New drug CX717 can temporarily improve performance and reverse the effects of sleep deprivation

Research in monkeys suggests that a new drug can temporarily improve performance and reverse the effects of sleep deprivation on the brain, which would be a breakthrough in helping shift workers, health professionals, military personnel and others who must function at top performance in spite of sleep deficits.

"In addition to improving performance under normal conditions, the drug restored performance that was impaired after sleep loss," said Samuel Deadwyler, Ph.D., senior researcher, from Wake Forest University School of Medicine. "Brain imaging revealed that one basis for the drug's effects was to reverse changes in brain patterns induced by sleep deprivation."

The study's results are reported in the journal PLoS Biology. The drug, currently known as CX717, is designed to act on a type of receptor located throughout the brain that is involved in cell-to-cell communication. It has been tested in sleep-deprived humans with positive results, according to the developer, Cortex Pharmaceuticals.

The Wake Forest research was funded by the U.S. Department of Defense Advanced Research Projects Agency, as part of a larger effort to mitigate or eliminate the effect of sleep deprivation on military personnel, and by the National Institutes of Health. In addition to Deadwyler, the research team included Linda J. Porrino, Ph.D., James Daunais, Ph.D., Robert Hampson, Ph.D., from the Department of Physiology and Pharmacology at Wake Forest, and Gary Rogers from Cortex Pharmaceuticals.

The researchers first tested normal, alert monkeys on a matching task similar to a video game. Each monkey was shown one clip art picture at one position on the screen, and after a delay of one to 30 seconds, picked the original out of a random display of two to six different images to get a juice reward. The monkeys were then given varying doses of the drug and re-tested. At the highest dose tested, the drug improved performance to near perfect for the easier trials and by about 15 percent overall.

Next, the monkeys were tested after they were sleep-deprived for 30 to 36 hours, which Deadwyler estimates is equivalent to humans going 72 hours without sleep. When compared to when they were alert, the monkeys' overall performance was reduced under all test conditions, even on the easiest trials. But, when the monkeys were again sleep-deprived and re-tested after being given CX717, their performance was restored to normal levels.

The researchers used positron emission tomography (PET) to gain images of brain activity while the animals were performing the matching task. These scans showed that the drug was able to reverse most of the changes in activity patterns that occurred with sleep deprivation – which may explain its success at increasing performance.

The PET images showed that when the monkeys were performing the task while sleep-deprived, activity in the frontal cortex, an area of the brain associated with higher mental processing, decreased and activity in the temporal lobe, associated with memory for recent events, increased. The researchers suspect that this might be the brain's way of compensating for the effects of sleep deprivation. After the drug was administered, the brain patterns in these regions returned to normal.

"The effect was to reverse the patterns of activation to the same as when the animal performed the task under normal conditions," Deadwyler said. "The drug didn't cause overall brain arousal, but increased the ability of certain affected areas to become active in a normal, non-sleep-deprived manner."

The drug, known as an ampakine, is designed to target AMPA receptors that are located throughout the brain. These receptors are part of the cellular communication process that involves the neurotransmitter glutamate. The drug prolongs the action of glutamate, allowing more effective communication. Because the drug acts differently from caffeine and other stimulants, it does not seem to result in side effects such as hyperactivity, distorted thinking or extended wakefulness.

"It's possible that ampakines could also be used to enhance other cognitive deficits, such as occur in Alzheimer's disease, after a stroke or other forms of dementia," Deadwyler said.