Circulating Melatonin Concentrations Research Articles

Unanticipated daytime melatonin secretion on a simulated night shift schedule generates a distinctive 24-h melatonin rhythm with antiphasic daytime and nighttime peaks.

The daily rhythm of plasma melatonin concentrations is typically unimodal, with one broad peak during the circadian night and near-undetectable levels during the circadian day. Light at night acutely suppresses melatonin secretion and phase shifts its endogenous circadian rhythm. In contrast, exposure to darkness during the circadian day has not generally been reported to increase circulating melatonin concentrations acutely. Here, in a highly-controlled simulated night shift protocol with 12-h inverted behavioral/environmental cycles, we unexpectedly found that circulating melatonin levels were significantly increased during daytime sleep (p < .0001). This resulted in a secondary melatonin peak during the circadian day in addition to the primary peak during the circadian night, when sleep occurred during the circadian day following an overnight shift. This distinctive diurnal melatonin rhythm with antiphasic peaks could not be readily anticipated from the behavioral/environmental factors in the protocol (e.g., light exposure, posture, diet, activity) or from current mathematical model simulations of circadian pacemaker output. The observation, therefore, challenges our current understanding of underlying physiological mechanisms that regulate melatonin secretion. Interestingly, the increase in melatonin concentration observed during daytime sleep was positively correlated with the change in timing of melatonin nighttime peak (p = .002), but not with the degree of light-induced melatonin suppression during nighttime wakefulness (p = .92). Both the increase in daytime melatonin concentrations and the change in the timing of the nighttime peak became larger after repeated exposure to simulated night shifts (p = .002 and p = .006, respectively). Furthermore, we found that melatonin secretion during daytime sleep was positively associated with an increase in 24-h glucose and insulin levels during the night shift protocol (p = .014 and p = .027, respectively). Future studies are needed to elucidate the key factor(s) driving the unexpected daytime melatonin secretion and the melatonin rhythm with antiphasic peaks during shifted sleep/wake schedules, the underlying mechanisms of their relationship with glucose metabolism, and the relevance for diabetes risk among shift workers.

Identification of the blue light intensity administered to one eye required to suppress bovine plasma melatonin and investigation into effects on milk production in grazing dairy cows

Long-day photoperiod is known to positively affect milk production in confinement dairy systems, and it has been hypothesized that pineal melatonin (MT) secretion plays a substantial role in this process. Specialized mammalian photoreceptors that regulate MT secretion are optimally stimulated by short wavelength blue light. We investigated the blue light intensity administered to one eye required to suppress MT secretion in nonlactating dairy cows, and subsequently examined effects on milk production in grazing dairy cows. Following a 14-d light-dark 8:16 h environmental conditioning period, 5 nonlactating Holstein-Friesian cows were exposed to treatments of <1, 70, 125, 175, and 225 lx for 8 additional hours using a 5 × 5 Latin square design. Light was administered via headpieces fitted with light-emitting diodes emitting blue light (465 nm) to the right eye. All cows were then exposed to a light-dark 16:8 h cycle for one night via the indoor lighting system (>200 lx white light). Plasma samples collected at regular intervals were assayed for MT. A dose-dependent effect of light treatment on mean circulating MT concentrations (and 95% CI) was observed [9.4 (7.2, 12.3), 5.0 (3.8, 6.6), 4.4 (3.3, 5.7), 3.3 (2.5, 4.3) and 1.7 (1.3, 2.3) pg/mL for treatments of 0, 70, 125, 175, and 225 lx, respectively. Only the 225 lx treatment acutely suppressed plasma melatonin concentration to levels similar to the light-dark 16:8 h treatment [1.9 (1.4, 2.5) pg/mL]. Forty spring-calving cows were blocked on parity, calving date and Economic Breeding Index for milk production and assigned to the control treatment or blue light to a single eye (LT) treatment from calving through 32 wk of lactation. The cows assigned to LT treatment were fitted with headpieces providing 225 lx of blue light to the right eye from 1700 until 0000 h. Mean milk production (and 95% CI) during 32 wk of lactation was not affected by treatment [20.3 (19.3, 21.3) vs. 20.9 (19.8, 22.0) kg/d, control and LT, respectively]. Within multiparous cows, a treatment by week interaction was detected, whereby LT treatment increased milk production during the first 12 wk of lactation [25.8 (24.3, 27.3) vs. 28.0 (26.5, 29.5) kg/d; +8.5%], but had no effect thereafter. Treatment did not affect plasma insulin-like growth factor 1. We identified the blue light intensity to one eye required to acutely suppress MT concentrations. Transient favorable effects on milk production were observed in multiparous cows. It remains unclear how single-eye blue light treatment affects galactopoiesis in grazing dairy cows, and further research is needed to explore whether this modality of light delivery represents a useful means to aid productivity in pasture-based dairy systems.

