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The amplitude of endogenous melatonin production is not affected by melatonin treatment in humans

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Matsumoto M, Sack RL, Blood ML, Lewy AJ. The amplitude of endogenous melatonin production is not affected by melatonin treatment in humans. J. Pineal Res. 1997; 22:42–44. © Munksgaard, Copenhagen A physiological dose of melatonin (0.5 mg) or placebo was given at bedtime to night shift workers (n=21) for seven days, and endogenous melatonin profiles were measured on the eighth day. The amplitude of endogenous melatonin secretion was unchanged by treatment. Also, a melatonin treatment trial using a 50 mg daily bedtime dose for 37 days to a blind subject resulted in no change in the endogenous melatonin profile. We conclude that circulating melatonin can shift the phase, but does not alter the amplitude, of pineal melatonin secretion.

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A physiological dose of orally administered melatonin shifts circadian rhythms in humans according to a phase-response curve (PRC) that is nearly opposite in phase with the PRCs for light exposure: melatonin delays circadian rhythms when administered in the morning and advances them when administered in the afternoon or early evening. The human melatonin PRC provides critical information for using melatonin to treat circadian phase sleep and mood disorders, as well as maladaptation to shift work and transmeridional air travel. The human melatonin PRC also provides the strongest evidence to date for a function of endogenous melatonin and its suppression by light in augmenting entrainment of circadian rhythms by the light-dark cycle.
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At two different times of year (spring and autumn) an oral preparation of the pineal neurohormone melatonin, or placebo, was administered to 12 healthy volunteers (10 men and two women in spring: the same group minus one man in autumn) daily at 1700 h for 1 month (spring), or 3 weeks (autumn) using a double-blind cross-over protocol. The daily dose was 2 mg melatonin in 5 ml corn-oil, and placebo consisted of the vehicle only. In spring the anterior pituitary hormones LH, PRL, GH together with T4, cortisol, testosterone and melatonin were measured at 1- to 6-h intervals for 24 h in plasma on the day following the last dose. In autumn PRL, cortisol and melatonin levels were measured on the last day of treatment. Subjective fatigue, mood and sleep records were kept throughout the studies. Melatonin increased early evening fatigue and actual sleep, but had no effect on mood: these results are reported in full elsewhere. Melatonin administration had no effect on the levels or 24-h rhythm of LH, GH, T4, testosterone or cortisol. An earlier fall in the nocturnal PRL was observed on both occasions. Overall PRL levels were higher in spring than in autumn. In five of the subjects, the secretion of endogenous melatonin was advanced by 1-3 h in the presence of exogenous melatonin. These observations suggest that the potential therapeutic use of melatonin as a hypnotic or in the treatment of jet lag is unlikely to be complicated by undesirable endocrine effects.
Article
The effects of implanting Silastic capsules containing melatonin on plasma melatonin and prolactin levels were investigated in pinealectomized (Px) and sham-operated sheep (SPx). Prior to implantation, melatonin was found in plasma samples obtained during the night period from SPx sheep (mean value 150 pg/ml), but could not be (less than 25 pg/ml) detected in plasma samples obtained during the day in SPx sheep or in any sample obtained during the night or day period in Px sheep. Following implantation, a constant basal plasma melatonin level of about 165 pg/ml was established in all sheep with a superimposed nighttime rise in SPx animals suggesting no diminution of endogenous melatonin production during the dark period. Following melatonin treatment, there was a marked depression in plasma prolactin levels in both SPx and Px sheep. These results are interpreted to indicate that 1) there is no negative feedback of melatonin upon its own synthesis and release, 2) that there is no circadian change in the rate of metabolism of melatonin and 3) that constant melatonin availability in sheep caused a depression in plasma prolactin levels similar to that found following exposure of animals to a short day.
Article
The pineal hormone melatonin regulates seasonal reproductive function and modulates circadian rhythms in mammals. We now report the cloning and characterization of a high affinity receptor for melatonin from the sheep and human. The receptor cDNAs encode proteins that are members of a newly discovered group within the G protein-coupled receptor family. Expression of the sheep and human receptors in COS-7 cells results in high affinity 2-[125I]iodomelatonin binding and pharmacological characteristics similar to endogenous high affinity receptors. Functional studies of NIH 3T3 cells stably expressing the sheep receptor show that the mammalian melatonin receptor is coupled to inhibition of adenylyl cyclase through a pertussis toxin-sensitive mechanism. In situ hybridization studies of melatonin receptor mRNA in several mammals reveal hybridization signals in the hypophyseal pars tuberalis and hypothalamic suprachiasmatic nucleus. The cloned high affinity receptor likely mediates the reproductive and circadian actions of melatonin in mammals.
