Modification of the hypothermic circadian cycles induced by DSIP and melatonin in pinealectomized and hypophysectomized rats

Both melatonin and DSIP (a nine amino acid peptide) effects have been previously shown to be (a) circadian rhythm related and (b) involved in inducing hypothermic effects in rats. In this study we report the hypothermia effects by each of these drugs alone and in combination when studied in normal (unoperated), pinealectomized, and hypophysectomized rats at various time points of the corresponding circadian cycle. A clear differential effect of drugs × time × preparation was found. While both DSIP and melatonin hypothermic effects were both circadian cycle dependent in intact rats the rhythmicity of melatonin hypothermic effect in pinealectomized rats, and DSIP hypothermic effect in hypophysectomized rats was missing. Although several hypotheses have been offered to account for the physiological mechanism(s) that govern the effects of the drugs, it is not yet possible to reliably relate the findings to existing neurochemical theory.     

Zeitgeber hierarchy in humans: resetting the circadian phase positions of blind people using melatonin

Four blind individuals who were thought to be entrained at an abnormal circadian phase position were reset to a more normal phase using exogenous melatonin administration. In one instance, circadian phase was shifted later. A fifth subject who was thought to be entrained was monitored over four years and eventually was shown to have a circadian period different from 24 h. These findings have implications for treating circadian phase abnormalities in the blind, for distinguishing between abnormally entrained and free-running blind individuals, and for informing the debate over zeitgeber hierarchy in humans.     

Low,but not high,doses of melatonin entrained a free-running blind person with a long circadian period

In a previous report, we were unable to entrain one out of seven totally blind people with free-running endogenous melatonin rhythms to 10 mg of exogenous melatonin. This person had the longest circadian period (24.9 h) of the group. We now find that this person can be entrained to 0.5 mg of melatonin, but not to 20 mg. These results are consistent with the idea that too much melatonin may spill over onto the wrong zone of the melatonin phase-response curve.     

Chronotype-dependent circadian rhythmicity of driving safety

Among the factors associated with driving safety, sleep-related variables constitute a leading cause of road accidents. Circadian fluctuations of driver’s somnolence has been previously linked to road safety. However, the role of chronotype in this relationship has been poorly investigated. Thus, the aim of the present work was to address whether driving performance is influenced by circadian patterns, in turn modulated by the driver’s chronotype and the time of day (i.e. synchrony effect). We assessed 47 healthy young adults with specific chronotypes in several simulated driving sessions, both in the morning and in the evening. We collected driving performance data, along with self-reported levels of activation prior to each driving session and other sleep-related variables. Participants drove less safely when testing times took place outside their optimal time of day, as determined by their chronotype and confirmed by self-reported levels of activation. These differences were more pronounced in the morning, when morning types shown a better driving performance. Our results suggest that chronotype plays an important role as a modulator of the relationship between the time of day and driving safety. Therefore, it is necessary to acknowledge this variable in theoretical models of driving behavior, and for the improvement of occupational accidents prevention programs.     

Low,but not high,doses of melatonin entrained a free-running blind person with a long circadian period

In a previous report, we were unable to entrain one out of seven totally blind people with free-running endogenous melatonin rhythms to 10 mg of exogenous melatonin. This person had the longest circadian period (24.9 h) of the group. We now find that this person can be entrained to 0.5 mg of melatonin, but not to 20 mg. These results are consistent with the idea that too much melatonin may spill over onto the wrong zone of the melatonin phase–response curve.     

