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1.
Introduction: The melatonin agonist LY 156735 (LY) is a new investigational drug under development to treat circadian rhythm disorders. The present study assessed the efficacy of LY to alleviate the symptoms of shift lag and to enhance readaptation of desynchronized circadian rhythms to a new time zone.

Subjects and methods: Eight healthy male volunteers of age 25-35 yr participated in three identical trials of 13d duration in a temporal isolation unit separated by washout intervals. A high dose (HD) of 5 mg and a low dose (LD) of 0.5 mg of LY and placebo (PL) were administered double-blinded in a three-period cross-over design. Each trial consisted of an adaptation period, a pre-shift period for baseline measurements, a simulated 9h phase-advance shift, and a post-shift period for follow-up. The time shift was performed at 23:00h of day 6 by advancing the laboratory time to 08:00h of day 7. Double-blind study medication was administered at 14:30h on day 6, and at 22:30h on days 7-10. Subjective ratings of jet lag, alertness, tenseness, and daytime fatigue were assessed using visual analog scales (VAS) and standardized questionnaires. The objective markers of readaptation included core body temperature, wrist actigraphy, cortisol and electrolyte excretion, and a battery of computerized performance tests.

Results: HD but not LD enhanced the readaptation speed of all physiological rhythms investigated, as demonstrated by a significantly faster movement of acrophases towards the post-shift target time. HD (p=0.05) significantly blunted the post-shift deterioration of performance in those tests that were sensitive to shift lag. Parameters of subjective well-being were not significantly affected by either dose.

Conclusion: This pilot study demonstrates the chronobiotic efficacy of LY when taken at a dose of 5 mg/d.  相似文献   

2.
The human sleep-wake cycle is generated by a circadian process, originating from the suprachiasmatic nuclei, in interaction with a separate oscillatory process: the sleep homeostat. The sleep-wake cycle is normally timed to occur at a specific phase relative to the external cycle of light-dark exposure. It is also timed at a specific phase relative to internal circadian rhythms, such as the pineal melatonin rhythm, the circadian sleep-wake propensity rhythm, and the rhythm of responsiveness of the circadian pacemaker to light. Variations in these internal and external phase relationships, such as those that occur in blindness, aging, morning and evening, and advanced and delayed sleep-phase syndrome, lead to sleep disruptions and complaints. Changes in ocular circadian photoreception, interindividual variation in the near-24-h intrinsic period of the circadian pacemaker, and sleep homeostasis can contribute to variations in external and internal phase. Recent findings on the physiological and molecular-genetic correlates of circadian sleep disorders suggest that the timing of the sleep-wake cycle and circadian rhythms is closely integrated but is, in part, regulated differentially.  相似文献   

3.
Summary The role of the hormone melatonin in the circadian system of pigeons (Columba livia) was investigated. Using an automatic infusion system, melatoni at physiological levels was delivered for 10 h each day to cannulated, pinealectomized (P-X) pigeons in constant darkness. These cyclic infusions of melatonin entrained feeding rhythms in P-X pigeons while vehicle infusions were ineffective entraining agents. When the retinae of P-X pigeons were removed (E-X), feeding rhythms were abolished in constant darkness. When cyclic melatonin infusions were delivered to these birds (E-X and P-X), feeding rhythmicity was restored whereas vehicle infusions alone did not restore rhythmicity. When melatonin infusions were terminated in E-X/P-X pigeons, feeding rhythms persisted for several days but eventually decayed. Blood melatonin levels were measured in both P-X and E-X/P-X birds infused cyclically with exogenous melatonin and were found to be within the physiological range both in level and pattern. These results strongly suggest that endogenous melatonin, released by the pineal gland and the retinae, regulates the timing of feeding rhythms by entraining other oscillators in the circadian system of the pigeon.Abbreviations P-X pinealectomized - E-X bilaterally enucleated - T period of infusion cycle - LD light: dark cycle - DD constant darkness  相似文献   

