Normal Role of Hypocretin/Orexin

There is now no doubt that hypocretin/orexin (Hcrt) deficiency is the cause of most narcolepsy in humans (1,2). It is also clear that mutations of the Hcrt system cause genetic narcolepsy in several animal species (3,4). Narcolepsy in these Hcrt deficiency situations is characterized by sleepiness during the normally active period and losses of muscle tone during waking periods called cataplexy. We know from observations in humans and in canine narcoleptics that such cataplectic episodes are accompanied by unimpaired consciousness, and it is reasonable to expect that this is also the case in rodent Hcrt mutant models. These findings lead to the conclusion that one of the functions of Hcrt is to prevent the symptoms of narcolepsy. In this chapter I will address the question of how this function of Hcrt might be achieved and consider evidence bearing on a more general role of Hcrt in behavioral control. It is unlikely that simply defining the differences in behavior between narcoleptic and normal individuals will illuminate all of the functions of Hcrt. It is virtually certain that a variety of brain systems compensate for the postnatal loss of Hcrt in humans by occupying vacated synaptic sites and by up and down regulation of receptors whose activity is altered by the loss of Hcrt. It is also likely that Hcrt mutants have developmental alterations that modify, and perhaps ameliorate, the effects of Hcrt mutations, thus masking some of the normal functions of Hcrt. An effective alternate strategy for determining the role of Hcrt is to observe fluctuations in its release in normal animals, in which the role will not be obfuscated by compensatory reorganization. Such observations, including studies of release using microdialysis and cerebrospinal fluid (CSF) assays, will indicate when this peptide is released. Ultimately, it may be possible to bridge the gulf between information gained from such observations and the pathology of narcolepsy, by better understanding the neurological adjustments that result form Hcrt dysfunction. One early theory of Hcrt function was that it was an "orexigenic" or appetitestimulating compound. This was based on initial observations that high doses of Hcrt injected into the lateral hypothalamus, a region whose stimulation is known to induce feeding, increased food intake. However, subsequent infusion studies did not always support these initial observations (5). We tested the hypothesis that