Chapter 14 The role of melatonin and light in the human circadian system

doi:10.1016/S0079-6123(08)60409-4

Progress in Brain Research

Volume 111, 1996, Pages 205-216

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This chapter focuses on the role of melatonin and light in the human circadian system. Unique to melatonin is that its production can be acutely suppressed by exposure to light during the night. Consequently, it was concluded that humans, unlike other primates, lacked the neural pathways that mediated light input to the human circadian pacemaker. These pathways have been well defined in animals and are delineated in the chapter. Humans may have seasonal rhythms that respond to the change in natural day length—indoor light in the winter evenings does not lengthen the photoperiod. Similarly, turning on room lights briefly in the middle of the night should not have much effect on the circadian rhythms. The second implication was that one could substitute bright artificial light for sunlight to experimentally, or perhaps therapeutically, manipulate biological rhythms in humans. Studies showed that melatonin could potentially shift some circadian rhythms, particularly the rhythm of sleepiness.

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Citation Excerpt :
The magnitude of phase shifts is time-dependent, and the maximal phase shifts result when melatonin is scheduled around dusk or dawn.36 The effect of exogenous melatonin is minimal when administered during the night, at least during the first-half of the night.37 Furthermore, similar to the effects of bright light, melatonin administered at an inappropriate time can actually worsen the patient's condition.
Circadian rhythm sleep disorders are common in clinical practice. The disorders covered in this review are delayed sleep phase disorder, advanced sleep phase disorder, free-running, irregular sleep–wake rhythm, jet lag disorder and shift work disorder. Bright light treatment and exogenous melatonin administration are considered to be the treatments of choice for these circadian rhythm sleep disorders. Circadian phase needs to be estimated in order to time the treatments appropriately. Inappropriately timed bright light and melatonin will likely worsen the condition. Measurements of core body temperature or endogenous melatonin rhythms will objectively assess circadian phase; however, such measurements are seldom or never used in a busy clinical practice. This review will focus on how to estimate circadian phase based on a careful patient history. Based on such estimations of circadian phase, we will recommend appropriate timing of bright light and/or melatonin in the different circadian rhythm sleep disorders. We hope this practical approach and simple recommendations will stimulate clinicians to treat patients with circadian rhythm sleep disorders.
The neurohormone melatonin as a marker, medicament, and mediator
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This chapter is an update of what was originally published several years ago (Vessely and Lewy, 2002). Melatonin is a hormone produced by the pineal gland during nighttime darkness under the control of the endogenous circadian pacemaker (ECP) in the suprachiasmatic nucleus of the hypothalamus. The ECP is entrained (synchronized) to the 24-h light/dark cycle. The endogenous melatonin profile can be used to assess the phase position (time) of the ECP, and both bright light exposure and exogenous melatonin can influence its phase. Totally blind people often have free-running circadian rhythms that are not entrained to the 24-h light/dark cycle. In these blind free-runners (BFRs), circadian phase drifts each day, causing recurrent insomnia; properly timed low-dose melatonin can entrain BFRs to the 24-h day. Sighted people can have circadianrhythm disturbances as well. Both light and melatonin can be used to delay or advance circadian rhythms that are out of phase due to jet travel, shift work, or advanced or delayed sleep phase syndromes. Another group of people with circadian rhythm disorders are those suffering from seasonal affective disorder (SAD), or winter depression. Most people with SAD have circadian rhythms that delay in the winter, causing them to develop depressed moods and vegetative symptoms; light therapy timed to cause phase advances can lead to clear improvement. Preliminary work suggests that low-dose melatonin therapy may also be beneficial in treating SAD. The function of endogenous melatonin in humans may be to entrain the third-trimester fetus and suckling newborn to the mother's sleep/wake cycle.
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Citation Excerpt :
During the daytime, for example, the SCN contained twice as many vasopressin-expressing neurons as during the night, with peak values in vasopressin cell number occurring in the early morning. In contrast to the general belief that human beings have few, if any, seasonal rhythms (Lewy and Sack, 1996), we observed strong seasonal fluctuations in the SCN. The number of vasopressin- and VIP-containing neurons in the SCN was found to alter in the course of a year, with August–September values being two times higher than April–May values (Hofman and Swaab, 1992b; Hofman, 2001; Fig. 2).
This chapter focuses on the role of human hypothalamus in metabolic and epidemic disorders. Various clinical observations illustrate the importance of hypothalamic mechanisms for governing satiety and hunger. In Diencephalic syndrome or hypothalamo-optic-pathway glioma, emaciation of the entire body is found in infancy and childhood. Lesions in the ventromedial hypothalamic area cause increased appetite and obesity, whereas tumors in the lateral hypothalamic area (LHA) may cause anorexia. Additionally, hypercortisolism in Cushing's syndrome or due to corticosteroid therapy may cause obesity accompanied by depression, hypertension, and circadian disturbances. Uncommon, intractable hypothalamic obesity syndrome occurs after cranial insults, which is often coupled with other hypothalamo–pituitary disturbances that may exacerbate obesity, such as growth hormone deficiency or hypothyroidism. In disorders of eating and metabolism, there is frequent hypothalamic comorbidity in terms of mood, sleep and rhythm disorders due to the intense hypothalamic interconnectivity and integrative mechanisms. These symptoms often occur in an episodic way and generally have a different prevalence for the sexes. Circadian and seasonal fluctuations and sleep disorders may also point to the involvement of the suprachiasmatic nucleus (SCN) in symptom expression.
Rapid determination of serum melatonin by ESI-MS-MS with direct sample injection
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This paper describes a rapid, simple and sensitive analytical method for the quantitative determination of melatonin in human serum by ESI–MS–MS with direct serum sample injection and on-line extraction. The method uses N-acetyltryptamine as the internal standard. It has high specificity and sensitivity for serum melatonin analysis. The internal calibration curve shows a wide linear range from 0.500 to 200 ng/ml with a correlation coefficient, R²>0.999. The limit of quantitation is 0.500 ng/ml and the limit of detection is 0.100 ng/ml with 10-μl sample injection. The recoveries of serum melatonin at three levels are approximately 70%. The intra-assay precision (n=5) is between 0.8 and 2.0% and the inter-assay precision (n=3) is between 1.5 and 5.9% over the calibration range. This method has a total analysis time of less than 9 min. It can be used for the measurement of melatonin in human blood.
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Chapter 14 The role of melatonin and light in the human circadian system

