Melatonin: Facts, Extrapolations and Clinical Trials.

Melatonin is a fascinating molecule that has captured the imagination of many scientists since its discovery in 1958. In recent times, the focus has changed from investigating its natural role as a transducer of biological time for physiological systems to hypothesized roles in virtually all clinical conditions. This goes along with the appearance of extensive literature claiming the (generally) positive benefits of high doses of melatonin in animal models and various clinical situations that would not be receptor-mediated. Based on the assumption that melatonin is safe, high doses have been administered to patients, including the elderly and children, in clinical trials. In this review, we critically review the corresponding literature, including the hypotheses that melatonin acts as a scavenger molecule, in particular in mitochondria, by trying not only to contextualize these interests but also by attempting to separate the wheat from the chaff (or the wishful thinking from the facts). We conclude that most claims remain hypotheses and that the experimental evidence used to promote them is limited and sometimes flawed. Our review will hopefully encourage clinical researchers to reflect on what melatonin can and cannot do and help move the field forward on a solid basis.

Four days of simulated shift work reduces insulin sensitivity in humans.

AIM: The aim of this study was to investigate the effects of 4 consecutive simulated night shifts on glucose homeostasis, mitochondrial function and central and peripheral rhythmicities compared with a simulated day shift schedule. METHODS: Seventeen healthy adults (8M:9F) matched for sleep, physical activity and dietary/fat intake participated in this study (night shift work n = 9; day shift work n = 8). Glucose tolerance and insulin sensitivity before and after 4 nights of shift work were measured by an intravenous glucose tolerance test and a hyperinsulinaemic euglycaemic clamp respectively. Muscles biopsies were obtained to determine insulin signalling and mitochondrial function. Central and peripheral rhythmicities were assessed by measuring salivary melatonin and expression of circadian genes from hair samples respectively. RESULTS: Fasting plasma glucose increased (4.4 ± 0.1 vs. 4.6 ± 0.1 mmol L-1 ; P = .001) and insulin sensitivity decreased (25 ± 7%, P < .05) following the night shift, with no changes following the day shift. Night shift work had no effect on skeletal muscle protein expression (PGC1α, UCP3, TFAM and mitochondria Complex II-V) or insulin-stimulated pAkt Ser473, pTBC1D4Ser318 and pTBC1D4Thr642. Importantly, the metabolic changes after simulated night shifts occurred despite no changes in the timing of melatonin rhythmicity or hair follicle cell clock gene expression across the wake period (Per3, Per1, Nr1d1 and Nr1d2). CONCLUSION: Only 4 days of simulated night shift work in healthy adults is sufficient to reduce insulin sensitivity which would be expected to increase the risk of T2D.

Melatonin implants do not alter estrogen feedback or advance puberty in gilts.

Puberty in pigs is often delayed during late summer and autumn, with long daylength the most likely cause. We hypothesised (1) that gilts born around the shortest day would have a later release from the negative feedback actions of estradiol than gilts born around the spring equinox and (2) melatonin treatment would result in an earlier release from estradiol negative feedback and advance the onset of puberty in gilts born around the spring equinox. We first determined the optimal number of estradiol implants required to monitor the release from estradiol negative feedback in ovariectomised gilts. Secondly we determined whether melatonin implants altered negative feedback in 4 cohorts of ovariectomised gilts born between the winter solstice and spring equinox, and in the following year whether melatonin altered the time of the first ovulation in 5 cohorts of intact gilts born between the winter solstice and spring equinox. Plasma LH and FSH increased between 126 and 210d of age (P<0.001) in each cohort (season), but there was no effect of cohort, melatonin treatment or interactions (P>0.05). Age at first detection of elevated plasma progesterone in untreated, intact gilts decreased across the 4 cohorts (P<0.05). Melatonin treatment of intact gilts failed to advance the age of puberty irrespective of their season of birth (P>0.05). In conclusion, while we confirmed that estradiol sensitivity is decreased as gilts age, we failed to demonstrate any effects of season or melatonin on estradiol feedback or melatonin on puberty.

Acute inhibition of casein kinase 1δ/ε rapidly delays peripheral clock gene rhythms.