Evening physical activity alters wrist temperature circadian rhythmicity

The adequate time to perform physical activity (PA) to maintain optimal circadian system health has not been defined. We studied the influence of morning and evening PA on circadian rhythmicity in 16 women with wrist temperature (WT). Participants performed controlled PA (45?min continuous-running) during 7 days in the morning (MPA) and evening (EPA) and results were compared with a no-exercise-week (C). EPA was characterized by a lower amplitude (evening: 0.028?±?0.01?°C versus control: 0.038?±?0.016?°C; p?<?0.05) less pronounced second-harmonic (power) (evening: 0.41?±?0.47 versus morning: 1.04?±?0.59); and achrophase delay (evening: 06:35?±?02:14?h versus morning: 04:51?±?01:11?h; p?<?0.05) as compared to MPA and C. Performing PA in the late evening might not be as beneficial as in the morning.     

in-silico study of arylalkylamine-nacetyltransferase enzyme to regulate circadian rhythmicity

Circadian Rhythmicity is present in the sleeping and breeding patterns of animals, including human beings and also related withbrain wave activity, hormone production, cell regeneration and other biological activities. Melatonin is thought to play importantroles in regulating circadian rhytmicity of the animals. Arylalkylamine-N-acetyltransferase (AANAT) is an enzyme which isresponsible for the melatonin metabolism. In this study AANAT enzyme is targeted for the control of sleeping sickness and otherirregular circadian rhythmicity by regulating the melatonin formation. AANAT protein 3D-structure was modeled, followed byloop modeling, refinement through energy minimization processes by molecular dynamics simulation and validation. Analysis ofthe Ramachandran plot shows 90.9% amino acids falls in the allowed region. The modeled protein was docked with N-AcetylSerotonin. Combinatorial library was generated by using N-Acetyl Serotonin as a reference molecule and molecules having 80%similarity to N-Acetyl Serotonin was selected from Zinc database. These molecules were virtually screened by MOLEGRO virtualdocker and top 5 molecules were selected and docked by using AutoDock. The AutoDock result shows that the ZINC01587152molecule is having best interactions with the receptor protein. On the basis of this study we can suggest that the ZINC01587152molecule is the best ligand against AANAT enzyme. It may be further synthesized and tested for sleep related disorders.     

Entrainment of the circadian locomotor activity rhythm in the Japanese newt by melatonin injections

We examined whether melatonin can act as a synchronizing agent within the circadian system of amphibians by testing the ability of melatonin injections to entrain the circadian locomotor activity rhythm of a newt (Cynops pyrrhogaster). Under constant darkness, all newts (13 cases) showing the free-running rhythms were subcutaneously injected with 10 g melatonin at the same time every other day for at least 30 days. Subsequently, they were injected with vehicle (1% ethanolic saline) instead of melatonin for at least another 30 days. In 10 of the 13 newts, the locomotor activity rhythms could be entrained to a period of 24 h by melatonin injections but not by vehicle injections. During the entrained steady-state, the active phase of an activity-rest cycle preceded the time of melatonin injections as previously reported in other diurnal species. These results suggest that the endogenous circadian rhythm of melatonin concentration may be involved in synchronizing circadian oscillator(s) within the newt's circadian system.     

Complex circadian regulation of pineal melatonin and wheel-running in Syrian hamsters

Circadian regulation of pineal melatonin content was studied in Syrian hamsters (Mesocricetus auratus), especially melatonin peak width and the temporal correlation to wheel-running activity. Melatonin was measured by radioimmunoassay in glands removed at different circadian times with respect to activity onset (= CT 12). Pineal melatonin peak width (h; for mean 125 pg/gland) and activity duration () were both 4–5 h longer after 12 or 27 weeks than after 5 or 6 days in continuous darkness (DD). Increased peak width was associated with a delay in the morning decline (M) of melatonin to baseline, correlated with a similar delay in wheel-running offset. In contrast, the evening rise (E) in melatonin occurred at approximately the same circadian phase regardless of the length of DD. Fifteen min light pulses produced similar phase-shifts in melatonin and activity. In a phase advance shift, M advanced at once, while E advanced only after several days of adjustment. Independent timing of shifts in the E and M components of the melatonin rhythm suggest that these events are controlled separately by at least two circadian oscillators whose mutual phase relationship determines melatonin peak width. This two-oscillator control of melatonin peak width is integral to the circadian mechanism of hamster photoperiodic time measurement.Abbreviations CT circadian time - DD continuous dark - L: D light: dark cycle - PMEL pineal melatonin - PRC phase response curve - RIA radioimmunoassay; , duration (h) of the active phase of the circadian wheel-running rhythm; , free-running period     

