Day-time naps and melatonin in blind people.
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Blindness↗
Biomedical subjects
J Arendt
Publications and source records attributed to J Arendt.
Melatonin-induced temperature suppression and its acute phase-shifting effects correlate in a dose-dependent manner in humans.
Melatonin is able to phase-shift the endogenous circadian clock and can induce acute temperature suppression. It is possible that there is a direct relationship between these phenomena. In a double-blind, placebo-controlled crossover study, 6 healthy volunteers maintained a regular sleep/wake cycle in a normal environment. From dusk until 24:00 h on days (D) 1-4 subjects remained in dim artificial lighting (< 50 lux) and darkness (< 1 lux) from 24:00-08:00 h. At 17:00 h on D3 either melatonin (0.05 mg, 0.5 mg or 5 mg) or placebo was administered. Melatonin treatment induced acute, dose-dependent temperature suppression and decrements in alertness and performance efficiency. On the night of D3, earlier sleep onset, offset and better sleep quality were associated with increasing doses of melatonin. The following day, a significant dose-dependent phase-advance in the plasma melatonin onset time and temperature nadir (D4-5) was observed with a trend for the alertness rhythm to phase-advance. A significant dose-response relationship existed between the dose of oral melatonin, the magnitude of temperature suppression and the degree of advance phase shift in the endogenous melatonin and temperature rhythms, suggesting that acute changes in body temperature by melatonin may be a primary event in phase-shifting mechanisms.
Administration, Oral↗
Characterisation of melatonin binding sites in the eye of the Japanese quail (Coturnix japonica).
Melatonin binding sites were examined in the quail eye using 2-[125]iodomelatonin. Radioreceptor assays indicated similar binding sites in membrane preparations of neural retina (NR) and choroid-retinal pigment epithelium (C-RPE) eye components. In both tissues binding of the radioligand was specific, saturable, and of high affinity [Kd values NR 50.8 +/- 19.5 pM, C-RPE 98.2 +/- 35.4 pM, mean +/- SEM (n = 4)] and low capacity (Bmax values NR 12.4 +/- 2.7 fmol/mg protein, C-RPE 21.5 +/- 3.2 fmol/mg protein). Kinetic studies demonstrated that association of 2-[125I]iodomelatonin was rapid and further that this binding was reversible upon the addition of 1 microM melatonin. The order of pharmacological potencies of various indoles tested in 2-[125I]iodomelatonin displacement studies was melatonin > 6-chloromelatonin > 6-hydroxymelatonin > N-acetylserotonin >> 5-methoxytryptophol > 5-hydroxytryptamine > 5-methoxytryptamine (5-hydroxytryptamine > 5-methoxytryptophol for C-RPE). Studies with guanine nucleotides indicated that the signal transduction mechanism of the binding site may involve a G-protein linkage. This melatonin binding site displays several pharmacological similarities with those investigated in the retina of other species and with those previously characterised in the quail brain.
Animals↗
Night-shift work in Antarctica: sleep characteristics and bright light treatment.
Changes in sleep parameters during and after night-shift and the effects of bright white (2500-3000 1x) and dim red (> 500 1x) light treatment on re adaptation after night-shift during winter were studied in 14 men on the British Antarctic Survey Base of Halley (75 degrees south). Subjects kept daily sleep diaries and mood ratings from one week before to three weeks after night-shift and received either full-spectrum white or dim red light treatment from 1100 to 1300 h daily during the first week after night-shift. Plasma melatonin (for 24 h at the end of weeks 1, 2 and 4), and urinary 6-sulfatoxymelatonin (aMT6s, for 48 h weekly) were measured. A significant (MANOVA; p < 0.05) improvement in sleep was seen during night shift (latency and duration) and with bright light treatment (latency). Melatonin and aMT6s rhythms delayed by 7-8 h during night-shift. The white light group readapted slowly, apparently by phase delay, as assessed by aMT6s measurement. The red light group readapted slightly, but significantly (ANOVA, p < 0.01) faster than the white light group.