Publisher Summary

Psychoneuroendocrinol.

Neurosci. Lett.

LifeSci.

Psychiatr. Res.

Lancet

Neurosci. Lett.

Physiol. Behav.

Neurosci. Lett.

Neurosci. Lett.

Melatonin assays in body fluids

J. Neural Trans. Suppl.

The pineal gland: basic physiology and clinical implications

Phase response of human melatonin rhythms to bright light in Antarctica

J. Physiol.

Some effects of melatonin and the control of its secretion in humans

Some effects of jet-lag and their alleviation by melatonin

Ergonomics

Melatonin: the internal zeitgeber of mammals?

Circadian rhythms: general features and endocrinological aspects

Circadian phase response curves for dark pulses in the hamster

J. Comp. Physiol. [A]

Stability in timing and amplitude of melatonin production across four seasons in humans

Sleep Res.

Bright light resets the human circadian pacemaker independent of the timing of the sleep-wake cycle

Science

Exposure to bright light and darkness to treat physiologic maladaptation to night work

N. Engl. J. Med.

Bright light induction of strong (Type O) resetting of the human circadian pacemaker

Science

Scheduled exposure to daylight: a potential strategy to reduce ‘jet lag’ following transmeridian flight

Psychopharmacol. Bull.

A functional analysis of circadian pacemakers in nocturnal rodents. II. The variability of phase response curves

J. Comp. Physiol.

Bright light in work-sleep schedules for shift workers: application of circadian rhythm principles

Squashing versus nudging circadian rhythms with artificial bright light: solutions for shift work?

Perspect. Biol. Med.

The pineal gland and mammalian photoperiodism

Neuroendocrinology

Synchronization of a circadian rhythm in pinealectomized European starlings by injections of melatonin

J. Comp. Physiol.

A human phase response curve for bright light pulses

Jpn. J. Psychiatr.

Effect of one minute exposure to light at night on rat pineal serotonin N-acetyltransferase and melatonin

J. Neurochem.

Two-oscillator structure of the pacemaker controlling the circadian rhythm of N-acetyltransferase in the rat pineal gland

J. Comp. Physiol. [A]

The circadian rhythm in plasma melatonin concentration of the urbanized man: the effect of summer and winter time

BrainRes.

Treatment of seasonal affective disorder with light in the evening

Br. J. Psychiat.

Light-induced suppression of endogenous circadian amplitude in humans

Nature

Corrections and additions to the history of light therapy and seasonal affective disorder [letter]

Arch. Gen. Psychiat.

Circadian rhythms in the pineal gland