Circadian rhythms are generated through a transcription-translation feedback loop involving clock genes and the casein kinases CSNK1D and CSNK1E. In this study, we investigated the effects of the casein kinase inhibitor PF-670462 (50 mg/kg) on rhythmic expression of clock genes in the liver, pancreas and suprachiasmatic nucleus (SCN) as well as plasma corticosterone, melatonin and running behaviour in rats and compared them to the responses to a 4 h extension of the light phase. PF-670462 acutely phase delayed the rhythmic transcription of Bmal1, Per1, Per2 and Nr1d1 in both liver and pancreas by 4.5 ± 1.3 and 4.5 ± 1.2 h, respectively, 1 day after administration. In the SCN, the rhythm of Nr1d1 and Dbp mRNA expression was delayed by 4.2 and 4 h, respectively. Despite these changes, the time of peak plasma melatonin secretion was not delayed, although the plasma corticosterone rhythm and onset of wheel-running activity were delayed by 2.1 and 1.1 h, respectively. These changes are in contrast to the effects of the 4 h light extension, which resulted in delays in peak expression of the clock genes of less than 1 h and no change in the melatonin or corticosterone rhythms. The ability of the casein kinase inhibitor to bring about large phase shifts in the rhythms of major metabolic target tissues may lead to new drugs being developed to rapidly phase adjust circadian rhythms to alleviate the metabolic impact of shift work.

Maternal endocrine adaptation throughout pregnancy to nutrient manipulation: consequences for sexually dimorphic programming of thyroid hormones and development of their progeny.

Maternal nutrient restriction during critical windows of fetal development alters postnatal growth, often in a sexually dimorphic manner. Intrauterine growth restriction is frequently characterized by accelerated growth and increased adiposity in later life. Thyroid hormones are implicated as part of the mechanism involved in this scenario via their actions within the hypothalamic-pituitary-thyroid axis. We fed high (H = 240%) and low (L = 70%) levels of recommended daily crude protein intake during the first and second trimesters of gestation to beef heifers to investigate effects to their progeny's plasma concentrations of free and total triiodothyronine (FT3 and TT3) and thyroxine (FT4 and TT4) from birth until weaning at 191 days of age (n = 68). The study design was a two-by-two factorial. For male progeny, exposure to maternal diets low in protein during the first trimester of gestation resulted in greater FT4 at birth (P < 0.05) which was subsequent to lower concentrations of leptin in maternal plasma at 271 days of gestation compared with their high-protein-exposed counterparts. These same animals went on to have greater milk intake during the latter half of the lactation period (P < 0.05) and exhibited faster rates of average daily gain (ADG) relative to birth weight during this time (P < 0.05). For all progeny, independent of sex, exposure to low-protein maternal diets during the second trimester of gestation resulted in greater FT3 relative to TT3 at birth. Because FT3 at birth and 29 days was positively associated with ADG (P < 0.05) and ADG relative to birth weight (P < 0.05), it is proposed that FT3 plays an integral role in catch-up growth in the bovine as per other species. Protein intake during the first and second trimesters of gestation has a sexually dimorphic effect on progeny plasma thyroid hormone concentrations, and these changes are associated with altered milk intake and postnatal growth pathway.

The effects of season and moderate nutritional restriction on ovarian function and oocyte nuclear maturation in cycling gilts.

The fertility of female pigs is impaired during summer and in response to restriction of feed intake, resulting in reduced productivity of the breeding herd. This study determined the effect of season and moderate nutritional restriction on ovarian function and oocyte developmental competence of cycling gilts. Eighty prepubescent gilts were used across two seasons-summer (S: January to March) and winter (W: June to August)-and received either a high (2.5× maintenance) or a moderately restricted (1.5× maintenance) feeding level for the first 19 days of their second estrous cycle. On Day 19, ovaries were collected post-slaughter. Diameters of all surface follicles over 1 mm were measured. All follicles ≥4 mm were aspirated and cumulus-oocyte complexes underwent in vitro maturation for ∼44 hours to assess oocyte developmental competence on the basis of metaphase II (MII) attainment. Moderate dietary nutrition reduced daily liveweight gain but did not affect the ovarian follicle population or oocyte developmental competence. The number of large follicles (≥6 mm) was lower during summer (S: 10.7 ± 1.74 vs. W: 15.5 ± 1.15, P < 0.05), as was the proportion of oocytes at the germinal vesicle stage of meiosis (S: 0.06 ± 0.02 vs. W: 0.08 ± 0.02, P < 0.05). However, the proportion of oocytes attaining MII was similar in summer and winter (S: 0.72 ± 0.04 and W: 0.69 ± 0.06, P > 0.05). Intrafollicular concentrations of luteinizing hormone were higher in summer (S: 43.05 ± 6.44 vs. W: 12.05 ± 5.12 ng/mL, P < 0.001), whereas estradiol was lower (S: 1.27 ± 0.36 vs. W: 27.52 ± 5.59 ng/mL, P < 0.001). In conclusion, our data demonstrated that in summer, follicle growth beyond 6 mm is impaired during the periovulatory period, without affecting oocyte meiotic competence. Importantly, these data also demonstrated that ovarian follicle growth and the capacity of oocytes to reach MII in vitro appear unaffected by moderate nutritional restriction during the preceding estrous cycle.

