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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 10 3618-3622
Copyright © 2000 by The Endocrine Society

Original Studies

Melatonin Does Not Shift Circadian Phase in Baboons1

Haiping Hao and Scott Rivkees2

Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06520

Address all correspondence and requests for reprints to: Dr. Scott A. Rivkees, Department of Pediatrics, Yale University School of Medicine, 464 Congress Avenue, YCHRC, Room 239, New Haven, Connecticut 06520. E-mail: scott.rivkees{at}yale.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
It has been suggested that the pineal hormone melatonin can modulate circadian rhythmicity and may have clinical utility in treating biological clock disorders. Thus, there is considerable clinical interest in using melatonin to treat disorders, such as jet-lag. Yet, despite growing enthusiasm for the use of melatonin, it is not clear whether melatonin indeed shifts the circadian phase in humans and other primate species. Thus, to assess whether melatonin can influence circadian phase, we studied the phase-shifting effects of melatonin on baboons to provide insights into the role of melatonin. Melatonin was administered orally to baboons (0.5, 3, 5, or 10 mg) either in the early morning hours from circadian time (CT) 0 to CT3 or late in the afternoon from CT9 to CT12, and changes in circadian phase were assessed. Surprisingly, at all doses and times tested, melatonin did not shift circadian phase. Physical activity was reduced after 5- and 10-mg doses given late in the afternoon, but not after doses given early in the morning. These observations suggest that melatonin does not shift circadian phase in baboons using doses similar to those prescribed for treating human circadian system disorders.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
CIRCADIAN RHYTHMS are expressed for a variety of biochemical, physiological, and behavioral processes in all mammals. These rhythms, under the control of a circadian clock located in the hypothalamic suprachiasmatic nuclei (SCN), persist in constant environmental conditions, indicating that they are endogenously generated (1). Endogenous rhythmicity is entrained to the external light-dark cycle, ensuring synchronization of physiological activities with the environment (2). Light is the most potent entraining stimulus, and the retinohypothalamic tract projecting from the retina to the SCN has been shown to be both necessary and sufficient for photic entrainment (2).

Acute changes in the circadian clock’s phase relationship with the outside world result in desynchronized endogenous and exogenous rhythms (3, 4). Such desynchronization occurs commonly after rapid travel across several time zones, resulting in jet-lag, or during rotating shift work. Desynchronization of internal and external clock phases can result in sleep difficulties, reduced alertness, and impaired job performance (4). Some blind individuals may also suffer from problems related to mismatched endogenous and environmental phases due to a lack of photic entrainment (3). Thus, there is considerable interest in developing nonphotic means for regulating circadian phase (5).

Recently, it has been suggested that the hormone melatonin may influence the circadian clock, and there is considerable interest in using melatonin to treat circadian rhythm disorders (6, 7). Melatonin is a pineal hormone that is produced and secreted during the dark phase of the circadian cycle (8). In mammals, rhythmic melatonin synthesis and secretion are regulated by the SCN (9, 10).

In mammals, there is some evidence to suggest that melatonin influences circadian clock function (8). High affinity melatonin receptors are present in the SCN of many species of mammals (11, 12, 13). In vitro melatonin can act directly on the SCN and affect electrical and metabolic rhythms (14, 15, 16). Daily injections of melatonin have also been shown to entrain and phase-shift activity rhythms in rodents. These entraining effects of melatonin are limited to the hours surrounding day-night transition (16). However, melatonin may not universally influence circadian function, as circadian phase is not affected by exogenous melatonin administration in hamsters (17, 18).

In humans, melatonin receptors have also been identified in the SCN (19). It has been suggested that melatonin administration results in acute shifts of hormonal, temperature, and sleep-wake rhythms (20, 21, 22). However, this is an area of controversy, as other investigators have found that melatonin does not alter circadian phase in humans treated with similar doses (23, 24).

Because of human study limitations, it has not been possible to study humans in constant conditions for prolonged periods to assess whether melatonin indeed shifts circadian phase. Thus, to test whether melatonin can shift circadian phase in primate species, we studied the effects of melatonin in baboons in carefully controlled conditions. Baboons were used because they are phylogenetically more closely related to human than other monkeys (25, 26), baboons are diurnal animals that have robust circadian rhythms in locomotor activity and hormone secretion (25, 27, 28, 29, 30), and the phase-shifting effects of light and light sensitivity are similar in baboons and humans (30). Melatonin receptors are present in baboon SCN (31, 32). Similar to other monkey species, there is a day-night rhythm in melatonin production in baboons (33). We now report that using melatonin doses similar to those used clinically, melatonin fails to shift circadian activity rhythms in baboons.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals

Three baboons (Papio spp.), 2–5 yr of age, were housed individually in rooms where lighting cycles could be strictly controlled. Phillips Cool White fluorescent lights provided illumination (Somerset, NJ). Dim red lights were kept on at all the times to provide background illumination when the white lights were turned off (darkness, 10 lux). Baboons were housed in 6 x 3.5 x 7-ft cages.

