What's Sleep Good For, Anyway?
Wakefulness hormone reverses some side effects of sleep loss

by Jim Schnabel

February 29, 2008

In a society that rewards productivity and encourages the daily use of caffeine and other stimulants, it’s natural to wonder how far we can go in cutting back on sleep. A number of studies indicate that we can’t go far at all without endangering our health.  But a recent trial in monkeys suggests that at least one major side effect of sleep loss can be reversed with a drug based on a naturally occurring hormone in the brain.

In the Dec. 26 Journal of Neuroscience, a team led by Sam Deadwyler, a professor of pharmacology at Wake Forest University, reported a series of trials in rhesus monkeys of orexin-A (also called hypocretin-1), a wakefulness hormone secreted by neurons in the hypothalamus.  After a day and a half of being forced to stay continuously awake, some of the monkeys were given cognitive tests that required the use of short-term, “working memory.” 

Those sleep-deprived monkeys who were not given the drug did much worse on the tests, as expected.  But the sleep-deprived monkeys given orexin-A performed about as well as they had when rested—and with the most potent delivery method, a nasal spray, they performed significantly better.

The study was partly funded by the Pentagon through its research agency, DARPA, which suggests that orexin nasal sprays might become standard issue for soldiers, sailors and pilots in the future—just as drugs such as modafinil and amphetamine are used in wartime today.

Orexin’s potential goes beyond military applications. Jerome Siegel, a neuroscientist at UCLA who co-authored the report, notes that an orexin drug, if safe and effective in humans, is most likely to be approved for use in narcolepsy and Parkinson’s disease, “the two situations where we know there’s a deficiency of orexin in the brain.”

For broader use, to keep ordinary, healthy people awake, Siegel acknowledges that there would be tradeoffs in terms of side effects. But he points out that even caffeine has side effects, and, unlike caffeine, orexin occurs naturally.

An evolutionary artifact?

Among sleep researchers, Siegel is known for his skepticism that sleep has a universal and vital biological function in animals.

“Why do some animals sleep two hours a day and other animals sleep 20 hours a day?” he asks. “I think it’s generally true in the animal kingdom that sleep time can be viewed as an evolutionarily adaptive thing, to limit activity” depending on the environment.

Siegel cites as an example the relatively long sleep periods of lions: “If a lion kills an antelope, the best strategy is for it to do nothing for the next few days, because if it does something it's going to have to kill an antelope again”—to replace the energy it burns— “and it’ll be vulnerable, because even antelope fight back.”

“There are many cases of animals that can reduce sleep for long periods of time with no rebound at all,” Siegel adds. “We had a paper in Nature in 2005 showing that when dolphins and killer whales give birth they become continuously active for months, with no possibility of extended periods of sleep. And they never show any obvious impairment during this period.”

That does not mean that we humans can easily dispense with sleep, he acknowledges. As we have evolved, certain important behaviors have crept into our sleep time. “One example is that growth hormone is released during slow-wave sleep in children," Siegel says. "And there is evidence that if young children have constantly disturbed sleep, their growth is impaired.”

Sleep and metabolism

Sleep in humans is also apparently connected to the normal regulation of energy use by the body. Large-scale surveys have linked reduced sleep to obesity. A recent study at the University of Chicago suggests that sleep deprivation could also lead to diabetes.

In the study, researchers in the laboratory of sleep specialist Eve Van Cauter prevented dozing human volunteers from falling into slow-wave sleep, a form of deep sleep. The result: disturbances in normal glucose regulation like those seen in diabetics.

“The decreased glucose tolerance and the increased risk of diabetes that exists in older adults could well be related to the poor sleep quality” normally seen in elderly people, Van Cauter says.

Could orexin-A come to the rescue?  The hormone is known to be involved in the regulation not only of wakefulness but also of energy consumption.  In the sleep-deprived monkeys in Deadwyler’s and Siegel’s study, positron emission tomography (PET) scans taken during cognitive tests showed that glucose metabolism in active brain areas was restored to normal when the monkeys were given orexin-A.

But Esra Tasali, the sleep researcher who led the slow-wave sleep study, notes that the underlying mechanisms connecting slow-wave sleep loss to diabetes-like changes in glucose tolerance throughout the body are “probably multifactorial.”  Siegel notes, too, that “the role of orexin in metabolism is at best unclear.

“I really doubt that it could alter the metabolic effects of sleep loss,” Siegel says.

There are other side effects of going without sleep.  Studies in animals and humans have suggested that sleep is essential for the maintenance of proper immune function, and also that it serves as a mental “down time” during which neurons can repair themselves and memories can be organized into long-term forms of storage—a key point for students cramming for exams, for example.  The monkeys in Deadwyler and Siegel’s study were not checked for effects on their long-term memory. “This would be an interesting area to test,” Deadwyler says.

Question of addictiveness

Developing an orexin-A drug also would require scrutiny of the link between the orexin system and addiction; rats hooked on alcohol lose the habit when their orexin systems are blocked. Modafinil (brand name Provigil) activates many of the same wakefulness-associated neurons as orexin-A despite its different chemical form, and although it might be less effective, it might also be less addictive.

“Orexin neurons connect to dopamine neurons, and there’s a [great deal of research] showing that dopamine is related to addictive behavior,” says Siegel. “I think there probably are people directly trying to look at that now.”

So far, orexin-A has attracted limited interest from the pharmaceutical industry. As a naturally occurring molecule, it isn’t easy to patent in the way that drug companies prefer.

“I spend a lot of time trying to persuade people to push this forward,” says Siegel.

In fact, the first big commercial use of drugs that target the orexin system in the brain might come from the opposite direction. Two companies, GlaxoSmithKline in the United Kingdom and Actelion in Switzerland, are conducting tests in humans of drugs that block the action of orexin in the brain—to help people get a good night's sleep.