Effect of feeding level on luteal function and progesterone concentration in the vena cava during early pregnancy in gilts.

This study assessed the effect of feeding level on progesterone concentration in the caudal vena cava during early pregnancy in gilts. Twenty-four Landrace gilts were allocated to either a high (2.8±0.02) or a low (1.5±0.01 kg day⁻¹) feeding level at Day 0 of pregnancy. Serial blood samples were collected every 15 min for 3 h before and 3 h after feeding on Days 6 and 9 of pregnancy. Embryo survival and development as well as in vitro luteal progesterone production were assessed at Day 10 of pregnancy. Progesterone concentration in the vena cava was pulsatile with gilts on the high feeding level having more pulses compared with Low gilts on Day 9 of pregnancy (P<0.05). On Day 6 the number of pulses did not differ significantly between treatments; however, the average progesterone concentration in the vena cava tended to be higher in the gilts on the high feeding level (P<0.10). Embryo survival at Day 10 was 92±3% for High gilts compared with 77±3% for Low gilts (P<0.05). No difference in embryo development between the treatments was seen. There was no difference between treatments in in vitro secretion of progesterone by luteal tissue. In conclusion, a high plane of nutrition positively affects progesterone secretion by the ovaries in early pregnancy.

Circadian regulation of reproduction: from gamete to offspring.

Few challenges are more critical to the survival of a species than reproduction. To ensure reproductive success, myriad aspects of physiology and behaviour need to be tightly orchestrated within the animal, as well as timed appropriately with the external environment. This is accomplished through an endogenous circadian timing system generated at the cellular level through a series of interlocked transcription/translation feedback loops, leading to the overt expression of circadian rhythms. These expression patterns are found throughout the body, and are intimately interwoven with both the timing and function of the reproductive process. In this review we highlight the many aspects of reproductive physiology in which circadian rhythms are known to play a role, including regulation of the estrus cycle, the LH surge and ovulation, the production and maturation of sperm and the timing of insemination and fertilisation. We will also describe roles for circadian rhythms in support of the preimplantation embryo in the oviduct, implantation/placentation, as well as the control of parturition and early postnatal life. There are several key differences in physiology between humans and the model systems used for the study of circadian disruption, and these challenges to interpretation will be discussed as part of this review.

Oocyte maturation and embryo survival in nulliparous female pigs (gilts) is improved by feeding a lupin-based high-fibre diet.

Inclusion of high levels of the high-fibre ingredient sugar-beet pulp in pre-mating diets has been shown to increase gonadotrophin concentrations and improve oocyte quality in nulliparous pigs (gilts). This study evaluated the effects of two alternative fibre sources on reproductive performance in gilts. Gilts received one of three diets from 3 weeks before puberty stimulation until Day 19 of the first oestrous cycle: control (39 g kg⁻¹ fibre), bran (500 g kg⁻¹ wheat bran, 65 g kg⁻¹ fibre) or lupin (350 g kg⁻¹ lupin, 118 g kg⁻¹ crude fibre). Diet did not affect circulating LH concentrations or ovarian follicle size. However, a higher percentage of oocytes collected from lupin-supplemented gilts reached metaphase II in vitro compared with those collected from bran-fed or control gilts (89±5% versus 72±5% and 66±5%, respectively; P<0.05). Furthermore, in a second experiment, gilts fed the same lupin-based diet before mating had improved embryo survival (92±5%) on Day 28 after mating compared with control gilts (76±4%; P<0.05). Therefore, feeding a high-fibre diet before mating can improve oocyte quality in gilts without changes in circulating LH, but this effect is dependent on the fibre source.

Rhythmic expression of clock and clock-controlled genes in the rat oviduct.

