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.     

Some reflections on the phylogeny and function of the pineal

The pineal gland is a universal feature of vertebrate organization and has been implicated in the control of rhythmic adaptations to daily and seasonal cycles. This paper considers three aspects of pineal function; the generation of a rhythmical endocrine signal (the nocturnal synthesis of melatonin) and the use of the signal in the regulation of circadian and photoperiodic functions. The shape of the nocturnal signal is determined by an interaction of afferent neural control and biochemical processes intrinsic to the pinealocyte. The nature of the effect of the signal upon circadian systems is unclear, and in adult mammals may not be a specific, direct influence upon the entrainment pathways of the oscillator. In the foetus, strong evidence exists for a physiological role of the maternal melatonin signal as a true internal zeitgeber, remnants of which may persist in the adult. Photoperiodic time measurement in adult and foetal mammals is critically dependent upon the melatonin signal. Indirect evidence indicates that several neural systems may be involved in the response to melatonin and consistent with this, a variety of central melatonin binding sites have been identified in the brain and pituitary. The intra-cellular actions of melatonin and the properties of melatonin responsive neural systems have yet to be identified, but in the context of photoperiodic time measurement, it is clear that the neural responses to melatonin are not dependent upon the circadian clock. The two central effects of melatonin; photoperiodic time measurement and circadian entrainment are probably mediated through completely separate mechanisms.     

The melatonin rhythm: both a clock and a calendar

The paper briefly reviews the data which shows that the circadian production and secretion of melatonin by the pineal gland can impart both daily, i.e., clock, and seasonal, i.e., calendar, information to the organism. The paper summarizes the 3 patterns of nocturnal melatonin production that have been described. Clearly, regardless of the pattern of nocturnal melatonin production a particular species normally displays, the duration of nightime elevated melatonin is proportional to the duration of the night length. Since daylength under natural conditions changes daily the melatonin rhythm, which adjusts to the photoperiod sends time of year information to the organism. The melatonin receptors which subserve the clock message sent by the pineal gland in the form of a melatonin cycle may reside in the biological clock itself, namely, the suprachiasmatic nuclei (SCN). The melatonin receptors that mediate seasonal changes in reproductive physiology are presumably those that are located on the pars tuberalis cells of the anterior pituitary gland. Besides these receptors which likely mediate clock and calendar information, melatonin receptors have been described in other organs. Interestingly, the distribution of melatonin receptors is highly species-specific. Whereas the clock and calendar information that the melatonin cycle imparts to the organism relies on cell membrane receptors, a fact that is of some interest considering the high lipophilicity of melatonin, recent studies indicate that other functions of melatonin may require no receptor whatsoever.     

Structures and molecules involved in generation and regulation of biological rhythms in vertebrates and invertebrates

Melatonin from the retina and the pineal gland functions in neuroendocrine hierarchies. Photoreceptors — eyes and extraretinal — detect light. Oscillators — pineal and suprachiasmatic nuclei — act as pacemakers. Driven neuroendocrine rhythms carry temporal hormone signals throughout the body. Light controls melatonin: light sets the phase of the melatonin rhythm and determines the duration of melatonin synthesis. By these means, circadian rhythms (e.g. in locomotor activity and body temperature) and seasonal rhythms (e.g. in reproduction) are controlled.     

Evidence for a modulation of the stress response by the pineal gland

Summary Wistar rats show a circadian variation in their response to stress. Pinealectomy exacerbates stress-induced gastric ulceration in rats. This effect is counteracted by melatonin administration.     

The pineal gland is very large and active in newborn antarctic seals

Summary The pineal gland of newborn elephant seals and Weddell seals is larger than in adult females. The gland is considerably larger at birth in Weddell seals than in elephant seals. The former experience greater extremes of temperature. Plasma melatonin concentrations in excess of 2000 pg/ml were recorded in the first days of life, compared with 20–50 pg/ml in adults.Acknowledgment. We thank members of the Australian National Antarctic Research Expedition to Macquarie Island for assistance with collection of elephant seal samples, in particular G. Burns, D. Carroll, G. Copson, R. Ledingham and S. Pye. The support of the National Science Foundation, USA, and personnel at the United States Antarctic Research Program base at McMurdo Sound, Antarctica, are gratefully acknowledged. The Tasmanian National Parks and Wildlife Service kindly issued permits to collect specimens at Macquarie Island.     