Sleep and circadian phase characteristics of adolescent and young adult males in a naturalistic summertime condition

Our aim was to compare the circadian phase characteristics of healthy adolescent and young adult males in a naturalistic summertime condition. A total of 19 adolescents (mean age 15.7 years) and 18 young adults (mean age 24.5 years) with no sleep problems took part in this study. Two-night polysomnographic (PSG) sleep recordings and 24h secretion patterns of urinary 6-sulfatoxymelatonin were monitored in all 37 subjects. Sleep-wake patterns were initially assessed at home using a standard sleep diary. Circadian assessment included the measure of dim light melatonin offset (DLMOff) and the morningness-eveningness (M/E) questionnaire. As expected, compared to young adults, adolescents habitually spent more nocturnal time in bed and spent more time (and percentage) in delta sleep. No difference was found between adolescents and young adults on multiple sleep latency test (MSLT) sleep onset latencies, M/E, melatonin secretion measures (24h total, nighttime, daytime, and night ratio), and DLMOff. For the subjects as a whole, correlational analyses revealed a significant association between the DLMOff and M/E and between both these phase markers and habitual bedtimes, habitual rising times, and melatonin secretion measures (daytime levels and the night ratio). No association was found between phase markers and daytime sleepiness or sleep consolidation parameters such as sleep efficiency or number of microarousals. These results together indicate that adolescents and young adults investigated during summertime showed similar circadian phase characteristics, and that, in these age groups, an evening phase preference is associated with a delayed melatonin secretion pattern and delayed habitual sleep patterns without a decrease in sleep consolidation or vigilance. (Chronobiology International, 17(4), 489-501, 2000)     

Timely administration of melatonin accelerates reentrainment to phase-shifted light-dark cycles in the field mouse Mus booduga

The effect of melatonin on the rate of reentrainment after a 6h phase delay and a 6h phase advance in the light-dark (LD) cycle was assayed in the nocturnal field mouse Mus booduga. After a phase delay of 6h in the LD cycle, a single dose of melatonin (1 mg/kg) was administered for three consecutive days at about CT4 (circadian time 4). After a phase advance of 6h in the LD cycle, melatonin was administered for three consecutive days at about CT22. Melatonin was found to accelerate reentrainment in both cases. Melatonin-treated animals took significantly fewer cycles to reentrain compared to vehicle-treated (50% dimethylsulfoxide [DMSO]) and nontreated control animals.     

Daily and circadian variation in the electroretinogram of the domestic fowl: effects of melatonin

Visual and circadian function are integrally related in birds, but the precise nature of their interaction is unknown. The present study determined whether visual sensitivity measured electroretinographically (ERG) in 7-week-old cockerels varies over the time of day, whether this rhythm persists in constant darkness (DD) and whether exogenous melatonin affects this ERG rhythmicity. ERG b-wave amplitude was rhythmic in LD and persisted in DD with peak amplitude during mid- to late afternoon in LD and mid-subjective day in DD, indicating that the ERG rhythm is endogenously generated. No daily or circadian variation in a-wave amplitude was observed, and ERG component latency and durations were not rhythmic. Intramuscular injection of 10 g/kg melatonin at ZT10 in LD significantly decreased b-wave amplitude but had no effect on a-wave. Intraocular injection of 600 pg melatonin, however, had no effect on any aspect of the ERG. These data indicate that a circadian clock regulates ocular sensitivity to light and that melatonin may mediate some or all of this effect. The level at which melatonin modulates retinal sensitivity is not known, but the present data suggest a central site rather than a direct effect of the hormone in the eye.Abbreviations DD constant darkness - ERG electroretinography - EW Edinger-Westphal nuclei - IMEL iodomelatonin - IO isthmooptic nucleus - LD light-dark cycle - SCG superior cervical ganglion - SCN suprachiasmatic nuclei - vSCN visual suprachiasmatic nucleus     