Article
A pre-requisite to understanding the physiological mechanisms of action of melatonin is the identification of the target sites where the hormone acts. The radioligand 2-[125I]iodomelatonin has been used extensively to localize binding sites in both the brain and peripheral tissues. In general these binding sites have been found to be high affinity, with Kd in the low picomolar range, and selective for structural analogues of melatonin. Also the affinity of these sites can generally be modulated by guanine nucleotides, consistent with the notion that they are putative G-protein coupled receptors. However, only a few studies have demonstrated that these putative receptors mediate biochemical and cellular responses. In the pars tuberalis (PT) and pars distalis (PD) of the pituitary, the amphibian melanophore and vertebrate retina, evidence indicates that melatonin acts to inhibit intracellular cyclic AMP through a G-protein coupled mechanism, demonstrating that this is a common signal transduction pathway for many melatonin receptors. However in the pars distalis the inhibition of calcium influx and membrane potential are also important mediators of melatonin effects.
Article
Melatonin is able to phase-shift the endogenous circadian clock and can induce acute temperature suppression. It is possible that there is a direct relationship between these phenomena. In a double-blind, placebo-controlled crossover study, 6 healthy volunteers maintained a regular sleep/wake cycle in a normal environment. From dusk until 24:00 h on days (D) 1-4 subjects remained in dim artificial lighting (< 50 lux) and darkness (< 1 lux) from 24:00-08:00 h. At 17:00 h on D3 either melatonin (0.05 mg, 0.5 mg or 5 mg) or placebo was administered. Melatonin treatment induced acute, dose-dependent temperature suppression and decrements in alertness and performance efficiency. On the night of D3, earlier sleep onset, offset and better sleep quality were associated with increasing doses of melatonin. The following day, a significant dose-dependent phase-advance in the plasma melatonin onset time and temperature nadir (D4-5) was observed with a trend for the alertness rhythm to phase-advance. A significant dose-response relationship existed between the dose of oral melatonin, the magnitude of temperature suppression and the degree of advance phase shift in the endogenous melatonin and temperature rhythms, suggesting that acute changes in body temperature by melatonin may be a primary event in phase-shifting mechanisms.
Article
The present study tested the hypothesis that daily melatonin treatments influence the biological clock mechanism controlling the circadian melatonin rhythm. Adult male and female Djungarian hamsters in light:dark = 16L:8D (lights on 0300-1900 h) were administered melatonin subcutaneously (s.c.) each day (5 micrograms/0.2 ml saline) in the morning at 1000 h (AM) or late afternoon at 1700 h (PM); controls received a vehicle injection (CON). After 14 days, pineal and serum melatonin concentrations were determined at various times on the last day of treatment and the next day in constant darkness (no treatment). The rhythm in pineal gland melatonin content was similar in each of the three groups on the last day of treatment (about 6 h duration). On the next day in constant dark, the rising phase was advanced and duration extended by 2 h or more in melatonin-treated hamsters compared to that in CONs (ANOVA). In circulation, the melatonin rhythm in AM and PM groups was phase advanced (onset and peak) on both days of the study. Thus duration was extended by up to 4.5 h compared to that in saline-treated controls. Moreover, amplitude of the nighttime serum melatonin rise was elevated up to fivefold relative to that in the CON group (ANOVA and Accumulated Sums analysis). The effects of repeated melatonin treatments on amplitude and phase of the serum melatonin rhythm raise the possibility that the circadian clock that controls pineal gland production of melatonin may also regulate melatonin secretion. From this and another study, the apparent half-life of melatonin in circulation was estimated to be 7.5 min; the melatonin injection initially produced pharmacological concentrations that were followed by low serum melatonin levels within 2 h. Thus, in both melatonin treatment groups, the data suggest that two distinct periods of elevated serum melatonin were present each day. The cellular mechanism for melatonin action must take into consideration how a brief interruption in elevated melatonin in circulation (about 1 h in the PM group) is recognized as a continuous duration (short daylength), whereas a more extended baseline period is transduced as an abbreviated or long daylength (about 7 h in the AM group). These data further suggest that the biological clock mechanism that generates the circadian melatonin rhythm is responsive to the influence of daily melatonin treatments and presumably to the feedback action of endogenous melatonin on its own rhythm in the Djungarian hamster in long days.