To avoid environmental influences on activity patterns, animals were housed in a restricted area in a basement animal care facility dedicated to our animals. The walls in the room were made of thick concrete, and no noise from outside the rooms could be heard from within. Animals were cared for by technicians once per day. Cage cleaning and food delivery were performed each day at a randomized time between 0700–1900 h. As previously reported (30), animal care procedures are not sufficient to entrain free running rhythms in baboons. These studies were approved by the Yale Animal Care and Use Committee.

Treatment paradigms

Baboons were exposed to 12-h light, 12-h dark cycles for at least 2 weeks. During the light portion of the cycle, the lighting intensity at the level of the cage was 200–500 lux. To examine expressed rhythmicity in constant conditions, animals were exposed to constant dim red light. Circadian phase was assessed from activity patterns (see below). At specific times of the circadian cycle (see below), melatonin (Sigma, St. Louis, MO) was administered orally in food for 3 consecutive days at the same time each day. This paradigm was used based on studies in humans and baboons that have revealed phase-shifting effects of light (30, 34).

Melatonin was administered orally to avoid injections. The animals readily ate the food to which melatonin in solution had been applied. All animals were observed to eat the melatonin-laden food after each treatment. In general, animals were treated 4 h or more after they had eaten their last meal.

Melatonin doses of 0.5, 3, 5, and 10 mg were selected to be similar to those reported for clinical use (21, 35, 36). Each dose was tested at least three times, at two different circadian phases in each animal (before activity offset and after activity onset) After each treatment, baboon activity was recorded for up to 2 weeks to determine possible phase shift and the circadian phase. In some studies melatonin levels were measured, as previously described (37), after administration of 0.5-mg doses given in the same food snack used in the treatment paradigms between 1200 and 1500 h. Samples were obtained 1 h after administration.

Data acquisition and analysis

Activity data were collected and analyzed using the Mini Mitter VitalView Data acquisition system (Mini Mitter Co., Inc., Sunriver, OR). Radio transmitters (VM-FH Disc 5cm, Mini Mitter Co., Inc.) were implanted sc in the flank or back of each animal under general anesthesia. Receivers were mounted outside the cages within the range of the radio signal for each transmitter. Data were collected continuously and stored in a computer for later analysis. Behavioral data were examined as double plotted actograms. Circadian phase was determined using Tau software (Mini Mitter Co., Inc.) and by visual assessment of activity onset and offset patterns as previously described (30).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
We have previously validated that baboons housed in constant conditions manifest free running circadian rhythms and that small phase shifts induced by light can be detected (30). Similar to what we previously reported, all baboons showed free running activity rhythms, with average periods of 23.7 ± 0.1, 23.9 ± 0.1, and 24.0 ± 0.1 h. When animals were placed in a reversed light-dark cycle, which was 12 h out of phase with their activity rhythms, for 1 week and then placed in a constant condition under dim red light, the new phase of their activity rhythms assumed that of the reversed lighting cycles, suggesting that there is no masking of circadian rhythm by any environmental factors. We also observed 3-h phase shifts after pulses of light given early in the subjective night. These observations indicate that the baboons express circadian rhythms, expressed rhythmicity is entrained by light/dark cycles, and the light shifts activity rhythms.

To validate that oral melatonin leads to increases in melatonin levels, serum melatonin levels were assessed in the morning in animals that received food not containing melatonin or food that contained 0.5 mg melatonin. Melatonin was measured in the blood 1 h later. In two animals that received the food alone (placebo), levels were 1.5 and 1.3 pg/mL. In two animals that received melatonin, levels were 108 and 168 pg/mL. Thus, as has been well described and validated in monkeys and humans (38, 39, 40), oral melatonin administration results in a large increase in circulating melatonin levels in baboons.

We next tested whether melatonin can shift circadian phase. First, 1-mg doses of melatonin were given to one baboon at circadian time (CT) 3, 12, 15, or 18 h. However, no shifts in circadian phase were observed.

Next, we administered melatonin (0.5, 3, 5, or 10 mg) to three baboons either during the early subjective day (CT0–3) or late subjective day (CT9–12) for 3 consecutive days for each dose (n = 2 or more trials/animal·dose). As described above, we could not detect any shifts in circadian phase after doses given in the morning or the evening (Figs. 1Go and 2Go).



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  		Figure 1. Melatonin did not phase-shift baboon locomotor activity rhythm at 0.5-mg (A) or 3-mg (B) doses. Actograms are shown with dark bars representing periods of activity. Animals were maintained in constant darkness. Arrows denote the timing of melatonin administration, and stars indicate the days of melatonin treatment. Data shown are from one animal for each treatment, and they are representative of those from two others.