Relationship between endogenous melatonin concentrations and uterine contractions in late third trimester of human pregnancy.

In humans, circulating levels of the hormone melatonin and the initiation of spontaneous labor are both higher at night than during the day. Since activation of uterine melatonin receptors can stimulate human in vitro uterine contractions and these receptors are only expressed on the uterine tissue of women in labor, we hypothesized that circulating melatonin concentrations would affect uterine contractions in vivo. We evaluated the impact of light-induced modulation of melatonin secretion on uterine contractions in women during late third trimester (~36-39weeks) of pregnancy in two inpatient protocols. We found a significant (P<0.05) positive linear association between circulating melatonin concentrations and the number of uterine contractions under both protocols. On average, uterine contractions increased between 1.4 and 2.1 contractions per 30minutes for every 10pg/mL*h increase in melatonin concentration. These findings have both basic science and clinical implications for pregnant women, since endogenous melatonin levels and melatonin receptor activity can be altered by light and/or pharmaceutical agents.

The presence and localization of melatonin receptors in the rat aorta.

Melatonin is involved in blood pressure modulation in rats and humans. Some of the effects of melatonin are presumably mediated via two G-protein-coupled receptors (MT(1) and MT(2)), but the distribution of MT(1) and MT(2) in the cardiovascular system remains to be explored comprehensively. We investigated the expression of both the receptors in the rat aorta on mRNA level by RT-PCR and real time RT-PCR as well as on protein level via western blotting and immunofluorescence microscopy. We verified MT(1) mRNA expression in the rat aorta and demonstrated the absence of MT(2) mRNA in this vessel type. MT(1) receptors were confirmed also at the protein level, and surprisingly they were preferentially localized to the tunica adventitia. Since no daily changes in MT(1) mRNA expression were detected, we suppose that the circadian changes in circulating melatonin concentrations are sufficient to mediate circadian effects of melatonin in the aorta. The localization of MT(1) in the tunica adventitia suggests an influence of melatonin on vasa vasorum function and signal transduction in the aorta wall.

Melatonin regulates delayed embryonic development in the short-nosed fruit bat, Cynopterus sphinx

The aim of the present study was to evaluate the seasonal variation in serum melatonin levels and their relationship to the changes in the serum progesterone level, ovarian steroidogenesis, and embryonic development during two successive pregnancies of Cynopterus sphinx. Circulating melatonin concentrations showed two peaks; one coincided with the period of low progesterone synthesis and delayed embryonic development, whereas the second peak coincided with regressing corpus luteum. This finding suggests that increased serum melatonin level during November-December may be responsible for delayed embryonic development by suppressing progesterone synthesis. The study showed increased melatonin receptors (MTNR1A and MTNR1B) in the corpus luteum and in the utero-embryonic unit during the period of delayed embryonic development. The in vitro study showed that a high dose of melatonin suppressed progesterone synthesis, whereas a lower dose of melatonin increased progesterone synthesis by the ovary. The effects of melatonin on ovarian steroidogenesis are mediated through changes in the expression of peripheral-type benzodiazepine receptor, P450 side chain cleavage enzyme, and LH receptor proteins. This study further showed a suppressive impact of melatonin on the progesterone receptor (PGR) in the utero-embryonic unit; this effect might contribute to delayed embryonic development in C. sphinx. The results of the present study thus suggest that a high circulating melatonin level has a dual contribution in retarding embryonic development in C. sphinx by impairing progesterone synthesis as well as by inhibiting progesterone action by reducing expression of PGR in the utero-embryonic unit.

