The neurobiological underpinning of the circadian wake signal.

The circadian wake drive is a mathematic representation of the observed increased propensity to stay awake late in the day, peaking in the hours just before anticipated bed time. It has been called the "forbidden zone" due to the difficulty in initiating sleep during this time and is responsible for the problems initiating sleep when traveling eastward, for maintaining daytime sleep in shift workers, and for initiating sleep in some individuals with insomnia. Evidence culled from studies in individuals with narcolepsy, who lack production of hypocretin (orexin) neuropeptides, as well as a primate model of human wake consolidation and pharmacologic studies of hypocretin antagonists indicate that hypocretin-1 may be the physiologic instantiation of the circadian wake drive. This review will discuss the evidence in support of this hypothesis.