4.
To systematically determine the effects of daytime exposure to sleep in darkness on human circadian phase, four groups of subjects participated in 4-day studies involving either no nap (control), a morning nap (0900-1500), an afternoon nap (1400-2000), or an evening nap (1900-0100) in darkness. Except during the scheduled sleep/dark periods, subjects remained awake under constant conditions, i.e., constant dim light exposure (36 lx), recumbence, and caloric intake. Blood samples were collected at 20-min intervals for 64 h to determine the onsets of nocturnal melatonin and thyrotropin secretion as markers of circadian phase before and after stimulus exposure. Sleep was polygraphically recorded. Exposure to sleep and darkness in the morning resulted in phase delays, whereas exposure in the evening resulted in phase advances relative to controls. Afternoon naps did not change circadian phase. These findings indicate that human circadian phase is dependent on the timing of darkness and/or sleep exposure and that strategies to treat circadian misalignment should consider not only the timing and intensity of light, but also the timing of darkness and/or sleep.  相似文献   

5.
Circadian physiology in the vertebrate retina is regulated by several neurotransmitters. In the lateral eyes of the green iguana the circadian rhythm of melatonin content peaks during the night while the rhythm of dopamine peaks during the day. In the present work, the authors explore the interaction of these 2 neurotransmitters during the circadian cycle. They depleted retinal dopamine with intravitreal injections of 6-hydroxydopamine (6-OHDA) and measured ocular melatonin content in vivo throughout 1 circadian cycle. The circadian rhythm of ocular melatonin not only persisted but increased 10-fold in amplitude. This increase was substantially reduced by the intraocular administration of dopamine. 6-OHDA-treated retinas, unlike those from untreated animals, did not express a circadian rhythm of melatonin synthesis in vitro. To deplete retinal melatonin, the authors pinealectomized iguanas and blocked retinal melatonin synthesis by depleting serotonin with intraocular injections of 5,6-dihydroxytryptamine. In animals so treated, they found that the circadian rhythm of retinal dopamine content was abolished, the levels of dopamine were lowered, and the levels of dopamine metabolites were greatly increased. The data suggest that in iguanas, the amplitude of the circadian rhythm of melatonin synthesis in the eye is suppressed by dopamine while the rhythm of dopamine depends, at least in part, on the presence of melatonin.  相似文献   

6.
The effects of circadian rhythmicity and time-awake on a simple motor task   总被引:1,自引:0,他引:1  
The aim of the study was to assess if a simple motor task, one that required muscle contractions well below maximum, showed evidence of circadian changes and time-awake. The task consisted of using a larger counter to flick a number of smaller counters to land as near as possible to the center of a target. The closer a counter landed next to the center of the target, the higher the score obtained. Two distances from the target were used (long and short), and 20 counters were flicked at each distance. The task was performed by 72 diurnally active healthy participants at six test sessions distributed every 4 h throughout the day (08:00 h, 12:00 h, ... , 04:00 h), so covering a circadian cycle. When performing the sessions, subjects had been awake for about 1, 4, ... , 20 h. Before each test session, sublingual temperature was measured, and estimates of the individual's fatigue and alertness were made. Clear normally phased circadian rhythms (p<0.0001) in oral temperature and alertness with mean peak time (i.e., acrophases of 17.2 h and 15.9 h, respectively) and fatigue (i.e., mean acrophase of 3.4 h) were detected. The total scores for both the long and short distances also showed circadian rhythms that peaked slightly before the temperature rhythm (by 2.31+/-0.91 h and 1.77+/-0.77 h, mean+/-SE, respectively), and the number of occasions that the target was missed altogether showed rhythms that were in anti-phase (mean acrophases=3.8 h and 4.1 h for the long and short distances, respectively) to that of total scores (mean acrophases=16.0 h and 15.2 h for the long and short distances, respectively). With the long and, particularly, short distances, there were generally significant correlations (r<0.0005) between both the measures of accuracy (total score and number of misses) and body temperature and time-awake. The accuracy of performance at this task seems to show circadian and time-awake effects, and so makes it of potential value in protocols where repetitive measurements during the course of a day are required.  相似文献   

