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PubMed1993

[Role of melatonin in human physiology and pathology. I. Circadian rhythm of melatonin secretion. Involvement of melatonin in reproductive physiology. Melatonin and hypothalamic-pituitary-adrenal cortex axis].

This paper summarizes the recent knowledge on the role of melatonin in humans. The first part of the present review considers the following aspects: circadian rhythm of melatonin excretion, melatonin in body fluids, melatonin influence on sexual maturation, changes of melatonin blood concentration during the menstrual cycle and pregnancy, and the influence of melatonin administration on prolactin concentration. Current views on the relationship between melatonin and the hypothalamo-pituitary-adrenal cortex axis, as well as on changes of melatonin concentration during hypothyreosis, hyperthyreosis, and hyperparathyroidism are also discussed.

Circadian Rhythm↗
PubMed1993

[Role of melatonin in human physiology and pathology. II. Involvement of melatonin in pathogenesis of affective and chronobiological disorders. Melatonin and the aging process. Melatonin and neoplasms].

In the second part of this review the role of melatonin in pathogenesis of affective diseases and chronobiological disorders is discussed. Current views on melatonin involvement in aging are presented. Clinical experiments on the possible usefulness of melatonin in treatment of various types of cancers and hypothetical mechanisms of oncostatic influence of melatonin are also summarized.

Aging↗
PubMed2004

Melatonin uptake and growth prevention in rat hepatoma 7288CTC in response to dietary melatonin: melatonin receptor-mediated inhibition of tumor linoleic acid metabolism to the growth signaling molecule 13-hydroxyoctadecadienoic acid and the potential role of phytomelatonin.

Both physiological and pharmacological levels of the pineal hormone melatonin exhibit substantial anticancer activity in tissue-isolated rat hepatoma 7288CTC via melatonin receptor-mediated blockade of tumor uptake of linoleic acid (LA) and its metabolism to the mitogenic signaling molecule 13-hydroxyoctadecadienoic acid (13-HODE). Melatonin is also present in significant amounts in edible plants and is supplied in nutritional supplements. We confirmed the presence of significant quantities of melatonin in 20 varieties of edible plants. In pinealectomized tumor-free rats, 3 weeks of ingestion of either 5 or 50 microg/day of melatonin contained in a semi-purified diet resulted in a dose-dependent elevation in steady-state plasma melatonin levels within the nocturnal physiological range. In pineal-intact tumor-bearing rats, the daily intake of 5 microg/day of melatonin for 3 weeks resulted in an enhanced amplitude and duration of the nocturnal melatonin levels within physiological circulating limits. The nocturnal melatonin amplitude in rats ingesting 500 ng of melatonin/day remained within the physiological range. A dose-related increase in tumor concentrations of melatonin occurred in animals ingesting melatonin from the diet. Perfusion of tumors in situ with physiological, nocturnal blood levels of melatonin resulted in a mean 31% uptake and retention of the melatonin. Chronic ingestion of 50 ng, 500 ng or 5 microg of melatonin/day supplied in a semi-purified 5% corn oil diet led to a significant dose-dependent reduction in the rates of tumor total fatty acid uptake, LA uptake, 13-HODE production and tumor growth. The co-ingestion of melatonin receptor antagonist S20928 completely blocked the effects and prevented the intra-tumoral accumulation of melatonin. Melatonin receptor-mediated suppression of tumor growth, LA uptake and metabolism, and stimulation of tumor melatonin uptake and retention in response to the dietary intake of phytomelatonin from edible plants or melatonin from nutritional supplements, could play an important role in cancer growth prevention.

Animals↗
PubMed2004

Melatonin desensitizes endogenous MT2 melatonin receptors in the rat suprachiasmatic nucleus: relevance for defining the periods of sensitivity of the mammalian circadian clock to melatonin.