The influence of season and age on circulating melatonin and leptin concentrations in Lipizzan fillies

Daily serum melatonin and leptin concentrations in 48 Lipizzan fillies, aged 1 to 3 years, have been measured during one year. Mean melatonin concentrations ranged from 7.08±0.43 pg/mL in 3-year olds to 9.02 ± 0.73 pg/mL in yearlings (P>0.05). In all age groups, circulating melatonin concentrations peaked in spring and early autumn and decreased in summer and early winter (P<0.001). The decrease of circulating melatonin levels could serve as a signal for resumption of ovarian activity in spring and for onset of anoestrus in autumn, but further investigations are needed to confirm this hypothesis. Mean annual leptin concentrations ranged from 2.55 ± 0.15 ng/mL in yearlings to 3.94 ± 0.32 ng/mL in 3-year olds (P<0.01); age-dependent differences were also observed during monthly samplings. In all age groups, the circulating leptin values were lowest in early spring and peaked in autumn (P<0.001). The rise of leptin levels in spring coincides with the period of resumption of ovarian activity and the decrease in winter with the anoestrous period of Lipizzan fillies, thus supporting the findings about the role of leptin in the regulation of the seasonal reproductive activity in mares.

Effects of continuous light and melatonin treatment on energy metabolism of the rat.

Melatonin affects food intake, body mass and adiposity of several mammals, but the effects of melatonin on energy metabolism remain largely unknown. This study investigated subacute effects of persistent melatonin treatment and continuous light on carbohydrate and fat metabolism of rat liver and kidney. The male and female rats (no.=40) were maintained either in 12L:12D photoperiod or in constant light. Half the rats in both lighting conditions were treated with continuous-release melatonin implants. Liver lipid concentrations, liver and kidney glucose-6-phosphatase, glycogen phosphorylase and lipase esterase activities, glycogen contents as well as plasma T4, T3, insulin, glucose and melatonin concentrations were determined. There was clear sexual dimorphism in the responses to exogenous melatonin and constant light. Continuous light stimulated carbohydrate metabolism of rat liver. Exogenous melatonin enhanced utilization of liver carbohydrates but suppressed hepatic lipolysis. Changes in normal circulating melatonin concentrations led to enhanced utilization of kidney carbohydrates supporting a role for melatonin in renal function. Both exogenous melatonin and constant light seem to have a strong regulatory effect on rat energy metabolism.

Melatonin treatment attenuates symptoms of acute nicotine withdrawal in humans

Nicotine withdrawlal is typically associated with negative changes in mood and performance, which often lead to relapse. We tested whether an oral 0.3-mg dose of melatonin administered 3.5 h after the nicotine withdrawal, and increasing circulating melatonin concentrations within the physiological range, affects the symptoms of acute 10-h (0800–1800 h) nicotine withdrawal in regular smokers. Self-reported ratings of mood, sleepiness, and cigarette craving were assessed hourly, using 17 visual analog scales (VAS). Computerized Four-Choice Reaction Time (FCRT) and Simple Auditory Reaction Time (SART) tests were used to assess performance every 2 h. Saliva samples were collected hourly, and salivary melatonin levels were measured using supersensitive radioimmunoassay. Compared with the placebo, melatonin treatment significantly reduced self-ratings of “anxious,” “restless,” “tense,” “irritable,” “angry,” “depressed,” “impatient,” and “craving for cigarettes.” Melatonin treatment did not significantly change the responses on the performance tests used. These data suggest that melatonin can help to counteract the acute effects of smoking cessation on mood.

Daily and photoperiodic 2-125I-melatonin binding changes in the pars tuberalis of the Syrian hamster (Mesocricetus auratus): effect of constant light exposure and pinealectomy.