7.
In previous entrainment studies, melatonin (MEL) was administered by handling the animal, but because such handling may act as a confounding variable, the results from these studies are equivocal. The authors used MEL administration techniques that do not involve direct handling of the animal. Long Evans rats were used, and core body temperature (CBT) and wheel-running activity were recorded. One group of rats received a daily 1-h time-fixed infusion of MEL or the vehicle via a subcutaneous catheter. Animals in a second group had timed access to drinking water involving daily presence of drinking water containing MEL or the vehicle for 2 h at a fixed time of the day. Following entrainment to LD 12:12, both groups were transferred to constant darkness to free-run under vehicle administration. MEL was then administered, and entrainment occurred when activity onset coincided with MEL onset. Under both regimens, entrainment of wheel-running and CBT rhythms showed equal phase-relation to the onset of MEL administration, and free-running reoccurred when MEL was withdrawn. The authors concluded that MEL administration via drinking water and via infusion represent efficient ways to synchronize free-running rhythms in rats.  相似文献   

8.
The UV-suppressive effect of topical melatonin was assessed at different application time points in a double-blind randomized clinical trial. The lower back of 20 healthy volunteers was treated with 0.6 mg/cm2 melatonin or vehicle either 15 min before or 1, 30 or 240 min after UV irradiation. The erythema was evaluated visually and measured by chromametry 24 h after irradiation. UV-absorbing effects of melatonin were measured at a concentration of 8 microg/ml with a spectrophotometer. Melatonin absorbs UV light at a wavelength of 225-275 nm which is clearly below the wavelength of UVA and UVB (290-390 nm). The visual score showed that application of melatonin 15 min before irradiation significantly suppressed erythema compared to treatment with vehicle alone (p < 0.001). Similar results were found by chromametry (p < 0.001). Treatment after irradiation showed no UV suppression. The erythema suppressive effect of melatonin might be explained by the radical-scavenging mechanism of quenching meanly hydroxyl radicals (.OH) which are known to be most present in sunburn reaction of the skin. The protective effect of the pre-irradiation treatment might be explained by penetration into the skin within 15 min and the presence in a local concentration at the irradiation time point.  相似文献   

9.
About 15% of the legally blind completely lack light perception. Most of these individuals have abnormally phased circadian rhythms and many free-run. Light treatment is not an option for them. However, melatonin treatment can be highly effective. A daily dose of 0.5 mg of melatonin usually results in entrainment. It has been suggested that treatment in individuals with circadian periods > 24 h should be initiated on the advance zone of the melatonin phase response curve, which was based on findings in which melatonin initiated on the delay zone were less likely to result in entrainment, even though treatment continued across all circadian phases. In the present study, 7 totally blind people started low-dose melatonin treatment (0.5 mg; 1 person was given 0.05 mg) on the delay zone. All entrained as circadian phase free-ran and the advance zone of the melatonin phase response curve coincided with the time of melatonin administration. These results are consistent with studies in other mammals. It does not appear that low-dose melatonin treatment needs to be initiated on the advance zone to induce eventual entrainment in blind people with free-running rhythms > 24 h. Therefore, it is not essential that circadian phase be ascertained before starting low-dose melatonin treatment of blind people.  相似文献   

10.
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12.
Melatonin and light synchronize the biological clock and are used to treat sleep/wake disturbances in humans. However, the two treatments affect circadian rhythms differently when they are combined than when they are administered individually. To elucidate the nature of the interaction between melatonin and light, the present study assessed the effect of melatonin on circadian timing and immediate-early gene expression in the suprachiasmatic nucleus (SCN) when administered in the presence of light. Male C3H/HeN mice, housed in constant dark in cages equipped with running wheels, were treated with either melatonin (90 microg, s.c.) or vehicle (3% ethanol-saline) 5 min prior to exposure to light (15 min, 300 lux) at various times in the circadian cycle. Combined treatment resulted in lower magnitude phase delays of circadian activity rhythms than those obtained with light alone during the early subjective night and advances in phase when melatonin and light were administered during the subjective day (p < .001). The reduction in phase delays with combined treatment at Circadian Time (CT) 14 was significant when light exposure measured 300 lux but not at lower light levels (p < .05). When light preceded melatonin administration, the inhibition of phase delays attained significance only when the light exposure reached 1000 lux (p < .05). Neither basal nor light-induced expression of c-fos mRNA in the SCN was modified by melatonin administration at CT 14 or CT 22. Together, these results suggest that combined administration of melatonin and light affect circadian timing in a manner not predicted by summing the two treatments given individually. Furthermore, the interaction is not likely to be due to inhibition of photic input to the clock by melatonin but might arise from a photically induced enhancement of melatonin's actions on circadian timing.  相似文献   