The hormone melatonin phase shifts circadian rhythms generated by the mammalian biological clock, the suprachiasmatic nucleus (SCN) of the hypothalamus, through activation of G protein-coupled MT2 melatonin receptors. This study demonstrated that pretreatment with physiological concentrations of melatonin (30-300 pM or 7-70 pg/mL) decreased the number of hMT2 melatonin receptors heterologously expressed in mammalian cells in a time and concentration-dependent manner. Furthermore, hMT2-GFP melatonin receptors heterologously expressed in immortalized SCN2.2 cells or in non-neuronal mammalian cells were internalized upon pretreatment with both physiological (300 pM or 70 pg/mL) and supraphysiological (10 nM or 2.3 ng/mL) concentrations of melatonin. The decrease in MT2 melatonin receptor number induced by melatonin (300 pM for 1 h) was reversible and reached almost full recovery after 8 h; however, after treatment with 10 nM melatonin full recovery was not attained even after 24 h. This recovery process was partially protein synthesis dependent. Furthermore, exposure to physiological concentrations of melatonin (300 pM) for a time mimicking the nocturnal surge (8 h) desensitized functional responses mediated through melatonin activation of endogenous MT2 receptors, i.e., stimulation of protein kinase C (PKC) in immortalized SCN2.2 cells and phase shifts of circadian rhythms of neuronal firing in the rat SCN brain slice. We conclude that in vivo the nightly secretion of melatonin desensitizes endogenous MT2 melatonin receptors in the mammalian SCN thereby providing a temporally integrated profile of sensitivity of the mammalian biological clock to a melatonin signal.

Animals↗
PubMed2005

A role of melatonin in neuroectodermal-mesodermal interactions: the hair follicle synthesizes melatonin and expresses functional melatonin receptors.

Since mammalian skin expresses the enzymatic apparatus for melatonin synthesis, it may be an extrapineal site of melatonin synthesis. However, evidence is still lacking that this is really the case in situ. Here, we demonstrate melatonin-like immunoreactivity (IR) in the outer root sheath (ORS) of mouse and human hair follicles (HFs), which corresponds to melatonin, as shown by radioimmunoassay and liquid chromatography/tandem mass spectrometry (LC/MS/MS). The melatonin concentration in organ-cultured mouse skin, mouse vibrissae follicles, and human scalp HFs far exceeds the respective melatonin serum level and is significantly increased ex vivo by stimulation with norepinephrine (NE), the key stimulus for pineal melatonin synthesis. By real-time PCR, transcripts for the melatonin membrane receptor MT2 and for the nuclear mediator of melatonin signaling, retinoid orphan receptor alpha (ROR)alpha, are detectable in murine back skin. Transcript levels for these receptors fluctuate in a hair cycle-dependent manner, and are maximal during apoptosis-driven HF regression (catagen). Melatonin may play a role in hair cycle regulation, since its receptors (MT2 and RORalpha) are expressed in murine skin in a hair cycle-dependent manner, and because it inhibits keratinocyte apoptosis and down-regulates ERalpha expression. Therefore, the HF is both, a prominent extrapineal melatonin source, and an important peripheral melatonin target tissue. Regulated intrafollicular melatonin synthesis and signaling may play a previously unrecognized role in the endogenous controls of hair growth, for example, by modulating keratinocyte apoptosis during catagen and by desensitizing the HF to estrogen signaling. As a prototypic neuroectodermal-mesodermal interaction model, the HF can be exploited for dissecting the obscure role of melatonin in such interactions in peripheral tissues.

Animals↗
PubMed1999

Melatonin and colon carcinogenesis. II. Intestinal melatonin-containing cells and serum melatonin level in rats with 1,2-dimethylhydrazine-induced colon tumors.

