arousal states. Included in this, will be a review of evidence suggesting an interaction between HCRT and corticotrophin-releasing factor (CRF) in the modulation of certain physiological and behavioral processes. Prior to discussion of this topic, it is useful to review briefly the concept of stress and the neurotransmitter systems implicated in the regulation of physiology and behavior in stress.

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