13.
Locusts demonstrate remarkable phenotypic plasticity driven by changes in population density. This density dependent phase polyphenism is associated with many physiological, behavioral, and morphological changes, including observations that cryptic solitarious (solitary-reared) individuals start to fly at dusk, whereas gregarious (crowd-reared) individuals are day-active. We have recorded for 24-36 h, from an identified visual output neuron, the descending contralateral movement detector (DCMD) of Schistocerca gregaria in solitarious and gregarious animals. DCMD signals impending collision and participates in flight avoidance maneuvers. The strength of DCMD's response to looming stimuli, characterized by the number of evoked spikes and peak firing rate, varies approximately sinusoidally with a period close to 24 h under constant light in solitarious locusts. In gregarious individuals the 24-h pattern is more complex, being modified by secondary ultradian rhythms. DCMD's strongest responses occur around expected dusk in solitarious locusts but up to 6 h earlier in gregarious locusts, matching the times of day at which locusts of each type are most active. We thus demonstrate a neuronal correlate of a temporal shift in behavior that is observed in gregarious locusts. Our ability to alter the nature of a circadian rhythm by manipulating the rearing density of locusts under identical light-dark cycles may provide important tools to investigate further the mechanisms underlying diurnal rhythmicity.  相似文献   

14.
Orthostatic intolerance (OI) is a major problem after spaceflight. Its etiology remains uncertain, but reports have pointed toward an individual susceptibility to OI. We hypothesized that individual predisposition plays an important role in post-bed rest OI. Twenty-four healthy male subjects were equilibrated on a constant diet, after which they underwent tilt-stand test (pre-TST). They then completed 14-16 days of head-down-tilt bed rest, and 14 of the subjects underwent repeat tilt-stand test (post-TST). During various phases, the following were performed: 24-h urine collections and hormonal measurements, plethysmography, and cardiovascular system identification (a noninvasive method to assess autonomic function and separately quantify parasympathetic and sympathetic responsiveness). Development of presyncope or syncope defined OI. During pre-TST, 11 subjects were intolerant and 13 were tolerant. At baseline, intolerant subjects had lower serum aldosterone (P < 0.01), higher excretion of potassium (P = 0.01), lower leg venous compliance (P = 0.03), higher supine parasympathetic responsiveness (P = 0.02), and lower standing sympathetic responsiveness (P = 0.048). Of the 14 subjects who completed post-TST, 9 were intolerant and 5 were tolerant. Intolerant subjects had lower baseline serum cortisol (P = 0.03) and a higher sodium level (P = 0.02) compared with tolerant subjects. Thus several physiological characteristics were associated with increased susceptibility to OI. We propose a new model for OI, whereby individuals with greater leg venous compliance recruit compensatory mechanisms (activation of the renin-angiotensin-aldosterone system and sympathetic nervous system, and withdrawal of the parasympathetic nervous system) in the face of daily postural challenges, which places them at an advantage to face orthostatic stress. With head-down-tilt bed rest, the stimulus to recruit compensatory mechanisms disappears, and differences between the two subgroups attenuate.  相似文献   

15.
The human melatonin 1a (hMella) receptor gene was screened for mutations using genomic DNA samples from patients with circadian rhythm sleep disorders and control subjects by single strand conformational polymorphism analysis (SSCP). We found seven mutations, two of which predict amino acid changes R54W and A157V, respectively. The prevalence of the R54W variant and that of the A157V variant were several times more common in non-24-h sleep-wake syndrome subjects than among control subjects, although the incidence was not significant in our study group. When expressed in COS-7 cells, the R54W mutant receptor exhibited significantly reduced B(max) and slightly enhanced affinity (reduced K(d)) compared to the wild type receptor, while the A157V variant receptor showed similar binding characteristics to the wild type. The identification of variants in the hMella receptor will provide a useful tool for analyzing genetic predisposition toward various diseases related to melatonin function and to clarify the physiological role of melatonin receptors in humans.  相似文献   