Adaptation, Psychological↗
Melatonin and adjustment to phase shift.
The pineal hormone melatonin has clear circadian phase-shifting effects in humans which have recently been formalized as a phase response curve. Its potential use in circadian rhythm disorders has been investigated in field studies of jet lag and shift work and in simulated phase shift. A substantial amount of information indicates that in the majority of subjects it hastens adaptation of both subjective and objective measures to forced shifts in time cues with few reported side-effects. Field studies of its use in adaptation to shift work are sparse and preliminary but the first indications are positive. In some blind subjects with sleep disturbance it can stabilize sleep onset time without necessarily entraining all circadian rhythms and it can advance sleep timing in delayed sleep-phase insomnia. Acute suppression of core body temperature may be an integral part of the phase-shifting mechanism.
Journal Article↗
Acute phase-shifting effects of melatonin associated with suppression of core body temperature in humans.
Appropriately administered melatonin is able to phase shift circadian rhythms, to induce transient sleepiness and to suppress core body temperature. The relationships between these phenomena have not been fully explored. In a double-blind, placebo-controlled crossover study, 8 healthy males maintained a regular sleep-wake cycle in a natural environment throughout. From dusk until 2400 h on days (D) 1-4 subjects were in dim artificial lighting (< 100 lux) with darkness (< 1 lux) from 2400-0800 h. Sunglasses were worn during the day when outside. At 1700 h on D3 either melatonin (5 mg) or placebo was administered. Saliva samples were collected at 30 min intervals, 1600-2400 h on D3 and D4, and subjective alertness rated at 30 min intervals from 1600-2400 h on D3 and hourly from 0800-2400 h D4. Sleep quality was rated on nights 2, 3 and 4 and core temperature was recorded throughout. Melatonin induced a significant suppression of temperature and alertness peaking 2.5 h after the dose, together with improved sleep quality on the night of D3 and a phase advance of the endogenous melatonin rhythm on D4. The degree of phase shift was related to the amount of temperature suppression in 6 of 7 subjects with detectable melatonin, suggesting that temperature suppression is an integral part of the phase-shifting mechanism.
Adult↗
Posture influences melatonin concentrations in plasma and saliva in humans.
Melatonin is extensively used as a circadian marker rhythm and thus any factors influencing its concentrations other than endogenous rhythmicity must be assessed. We report here the effects of posture on melatonin concentrations in plasma and saliva. The study was performed during the rising phase of the melatonin rhythm between 21:00 and 01:30 h. From 23:00 h, 7 healthy subjects remained sitting until 24:00 h and in dim light (< 10 lux) until 01:30 h. From 24:00 h, they assumed a different postural position in one of the following stages: Stage 1a: 24:00-00:30 h-standing, 00:30-01:00 h-supine, 01:00-01:30 h-standing; Stage 1b-reverse of Stage 1a; Stage 2a: 24:00-01:30 h-supine; and Stage 2b: 24:00-01:30 h-standing. Blood and saliva samples were obtained every hour from 21:00-24:00 h and then every 10 min from 24:00-01:30 h. Plasma and salivary melatonin concentrations, measured by radioimmunoassay, increased when moving from a supine to a standing position and decreased when these positions were reversed. These changes, as seen with other blood components, can be explained through the influence of gravity which causes a decrease in plasma volume on standing and an increase in plasma volume on lying down.
Adult↗
Clinical perspectives for melatonin and its agonists.
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Animals↗
Comparison of the effects of acute fluvoxamine and desipramine administration on melatonin and cortisol production in humans.
