Development of melatonin rhythm in the pineal gland and eyes of chick embryo

A melatonin rhythm was observed in the pineals of 18-day-old chick embryos incubated under a light-dark regime of 186 h. A low pineal melatonin content was found during the light phase of the day. Concentrations started to increase 2 h after dark onset and reached maximum levels after 4 h of darkness. The amplitude of the pineal melatonin rhythm increased considerably after 2 days and night-time concentrations in 20-day-old embryos were more than 5 times higher than in 18-day-old ones. Significant day/night differences in melatonin production were found both in pineals and eyes. Exposure of eggs to 1 h of light during the dark period decreased the high melatonin concentrations in the eyes but not in the pineals of the 20-day-old chick embryo. The results suggest that in this precocial bird at least part of the circadian system may already operate during embryonic life.     

Development of post-hatching melatonin rhythm in zebra finches (Poephila guttata)

We examined levels of melatonin in the pineal, eyes and plasma over a 24 h period during development in the altricial zebra finch. Beginning as early as 2 days after hatching there was a distinct 24 h rhythm in melatonin in the pineal and plasma. Beginning at day seven after hatching there was also a 24 h rhythm present in the eyes. In the pineal and eyes the amplitude of the 24 h rhythm increased with age. In contrast, the amplitude of the plasma melatonin rhythm at 2 days was already within the range of adults and did not increase with age. These results confirm and expand earlier findings in the European starling and parallel those from precocial birds indicating that the circadian system is already competent at or shortly after hatching even in atricial birds.     

The occurrence and physiological functions of melatonin in the most primitive eumetazoans,the planarians

Asexual planarians of the speciesDugesia dorotocephala exhibit a distinct circadian rhythm of fissoning (asexual reproduction) under the influence of normal photoperiod; fissioning occurs only at night. This rhythm is broken down by continuous illumination, continuous darkness or by decapitation. The fissioning rate increases when planarians are exposed to light for less than 1 hour/day or when they are decapitated. Fissioning of decapitated planarians is suppressed by continuous treatment with melatonin, whereas fissioning resumes when these are returned to normal culture water. Interestingly, fissioning occurs at night when decapitates are treated with melatonin in the daytime, while it is observed in the daytime with night-time melatonin treatment. Endogenous melatonin was detected by HPLC and RIA. The endogenous melatonin level is always higher in those heads collected in the scotophase than in those collected in the photophase. A type of neurosecretory cell, which may synthesize melatonin, is found in the assembly of photoreceptor cells.     

The contribution of extrapineal sites of melatonin synthesis to circulating melatonin levels in higher vertebrates

While the production of melatonin in higher vertebrates occurs in other organs and tissues besides the pineal, the contribution of extrapineal sites of melatonin synthesis such as the retina, the Harderian glands and the gut to circulating melatonin levels is still a matter of debate. The amount of melatonin found in the gastrointestinal tract is much higher than in any other organ including the pineal and the gut appears to make a significant contribution to circulating melatonin at least under certain conditions. The gut has been identified to be the major source of the elevated plasma concentrations of melatonin seen after tryptophan administration and of the changes of circulating melatonin level induced by the feeding regime. Whereas the circadian and circannual fluctuations of the concentration of melatonin in the blood seem to be triggered by changes of the photoenvironment and its effect of pineal melatonin formation, basal daytime melatonin levels and the extent of their elevation at nighttime appear to be additionally controlled by nutritional factors, such as the amount and the composition of ingested food and therefore availability of tryptophan as a rate-limiting precursor of melatonin formation by the enterochromaffin cells of the gastrointestinal tract.     

The pineal and melatonin: Regulators of circadian function in lower vertebrates

Summary The pineal has been identified as a major circadian pacemaker within the circadian system of a number of lower vertebrates although other pacemaking sites have been implicated as well. The rhythmic synthesis and secretion of the pineal hormone, melatonin, is suggested as the mechanism by which the pineal controls circadian oscillators located elsewhere. Both light and temperature cycles can entrain the pineal melatonin rhythm. The pineal, therefore, acts as a photo and thermoendocrine transducer which functions to synchronize internal cycle with cycles in the environment. A model is presented which portrays the pineal as a major component of a multioscillator circadian system and which suggests how these multiple circadian clocks are coupled to each other and to cycles of light and temperature in the external world.     