β-Methyl carboline,a benzodiazepine inverse agonist,attenuates the effect of triazolam on the circadian rhythm of locomotor activity

Summary The benzodiazepine triazolam, the benzodiazepine inverse agonist, -methyl carboline (-CCM) or both, were administered to adult male hamsters under conditions of constant light. When given alone, triazolam induced phase advances in the circadian activity rhythm of about 90 min, while -CCM when given alone, had no effect on phase of the activity rhythm. However, when triazolam and -CCM were given at the same time, the magnitude of the phase advances induced by triazolam were attenuated to about 30 min. These data, in conjunction with previous results, provide pharmacological evidence for a GABAergic system involved in the regulation of a central circadian pacemaker.     

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.     

Photoreceptors in the pineal of lower vertebrates: Functional aspects

Summary The pineal of lower vertebrates characteristically contains true and modified photoreceptors with functional und structural homologies to retinal photoreceptors. Afferent nerves convey photic information from the pineal to sensory areas of the brain stem. Light also influences synthetic activity within the organ, controlling the rhythm in melatonin production which is generated endogenously. The molecular mechanisms underlying this rhythmic event are described and the hypothesis advanced that the pineal transduces several forms of environmental stimulus involved in the regulation of rhythmic function.     

Bilateral lesions of suprachiasmatic nucleus eliminate circadian rhythms of oxygen consumption and the respiratory quotient in rats

Summary Bilateral lesions of the suprachiasmatic nucleus of the hypothalamus of rats abolished circadian rhythms of oxygen consumption and of the respiratory quotient (RQ). The RQ remained constant at a level intermediate between the maximum (about 1.0) and minimum (about 0.9) values in control animals.     

Presence in and effects of pineal indoleamines at very low level of phylogeny

The unicellular organism Tetrahymena contains serotonin and is able to take up the hormone from its mileiu. The serotonin content of the cell changes as a function of the presence of foreign exogenous hormones. This indicates a possible role of serotonin as a chemical mediator. Exogenous serotonin stimulates the RNA synthesis of Tetrahymena, and it was the only one among the hormones studied which kept the RNA level durably high. Serotonin stimulates phagocytosis and growth of Tetrahymena, and its precursors also stimulate growth. Serotonin can imprint Tetrahymena, and as a consequence of this the effect of the hormone increases in the case of further encounters. Treatment with serotonin-related molecules soon after imprinting can reduce the effect of imprinting. Melatonin can contract the pigment cells of Planaria; however, its precursors serotonin and tryptamine can do this more intensely. Both melatonin and serotonin can influenc the regeneration of Planaria, with effects which differ when different phenomena are studied. Evolutionary theories are discussed.     

Maturation of the pineal melatonin rhythm in long- and short-day reared Djungarian hamsters

Summary Male Djungarian hamsters, reared under long (16L/8D) or short (10L/14D) days, were sacrificed at various ages during the day or night, or at night following a 30-min light pulse. The pineal melatonin rhythm matured similarly under long and short days by 20 days of age. The results are discussed in context of the hypothesis that melatonin mediates the photoperiod effects which forestall puberty in short-day reared hamsters.Supported by NIH research grant HD-05481.     

Neither prolactin nor growth hormone restore the nocturnal rise in pineal N-acetyltransferase activity or melatonin content in hypophysectomized rats

Summary Hypophysectomy in adult male rats greatly attenuated the nocturnal rise in both pineal N-acetyltransferase (NAT) activity and melatonin content. High nighttime levels of NAT and melatonin were not restored by treating the animals with either prolactin or growth hormone, alone or in combination. Treating intact rats with bromocriptine, which depresses circulating prolactin levels, also was without effect on pineal melatonin synthesis. It appears that neither prolactin nor growth hormone are of major importance in determining pineal melatonin production.     