1. Acute administration of the specific serotonin uptake inhibitor, fluvoxamine (100 mg at 16.00 h), markedly increased nocturnal plasma melatonin concentrations, with high levels extending into the morning hours. 2. Acute administration of the noradrenaline uptake inhibitor, desipramine (DMI) (100 mg at 16.00 h), increased evening plasma melatonin concentrations. 3. Both drug treatments increased the duration of melatonin secretion, fluvoxamine significantly delaying the offset time and DMI significantly advancing the onset time. 4. The stimulatory effect of DMI on plasma melatonin was mirrored by increased urinary 6-sulphatoxymelatonin (aMT6s) excretion. 5. On the contrary, there was no correlation between plasma melatonin and urinary aMT6s concentrations following fluvoxamine treatment, suggesting that fluvoxamine may inhibit the metabolism of melatonin. 6. Treatment with DMI increased plasma cortisol concentrations in the evening and early morning, treatment with fluvoxamine increased plasma cortisol at 03.00 h, 10.00 h and 11.00 h. 7. The drug treatments affected different aspects of the nocturnal plasma melatonin profile suggesting that the amplitude of the melatonin rhythm may depend upon serotonin availability and/or melatonin metabolism whilst the onset of melatonin production depends upon noradrenaline availability.
Adult↗
Phase-shifts in melatonin, 6-sulphatoxymelatonin and alertness rhythms after treatment with moderately bright light at night.
OBJECTIVES: Shift work and rapid travel across several time zones leads to desynchronization of internal circadian rhythms from the external environment and from each other with consequent problems of behaviour, physiology and performance. Field studies of travellers and shift workers are expensive and difficult to control. This investigation concerns the simulation of such rhythm disturbance in a laboratory environment. The main objectives are to assess the ability of controlled exposure to moderately bright light and darkness/sleep to delay circadian rhythms in volunteers without environmental isolation and, secondly, to evaluate the use of different indices of melatonin (MT) secretion together with self-rated alertness as marker rhythms. PATIENTS: Six normal volunteers aged 22-26 years (mean +/- SD 24.3 +/- 1.4). DESIGN: Subjects were exposed to the following periods of moderately bright light (1200 lux) on three consecutive days in early December 1991: Day (D)1: 2000-0200 h, D2: 2200-0400 h and D3: 2400-0600 h. Each period was followed by 8 hours of darkness (< 1 lux). Hourly blood, sequential 4-hourly urine (8-hourly when asleep) and hourly saliva (except when asleep) samples were taken throughout a 24-hour period on D0 (baseline), D4 (1 day post-light treatment) and D7 (4 days post-light treatment). During waking hours, subjective alertness was rated every 2 hours on a visual analogue scale. MEASUREMENTS: MT was measured in plasma and saliva, and its metabolite, 6-sulphatoxymelatonin (aMT6s), was measured in urine. MT, aMT6s and alertness scores were analysed by ANOVA and a cosinor analysis program. RESULTS: A delay shift was present in the aMT6s, plasma MT and salivary MT rhythms (degree of shift: 2.67 +/- 0.3 h (P < 0.001, n = 5); 2.35 +/- 0.29 h (P < 0.001, n = 6); and 1.97 +/- 0.32 h (P < 0.01, n = 6), mean +/- SEM, respectively) 1 day post-light treatment compared to baseline. Adaptation to the initial phase position was apparent by the 4th post-treatment day. Significant correlations were obtained between plasma MT onset (degree of shift: 3.12 +/- 0.74 h (P < 0.001, n = 6, mean +/- SEM)) and the acrophases (calculated peak times) of plasma MT (P < 0.001), salivary MT (P < 0.05) and urinary aMT6s (P < 0.01). A significant phase delay in the alertness rhythm was also evident 1 day post-treatment (3.08 +/- 0.67 h (P < 0.01, n = 6, mean +/- SEM)) with adaptation by the 2nd post-treatment day. CONCLUSIONS: This study suggests that these methods of determining MT secretion are comparable and give reliable assessments of the MT circadian phase position even after a phase-shift. Significant phase-shifts of similar magnitude can be induced in both MT and alertness rhythms using moderate intensity bright light at night.
Adult↗
Light therapy in seasonal affective disorder is independent of time of day or circadian phase.