The rhythmic expression of clock and clock-controlled genes in the rat oviduct was investigated by real time RT-PCR. per1, per2, Clock, Bmal1, cry1 and cry2 were all expressed in the oviduct. With 4-hourly sampling over 24 h in a normal photoperiod, analysis of variance indicated that per2 and Bmal1 had highly significant sinusoidal-like changes with an amplitude of 3- and 10-fold respectively. Of the other clock genes, per1 and cry1 had non-significant rhythm amplitudes of 2.5- and 1.8-fold respectively. Using the same experimental approach the rhythmic expression of Bmal1, per1 and per2 mRNA in the liver was found to be highly significant with amplitudes of approximately 20-, 10- and 5-fold respectively. The expression of the clock-controlled transcription factors DBP and Rev-erb alpha showed significant rhythmicity in the oviduct with 5-fold changes in amplitude for both genes. Plasminogen activator inhibitor-1 (PAI-1), which has been implicated in oviduct function during the preimplantation period, also had a significant rhythm of expression (2.5-fold amplitude), peaking at the same time as the other clock-controlled genes, DBP and Rev-erb alpha. These results show for the first time that the female reproductive tract is inherently rhythmic and suggests that the developing embryo may be subjected to rhythmic changes in the environment created by the oviduct during transition to the uterus.

Extraocular light exposure does not phase shift saliva melatonin rhythms in sleeping subjects.

Preliminary work in humans suggests that extraocular light can shift circadian phase. If confirmed, extraocular light may be of therapeutic benefit in the treatment of circadian-related sleep disorders with the advantage over ocular exposure that it can be administered while subjects are asleep. In sleeping subjects, however, the effect of extraocular light exposure on circadian phase has yet to be fully tested. Likewise, there is limited data on the acute effects of extraocular light on sleep and body temperature that may influence its clinical utility Thirteen subjects [3F, 10M; mean (SD) age = 22.1 (3.0)y] participated in a protocol that totaled 7 nights in the laboratory consisting of a screening phase measurement night followed 1 week later by two counterbalanced experimental sessions each of 3 consecutive nights (habituation, treatment, and posttreatment phase measurement night) separated by 4 days. Saliva was collected for melatonin measurement every half hour from 1800 to 0300 h on the screening night and both the posttreatment phase measurement nights. On the treatment nights, continuous measures of rectal temperature and polysomnographic sleep were collected and overnight urine for measurement of total nocturnal urinary 6-sulphatoxymelatonin excretion. To test for the phase-delaying effects of extraocular light, subjects received either placebo or extraocular light (11,000 lux) behind the right knee from 0100 to 0400 h. Treatment had no significant effect on the onset of saliva melatonin secretion, phase of nocturnal core body temperature, or urinary 6-sulfatoxymelatonin excretion, but a small increase was observed in wakefulness over the light administration period. In summary, extraocular light was not shown to delay circadian phase but was shown to increase wakefulness. The authors suggest that the present protocol has limited application as a treatment for circadian-related sleep disorders.

Melatonin in mice: rhythms, response to light, adrenergic stimulation, and metabolism.

There has been relatively little research conducted on pineal melatonin production in laboratory mice, in part, due to the lack of appropriate assays. We studied the pineal and plasma rhythm, response to light, adrenergic stimulation, and metabolism of melatonin in CBA mice. With the use of a sensitive and specific melatonin RIA, melatonin was detected in the pineal glands at all times of the day >21 fmol/gland in CBA mice but not in C57Bl mice. Both plasma and pineal melatonin levels peaked 2 h before dawn in a 12:12-h light-dark photoperiod (162 +/- 31 pM and 1,804 +/- 514 fmol/gland, respectively). A brief light pulse (200 lx/15 min), 2 h before lights on, suppressed both plasma and pineal melatonin to near basal levels within 30 min. Exposure to light pulses 4 h after lights off or 2 h before lights on resulted in delays and advances, respectively, in the early morning decline of plasma and pineal melatonin on the next cycle. Administration of the beta-adrenergic agonist isoproterenol (20 mg/kg) 2 and 4 h after lights on in the morning resulted in a fivefold increase in plasma and pineal melatonin 2.5 to 3 h after the first injection. In the mouse, unlike the rat, melatonin was shown to be metabolized almost exclusively to 6-glucuronylmelatonin rather than 6-sulphatoxymelatonin. These studies have shown that the appropriate methodological tools are now available for studying melatonin rhythms in mice.

The pattern of melatonin secretion is rhythmic in the domestic pig and responds rapidly to changes in daylength.

