An international team of scientists led by the University of California Los Angeles has found that levels of a peptide called hypocretin (also known as orexin) greatly increase when humans are happy but decrease when they are sad.

The finding, published online in the journal Nature Communications, suggests that boosting hypocretin could elevate both mood and alertness in humans, thus laying the foundation for possible future treatments of psychiatric disorders like depression.

The team also measured for the first time the release of another peptide, this one called melanin concentrating hormone (MCH). They found that its release was minimal in waking but greatly increased during sleep, suggesting a key role for this peptide in making humans sleepy.

“The current findings explain the sleepiness of narcolepsy, as well as the depression that frequently accompanies this disorder,” said senior author Prof Jerome Siegel of the University of California Los Angeles’ Semel Institute for Neuroscience and Human Behavior. “The findings also suggest that hypocretin deficiency may underlie depression from other causes.”

“Depression is the leading cause of psychiatric disability in the U.S,” Prof Siegel said. “More than 6 percent of the population is affected each year, with lifetime prevalence exceeding 15 percent. Yet the use of antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), has not been based on evidence of a deficiency, or excess, of any neurotransmitter. Several recent studies have questioned whether SSRIs, as well as other depression-fighting drugs, are any more effective than placebos.”

In the current study, the researchers obtained their data on both hypocretin and MCH directly from the brains of eight patients who were being treated for intractable epilepsy. The patients had been implanted with intracranial depth electrodes to identify seizure foci for potential surgical treatment. The location of electrodes was based solely on clinical criteria. The researchers, with the patients’ consent, used these same electrodes to ‘piggyback’ their research. A membrane similar to that used for kidney dialysis and a very sensitive radioimmunoassay procedure were used to measure the release of hypocretin and MCH.

The patients were recorded while they watched television; engaged in social interactions such as talking to physicians, nursing staff or family; ate; underwent various clinical manipulations; and experienced sleep-wake transitions. Notes of activities were made throughout the study every 15 minutes in synchrony with a 15-minute microdialysis sample collection by a researcher in the patients’ rooms.

The subjects rated their moods and attitudes on a questionnaire, which was administered every hour during waking.

The researchers found that hypocretin levels were not linked to arousal in general but were maximized during positive emotions, anger, social interactions and awakening. In contrast, MCH levels were maximal during sleep onset and minimal during social interactions.

“These results suggest a previously unappreciated emotional specificity in the activation of arousal and sleep in humans,” Prof Siegel said. “The findings suggest that abnormalities in the pattern of activation of these systems may contribute to a number of psychiatric disorders.”

“Hypocretin antagonists are now being developed by several drug companies for use as sleeping pills. The current work suggests that these drugs will alter mood as well sleep tendency.”

The team has also previously reported that hypocretin is required for the ‘pursuit of pleasure’ in rodents but plays no role in avoidance behavior. “These results, in conjunction with the current findings, suggest that hypocretin administration will elevate both mood and alertness in humans,” Prof Siegel said.

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Bibliographic information: Ashley M. Blouin et al. Human hypocretin and melanin-concentrating hormone levels are linked to emotion and social interaction. Nature Communications 4, article number: 1547; doi: 10.1038/ncomms2461