 


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  		Figure 2. Melatonin did not phase-shift baboon locomotor activity rhythms at 5-mg (A) or 10-mg (B) doses. However, melatonin administered late in the subjective day acutely reduced activity level. Actograms are shown with dark bars representing periods of activity. Animals were maintained in constant darkness. Arrows indicate the timing of melatonin administration, and stars indicate the days of melatonin treatment. Data shown are from one animal and are representative of those from two others.

 
Although melatonin did not shift activity rhythms at any of the doses tested, melatonin acutely reduced activity levels after 5 or 10 mg given between CT9–12 (Fig. 2Go). In contrast to that observed after evening doses, 5- or 10-mg doses administered during the early subjective day had no effect on activity (Figs. 1Go and 2Go). Doses of 0.3 and 3 mg melatonin did not reduce activity levels at any time tested.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In nonmammalian vertebrates, the pineal hormone melatonin is an important component of the circadian system (41). In birds and lizards, pinealectomy disrupts or abolishes circadian rhythms, and exogenous melatonin entrains circadian phase (41). In contrast, in mammals, melatonin is not essential for expressed rhythmicity (8, 42), as pinealectomy has little or no effect on expressed rhythmicity (43, 44).

Interest in the potential role of melatonin in mammalian circadian organization increased greatly when melatonin administration was found to entrain locomotor and drinking rhythms in Long-Evans rats (45). However, melatonin injections have not been observed to affect circadian phase in hamsters orin studies involving rats (17, 18).

In humans, it has also been suggested that circadian rhythmicity may be affected by melatonin. Daily oral melatonin administration to free-running blind individuals has been shown to entrain activity patterns to the 24-h light-dark cycle (6, 22, 46, 47, 48). Melatonin has also been shown to help alleviate the symptoms of jet-lag (6). However, after melatonin treatment, circadian phase estimated from humoral rhythms is not in phase with rest-activity patterns, suggesting that symptomatic improvements may not be due to shifting circadian phase (23, 24, 49).

In humans, a phase-response curve to melatonin has been proposed using dim light melatonin onset as a phase marker (50, 51). Those studies showed that the human phase response curve to melatonin was about 12 h out of phase with the phase response curve to light. It has been suggested that the optimal time for administering melatonin to cause a phase advance is in the afternoon (2–3 h before dusk), whereas the optimal time to cause a phase delay is just after sleep offset (2–3 h after dawn) (51). In those studies circadian phase was assessed the day after treatment. Modest phase shifts of about 60 min were observed relative to phase shifts of 29 min with placebo (51).

To further characterize the effects of melatonin on circadian phase in primates and determine whether melatonin can indeed influence primate circadian phase, we studied baboons under conditions favorable for detecting small phase shifts by continuously monitoring animals for up to 2 weeks after drug treatments. Showing the utility of this approach, we could observe free running rhythms and small phase shifts after short light pulses. Surprisingly, we could not detect any effect of melatonin on circadian phase. The only treatment effect that we observed was reduced activity after higher dosages of 5 or 10 mg given late in the subjective day. Other hypnotic agents have also been shown to be more potent late in the day than at earlier times (52).

Because we were not studying animals with indwelling catheter, melatonin levels were not measured routinely after all doses. However, available evidence suggests that the oral doses were effective for several reasons. First, it is well recognized that oral doses of melatonin are promptly absorbed and can lead to high circulating levels of melatonin (31, 38, 39, 40). Second, there is no known example of impaired melatonin absorption regardless of dietary conditions or time of day. Third, we show that melatonin levels rise more than 100-fold after oral doses under the same treatment conditions as those used in this study. Fourth, we have a bioassay of melatonin effects in our studies, as the baboons became sleepy after the treatment, which is reflected in the decreased activity after doses. By direct observation, we also confirmed that the animals ate the melatonin-laden food.

Note that we recognize that differences in responses to melatonin between baboons and humans may explain why we cannot detect phase shifts after melatonin treatment. However, we and others have found that baboons and other monkeys are excellent models for human circadian physiology (10, 53, 54, 55). We are also unaware of major differences in circadian physiology among baboons and other Old World, nonhuman primates and man. Thus, it is also possible that the situation in monkeys is similar to that found in man.

Overall, our observations indicate that using doses of melatonin similar to those prescribed for treating human circadian disorders does not phase-shift the circadian phase in baboons. These observations raise the possibility that the effects of melatonin seen in the treatment of jet-lag or other circadian disorders are not due to the phase-shifting effects of this commonly used pineal hormone, but may be due to hypnotic properties.


   Footnotes
 
1 This work was supported by NIH Grant RO1-NS-32624 (to S.A.R.) and a James Hudson Brown-Alexander Brown Coxe fellowship (to H.H.). Back

2 Donaghue Medical Research Foundation Investigator. Back

Received April 4, 2000.

Revised May 19, 2000.

Accepted June 27, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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