Image source: New York Times A little over a decade ago, scientists discovered that narcolepsy, the neurological disorder that leads to episodes of irresistible sleepiness, is caused by the loss of brain cells that produce hypocretin, a neurotransmitter that promotes wakefulness.But the discovery did not shed light on two other mysterious problems associated with the disorder. Narcoleptics have profoundly high rates of depression — up to six times the rate in the general population — and they have a tendency to collapse when swept by some emotions, a phenomenon known as cataplexy.Now research shows that in addition to regulating sleep, hypocretin also appears to govern emotion, particularly experiences of joy and happiness.The study has implications that extend beyond narcolepsy. It suggests that the brain has several different arousal systems, and that one of them, driven by hypocretin, has the specific function of keeping people awake for pleasure.It also raises concerns that drugs that block hypocretin could potentially cause depression and other unexpected side effects. One such medication, a sleeping pill from Merck called suvorexant that works by blocking hypocretin, essentially causing narcolepsy for a night, is awaiting government approval.The new research, published this month in the journal Nature Communications, involved a small group of patients with epilepsy who had special electrodes implanted in their brains that could directly monitor seizure activity and hypocretin levels around the clock.“Apart from their seizure disorder, these patients were normal,” said Dr. Jerome Siegel of the V.A. greater Los Angeles Healthcare System, the study leader and a psychiatry professor at U.C.L.A. “They’re watching TV, they’re talking to their relatives, walking around the hospital, going to the bathroom. They’re not mentally handicapped in any way, and we are observing them with video and periodically asking them to complete forms indicating how they feel – whether they’re happy or sad, hungry or thirsty, in pain or not.”Dr. Siegel, along with graduate student Ashley Blouin and their colleagues, expected to find that the ebb and flow of hypocretin mirrored the sleep cycle, rising in the morning and falling at night.“But what we found was more complex,” Dr. Siegel said. “The maximal release of hypocretin was not really related to arousal in the usual way. It happened during waking for sure, but the maximal release was simply when people reported they were happy.”The findings showed that hypocretin levels surged when the patients experienced joy and pleasure – while watching a favorite team win a baseball game, for example, or spending time with family. But when they experienced pain from their surgical implant, or anxiety about their medical situation, their levels of hypocretin fell.Dr. Siegel has shown in animal studies that hypocretin is associated with reward-seeking behavior. Release a dog into a yard to run, dig and play, and its hypocretin levels soar. But force the same dog to run on a treadmill, and its hypocretin levels remain flat. Similarly, hypocretin levels fall when mice are forced to press a bar to escape an unpleasant shock, but spike when the same animals press a bar to obtain food.“This shows that hypocretin is related to a particular kind of arousal,” said Dr. Siegel. “There is an arousal system in the brain whose function is keeping you awake for pleasure, to get rewards. It is related to positive affect, and in its absence you have a deficit in pleasure seeking.”In narcoleptics, cataplexy is most frequently caused by sudden joy. It is not uncommon to see someone with narcolepsy abruptly lose all muscle tone and collapse when laughing.But in some ways, we can all relate.“In almost every culture there’s an expression equivalent to falling down with laughter,” Dr. Siegel said. “Normal individuals don’t actually fall down. They may brace themselves or sit down. But narcoleptics will feel weak and unable to speak. In some instances they’ll fall down and won’t be able to get up for a few minutes.”In most people, laughter causes a surge of hypocretin, which maintains muscle tone. But in narcoleptics, the hormone is largely absent, and the system goes haywire.In narcoleptics, the loss of this pleasure-seeking hormone has severe effects on mood. Narcoleptics are prone to depression, and they have a strange resistance to addiction. Some of the medications used to treat narcolepsy are notoriously addictive, like amphetamines and GHB, the so-called date-rape drug. Yet narcoleptics generally do not abuse them.“They’re missing this working-for-pleasure system,” Dr. Siegel said. “When hypocretin is missing, you have a deficit in getting addicted and a deficiency in getting interested in things — that’s what depression is.”So, could a sleep aid like suvorexant, which reduces hypocretin, lead to depression in a healthy person? In clinical trials involving thousands of patients, the drug helped people with insomnia fall asleep faster and stay asleep longer than placebo. And there were no signs that it induced depression or caused falls resembling cataplexy, said Dr. Darryle Schoepp, senior vice president at Merck.“We had to measure psychiatric mood, including depression,” he said, “and we didn’t see anything worrisome there.”But Dr. Siegel said it is too soon to say that tinkering with hypocretin will not create unwanted consequences.“The initial reports are rosy,” he said. “But they come from a drug company with an enormous investment. And there is a long list of drugs acting on the brain whose severe problems were only identified after millions of people were taking them.”
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