OBJECTIVE: We tested the hypothesis that phase-delayed circadian rhythms underlie seasonal affective disorder (SAD) by measuring phase position of 6-sulfatoxymelatonin excretion and comparing antidepressant response to morning or evening light given as a first treatment. DESIGN: Randomized controlled trial. SETTING: Ambulatory. PATIENTS: Thirty-two women and seven men with SAD. INTERVENTION: Light therapy (2500 lux for 1 hour for 1 week) was administered either at 7 AM or 10 PM, preceded by a baseline week and followed by a withdrawal week. RESULTS: Our SAD patient sample was moderately depressed (Hamilton Depression Scale [HAM-D] score 18); a HAM-D reduction of 50% or more was found in 12 of 18 patients given morning and in 15 of 21 patients given evening light (70% response rate). Response was not dependent on age, gender, stage of the menstrual cycle, time of year, or on the timing or duration of sleep. Urinary 6-sulfatoxymelatonin was measured in 30 patients; 22 had phase-delayed circadian rhythms. However, phase position was correlated neither with depth of depression nor with a preferential response to morning or evening light. COMMENT: Both morning and evening light therapy improved depressive symptoms in patients with SAD independent of their circadian phase or sleep timing. These findings argue against a circadian phase-delay hypothesis of the pathophysiology of SAD, or the necessity of a phase-advance by morning light for clinical efficacy. They additionally suggest more practicable and flexible schedules for light therapy in SAD, since time of day is not crucial.
Age Factors↗
Rapid direct measurement of melatonin in saliva using an iodinated tracer and solid phase second antibody.
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Antibodies↗
Seasonal affective disorder: response to light as measured by electroencephalogram, melatonin suppression, and cerebral blood flow.
This study was designed to test the hypothesis that patients with SAD have significantly different physiological responses to light than healthy age- and sex-matched controls. We studied retinal contrast sensitivity, visual evoked EEG responses, and melatonin suppression by, and cerebral blood flow response to, full-spectrum artificial daylight. There was no significant difference between 10 patients and 11 controls in retinal contrast sensitivity, or amplitude or latency of N2, P2, P100 or P300 on EEG. We compared melatonin suppression in 12 SAD patients and 12 controls. During exposure to 500 lux and 1500 lux artificial daylight both the SAD patients and controls had a significant melatonin percentage suppression; however, the percentage suppression did not differ significantly between the SAD patients and the controls. In addition, we carried out a small pilot study into the effect of light on cerebral blood flow in four SAD patients and four controls. Before exposure to 1500 lux artificial daylight there was no significant difference between patients and controls in global, regional or cerebral hemispheric blood flow. After light exposure the SAD patients and controls had a significantly different percentage change in cerebral blood flow. We suggest that patients with SAD do not have significantly physiological responses to light than controls, except perhaps in cerebral blood flow. Furthermore, mechanisms other than supersensitivity of melatonin suppression must explain both the pathophysiology of the disorder and its response to treatment with light.
Bipolar Disorder↗
Melatonin rhythms in seasonal affective disorder.
We examined 24-hour melatonin rhythms from 20 patients with seasonal affective disorder (SAD) and 20 healthy volunteers. Patients and controls were individually matched for age, sex, and month of study. Plasma samples were taken at hourly intervals, and were assayed for melatonin by radio-immunoassay. The 24-hourly melatonin estimations for each individual were fitted to a cosine curve, and the significance of the curve fits was calculated. Two analyses were performed. In analysis 1 the following were calculated: (a) cosine fit, (b) significance of fits, (c) mean amplitude and acrophase (peak) and (d) mean melatonin levels. The curve fits were highly significant for all but three subjects (two patients, one control), but there were no significant differences in any measure between the two groups. In analysis 2 the comparisons were repeated and restricted to the 18 patients and 19 controls in whom there was a significantly significant melatonin rhythm. Again there were no significant differences between groups. These results suggest that the circadian rhythm of melatonin is not abnormal in SAD, and that the therapeutic effect of light in SAD is not mediated by phase shifts in melatonin secretion.
Adult↗
Can melatonin improve shift workers' tolerance of the night shift? Some preliminary findings.