Using quantitative autoradiography, 2-125I-melatonin binding was investigated throughout the light/dark cycle in the pars tuberalis (PT) of the pituitary of adult Syrian hamsters kept for 8 weeks either in long or short photoperiod (LP or SP, respectively). Melatonin receptor density in the PT displayed photoperiod dependent daily variations (maximal values in LP). Indeed, in LP, melatonin receptor density underwent strong daily variations with maximal values during the first half of the light period and minimal values at the end of the night. These variations depended on changes in the maximal binding (Bmax) without differences in the dissociation constant (Kd). In contrast, PT melatonin receptor density was constant and at a very low level throughout the light:dark cycle in SP exposed animals. Daily PT melatonin receptor density variations of LP exposed animals were abolished by pinealectomy or continuous light exposure. These results show clearly that both at the daily and at the seasonal level the regulation of PT melatonin receptors is strongly dependent on circulating melatonin concentrations in the Syrian hamster, but that other regulatory factors, yet unclarified, might also play a role.

Melatonin Rhythms in Atlantic Salmon ( Salmo salar) Maintained under Natural and Out-of-Phase Photoperiods

Diel changes in circulating melatonin were measured in juvenile Atlantic salmon, Salmo salar, maintained under natural and out-or-phase seasonal photocyles. Under natural day lengths of autumn, winter, spring, and summer circulating melatonin levels were inversely related to light intensity, with levels low during the day and high at night. The duration of the nocturnal increase in circulating melatonin was related to the duration of darkness,i.e., longer in winter than in summer. Under simulated seasonal photocycles circulating melatonin concentrations measured in August, October, and December were also elevated for the duration of darkness,irrespective of whether the photoperiods were synchronized or 6 months out-of-phase with the natural light and temperature cycles. Circulating melatonin also provided an accurate representation of the prevailing photoperiod in fish initially maintained on simulated natural photocycles, either synchronized or 6 months out-of-phase with the natural light cycle, and then held for 3 months on daylengths approcimating the summer and winter solstices. Well-defined melatonin rhythms were always present, irrespective of time of year, photoperiod, and temperature. The amplitude of the nocturnal increase in circulating melatonin was similar in groups of fish maintained under simulated seasonal photoperiods 6 months out-of-phase with each other, but otherwise identical conditions, indicating that daylength per se did not influence the amplitude of the melatonin rhythm. The amplitude of the melatonin rhythm was slightly higher during the summer months, suggesting that temperature may modify circulating melatonin levels. These results demonstrate that circulating melatonin profiles always reflect the prevailing daylength and hence have the potential to provide the Atlantic salmon with accurate information on daily calendar time, which could be utilised to time daily and seasonal events.

Sleep disorders and melatonin rhythms in elderly people.

Biological aging is often associated with problems with sleep and daytime napping.1 There is considerable evidence linking melatonin, produced by the pineal gland, with the sleep-wake cycle. When administered orally to humans or animals it enhances sleep2 and has a synchronising effect on circadian rhythms. Circulating melatonin concentrations decrease in old age, and its time of secretion is delayed.3 We examined whether sleep disorders in old age were associated with changes in concentration of 6-sulphatoxymelatonin, the major urinary measure of melatonin. The study population comprised four groups: (a) eight independently living patients with insomnia (four men, four women, mean age 73.1 (SD 3.9)); (b) 15 patients with insomnia (five men, 10 women, mean age 82.1 (8.8)) who had lived a minimum of six months in a nursing home; (c) 25 elderly patients without sleep disorders (19 …

The pineal hormone melatonin inhibits DNA-adduct formation induced by the chemical carcinogen safrole in vivo

Melatonin inhibits DNA-adduct formation induced by the chemical carcinogen safrole in a dose-dependent manner. Total DNA-adduct formation after in vivo administration of 300 mg/kg safrole measured by 32P-postlabeling analysis of carcinogen-modified DNA in rat liver was 36 751 ± 2290 counts/min/10 μg DNA. Coad-ministration of 300 mg/kg safrole with either 0.2 mg/kg (low dose) or 0.4 mg/kg (high dose) melatonin reduced DNA-adduct formation induced by safrole to 22 182 ± 987 counts/min/10 μg DNA and 462 ± 283 counts/min/10 μg DNA, respectively. Circulating melatonin concentrations at the termination of the study in safrole, low melatonin and high melatonin groups were 50 ± 8, 3140 ± 430 and 10 040 ± 2610 pg/ml serum, respectively. The results suggest that melatonin protects against safrole associated DNA damage.