Complete suprachiasmatic lesions eliminate circadian rhythmicity of body temperature and locomotor activity in golden hamsters

The effects of suprachiasmatic and control lesions on the circadian rhythms of locomotor activity and body temperature were studied in golden hamsters (Mesocricetus auratus) maintained in constant light as well as constant darkness. Large suprachiasmatic lesions, but not control lesions, eliminated circadian rhythmicity in locomotor activity as well as in body temperature. Analysis of the robustness of the rhythms of locomotor activity and body temperature in unlesioned and lesioned animals suggests that, because body temperature rhythmicity is more robust than locomotor rhythmicity, lesions that spare a small number of suprachiasmatic cells might abolish the latter but not the former. Our results do not support the hypothesis that the body temperature rhythm is controlled by a circadian pacemaker distinct from the main pacemaker located in the suprachiasmatic nuclei.     

Effects of suprachiasmatic nuclei lesions on circadian and ultradian rhythms in body temperature in ocular enucleated rats

Abstract

To test the hypothesis that an oscillator located outside the suprachiasmatic nuclei (SCN) controls the circadian rhythm of body temperature, we conducted a study with 14 blinded rats, 10 of which receiving a SCN lesion. Body temperature was automatically and continuously recorded for about one month by intraperitoneal radio transmitters. Food intake, drinking and locomotor activity were also recorded. Periodograms revealed that 3 rats with histologically verified total bilateral SCN lesions did not exhibit any circadian rhythmicity. The 7 other rats appeared to have partial lesions. They showed shortening of period and severe amplitude reduction in all functions. Thus, no support was found for the hypothesis of a separate circadian ‘temperature oscillator’ located outside the SCN. Nevertheless, after large partial lesions body temperature showed more persistency than some of the other behavioral rhythms.

Ultradian rhythms in temperature persisted after partial and total lesions. Other functions showed parallel ultradian rhythms. In intact rats the ultradian peaks were restricted predominantly to the subjective night. After total lesions these peaks became more or less homogeneously distributed in time but more heterogeneously after partial lesions. So the SCN plays a role in the temporal structure of ultradian rhythms but does not generate them. Non‐24‐hour actograms showed instabilities of period and phase of ultradian rhythms. Intact and lesioned rats were similar with respect to the mean (about 3.5 hrs) and standard deviation (about 1.5 hrs) of ultradian periods in temperature. These features indicate that a mechanism outside the SCN is underlying ultradian rhythmicity, capable of generating short‐term oscillations. Two approaches, homeostatic sleep‐wake relaxation oscillations and multiple circadian oscillators, are discussed.     

Circadian rhythms of melatonin in European starlings exposed to different lighting conditions: relationship with locomotor and feeding rhythms

In passerine birds, the periodic secretion of melatonin by the pineal organ represents an important component of the pacemaker that controls overt circadian functions. The daily phase of low melatonin secretion generally coincides with the phase of intense activity, but the precise relationship between the melatonin and the behavioral rhythms has not been studied. Therefore, we investigated in European starlings (Sturnus vulgaris) (1) the temporal relationship between the circadian plasma melatonin rhythm and the rhythms in locomotor activity and feeding; (2) the persistence of the melatonin rhythm in constant conditions; and (3) the effects of light intensity on synchronized and free-running melatonin and behavioral rhythms. There was a marked rhythm in plasma melatonin with high levels at night and/or the inactive phase of the behavioral cycles in almost all birds. Like the behavioral rhythms, the melatonin rhythm persisted for at least 50 days in constant dim light. In the synchronized state, higher daytime light intensity resulted in more tightly synchronized rhythms and a delayed melatonin peak. While all three rhythms usually assumed a rather constant phase relationship to each other, in one bird the two behavioral rhythms dissociated from each other. In this case, the melatonin rhythm retained the appropriate phase relationship with the feeding rhythm. Accepted: 10 December 1999     