Two-month-old outbred female LIO rats were injected weekly with a single dose of 1,2-dimethylhydrazine (DMH; 21 mg/kg of body weight) administered s.c. for 15 consecutive weeks. From the day of the 1st injection of the carcinogen the part of rats were given five days a week during the night time (from 18.00 h to 08.00 h) melatonin dissolved in tap water, 20 mg/l. The experiment was terminated in 6 months after the first injection of the carcinogen. The concentration of melatonin in the serum was estimated by radioimmunoassay in rats exposed to DMH alone or in intact control rats in the morning (between 10.00 and 11.00 hours) and night (between 24.00 and 01.00 hours) time. Number of melatonin-containing cells (M-cells) and their optical density were estimated by immunohistology in normal mucosa of glandular stomach, duodenum, ileum and descending colon of tumor-bearing animals from groups exposed to DMH or DMH+melatonin. It was shown that serum melatonin levels in rats with colon tumors was increased as compared with controls. However there was no diurnal rhythm of serum melatonin of colon tumor-bearing animals as compared to intact controls. The number of M-cells was decreased in all tissues studied in rats with DMH-induced colon tumors in comparison to corresponding controls: by 2.0 times in stomach, by 1.8 time in duodenum, by 1.3 times in ileum, and by 1.8 times in colon. In ileum and colon of rats treated with DMH+melatonin the number of M-cells was similar to control level whereas in stomach and duodenum this number was significantly higher than that in rats treated with DMH alone, but less than in corresponding controls. Relative content of melatonin in enterochromaffin cells of all parts of gastrointestinal tract evaluated as optical density of the cells and was decreased in rats exposed with DMH alone in comparison to the controls and was normalized and similar to the norm level in rats treated with DMH+melatonin. Thus, exogenous melatonin prevent a decrease in numbers of melatonin-containing cells as was observed in gastrointestinal tract (GIT) of rats exposed to DMH. This preventive action of melatonin correlated well with its anticarcinogenic effect.

1,2-Dimethylhydrazine↗
PubMed2000

Chimeric melatonin mt1 and melatonin-related receptors. Identification of domains and residues participating in ligand binding and receptor activation of the melatonin mt1 receptor.

Melatonin receptors bind and become activated by melatonin. The melatonin-related receptor, despite sharing considerable amino acid sequence identity with melatonin receptors, does not bind melatonin and is currently an orphan G protein-coupled receptor. To investigate the structure and function of both receptors, we engineered a series of 14 chimeric receptor constructs, allowing us to determine the relative contribution of each transmembrane domain to ligand binding and receptor function. Results identified that when sequences encoding transmembrane domains 1, 2, 3, 5, or 7 of the melatonin mt(1) receptor were replaced by the corresponding domains of the melatonin-related receptor, the resultant chimeric receptors all displayed specific 2-[(125)I]iodomelatonin binding. Replacement of sequences incorporating transmembrane domains 4 or 6, however, resulted in chimeric receptors that displayed no detectable 2-[(125)I]iodomelatonin binding. The subsequent testing of a "reverse" chimeric receptor in which sequences encoding transmembrane domains 4 and 6 of the melatonin-related receptor were replaced by the corresponding melatonin mt(1) receptor sequences identified specific 2-[(125)I]iodomelatonin binding and melatonin-mediated modulation of cyclic AMP levels. To further investigate these findings, site-directed mutagenesis was performed on residues within transmembrane domain 6 of the melatonin mt(1) receptor. This identified Gly(258) (Gly(6.55)) as a critical residue required for high affinity ligand binding and receptor function.

Animals↗
PubMed1990

Melatonin receptors and signal transduction in melatonin-sensitive and melatonin-insensitive populations of white-footed mice (Peromyscus leucopus).

The pineal hormone melatonin times seasonal alterations in reproductive function in photoperiodic mammals. In white-footed mice, there is variation in responsiveness to the reproductive effects of melatonin between populations originating in different locations; mice from Connecticut (CT) respond normally to melatonin, while mice from Georgia (GA) appear insensitive to melatonin. In the present paper, we compare melatonin receptor distribution and a second messenger response to melatonin in white-footed mice from CT and GA. Specific binding of 125I-labeled melatonin (I-MEL) was observed in a variety of brain regions in each population, but there were no consistent differences in the distribution or intensity of I-MEL binding between the populations. Furthermore, melatonin inhibited forskolin-stimulated cAMP accumulation in median eminence/pars tuberalis explants from both populations. These results suggest that insensitivity to melatonin in GA mice is not due to a gross defect in melatonin receptors or receptor-effector coupling.