Daily pattern of melatonin secretion in an Antarctic bird, the emperor penguin, Aptenodytes forsteri: Seasonal variations, effect of constant illumination and of administration of isoproterenol or propranolol

Daily variations in circulating melatonin concentrations have been measured at monthly intervals from April to December 1986 in an Antarctic bird, the emperor penguin, Aptenodytes forsteri, maintained under natural conditions. Both duration of the elevated nighttime melatonin levels and amplitude of the day-night rhythm displays an annual variation closely related to variations in the daylength. Duration of the nocturnal peak of melatonin secretion depended upon the duration of the darkness, decreasing with increasing daylength and disappearing completely during the summer solstice. The duration of the nighttime melatonin peak melatonin increased inversely with decreasing daylength. The amplitude of the day-night rhythm decreased in such a way that the nocturnal peak of melatonin completely disappeared during the winter solstice. Three days of constant illumination in September did not suppress the nighttime peak of melatonin secretion. The response of melatonin secretion, decreasing after β-adrenergic agonist treatment and increasing after antagonist treatment, reinforces the hypothesis that in birds the regulation of melatonin synthesis differs from that of the rat. Receptors other than β receptors may be involved.

5‐Methoxypsoralen enhances plasma melatonin concentrations in the male rat: Non‐noradrenergic‐mediated stimulation and lack of effect in pinealectomized animals

Previous studies have shown that 8-methoxypsoralen (8-MOP) is able to enhance melatonin secretion from rat pineal glands. The effect of another psoralen, 5-methoxypsoralen (5-MOP) on plasma melatonin concentrations alone or in combination with isoproterenol (Iso, 10 mg/kg BW, i.p.) or propranolol (Prop, 20 mg/kg BW, s.c.) was studied in the rat. An increase in plasma melatonin concentrations was observed 1 h after psoralen administration and lasted 8 h. The stimulatory effect of 5-MOP on circulating melatonin concentrations was dose dependent above 5-mg/kg, BW. 5-MOP also potentiated the Iso-induced rise in plasma melatonin levels. Furthermore, Prop did not block the effect of 5-MOP, indicating that the psoralen acts independently of the noradrenergic system controlling pineal melatonin synthesis. No increase in plasma melatonin levels was observed in pinealectomized (Px) animals after injection of 5-MOP (20 mg/kg BW) or 8-MOP (20 mg/kg BW). This demonstrates that the rise in plasma melatonin concentrations observed after treatment requires the presence of the pineal gland, and that neither 5-MOP nor 8-MOP stimulates melatonin release from other structures such as the retina or Harderian gland.

Effect of rumen degradable bolus containing melatonin or progestagen pessary plus pregnant mare serum gonadotropin on estrus response and lambing rate in ewes

Two practical regimens designed to induce estrus and ovulation in ewes in late anestrus were compared. Forty ewes were given a soluble glass rumen bolus containing 150 mg melatonin on July 9 and were joined with two vasectomized rams on July 23 and with three fertile rams on August 6. A second group of 40 ewes was treated with an intravaginal progestagen pessary (60mg medroxy-progesterone acetate) on July 23. Following pessary removal after 12 d, ewes were given 750 IU of pregnant mare serum gonadotropin (PMSG). Five fertile rams were joined with these ewes 48 h after progestagen removal. Melatonin concentrations were determined in single blood samples collected in early afternoon of July 21. Mating dates, lambing dates and litter sizes were recorded. Date of mating was significantly later in ewes treated with melatonin compared with those treated with progestagen plus PMSG (P<0.0001). All ewes given melatonin were mated within 4 wk, and those on progestagen plus PMSG treatment within one day of fertile ram introduction. Thirty-four ewes (85%) allocated to melatonin treatment and 36 (90%) allocated to progestagen plus PMSG treatment lambed (P>0.05). Mean (±SEM) lambing date was later in melatonin-treated ewes (January 17±1.2 d) compared to those given progestagen plus PMSG (December 30±0.6 d; P<0.0001). Mean litter size was lower in melatonin-treated ewes (1.5±0.1) compared with those given progestagen plus PMSG (2.0±0.1; P<0.001). Plasma melatonin concentrations indicated that 9 of 40 ewes treated with melatonin had circulating melatonin concentrations of less than 16 pg/ml. It is concluded that under conditions that existed in this experiment, treatment with progestagen plus PMSG in late anestrus resulted in more synchronous mating and lambing and a higher litter size than that following administration of a soluble glass rumen-degradable bolus containing melatonin.

