New Clues to Why We Snooze

By monitoring the brains of napping and active cats, scientists have pinpointed a natural brain chemical that brings on a deep slumber after prolonged wakefulness. The findings, reported in tomorrow's issue of Science,* could lead to better drugs for helping people sleep.

Although the need to sleep is clear, the exact changes in the brain that cause a person to drop off have been hard to identify. However, indirect evidence pointed to adenosine, which is produced when the molecule ATP (adenosine triphosphate) is broken down to provide energy for active cells. Studies of brain slices have shown, for example, that adenosine binds to and interferes with receptors on cholinergic neurons, the alertness-controlling cells found mainly in the basal forebrain. That suggested that it might induce sleepiness by inhibiting the activity of those neurons. But the effects of adenosine had never been demonstrated in live animals, says Robert McCarley, a neurophysiologist at Harvard Medical School.

To try to pin down its role, McCarley and his team first tracked the levels of adenosine by extracting samples of brain fluid from cats throughout normal sleep-wake cycles. They found that the concentration of adenosine rises steadily during periods of alertness, when the brain uses the most energy, and drops during naps or deep sleep. When the cats were kept awake by encouraging them to play with toy lizards for 6 hours--an unusually long stretch between cat naps--adenosine levels soared higher than during normal states of alertness.

The team then investigated whether the chemical might be inducing sleep by acting on the cholinergic neurons in the basal forebrain. They infused the region with NBTI, a chemical that jacks up adenosine levels. As expected, the cats became drowsy. In contrast, a control dose, infused to the thalamus (which naturally accumulates high levels of adenosine, but does not have cholinergic neurons) did not affect alertness. McCarley speculates that when a neuron has burned most of its ATP, adenosine levels build up, leak out, and bind to cholinergic receptors, inducing the need for sleep.

The study provides the first evidence in animals for a physiological basis of the need for sleep, says the study's leader, Tarja Porkka-Heiskanen, a visiting neuroscientist at Harvard Medical School. It also suggests the possibility of designing better sleeping pills by finding compounds that mimic adenosine's effects, says McCarley, who points out that current drugs do not target the adenosine receptors. And even though cats are notorious for sleeping all the time, "I would be surprised if humans didn't work the same way," says Tom Dunwiddie, a neuropharmacologist at the University of Colorado's Health Sciences Center in Denver.

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