16.
Male SPF bred Wistar rats were adapted to natural light (N) and to a 12:12 h (light-dark) artificial light (A) regimen in the course of the year. The rats were analyzed at 3 h intervals during 24 h approximately at the time of the vernal and autumnal equinox and at the winter and summer solistice. Serum insulin circadian oscillations depended on the season, being different in various light regimens. The mesors were the highest during summer, the lowest during winter in both regimens. The external acrophases of insulin in the N differed from those in the A group, contrary to the computative ones. The annual mean of serum insulin concentration was lower in the N than in the A group. The circadian oscillations of corticosterone were influenced primarily by the time of year. The mesors were the highest during summer, lower in winter and spring in N and A group. The computative acrophases were similar in both groups in all seasons except spring. The external acrophase was similar in both regimens during the year. The response of insulin, a major anabolic hormone, to various light regimens during the day and year was different from that of corticosterone, a major hormone of the stress reaction.  相似文献   

17.
Neonatal melatonin treatment caused a significant increase in thyroxine (T4) level at one month of age. Preexposure to melatonin in neonatal age and reexposure after one month accounted for a still greater increase in T4 production. Rats neonatally exposed to melatonin did not respond to TSH at one month of age.  相似文献   

18.
Male SPF rats (Wistar strain) were adapted in the course of the year to natural light (N) and to a 12:12 h (light:dark) artificial light (A) regimen. At approximately the spring and autumn equinox and the summer and winter solstice, rats were killed at 3-h intervals over a 24 h period and their serum thyroxine (T4), triiodothyronine (T3) and reverse T3 levels were determined. The light regimen and time of year significantly influenced the basic characteristics of the oscillations of the hormones. In the N regimen, T4 levels (T3 levels less) culminated in all seasons in correlation to sunrise. In the A regimen they culminated irregularly after daybreak. In animals with the N regimen, the oscillations of the hormones were rhythmic in all seasons, but in the A regimen in only some seasons. In the N regimen, the mean daily T4 concentration value (the mesor) was the highest in the spring and the lowest in the autumn; in the A regimen the mesors were the same, except for a low mesor in the autumn. In both light regimens, the T3 mesors were the highest in the autumn and low in the winter; the rT3 mesors were a mirror image of the T3 mesors. The annual mean of serum T4 concentrations was lower in the N group than in the A group.  相似文献   

19.

Subterranean Sericesthis geminata (Boisduval) beetles emerge from the soil daily during the flight season. Emergence and flight are initiated within 15 min after sunset. The beetles are active above the soil surface as the intensity of illumination decreases from 240 lux to 0.7 lux.

If young adult beetles still in their pupal cells in the soil are placed under constant, low‐intensity illumination, they first emerge at any time of day, showing no cyclical diurnal activity pattern. When such beetles are exposed to diurnal fluctuations in illuminance, the first emergence and flight occur at dusk. These beetles subsequently show a diurnal rhythm in their activity, even when exposed to constant environmental conditions. This endogenous activity cycle has a period of about 22 h, and is synchronised with diurnal fluctuations in light intensity. It is reset in response to a change in the photoperiod.

The data suggest that, after initial emergence from the soil, daily crepuscular activity is initiated by an endogenously controlled activity rhythm which causes the beetles to burrow to the soil surface shortly before dusk. At the soil surface they are exposed to fluctuations in the duration and intensity of illumination which may reset the endogenous rhythm, affecting the time of subsequent emergence.  相似文献   

20.
Ten male volunteers underwent a period of prolonged bed rest. Four subjects performed exercise countermeasures 2-3 times per week, while 6 subjects received no countermeasures. After bed rest plantarflexor force declined significantly (P < 0.001) in both exercise (-42%) and control (-55%) groups. The internal architecture of the gastrocnemius medialis (GM) muscle was significantly altered. This was associated with a reduction in fascicle shortening during isometric contraction. Exercise countermeasures partially mitigated the loss of muscle force and function following 90 days of bed rest.  相似文献   

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