An Approach to Determining the Functions of Hypocretin (orexin)

Many papers on hypocretins/orexins begin with a list of the functions they regulate. Included in these lists are some of the following: sleep, food intake, water intake, gastric acid secretion, blood pressure, heart rate, movement, muscle tone, arousal, release of lutenizing hormone, corticosterone, insulin, growth hormone and prolactin. It is also reported that hypocretin/orexin coordinates monoamine, acetylcholine and amino acid release. Finally it is well established that the loss of hypocretin neurons is linked to narcolepsy (reviewed in ref. 1). One can anticipate that with further research the "laundry list" of hypocretin functions will continue to grow. Although the finding of links between hypocretin/orexin and a wide range of behaviors and physiological changes, is useful, it is obvious that a simple catalog of hypocretin/orexin relations does not provide a fundamental insight into its function(s). It is analogous to saying that the biceps muscle is involved in eating, drinking, motor activity, sexual behavior; sleep etc., because its activity is strongly modulated during all of these behaviors. In terms of its putative arousal functions, it is not sufficient to say that hypocretin/orexin is arousal related. A number of brain systems are active during arousal. Does hypocretin/orexin play a unique role? How does hypocretin's role in each of these behaviors or control mechanisms differ from that of other neurotransmitter systems? How does the loss of hypocretin/orexin explain the symptoms of narcolepsy? Is abnormal hypocretin/orexin function involved in all cases of human narcolepsy, including those with normal hypocretin/orexin levels in the CSF and no mutation of the hypocretin/orexin system? The theme of this chapter is that some answers are beginning to emerge from the hypocretin/orexin literature, although much remains to be done.