The aim of the study was to investigate the capability of pigs to respond to abrupt changes in lighting conditions by means of alterations in circadian melatonin profiles. Sixteen pre-pubertal crossbred male pigs weighing 40-45 kg were housed in individual pens in four temperature- and lighting-controlled climate rooms (four pigs per room). In two rooms there was a light-dark cycle of 16 L:8 D (Group A) and in two other rooms 8 L:16 D (Group B). Under both lighting regimens light intensity at pig eye-level was 220-240 lx during the light phase and less than 7 lx (red light) during the dark phase. The lighting regimens were changed after 2 wks to the opposite regimen and the change was repeated after a further 2 wks, so that animals ended up with the same light cycle with which they started. Blood was sampled at 2-hr intervals for 48 hr spanning each time of change in lighting. A further 24-hr sampling was performed at the end of the experiment (2 wks after the last change) in both groups and 1 wk after the change from short to long day lighting in Group A. On 83/86 occasions, pigs exhibited a clear circadian rhythm in plasma melatonin under both lighting regimens. Pigs responded immediately to the change from long to short day lighting by advancing melatonin secretion to the earlier lights-off time and some pigs were able to extend secretion to the delayed lights-on time. For short to long day changeover there was a small immediate response, with secretion pattern following the previously entrained endogenous rhythm to within 3 hr of the previous lights-on time. After 1 wk commencement of secretion was delayed by up to 2 hr, while after 2 wks some pigs were able to delay commencement of secretion until lights-off or to cease at lights-on. It is concluded that the domestic pig is able to commence adjustment to abrupt changes in photoperiod within a 1-wk acclimatization by altering circadian melatonin secretion. The present study suggests that it may be possible to use simplified lighting regimens instead of stepwise changing lighting programs in commercial piggeries to reduce the influence of season on production.

Phase response relationships between light pulses and the melatonin rhythm in rats.

There is some controversy whether phase response curves constructed from studies conducted after acute release into constant darkness (Type II) or after prolonged constant darkness are comparable. This study investigated the effects of brief low-intensity light pulses on the onset of 6-sulphatoxymelatonin excretion in rats 48 to 60 h after lights-off and after 14 days of continuous darkness. In the former condition, maximum phase delays occurred between 4 and 6 h after expected lights-off, but no phase advances were observed within 2 days of the presentation of the stimulus. When the times of the pulses were plotted in relation to the individual onsets, peak light-induced phase delays occurred 0 to 2 h after melatonin onset. After 14 days in continuous darkness, the peak phase delays also occurred 0 to 2 h after melatonin onset and were slightly but significantly smaller. No significant phase advances were observed. In a separate small series of experiments, the temperature rhythm of rats was shown to be delayed by a comparable degree to that of melatonin by light pulses 2 and 4 h after expected lights-off under the Type II conditions. It is concluded that phase response curves conducted under Type I and Type II conditions are comparable.

The impact of fetal size and length of gestation on 6-sulphatoxymelatonin excretion in adult life.

Recent studies have shown that intrauterine growth retardation or fetal distress in human infants is associated with a pronounced reduction in melatonin secretion during the first 3 months of life. It is not known whether these associations persist beyond infancy. We have therefore examined the relationship between birthsize and melatonin secretion in 159 men and women aged 20, born in Adelaide, South Australia. Melatonin secretion was estimated by analysing the overnight urinary excretion of 6-sulphatoxymelatonin. The overnight excretion ranged from 1.7 to 128.9 nmoles/subject, was higher in women than in men (46.5 vs 34.1 nmoles, P = 0.003) and was significantly negatively correlated with the body mass index (P = 0.006). Excretion correlated with both birthweight and ponderal index at birth (P = 0.04 and P = 0.01 respectively after adjustment for gestational age) and also fell with increased duration of gestation (P = 0.007). The effects of adult body mass index added to that of low birthweight in predicting 6-sulphatoxymelatonin excretion. These data suggest that urinary 6-sulphatoxymelatonin excretion was impaired in adults who were growth restricted prenatally or were delivered after 40 weeks gestation.

Serotonin, excitatory amino acids and the photic control of melatonin rhythms and SCN c-FOS in the rat.

