Understanding Sleep

Melatonin

Hormones released in the body are involved in certain aspects of homeostasis, including regulating the circadian rhythms established by the SCN of the hypothalamus. Melatonin is an endocrine hormone that is principally produced and released into the blood by the pineal gland. The levels of melatonin fluctuate according to light exposure (highest during darkness and sleep, and lowest in bright sunlight) and it is proposed that melatonin acts as a time ‘cue’, entraining the body’s circadian rhythm to conventional environmental patterns. For example, melatonin has been identified as a sleep-anticipating signal and as an important physiological regulator of the sleep–wake cycle overall.¹

Natural secretion profile and roles of melatonin

The circadian pattern of melatonin production and release by the pineal gland is controlled by the SCN of the hypothalamus.²Retinal exposure to light is the major influence synchronising pineal melatonin secretion with the 24-hour day/night cycle, with plasma levels increasing throughout the evening, peaking in the middle of the night and, thereafter, decreasing to low levels that are maintained throughout the day (Figure 1).³ The density of melatonin receptors in the SCN also fluctuates during a 24-hour period in parallel to the endogenous melatonin concentration, i.e., low during the day, and high during the night.⁴

The time and duration of the melatonin peak encode information on the time and length of day to the brain, including the SCN and peripheral organs. Thus, melatonin can ‘phase-shift’ the endogenous circadian clock and entrain sleep–wake rhythms.⁵

The importance of melatonin in the regulation of human sleep was initially indicated by observations that it was secreted primarily during the night,⁶ and that there was a close relationship between the night-time increase in melatonin levels and the timing of human sleep.^7,8 In blind individuals, melatonin is not produced with the same rhythm as sighted people, such that daytime peaks of melatonin levels have been positively correlated with periods of daytime sleep.⁹

One specific role proposed for melatonin in the sleep–wake cycle is regulating sleep-anticipation by opening the ‘gate’ to night-time sleepiness via the inhibition of the wakefulness/arousal signal produced by activity of the SCN. This is thought to be mediated by the MT₁ receptor, which inhibits firing of the SCN neurones.¹⁰ SCN neurones are active during the day, but relatively quiet at night, and the highest level of SCN activity occurs immediately prior to the opening of the sleep ‘gate’.¹⁰ A sharp increase in drowsiness then occurs approximately 2 hours after the onset of melatonin production^.3,11,12 A study in humans showed that afternoon administration of melatonin advanced the sleep ‘gate’ by 2 hours, while exposure to bright evening light between 20:00 and 22:00 delayed the night-time increase in melatonin and the resulting opening of the sleep ‘gate’.^3,13

Melatonin release therefore serves to promote sleep onset in humans, and its pulsatile release during stages of light sleep induces deep sleep and prevents awakening.³ However, it is important to note that melatonin is not a sedative, but a signal of darkness/night-time – indicated by the fact that, in nocturnal animals, melatonin induces wake rather than sleep during the night.¹ The means by which melatonin induces recognised darkness-associated behaviour (whether sleep or wakefulness) is not elucidated.

Via its action on the MT₂ receptor, melatonin is also involved in inducing light/dark ‘phase-shifts’, and therefore entraining circadian rhythms.¹⁴

References:
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