Animals↗
PubMed1993

Melatonin and the circadian clock in mink: effects of daily injections of melatonin on circadian rhythm of locomotor activity and autoradiographic localization of melatonin binding sites.

The present study examines a putative effect of exogenous melatonin on the circadian organization of the mink. Two approaches were used to determine first whether entrainment of free-running rhythms of locomotor activity in constant darkness can be obtained by daily melatonin injections, thus demonstrating a control of melatonin on the clock generating circadian rhythms, the suprachiasmatic nucleus of the hypothalamus. Entrainment was never obtained in the 8 vehicle-injected females and 7 out of the 8 melatonin injected-ones. In 3 females free-running in constant darkness, a phase advance followed by a few days of transient effect was observed when melatonin injections coincided with the onset of activity. However, the comparison of the regression of the daily activity onset related to successive days by covariance analysis revealed that true entrainment was effective in only 1 female. Second, we examined the distribution of melatonin binding sites within the brain of juvenile and adult mink using an in vitro autoradiographic procedure with [125I]2-iodomelatonin. No binding sites were observed in the suprachiasmatic nucleus of any of the animals. However, all animals displayed a high density of melatonin binding sites in the pars tuberalis of the pituitary. The relation between a modulatory control of melatonin on the circadian clock and the presence and density of melatonin binding sites in the clock is discussed. In mink, melatonin does not seem to act as an internal Zeitgeber.

Animals↗
PubMed1995

Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates.

Twenty-four edible plants were investigated for the presence of melatonin, heretofore considered to be a molecule found only in the animal kingdom. The amount of melatonin in different plants varied greatly with highest melatonin being present in plants of the rice family. Melatonin was identified by radioimmunoassay and verified by high performance liquid chromatography with fluorescence detection. Feeding a diet containing plant products rich in melatonin to chicks increased radioimmunoassayable levels of melatonin in their blood. Likewise, melatonin extracted from plants inhibited binding of [125I]iodomelatonin to rabbit brain. Thus, melatonin ingested in foodstuffs enters the blood and is capable of binding to melatonin binding sites in the brain of mammals.

Animals↗
PubMed1988

How does melatonin code for day length in the ewe: duration of nocturnal melatonin release or coincidence of melatonin with a light-entrained sensitive period?

The main objective of the study was to test the hypothesis that the phase of melatonin release with respect to the light-dark cycle mediates the effects of photoperiod on the reproductive response of the ewe. To test the phase hypothesis, we eliminated endogenous melatonin secretion by pinealectomy and then restored physiological levels of serum melatonin with rises of the same duration but at different phases of the light-dark cycle (either at night or in the middle of the day). Serum melatonin patterns were determined by radioimmunoassay in samples taken hourly for 24 h. The reproductive state was monitored by measuring serum luteinizing hormone (LH) in ovariectomized ewes treated with constant-release estradiol implants. Infusion of a long-day pattern of melatonin was equally effective in maintaining reproductive suppression when given during the night or the middle of the day. LH remained low for approximately 150 days and then rose as ewes became refractory to the inhibitory melatonin signal. These results do not support the phase hypothesis. Rather, they are consistent with the hypothesis that the duration of the nocturnal secretion of melatonin codes for day length.

Animals↗
PubMed1993

Daily rhythms of melatonin binding sites in the rat pars tuberalis and suprachiasmatic nuclei; evidence for a regulation of melatonin receptors by melatonin itself.