There is a growing acceptance that serotonergic pathways to the suprachiasmatic nucleus play an important role in the mediation and modulation of light entrainment of rhythms. In this study administration of the 5-HT(2A/2C) agonist (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI, 0.5 mg/kg) at mid dark caused a phase shift in the onset of the urinary excretion of 6-sulphatoxymelatonin in rats that was sustained for at least 8 days and was blocked by the specific 5-HT(2C) antagonist SB-242084. Administration of DOI (2 mg/kg) across the night resulted in the appearance of c-FOS in the nucleus of cells in the suprachiasmatic nucleus during subjective darkness, but did not cause induction at the time of expected lights on (CT0). By contrast light exposure induced c-fos throughout the night including CT0. Administration of the NMDA receptor antagonist MK-801 (3 mg/kg) prior to light pulses had no effect on c-fos in the first part of the night, but towards the expected time of lights on, became progressively more potent, such that by CT0, light induction of c-fos was almost completely inhibited. These results provide further evidence that serotonin plays a role in the mediation of light effects on rhythms in the rat.

The photophase light intensity does not affect the scotophase melatonin response in the domestic pig.

This study investigated the effects of the photophase light intensity on the scotophase melatonin response. Twelve, 8-month-old crossbred gilts were allocated to three groups of four and housed in temperature- and lighting-controlled climate rooms. The rooms had a light intensity of 40, 200 or 10,000 lx and a light-dark cycle of 12 L:12 D. The gilts were allowed to acclimatize to a new lighting regimen for 1 week before being sampled at 2h intervals for 24h. Following the sampling, pigs were transferred under a different light intensity, allowed to adjust for 1 week and sampled again. The procedure was repeated three times so that all the groups went through all three lighting regimens (light intensities). All the gilts exhibited a clear circadian serum melatonin rhythm under each lighting regimen with high melatonin concentrations occurring during the scotophase. There was no difference in the scotophase melatonin response in terms of mean concentrations or duration of increased melatonin levels within or between the groups under different lighting regimens. There was considerable inter-individual variation in the dark phase melatonin response but the individual profiles were consistent under the different lighting regimens. It is concluded that when a certain threshold light intensity (<40lx) is exceeded, the photophase light intensity has no effect on the scotophase melatonin response. These results imply that extremely high light intensities during the photophase would provide no additional benefits compared with normal comfortable light intensity, if artificial lighting programs were introduced to commercial piggeries in order to reduce seasonal effects on reproduction.

Attenuation of sleep propensity, core hypothermia, and peripheral heat loss after temazepam tolerance.

If changes in thermoregulation mediate sleepiness induced by sedative/hypnotics, then a reduction in the soporific efficacy (tolerance) of these agents may be accompanied by a concomitant reduction in their thermoregulatory effects. We compared the thermoregulatory and soporific effects of acute temazepam (30 mg at 1400) in 11 young male subjects before and immediately after 7 consecutive days of temazepam (30 mg). Subjects lay supine (0800-2030), while foot (T(ft)) and rectal (T(c)) temperatures were recorded. Sleep onset latency (SOL) was measured hourly using 20-min multiple sleep latency tests. Relative to placebo, temazepam significantly reduced both T(c) and SOL (-0.31 degrees C and 14.1 min) while increasing T(ft) (3.39 degrees C). A significant tolerance developed after the week of temazepam, with a mean reduction in soporific efficacy of 4.0 +/- 0.8 min. This was accompanied by a concomitant attenuation in both T(c) (-0.16 degrees C) and T(ft) (1.44 degrees C). Furthermore, SOL was temporally related to T(ft) and the maximum rate of decline in T(c) before and after tolerance. Together, these results indicate that the thermoregulatory system may be functionally involved in the regulation of sleepiness.

Melatonin and development: physiology and pharmacology.

This review discusses the development of melatonin rhythmicity in humans and the factors that may alter the appearance of melatonin rhythms. The literature on the possible consequences of disordered melatonin production in relation to Sudden Infant Death Syndrome, fetal origins of adult disease, and scoliosis is critically reviewed. Finally, the emerging use of melatonin to correct sleep disorders in infants and children is reviewed.

The ontogeny of induction of c-fos in the rat SCN by a 5-HT(2A/2C) agonist.

The induction of c-fos in the suprachiasmatic nucleus (SCN) by the 5-HT(2A/2C) agonist, DOI was studied at mid-dark in neonatal rats. The number of cells expressing c-FOS immunoreactivity following DOI was low 3 days after birth, but increased rapidly over the next 3 days. By contrast, light exposure stimulated cells throughout this period. These results are consistent with the arrival of serotonergic afferents at the SCN and their role in the entrainment of rhythms.