The pineal and melatonin: Regulators of circadian function in lower vertebrates

Summary The pineal has been identified as a major circadian pacemaker within the circadian system of a number of lower vertebrates although other pacemaking sites have been implicated as well. The rhythmic synthesis and secretion of the pineal hormone, melatonin, is suggested as the mechanism by which the pineal controls circadian oscillators located elsewhere. Both light and temperature cycles can entrain the pineal melatonin rhythm. The pineal, therefore, acts as a photo and thermoendocrine transducer which functions to synchronize internal cycle with cycles in the environment. A model is presented which portrays the pineal as a major component of a multioscillator circadian system and which suggests how these multiple circadian clocks are coupled to each other and to cycles of light and temperature in the external world.     

Single injections of triazolam,a short-acting benzodiazepine,lengthen the period of the circadian activity rhythm in golden hamsters

Single injections of the benzodiazepine, triazolam, induce phase shifts and cause a lengthening of the circadian activity rhythm in the golden hamster. The effect of triazolam on period depends on the phase of injection, but is not dependent on the direction of the phase shifts. Triazolam injections caused increases in period that were associated with phase advances as well as phase delays in the activity rhythm. This relationship between triazolam-induced phase shifts and changes in period is different from the relationship between light-induced phase shifts and period changes.     

Seasonal pattern of melatonin excretion in humans: relationship to daylength variation rate and geomagnetic field fluctuations

In order to investigate the influence of various environmental parameters on melatonin excretion, the night-time urinary melatonin excretion of 16 healthy volunteers was measured in samples collected monthly over a period of one year. No significant interindividual differences were detected in the monthly rate of change of melatonin excretion. A seasonal bimodal pattern did, however, emerge. Peak values were observed in June and November. In these months a combination of high daylength stability and low values of the vertical component of the geomagnetic field was recorded. Trough values were found in April and August–October when low daylength stability was combined with high values of the vertical component of the geomagnetic field. We propose that the daylength variation rate, and the fluctuations of the vertical component of the geomagnetic field, interact to induce the changes in melatonin secretion which signalize the different seasons in humans.     

Conformational stability and basal metabolic rate: Reexamination of the case of myoglobin

Summary The free energy of unfolding of several myoglobins from different animal species has been determined from their denatunation pattern by using the ligand binding model. The results indicate that no simple correlation exists between the free energy of unfolding of myoglobin and the basal metabolic rate of the animal species from which the myoglobin was isolated     

Continuous light abolishes the maternal entrainment of the circadian activity rhythm of the pups in the field mouse

Summary 1212-h cycles of presence and absence of mother mouse act as a zeitgeber and entrain the circadian rhythm of locomotor activity in the pups ofMus booduga under continuous darkness or continuous dim light. Continuous higher illumination of 15–25 lx abolishes this impressive maternal entrainment.Acknowledgment. We are grateful to the DST, Government of India, for financial support under their IRHPA scheme. N.V. is the recipient of a Senior Research Fellowship of CSIR, New Delhi. We thank Dr. R. Subbaraj for discussions.     

Effects of vitamin B12 on plasma melatonin rhythm in humans: Increased light sensitivity phase-advances the circadian clock?

Vitamin B12 (methylcobalamine) was administered orally (3 mg/day) to 9 healthy subjects for 4 weeks. Nocturnal melatonin levels after exposure to bright light (ca. 2500 lx) were determined, as well as the levels of plasma melatonin over 24 h. The timing of sleep was also recorded. Vitamin B12 was given blind to the subjects and crossed over with placebo. We found that the 24-h melatlonin rhythm was significantly phase-advanced (1.1. h) in the vitamin B12 trial as compared with that in the placebo trial. In addition, the 24-h mean of plasma melatonin level was much lower in the vitamin B12 traial than with the placebo. Furthermore, the nocturnal melatonin levels during bright light exposure were significantly lower in the vitamin B12 trial than with the placebo. On the other hand, vitamin B12 did not affect the timing of sleep. These findings raise the possibility that vitamin B12 phase-advances the human circadian rhythm by increasing the light sensitivity of the circadian clock.     

Effects of vitamin B12 on plasma melatonin rhythm in humans: increased light sensitivity phase-advances the circadian clock?