Using quantitative autoradiography, the density of melatonin binding sites has been measured in the rat pars tuberalis (PT) and suprachiasmatic nuclei (SCN) every 4 h throughout a 24-hour period in animals kept in a light regime of 12L/12D (with lights on at 07.00 h). Slices of PT and SCN were incubated in the presence of 180 and 172 pM, respectively, of 2-125I-melatonin. In both structures investigated, specific 2-125I-melatonin binding sites showed similar rhythms throughout the 24-hour period with a maximum at 16.00 h (PT: 46.9 +/- 2.8 fmol/mg protein, n = 5 and SCN: 5.12 +/- 0.30 fmol/mg protein, n = 5) and a minimum at 4.00 h (PT: 28.5 +/- 4.5 fmol/mg protein, n = 5 and SCN: 3.07 +/- 0.39 fmol/mg protein, n = 5). Similar experiments performed on PT of animals kept in constant light (LL) for 3 days revealed a lack of variations of melatonin binding site density, all the values being significantly higher than those of the respective 12L/12D group (concentration of 2-125I-melatonin used: 180 pM). All these preliminary results were confirmed by saturation studies performed at 16.00 and 4.00 h using quantitative autoradiography and in 12L/12D animals, using radioreceptor binding assays on isolated PT membranes. In 12L/12D animals, the maximum number of melatonin binding sites (Bmax) of both SCN and PT was significantly higher at 16.00 h than at 4.00 h. In all these cases, however, the dissociation constant (Kd) failed to show any significant daily variation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Prolactin response in Border-Leicester x merino ewes to administration of melatonin, melatonin analogues, a melatonin metabolite and 6-methoxybenzoxazolinone.

The effect of structural modifications of the melatonin molecule on plasma half-life of the analogues and basal prolactin secretion was studied in Border-Leicester x Merino ewes. Halogenation at position 6 and/or unsaturation of the 2,3-double bond of the melatonin molecule slightly lengthened the half-life of the analogues. Melatonin, 6-chloromelatonin, 2,3-dihydromelatonin and 6-chloro-2,3-dihydromelatonin decreased plasma prolactin to 31, 45, 54 and 48% of control levels respectively when administered daily (100 micrograms at 1600 h) for 21 days. The brain metabolite of melatonin, N-acetyl-N'-formyl-5-methoxykynurenamine, and the putative natural melatonin analogue, 6-methoxybenzoxazolinone, failed to affect prolactin levels when administered in a similar manner. These results indicate that certain structural modifications to the melatonin molecule can be tolerated biologically; however, the modifications reported here still did not prevent rapid clearance from the circulation.

Animals↗
PubMed2001

Melatonin for preventing and treating jet lag.

BACKGROUND: Jet-lag commonly affects air travellers who cross several time zones. It results from the body's internal rhythms being out of step with the day-night cycle at the destination. Melatonin is a pineal hormone that plays a central part in regulating bodily rhythms and has been used as a drug to re-align them with the outside world. OBJECTIVES: To assess the effectiveness of oral melatonin taken in different dosage regimens for alleviating jet-lag after air travel across several time zones. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register, MEDLINE, EMBASE, PsychLit and Science Citation Index electronically, and the journals 'Aviation, Space and Environmental Medicine' and 'Sleep' by hand. We searched citation lists of relevant studies for other relevant trials. We asked principal authors of relevant studies to tell us about unpublished trials. Reports of adverse events linked to melatonin use outside randomised trials were searched for systematically in 'Side Effects of Drugs' (SED) and SED Annuals, 'Reactions Weekly', MEDLINE, and the adverse drug reactions databases of the WHO Uppsala Monitoring Centre (UMC) and the US Food & Drug Administration. SELECTION CRITERIA: Randomised trials in airline passengers, airline staff or military personnel given oral melatonin, compared with placebo or other medication. Outcome measures should consist of subjective rating of jet-lag or related components, such as subjective wellbeing, daytime tiredness, onset and quality of sleep, psychological functioning, duration of return to normal, or indicators of circadian rhythms. DATA COLLECTION AND ANALYSIS: : Ten trials met the inclusion criteria. All compared melatonin with placebo; one in addition compared it with a hypnotic, zolpidem. Nine of the trials were of adequate quality to contribute to the assessment, one had a design fault and could not be used in the assessment. Reports of adverse events outside trials were found through MEDLINE, 'Reactions Weekly', and in the WHO UMC database. MAIN RESULTS: : Nine of the ten trials found that melatonin, taken close to the target bedtime at the destination (10pm to midnight), decreased jet-lag from flights crossing five or more time zones. Daily doses of melatonin between 0.5 and 5mg are similarly effective, except that people fall asleep faster and sleep better after 5mg than 0.5mg. Doses above 5mg appear to be no more effective. The relative ineffectiveness of 2mg slow-release melatonin suggests that a short-lived higher peak concentration of melatonin works better. Based on the review, the number needed to treat (NNT) is 2. The benefit is likely to be greater the more time zones are crossed, and less for westward flights. The timing of the melatonin dose is important: if it is taken at the wrong time, early in the day, it is liable to cause sleepiness and delay adaptation to local time. The incidence of other side effects is low. Case reports suggest that people with epilepsy, and patients taking warfarin may come to harm from melatonin. REVIEWER'S CONCLUSIONS: Melatonin is remarkably effective in preventing or reducing jet-lag, and occasional short-term use appears to be safe. It should be recommended to adult travellers flying across five or more time zones, particularly in an easterly direction, and especially if they have experienced jet-lag on previous journeys. Travellers crossing 2-4 time zones can also use it if need be. The pharmacology and toxicology of melatonin needs systematic study, and routine pharmaceutical quality control of melatonin products must be established. The effects of melatonin in people with epilepsy, and a possible interaction with warfarin, need investigation.

