Are You Happy? You Might Have Hypocretin to Thank

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Move over dopamine, there’s a new “pleasure” molecule that could broaden our understanding of the chemistry of joy, laughter, addiction and even anger.

As prolific as the recent research on dopamine has been, neuroscientists have long recognized that all of the subtle varieties of human happiness couldn’t possibly be embodied in a single brain chemical, especially one that is also released under severe stress.

Enter hypocretin.  Hypocretin is a brain chemical with neurons that are located in the same areas where dopamine acts to influence feelings of pleasure and reward, so the two agents probably work together. Also known as orexin because two different groups discovered it simultaneously, for years it was primarily associated with sleep and appetite.

In 2000, Jerome Siegel, professor of psychiatry at University of California Los Angeles and his colleagues found that people who suffered from the profound daytime sleepiness and sudden muscle weakness associated with narcolepsy also showed an absence of neurons in the brain that regulate hypocretin.

In a new study published in Nature Communications, Siegel’s group now reports that hypocretin-1 (there are two types of the brain chemical) levels rise in concert with positive emotions, social interactions and, oddly, anger. Studying eight patients with epilepsy who had brain implants to determine the source of their intractable seizures, the researchers measured how levels of hypocretin-1 and a hormone called MCH rose and fell.

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In the epilepsy study, these implanted electrodes would tell the doctors whether the seizures started on just one side of the brain or on both sides; only patients whose seizures originated on one side of the brain could then take advantage of a surgery that essentially cures about 70% of those getting the operation. Once the devices were implanted, the participants were hospitalized and monitored 24/7 for days until they developed a seizure.  Other than having epilepsy, the patients’ brains and emotions were normal.

The setting provided a perfect opportunity for Siegel to also track brain chemical changes triggered by the happy news that surgery for some patients would be possible. “These patients are experiencing a lot of emotion,” he says. “Sometimes they are in pain. If the surgery is successful, they’ll be seizure-free. [In other cases], there’s nothing we can do. This is a golden opportunity to get some deeper understanding of [these chemicals].”

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When patients got good news about surgery, their levels of hypocretin-1 were highest. The same peaks occurred when they laughed or warmly interacted with family and friends. These findings matched up with the previous investigations linking hypocretin with narcolepsy. People with narcolepsy, who largely lack hypocretin, for example, tend to have high rates of depression, which may in part be connected to their lower levels of a brain chemical associated with good mood.

Secondly, genuine laughter is the most common trigger for an attack of cataplexy, a symptom of narcolepsy in which people lose all muscle tone to the point of falling down and being unable to move. Of course, people without narcolepsy can also briefly be immobilized by laughter. But in narcolepsy, this weakness progresses to the point of short-term paralysis.  And that suggests that during joyous or hilarious moments, hypocretin may normally be responsible for keeping laughter’s ability to overtake muscle control in check.

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Calling the research “thought-provoking,” Dr. Antonello Bonci, scientific director of the National Institute on Drug Abuse, who was not associated with the research, says, “This is to my knowledge the first study that has measured these [substances] in humans under a variety of quite complex behavioral situations.”

But why would a brain chemical involved in narcolepsy and cataplexy be associated with happiness?  No one knows, but it’s clear that the neat divisions that researchers like to create between functions that make studying the brain easier are artificial ones, and that the same chemicals have multiple, and widely divergent, uses in the brain.

And that’s the case for hypocretin-1 as well. Not only did levels of the brain chemical surge when the patients in the study experienced happy emotions, but when they got angry as well. Anger, too, is a common trigger for cataplexy in narcolepsy.  And while happiness and anger are opposing emotions, their regulation may be governed by a common agent — hypocretin — which may be involved in maintaining control during states of high emotion.

Such overlapping functions may also mean that hypocretin research could open up new understanding about addictions as well. Research in animals linked hypocretin to the craving for pleasurable experiences provided by drugs and high fat foods. “Hypocretin facilitates reward-related behaviors, drug-seeking behaviors and drug-induced strengthening of brain cell connections,” says Bonci, noting that “inactivation of hypocretin receptors in the brain drastically reduces drug seeking and high-fat food consumption.”

In fact, stimulating the neurons that release hypocretin seems enjoyable for rodents, who prefer to hang out in spaces that generate the surge in hypocretin, in the same way they do if given cocaine or morphine. Blocking hypocretin, however, prevents the animals from developing this addiction-like behavior.

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Does that mean that people with narcolepsy, because they have lower levels of hypocretin, enjoy a reduced risk of addiction? Indeed, that’s what researchers have observed, at least anecdotally. Although narcolepsy is typically treated with addictive drugs like amphetamines or other stimulants, as well as the “date rape” drug GHB, cases of addiction are rare in this group.

That suggests that drugs to block hypocretin might hold promise for addiction treatment. One such drug, already close to approval, was developed to treat insomnia but may provide useful insights into addiction as well. Merck’s compound, suvorexant, was designed to take advantage of the fact that an absence of hypocretin function is behind narcolepsy and intense sleepiness, and that mimicking this low hypocretin effect by temporarily blocking the chemical’s activity may be an effective way to induce sleepiness in insomniacs. Based on the preliminary work showing that narcoleptics are less likely to become addicted to drugs, it’s possible that suvorexant or other agents like it may also lower the risk of addiction, although additional, separate studies would have to be conducted to investigate that possibility.

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In the meantime, it’s clear that the chemistry of happiness — and anger, sleep and addictions — just got more complicated.