The role of the pineal and the retinae in the expression of circadian locomotor rhythmicity in the ruin lizard,Podarcis sicula

Summary A marked interspecific variability in the role played by the pineal and the retinae characterizes the circadian system of lizards. I examined the role played by these structures in a new model species, the ruin lizard, Podarcis sicula. In constant temperature and darkness pinealectomy as well as bilateral removal of the retinae produced significant changes (both lengthening and shortening) in the freerunning period of locomotor rhythms. Circadian activity time was also affected by pinealectomy. Circadian locomotor rhythmicity persisted in all cases even when both operations were combined in the same individuals. This demonstrates in Podarcis sicula the existence of an oscillatory system outside the pineal and the retinae which can drive locomotor rhythms. The period changes recorded after pinealectomy as well as after bilateral removal of the retinae specifically suggest that both the pineal and the retinae play a modulating role on circadian oscillators located elsewhere in the system, with the final effect of stabilizing the overt rhythms.Abbreviations DD constant darkness - LL constant light - PIN-X pinealectomy - RET-X bilateral removal of the retinae - SHAM sham pinealectomy - circadian activity time - freerunning circadian period     

Role of morning melatonin administration and attenuation of sunlight exposure in improving adaptation of night-shift workers

The authors studied whether melatonin administration improves adaptation of workers to nightshift and if its beneficial effect is enhanced by attenuation of morning sunlight exposure. Twelve nightshift nurses received three treatments: Placebo (Pla), Melatonin (Mel), and Melatonin with Sunglasses (Mel-S). Each treatment procedure was administered for 2 d of different 4d nightshifts in a repeated measures crossover design. In Pla, nurses were treated with placebo before daytime sleep and allowed exposure to morning sunlight. In Mel, 6 mg of melatonin was similarly administered before daytime sleep with morning sunlight permitted. In Mel-S, 6 mg of melatonin was given as in Mel, with sunglasses worn in the morning to attenuate sunlight exposure. Placebo or melatonin was administered during days 2 and 3 when the first and second daytime sleep occurred. Nocturnal alertness and performance plus daytime sleep and mood states were assessed during all three treatments. The sleep period and total sleep times were significantly increased by melatonin treatments; yet, nocturnal alertness was only marginally improved. There were no differences between Mel and Mel-S. Performance tests revealed no difference between Pla and melatonin treatments. Melatonin exerted modest benefit in improving the adaptation of workers to nightshift, and its effect was not enhanced by attenuation of morning sunlight exposure.     

Melatonin Treatment Effects on Adolescent Students' Sleep Timing and Sleepiness in a Placebo-Controlled Crossover Study

During the last few decades, the incidence of sleep-onset insomnia, due to delay of circadian phase, has increased substantially among adolescents all over the world. We wanted to investigate whether a small dose of melatonin given daily, administered in the afternoon, could advance the sleep timing in teenagers. Twenty-one students, aged 14–19 yrs, with sleep-onset difficulties during school weeks were recruited. The study was a randomized, double blind, placebo (PL)-controlled crossover trial, lasting 5 wks. During the first 6 d in wks 2 and 4, the students received either PL or melatonin (1 mg) capsules between 16:30 and 18:00 h. During the first 6 d of wk 5, all students received melatonin. Wks 1 and 3 were capsule-free. In the last evening of each week and the following morning, the students produced saliva samples at home for later melatonin analysis. The samples were produced the same time each week, as late as possible in the evening and as early as possible in the morning. Both the student and one parent received automatic mobile text messages 15 min before saliva sampling times and capsule intake at agreed times. Diaries with registration of presumed sleep, subjective sleepiness during the day (Karolinska Sleepiness Scale, KSS) and times for capsule intake and saliva samplings were completed each day. Primary analysis over 5 wks gave significant results for melatonin, sleep and KSS. Post hoc analysis showed that reported sleep-onset times were advanced after melatonin school weeks compared with PL school weeks (p < .005) and that sleep length was longer (p < .05). After the last melatonin school week, the students fell asleep 68 min earlier and slept 62 min longer each night compared with the baseline week. Morning melatonin values in saliva diminished compared with PL (p < .001) and evening values increased (p < .001), indicating a possible sleep phase advance. Compared with PL school weeks, the students reported less wake up (p < .05), less school daytime sleepiness (p < .05) and increased evening sleepiness (p < .005) during melatonin weeks. We conclude that a small dose of melatonin given daily, administered in the afternoon, could advance the sleep timing and make the students more alert during school days even if they continued their often irregular sleep habits during weekends. (Author correspondence: arne.lowden@stress.su.se)     