Antioxidants↗
PubMed1990

Fluctuation of blood melatonin concentrations with age: result of changes in pineal melatonin secretion, body growth, and aging.

Melatonin in the systemic circulation of rats fluctuates with age, and the causes for such changes were investigated. Male rats (aged 7 days, 16 days, 18 days, 20 days, 30 days, 48 days, 60 days, and greater than 17 months) were adapted under a lighting regime of 12L:12D for at least 7 days. Pineals and blood samples from the trunk or confluens sinuum were collected in the dark period. Melatonin in tissues was extracted, identified, and determined by gas chromatography-mass spectrometry (GC-MS) and/or radioimmunoassay. Tissue melatonin levels obtained by radioimmunoassay correlated closely with those quantified by GC-MS. Thus, the melatonin radioimmunoassay used is a reliable assay method for melatonin in the plasma and pineal of the rat. Plasma melatonin in the confluens sinuum of rats exhibited episodic release superimposed on a basal release pattern. It was suggested that there are two pools of melatonin in the pineal gland, a readily releasable pool and a bound pool. The mean plasma levels of melatonin in the confluens sinuum of rats increased with age with the highest level recorded at 60 days old and declined to a lower level at greater than 17 months old. The above age-related changes, being similar to the alterations in pineal melatonin levels with growth and aging, suggest that, under our experimental conditions, levels of pineal melatonin increase or decrease with its secretory rate. In developing rats, the age-related increase in the rate of secretion of pineal melatonin as reflected by increases in melatonin levels in the confluens sinuum or pineal melatonin content before adulthood is different from the changes in melatonin levels in the systemic circulation which showed an early developmental rise, followed by an active period and then a prepubertal decline. However, when the body weight was taken into consideration, changes in the levels of pineal melatonin content per 100 gm body weight or the calculated blood melatonin levels (plasma melatonin in the confluens sinuum/body:head ratio) correlated well with the fluctuation of serum melatonin in the systemic circulation. Thus, the developmental changes in the concentrations of melatonin in the general circulation are the result of 1) changes in the rate of pineal melatonin secretion and 2) increase in the dilution factor because of increase in body size. In old rats, levels of plasma melatonin in the confluens sinuum and pineal melatonin content decreased indicating a decline in the rate of pineal melatonin secretion.(ABSTRACT TRUNCATED AT 400 WORDS)

Age Factors↗
PubMed1996

Daily melatonin treatments regulate the circadian melatonin rhythm in the adult Djungarian hamster.

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.

Animals↗
PubMed2002

Dual coupling of MT(1) and MT(2) melatonin receptors to cyclic AMP and phosphoinositide signal transduction cascades and their regulation following melatonin exposure.