Pineal and circulating melatonin rhythms in the box turtle, Terrapene carolina triunguis: Effect of photoperiod, light pulse, and environmental temperature

Pineal and circulating melatonin concentrations have been measured throughout the 24-hr cycle in the box turtle, Terrapene carolina triunguis, under different conditions of photoperiod and temperature. An obvious effect of photoperiod on the duration of the night rise of pineal and circulating melatonin is observed; the period of elevated melatonin is 4.30 hr in long photoperiod (18L:6D) and 11.00 hr in short photoperiod (8L:16D). A single pulse of 1 hr illumination beginning 1.30 hr after the onset of darkness, in a 16L:8D cycle, has no effect on pineal or circulating melatonin levels. A clear effect of environmental temperature on the amplitude of the day-night rhythm of melatonin production is observed. A possible role of the pineal of poikilotherms in the transduction of several environmental factors, via the daily pattern of melatonin secretion, is hypothesized.

The effect of photoperiod on diurnal rhythms of serum gonadotrophins, prolactin and melatonin in ovariectomized heifers

Fourteen heifers, ovariectomized prepubertally, were used in two experiments to test the hypotheses that (1) there are diurnal patterns in circulating concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin and melatonin and (2) that these diurnal patterns would be altered by changing photoperiod. In experiment 1 (Exp. 1) animals were randomly assigned to either increasing photoperiod (I) (n = 7) or decreasing photoperiod (D) (n = 7) for a period of 8 weeks. In the second experiment (Exp. 2) four heifers from each photoperiod group were assigned to the opposite treatment for another 4 weeks forming four subgroups; continued increasing photoperiod (II) (n = 3), increasing followed by decreasing photoperiod (ID) (n = 4), decreasing followed by increasing photoperiod (DI) (n = 4) and continued decreasing photoperiod (DD) (n = 3). At weeks 4, 8 (Exp. 1) and 12 (Exp. 2) the animals were cannulated and blood samples were taken hourly from 1030 hr to 0830 hr (23 samples). In Exp. 1, animals exposed to either I or D did not differ in circulating concentrations of LH, FSH, prolactin and melatonin. Concentrations of LH and melatonin but not FSH or prolactin were higher in animals during the scotophase than the photophase. In Exp. 2 LH, FSH and prolactin, but not melatonin concentrations were higher in animals exposed to I (II and ID) than D (DI and DD). Animals exposed to I had higher circulating concentrations of FSH and animals exposed to both I and D had higher concentrations of melatonin during the scotophase. Neither LH nor prolactin concentrations differed between scotophase and photophase. The abrupt switch from one photoperiod treatment to the other did not significantly affect LH, FSH or prolactin but did alter the patterns and concentrations of circulating melatonin. Animals that remained in the same photoperiod treatment had similar melatonin concentrations; but animals changed from I to D had higher serum melatonin concentrations than those changed from D to I. These data support the hypothesis that there are diurnal changes in circulating concentrations of melatonin in the prepubertal bovine female, with concentrations higher during scotophase than photophase. In addition, under certain photoperiodic conditions there were diurnal rhythms in gonadotropins. These data also support the hypothesis that changing photoperiod alters the diurnal pattern in circulating melatonin concentrations.