The pineal hormone melatonin is potentially useful in the treatment of disorders, especially sleep disorders, associated with circadian rhythm disturbance. We have examined its effects on sleep, mood, and behaviour in a double-blind, placebo-controlled study of a small group of police officers working spans of seven successive night shifts. Compared to placebo, and to no treatment, melatonin (5 mg) taken at the desired bedtime improved problems related to sleep and increased alertness during working hours, especially during the early morning. In letter-target performance tests visual search speed and accuracy were either unchanged or slightly improved. Memory scanning speed and perception of mental load were adversely affected. This preliminary study suggests that melatonin has beneficial effects on sleep and alertness, but that its effects on performance need careful evaluation.
Adult↗
Melatonin suppression in human subjects by bright and dim light in antarctica: time and season-dependent effects.
Full-spectrum light, of sufficiently high intensity, will suppress the secretion of melatonin at night in humans. Individual sensitivity to such suppression is variable, and the factors determining such sensitivity are largely unknown. By analogy with animal work previous short or long-term exposure to different light intensities may be an important determinant. We exploited the Antarctic environment to investigate these possibilities. Groups of healthy men, living on the British Antarctic Survey Base at Halley (75 degrees South) were exposed to dim (range 290-310 lux) and bright (range 2100-2300 lux) light either from 01.00-02.00 h or 05.00-0.600 h, both in winter and in summer. Plasma melatonin concentrations were determined by radioimmunoassay in serial blood samples taken before, during and after light treatment, and in control (darkness) conditions. Light suppression of melatonin was more effective in the latter part of the night in winter and this was particularly well-differentiated for dim light.
Adult↗
The acute and chronic effects of (+) and (-) oxaprotiline upon melatonin secretion in normal subjects.
Ten healthy male subjects were treated for three weeks with (+)oxaprotiline, a selective inhibitor of noradrenaline (NA) uptake and with (-)oxaprotiline which does not inhibit NA uptake. Plasma melatonin concentrations were measured throughout the night at 0, 1, 7 and 21 days and were higher during treatment with (+)oxaprotiline than with (-)oxaprotiline for the entire three weeks of treatment. Since NA stimulates the production and secretion of melatonin, these results are consistent with a sustained increase in noradrenergic activity within the pineal, during 21 days of treatment with an effective NA uptake inhibitor.
Administration, Oral↗
In vitro autoradiographical localization of melatonin binding sites in the caprine brain.
The recent development of a specific 2-[125I]-iodo-melatonin ligand has led to the identification of 125I-melatonin binding sites in the brains of numerous mammalian species. The present study reports the localization of 125I-melatonin binding sites in the brain of the dairy goat. Six previously untreated female goats, aged 5-7 years, were culled under natural light between 0900 and 1100. Brains and pituitaries were immediately dissected out and frozen on dry ice. Both transverse and sagittal sections of frozen brain were cut 20 microns thick and thaw-mounted onto gelatin-coated slides. Three consecutive sections were cut at intervals throughout the brain, mounted onto three slides, labeled A, B, and C, and thusly treated: (A) incubated for 2 hr at room temperature in a 50 pM solution of 125I-melatonin; (B) incubated for 2 hr at room temperature in a 50 pM solution of 125I-melatonin plus 1 microM cold melatonin; (C) fixed in Clarke's fluid and stained with toluidine blue. After incubation, A (specific) and B (nonspecific) slides were washed three times in ice-cold Tris-HCl buffer (pH 7.7), air-dried, exposed to an X-ray film for 2 weeks at -20 degrees C, and then fixed and stained. Specific 125I-melatonin binding sites were found in the pars tuberalis (PT), the area of the suprachiasmatic nucleus (SCN), preoptic area (POA), fornix/mediolateral septal areas, hippocampus, and the cerebral cortex. 125I-melatonin did not bind in the hindbrain, midbrain, neurohypophysis, pars intermedia or pars distalis of the adenohypophysis, or the pineal.
Animals↗