Hormonal and pharmacological manipulation of the circadian clock: recent developments and future strategies

The mammalian circadian oscillator, located in the suprachiasmatic nuclei of the anterior hypothalamus, serves as the principal source of rhythmic temporal information for virtually all physiologic processes in the organism, including the alternating expression of sleep and wakefulness. Recent studies, in both animal models and human subjects, have demonstrated the important modulation of sleep and wakefulness mediated by the circadian clock. Independent of other factors, notably prior sleep-wake history, the circadian clock potentiates wakefulness (and alertness) at one phase of the diurnal cycle, while facilitating sleep and its attendant processes at the opposite phase. The adaptive advantage of synchronizing sleep-wake behaviors with the daily changes in the external environment is clear. But in a modern world where the constraints of environmental time are less and less important, the circadian clock still imposes rigid boundaries on the timing of sleep and alert wakefulness that are increasingly perceived as limitations on human performance. This conflict underlies the sleep "disorders" of jet lag and shiftwork sleep disruption, problems that are not really diseases at all, but instead reflect normal function of circadian timing in the context of extraordinary demands on sleep-wake scheduling. Whatever their proper classification, both jet lag and shiftwork insomnia represent important societal problems deserving of public health and medical attention. Barring a worldwide rejection of air-travel, jet lag will continue to afflict tens of thousands of people annually. The effects of jet lag on human performance, while typically transient, can nonetheless be significant, affecting commerce, government, and even the outcome of professional sports contests. More important, only a global regression to an agrarian economy will eliminate the problem of tens of millions of workers in this country who regularly attempt to work at night and sleep during the day. In contrast to jet lag, shiftwork produces chronic sleep disruption lasting for the duration of shiftwork exposure. For while individual differences in the ability to adjust to a nocturnal work schedule clearly exist, recent studies suggest that few if any night workers regularly experience restful and restorative day sleep equivalent to that considered normal at night. This chronic sleep limitation is associated with significant increases in a number of consequent problems including sleepiness-related accidents, social disruption, and psychiatric disturbances. In addition, chronic exposure to shiftwork has now been shown to be an independent risk factor for the development of both cardiovascular and gastrointestinal diseases. While these epidemiological studies have not identified the specific aspect of shiftwork that is associated with increased risk of these disorders, the chronic limitation and disruption is foremost among plausible factors. The most important aspect of human circadian physiology that limits adaptation to the extreme schedules inherent in shiftwork and jet travel is the primacy of light among entraining signals, or zeitgebers. Exposure to sunlight for night shiftworkers, or for jet travelers at their destination, results in maintenance (or resetting) of the clock to environmental time. This response can be prevented or overridden with extraordinary avoidance of sunlight or with provision of artificial light of sufficient duration and intensity to negate the sunlight signal, an approach shown to be effective in the treatment of shiftwork sleep disruption. Practical issues sharply limit the application of artificial lighting to all shiftwork settings, however, and the role for a pharmacological chronobiotic agent capable of accomplishing the same end is potentially very large (Copinschi et al., 1995; Jamieson et al., 1998). For example, the effects of zolpidem vs. placebo on sleep, daytime alertness, and fatigue in travelers who complain of jet lag was co