Vitamin B12 (methylcobalamin) was administered orally (3 mg/day) to 9 healthy subjects for 4 weeks. Nocturnal melatonin levels after exposure to bright light (ca. 2500 lx) were determined, as well as the levels of plasma melatonin over 24 h. The timing of sleep was also recorded. Vitamin B12 was given blind to the subjects and crossed over with placebo. We found that the 24-h melatonin rhythm was significantly phase-advanced (1.1 h) in the vitamin B12 trial as compared with that in the placebo trial. In addition, the 24-h mean of plasma melatonin level was much lower in the vitamin B12 trial than with the placebo. Furthermore, the nocturnal melatonin levels during bright light exposure were significantly lower in the vitamin B12 trial than with the placebo. On the other hand, vitamin B12 did not affect the timing of sleep. These findings raise the possibility that vitamin B12 phase-advances the human circadian rhythm by increasing the light sensitivity of the circadian clock.     

Clinical aspects of the melatonin action: impact of development,aging, and puberty,involvement of melatonin in psychiatric disease and importance of neuroimmunoendocrine interactions

During the last decade we have learned much on physiological changes in the secretion of the pineal hormone melatonin (MLT) in man. Reportedly, there is little or no MLT secreted before age 3 months. Then MLT production commences, becmes circadian, and reaches highest nocturnal levels at the age of 1–3 years. During all of childhood nocturnal peak levles drop progressively by 80% until adult levels are reached. This alteration appears to be the consequence of increasing body size in face of constant MLT production during childhood. The biological significance of this MLT alteration is presently unknown. Because of conceptual considerations, major depressive syndrome (MDS) and seasonal affective disorder (SAD) have been in the focus of pineal research for several years. Although in these disorders alterations in MLT levels could not be substantiated, light therapy, a consequence of this research, was discovered as an effective treatment for SAD and perhaps for MDS. In addition, there is some recent evidence for low MLT levels in schizophrenia. Finally, the potential effect of MLT in neuroimmunoendocrine interactions is presently explored. Reportedly, in vitro studies and animal experiments give evidence for a modulatory role of MLT in the immune response. However, the exact way of this possible action of MLT remains to be clarified. Clinical studies are too scant for a meaningful estimation of MLT's involvement in human neuroimmunoendocrine interactions.     

Induction of cyst formation by low temperature in the dinoflagellateGonyaulax polyedra Stein: Dependence on circadian phase and requirement of light

Encystment, which at a temperature of 15°C is photoperiodically controlled inGonyaulax polyedra, can also be induced by a decrease of temperature, from 20 to 10 or 8°C in the absence of photoperiodic signals. The cyst-inducing capacity of the decrease in temperature depends on the circadian phase: in constant light, the maximum of sensitivity was found at the beginning of subjective night. In a light/dark cycle, however, cyst formation was reduced during dark phase, indicating that light is required for the process of encystment. A similar light dependence was seen in the effect of the physiologically occurring cyst inducer 5-methoxytryptamine, but not in the encystment response to the protonophores monensin and nigericin.     

The presence and function of melatonin and structurally related indoleamines in a dinoflagellate,and a hypothesis on the evolutionary significance of these tryptophan metabolites in unicellulars

The bioluminescent dinoflagellateGonyaulax polyedra contains various indoleamines, in particular, melatonin and 5-methoxytryptamine, as well as enzymes of their biosynthetic pathway. Melatonin exhibits a high-amplitude circadian rhythm characterized by a dramatic increase shortly after the onset of darkness. The maximum of melatonin is followed by a peak of 5-methoxytryptamine. These 5-methoxylated indoleamines seem to be involved in the mediation of the information darkness.G. polyedra shows a short-day response, which consists in the formation of asexual cysts. Light break experiments demonstrate the photoperiodic nature of this reaction. Cells become sensitive to short days only upon exposure to a lowered temperature (<16°C). Melatonin mimics the short-day effect, but only at decreased temperature. 5-Methoxytryptamine is even a better inducer of cyst formation, acting also at 20°C and in any lighting schedule, including LL. Cyst induction is associated with stimulation of bioluminescence and cytoplasmic acidification. A model on the intracellular pathway of photoperiodic information transduction assumes increased deacetylation of melatonin under cyst-inducing conditions, binding of 5-methoxytryptamine to the membrane of an acidic vacuole, proton transfer to the cytoplasm, and decreased intracellular pH as the stimulus for encystment. Melatonin shows the property of a scavenger of superoxide anions. This reaction, which is efficiently catalyzed by hemin, leads to the formation of a substituted kynuramine (AFMK). Destruction of melatonin by light-induced superoxide anions in the presence of cellular hemin may represent a property which, during evolution, has made this molecule suitable as an indicator of darkness. On the other hand, AFMK, which is formed under illumination, might have become a mediator of the information light. Photoperiodism inGonyaulax shows surprising parallels to that in mammals, but allows the analysis of this phenomenon at an entirely cellular level.