NICHD scientists identify molecule that may help control sleep and wake cycles

Molecule may act with melatonin to regulate biological timing

Wednesdsay, May 24, 2017

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A molecule may work with the hormone melatonin to regulate 24-hour changes in metabolism, including sleep and wake cycles, according to researchers at the National Institutes of Health and other institutions. The researchers identified N-acetyltryptamine in the blood of humans and two animal species. They found that the molecule increases in the blood at night and decreases during the day, in parallel with levels of melatonin.

Like a key fits into a lock, melatonin binds to specialized molecules, or receptors, on the surface of cells, to regulate organs and tissues. The researchers theorize that because N-acetyltryptamine binds to melatonin receptors, it could act as a melatonin substitute or it could compete with melatonin, inhibiting its effects. The study appeared in the Journal of Biological Rhythms.


Melatonin is a natural hormone that plays a role in sleep and waking. Production of the hormone rises in the evening and falls during daylight hours. N-acetyltryptamine, like melatonin, is produced from the amino acid tryptophan. Melatonin is known to have a broad range of effects. However, little is known about N-acetyltryptamine, which has only been used in laboratory studies to help understand how melatonin functions.  

N-acetyltryptamine has a structure  similar to melatonin and binds to the melatonin receptor, but has a much weaker chemical attraction to the receptor. Before the current study, there was no method available to test for the substance in the blood. The investigators devised a new method to measure N-acetyltryptamine, combining two techniques for measuring low levels of chemicals in blood and other complex materials: high performance liquid chromatograpy and tandem mass spectrometry.


The researchers analyzed blood and tissue samples from humans, rats, and rhesus monkeys. They found that N-acetyltryptamine is present in all three species in the blood, in the retina, and in the pineal gland, a small gland in the brain that regulates sleep and waking. The researchers also determined that, like melatonin, levels of N-acetyltryptamine in the blood increase at night and fall during daylight hours.


“This advance points to the possibility that N-acetyltryptamine might also have a role in biological time-keeping,” said the study’s senior author, David Klein, Ph.D., of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Based on the less complex structure of N-acetyltryptamine and the attraction of both to the melatonin receptor, Dr. Klein believes that N-acetyltryptamine is the original time-keeping compound from which melatonin later arose during the course of evolution.

He suspects that it is unlikely that N-acetyltryptamine works directly with melatonin to regulate sleep and waking cycles as a hormone: It binds only weakly to the melatonin receptor and is present in the blood at low levels. He thinks it is more likely that N-acetyltryptamine works at a local level in tissues where it is synthesized, such as in the pineal gland.

Next Steps

Dr. Klein and his colleagues hope to decipher the role of N-acetyltryptamine in the sleep-wake cycle. They also aim to investigate whether it also plays a role in vision. Similarly, although it is likely that N-acetyltryptamine exerts its effects through the melatonin receptor, they hope to investigate whether it interacts with other molecules, including receptors.  


Backlund, PS, et al. Daily Rhythm in Plasma N-Acetyltryptamine. 10.1177/0748730417700458 External Web Site Policy

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