A chronobiotic is an agent that can cause phase adjustment of the

circadian rhythm A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., Endogeny (biology), endogeno ...

(biological body clock). That is, it is a substance capable of therapeutically

entraining Entrainment may refer to: * Air entrainment, the intentional creation of tiny air bubbles in concrete * Brainwave entrainment, the practice of entraining one's brainwaves to a desired frequency * Entrainment (biomusicology), the synchronization of ...

or re-entraining long-term desynchronized or short-term dissociated

s in

mammal Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...

s, or prophylactically preventing their disruption following an environmental insult such as is caused by rapid travel across several time zones. The most widely recognized chronobiotic is the hormone

melatonin Melatonin is a natural product found in plants and animals. It is primarily known in animals as a hormone released by the pineal gland in the brain at night, and has long been associated with control of the sleep–wake cycle. In vertebrates ...

, secreted at night in both diurnal and

nocturnal Nocturnality is an animal behavior characterized by being active during the night and sleeping during the day. The common adjective is "nocturnal", versus diurnal meaning the opposite. Nocturnal creatures generally have highly developed sens ...

species.

History

The concept of chronobiotics arose from the characterization of the

pineal gland The pineal gland, conarium, or epiphysis cerebri, is a small endocrine gland in the brain of most vertebrates. The pineal gland produces melatonin, a serotonin-derived hormone which modulates sleep, sleep patterns in both circadian rhythm, circ ...

. In 1917, Carey Pratt McCord and Floyd Pierpont Allen at

Johns Hopkins University Johns Hopkins University (Johns Hopkins, Hopkins, or JHU) is a private university, private research university in Baltimore, Maryland. Founded in 1876, Johns Hopkins is the oldest research university in the United States and in the western hem ...

demonstrated that tadpoles hatched in water that contained crushed pineal gland were much lighter in color than tadpoles hatched in normal water. No one could explain this phenomenon, and pineal gland research halted until the 1950s. Mark Altschule and Julian Kitay, both physicians at

Harvard Harvard University is a private Ivy League research university in Cambridge, Massachusetts. Founded in 1636 as Harvard College and named for its first benefactor, the Puritan clergyman John Harvard, it is the oldest institution of higher le ...

, summarized the body of pineal gland literature in the 1950s. Their main conclusion was that pineal gland hormones affected the size of rats' gonads, although the hormones had not yet been identified. Melatonin was originally discovered by Aaron Lerner, a

Yale Yale University is a private research university in New Haven, Connecticut. Established in 1701 as the Collegiate School, it is the third-oldest institution of higher education in the United States and among the most prestigious in the wor ...

dermatologist, and colleagues, who had hoped it could be used to treat

vitiligo Vitiligo is a disorder that causes the skin to lose its color. Specific causes are unknown but studies suggest a link to immune system changes. Signs and symptoms The only sign of vitiligo is the presence of pale patchy areas of depigmen ...

. Although melatonin did not prove to be relevant to dermatology treatments, it was quickly confirmed to be secreted by the pineal gland to affect the brain. Further research found that

circadian A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., endogenous) and responds to ...

melatonin rhythms persisted under constant darkness, which suggested that light alone is not responsible for the cycle of melatonin secretion. Rather, endogenous melatonin serves to internalize light cues, making melatonin responsible for modulating neuroendocrine functions. The

suprachiasmatic nucleus The suprachiasmatic nucleus or nuclei (SCN) is a tiny region of the brain in the hypothalamus, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms. The neuronal and hormonal activities it generates regula ...

, or SCN, is a small region within the anterior

hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...

of the brain that is responsible for orienting the organism's internal measurement of time to external time cues like daylight. The SCN was first identified to be the "circadian pacemaker" responsible for generating circadian rhythms in 1972. Both Robert Moore at the

University of Chicago The University of Chicago (UChicago, Chicago, U of C, or UChi) is a private research university in Chicago, Illinois. Its main campus is located in Chicago's Hyde Park neighborhood. The University of Chicago is consistently ranked among the b ...

and Irving Zucker at the

University of California, Berkeley The University of California, Berkeley (UC Berkeley, Berkeley, Cal, or California) is a public land-grant research university in Berkeley, California. Established in 1868 as the University of California, it is the state's first land-grant u ...

linked the SCN to circadian rhythmicity at the same time by

lesion A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals. Types There is no designated classifi ...

ing regions of the brain and observing their effects on circadian rhythms. When the SCN region was lesioned in rodents, the rodents did not exhibit circadian rhythms, which established the SCN as the circadian pacemaker. Robert Moore and David Klein first studied the SCN in the context of melatonin secretion by the pineal gland in 1974. Melatonin has been established as a reliable output of the SCN's timekeeping property, and melatonin research has been coupled with SCN research since 1974. Because melatonin is secreted according to signals to the pineal gland from the SCN, exogenous melatonin taken as a chronobiotic can affect feedback to the SCN and its subsequent circadian rhythms.

Types

Quiadon

Quiadon (mepiprazole dihydrochloride) was one of the first chronobiotics used to affect

s in humans. A 3-alkyl pyrazolyl

piperazine Piperazine () is an organic compound that consists of a six-membered ring containing two nitrogen atoms at opposite positions in the ring. Piperazine exists as small alkaline deliquescent crystals with a saline taste. The piperazines are a broad ...

, Quiadon is a

serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...

-depleting

tranquilizer A tranquilizer is a drug that is designed for the treatment of anxiety, fear, tension, agitation, and disturbances of the mind, specifically to reduce states of anxiety and tension. Etymology Tranquilizer, as a term, was first used by F.F. Yonk ...

. However, the original study performed by H.W. Simpson and colleagues in 1973 delivered inconclusive results, and Quiadon was never put on the market for human use.

Melatonin

Melatonin is a natural hormone produced by the body to encode nighttime. Endogenous melatonin is secreted daily in all mammals beginning after sunset and ending just before sunrise. Melatonin's chronobiotic property was initially suspected in the late 1980s when a high density of high-affinity melatonin receptors was discovered in the

SCN SCN may stand for: Science and technology *Switched circuit network, i.e. the public switched telephone network *Server change number, a counter variable used in client-server architecture *System change number, a stamp that defines a committed ...

. Little is known about the long-term effects of taking melatonin.

Melatonin receptor agonists

Chrononutrition

The field of chrononutrition was established after dietary

tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α- carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromatic ...

was shown to synchronize the circadian rhythm with environmental time cues in 1968. Melatonin, which is also known for its chronobiotic properties, is synthesized from tryptophan. It is not only the nutrient that is relevant to chrononutrition, but the timing of nutrient consumption. By strategically planning meal times, the body can become resynchronized with exogenous time.

References

{{reflist