Increased REM sleep associated with melatonin deficiency after pinealectomy: a case study

The objectives of the investigation were to assess hypersomnia, which progressively appeared in a young patient after a pinealectomy, chemotherapy, and radiotherapy for a typical germinoma, as well as the potential benefit of melatonin administration in the absence of its endogenous secretion. 24 h ambulatory polysomnography and the Multiple Sleep Latency Test (MSLT) were performed; in addition, daily plasma melatonin, cortisol, growth hormone, prolactin, and rectal temperature profiles were determined before and during melatonin treatment (one 2 mg capsule given nightly at 21:00 h for 4 weeks). MSLT showed abnormal sleep latency and two REM sleep onsets. Nighttime total sleep duration was lengthened, mainly as a consequence of an increased REM sleep duration. These parameters were slightly modified by melatonin replacement. Plasma melatonin levels, which were constantly nil in the basal condition, were increased to supraphysiological values with melatonin treatment. The plasma cortisol profile showed nycthemeral variation within the normal range, and the growth hormone profile showed supplementary diurnal peaks. Melatonin treatment did not modify the secretion of either hormone. The plasma prolactin profile did not display a physiological nocturnal increase in the basal condition; however, it did during melatonin treatment, with the rise coinciding with the nocturnal peak of melatonin concentration. A 24 h temperature rhythm of normal amplitude was persistent, though the mean level was decreased and the rhythm was dampened during melatonin treatment. The role of radiotherapy on the studied parameters cannot be excluded; the findings of this case study suggest that the observed hypersomnia is not the result of melatonin deficiency alone. Overall, melatonin treatment was well tolerated, but the benefit on the sleep abnormality, especially on daytime REM sleep, was minor, requiring the re-introduction of modafinil treatment.     

Effects of twilights on circadian entrainment patterns and reentrainment rates in squirrel monkeys

Entrainment patterns of the circadian rhythms of body temperature and locomotor activity were compared in 6 squirrel monkeys (Saimiri sciureus) exposed to daily illumination cycles with abrupt transitions between light and darkness (LD-rectangular) or with gradual dawn and dusk transitions simulating natural twilights at the equator (LD-twilight). Daytime light intensity was 500 lux, and the total amount of light emitted per day was the same in the two conditions. Mean daytime body temperature levels were stable in LD-rectangular but increased gradually in LD-twilight, reaching peak levels during the dusk twilight. Locomotor activity showed a similar pattern, but with an additional, secondary peak near the end of dawn. Activity duration was about 0.5 h longer in LD-twilight than in LD-rectangular, but the time of activity midpoint was similar in the two conditions. Reentrainment of the body temperature rhythm was faster following an 8-h advance of the LD cycle than following an 8-h delay, but did not differ significantly between the two LD conditions. These results provide no evidence that the inclusion of twilight transitions affected the strength of the LD Zeitgeber, and suggest that the observed differences in the daily patterns reflected direct effects of light intensity on locomotor activity and body temperature rather than an effect of twilights on circadian entrainment mechanisms.Abbreviation LD light-dark