In this investigation, we wanted to determine whether MT(1) or MT(2) melatonin receptors are capable of coupling to the phosphoinositide (PI) signal transduction cascade. In addition, we wanted to assess the effects of chronic melatonin exposure on MT(1) and MT(2) melatonin receptor-mediated stimulation of PI hydrolysis. We also assessed the effects of chronic melatonin exposure on other parameters of the MT(2) melatonin receptor function including total specific 2-[125I]-iodomelatonin binding, the affinity of melatonin for the receptor, and melatonin (1nM)-mediated inhibition of cyclic 3',5'-adenosine monophosphate (cAMP) accumulation. Investigation of the PI signal transduction cascade activated by either the MT(1) or MT(2) melatonin receptor expressed in Chinese hamster ovary (CHO) cells showed that melatonin (1pM to 1mM) was able to stimulate the formation of PIs to approximately 40-60% over basal [EC(50): MT(1)=29nM (2-300nM) and MT(2)=1.1nM (0.32-3.5nM), N=5]. This response was mediated via receptors based upon the findings that melatonin did not stimulate the formation of PIs in CHO cells devoid of receptor and that antagonism of MT(2) melatonin receptors by 4P-PDOT (AH 024; 4-phenyl-2-propionamidotetralin) attenuated melatonin-mediated stimulation of PI hydrolysis in CHO cells expressing the MT(2) melatonin receptor. The consequence of chronic melatonin exposure on MT(1) and MT(2) receptor function was also examined. Pretreatment of either MT(1)- or MT(2)-CHO cells with melatonin (1 microM for 5hr) resulted in: (a) a complete loss of melatonin-mediated stimulation of PI hydrolysis, and (b) an attenuation of melatonin (1nM)-mediated inhibition of forskolin-induced cAMP accumulation by approximately 20-40%. The desensitization of the PI hydrolysis signal transduction cascades coupled to either MT(1) or MT(2) melatonin receptors following chronic melatonin exposure was not due to depleted phospholipid pools, to elevated basal levels, or to decreases in receptor affinity and density. This dual coupling of melatonin receptors to different signal transduction cascades may contribute to the diversity of melatonin receptor function in vivo.

Analysis of Variance↗
PubMed2002

Testicular and somatic growth in Siberian hamsters depend on the melatonin-free interval between twice daily melatonin signals.

In Siberian hamsters, day length is encoded by the duration of the nocturnal melatonin signal; short and long melatonin signals over the course of several weeks stimulate and inhibit somatic and gonadal development, respectively, in prepubertal males. We sought to determine whether juvenile male Siberian hamsters respond to multiple melatonin signals each day and the manner in which the sequence of melatonin signals and the duration of the melatonin-free interval between signals affects development. Twenty-one day old male Siberian hamsters, gestated and maintained in a short-day photoperiod of 10 h light/day (10 L), were transferred to constant light to suppress endogenous melatonin secretion and received s.c. infusions of melatonin or saline for 12 days. Hamsters infused with saline retained small testes, whereas one short melatonin infusion each day resulted in significant testicular growth. Other hamsters were provided with two melatonin signals each day, one long (9 h) and one short (4 or 5 h); the order in which these signals was administered and the duration of the melatonin-free interval after each signal varied between groups. In asymmetrical melatonin infusions, the first and second daily infusions were followed by 3-h and 7-h melatonin-free intervals, respectively, whereas in symmetrical infusions, each melatonin signal was followed by a 5-h melatonin-free interval. In the asymmetrical sequence, the melatonin signal that immediately preceded the longer melatonin-free interval determined the rate gonadal growth. Equal melatonin-free intervals after each of the long and short daily melatonin infusions produced intermediate increases in gonadal and somatic development. The hypothalamic-pituitary-gonadal axis of Siberian hamsters can respond to multiple melatonin signals each day, with the rate of testicular growth determined primarily by the duration of the melatonin-free interval following each infusion.

Animals↗