Pineal melatonin rhythms and the timing of puberty in mammals

Summary The direction of change in daylength provides the seasonal time cue for the timing of puberty in many mammalian species. The pattern of melatonin secretion from the pineal gland transduces the environmental light-dark cycle into a signal influencing the neuroendocrine control of sexual maturation. The change in duration of nocturnal melatonin secretion is probably the key feature of the melatonin signal which conveys daylength information. This information may also be used by neuroendocrine axes controlling seasonal changes in pelage colour, growth and metabolism. The mechanism of action of melatonin on neuroendocrine pathways is unknow. Although the ability to synthesize and secrete melatonin in a pattern that reflects the duration of the night may not occur until the postnatal period, the rodent and ovine foetus has the ability to respond in utero to photoperiodic cues to which its mother is exposed in late gestation. Transplacental passage of maternal melatonin is likely to be the mechanism by which photoperiodic cues reach the foetus. Species which do not exhibit seasonal patterns of puberty, such as the human, also secrete melatonin in a pattern which reflects the environmental light-dark cycle, but they do not respond reproductively to the seasonal melatonin information.     

Ultrastructure and biochemistry of the pineal organ in deep-sea lanternfishes (Myctophidae)

Summary Pineal structural and biochemical adaptations in lanternfishes included: 1) few photoreceptor outer segment discs; 2) conventional synapses between photoreceptors and pineal neurons; and 3) low levels (0–60 pg/pineal) of serotonin compared to those (>1.0 ng/pineal) in the goldfish pineal organ. These findings suggest reduced photosensory and/or neuroendocrine functions in these deep-sea fishes.     

Potentiating effect of phenylephrine on isoproterenol activation of thyroxine type II deiodinase in the pineal gland of adult rats

In the present study we show, for the first time, that phenylephrine (PHE), an -adrenergic receptor agonist, potentiates the effect of isoproterenol (ISO), a -adrenergic agonist, in activating pineal type II5-deiodinase (5-D) activity. The potentiating effect of PHE was observed only at doses of ISO which induce submaximal activation of the enzyme. However, at doses which lead to maximal activation of the enzyme, PHE was ineffective. The results suggest that not only -, but also -adrenergic receptors, are involved in the sympathetic noradrenergic regulation of pineal 5-D activity in the adult rat.     

Melatonin: presence and formation in invertebrates

In vertebrates, it is now clearly demonstrated that the pineal gland is implicated in conveying photoperiodic information via the daily pattern of melatonin secretion. Invertebrates, like vertebrates, use photoperiodic changes as a temporal cue to initiate physiological processes such as reproduction or diapause. How this information is integrated in invertebrates remains an unsolved question. Our review will be an attempt to evaluate the possible role of melatonin in conveying photoperiodic information in invertebrates. It is now well demonstrated in both vertebrates and invertebrates that melatonin as well as its precursors or synthesizing enzymes are present in various organs implicated in photoreceptive processes or in circadian pacemaking. Melatonin, serotonin or N-acetyltransferase have been found in the head, the eyes, the optic lobe and the brain of various invertebrate species. In some species it has also been shown that melatonin is produced rhythmically with high concentrations reached during the dark period. Moreover, the physiological effects of melatonin on various periodic processes such as rhythmic contractions in coelenterates, fissioning of asexual planarians or reproductive events in flies have been reported in the literature. All these results support the hypothesis (refs 36, 37) that melatonin is not solely a pineal hormone but that it may be an evolutionary conservative molecule principally involved in the transduction of photoperiodic information in all living organisms.     

Similarity between the effects of suprachiasmatic nuclei lesions and of pinealectomy on gonadotropin release in ovariectomized,sulpiride-treated and melatonin-replaced rats

The aim of this study was to compare the effects of pineal indole treatments on LH and FSH release in pinealectomized and suprachiasmatic lesioned and ovariectomized rats rendered hyperprolactinemic by acute sulpiride treatment. pinealectomy or suprachiasmatic nuclei lesions in female rats both decreased plasma LH and FHS at 10, but not at 20 d after surgery, whereas the daily afternoon administration of melatonin effectively restored levels of both gonadotropins to control values. In ovariectomized rats, pinealectomy or suprachiasmatic nuclei lesions were ineffective in counteracting the high plasma levels of LH and FSH. However, sulpiride treatment in both pinealectomized and suprachiasmatic nuclei lesioned and castrated female rats significantly decreased the levels of LH and FSH, an effect which was counteracted by daily afternoon melatonin administration. Other pineal indoles tested, i.e., 5-hydroxy- and 5-methoxytryptophol, were ineffective in regulating gonadotropin levels. The results suggest that the pineal gland, through its hormone melatonin, can modulate gonadotropin secretion by acting on a dopamine mechanism independent of hypothalamic suprachiasmatic areas.     

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.