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1 Neurobiologie des Fonctions
Rythmiques et Saisonnières, Daily administration of melatonin or
S20098, a melatonin agonist, is known to entrain the free-running
circadian rhythms of rats. The effects of the duration of
administration on entrainment were studied. The animals demonstrated
free-running circadian rhythms (running-wheel activity, body
temperature, general activity) in constant darkness. Daily
infusions of melatonin or S20098 for 1, 8, or 16 h entrained the
circadian rhythms to 24 h. Two daily infusions of 1 h (separated by 8 h) entrained the activity peak within the shorter time interval. The
entraining properties of melatonin and S20098 were similar and were
affected neither by pinealectomy nor by infusion of 1- or 8-h duration.
However, with 16-h infusion, less than half of the animals became
entrained. Once entrained, the phase angle between the onset of
infusion and the rhythms (onset of activity or acrophase of body
temperature) increased with the duration of infusion. Before
entrainment, the free-running period increased with the duration of
infusion, an effect that was not predictable from the phase response curve.
entrainment
IN MAMMALS, many physiological and behavioral functions
present circadian variations. This rhythmic pattern is generated by a
circadian oscillator localized in the suprachiasmatic nuclei of the
hypothalamus (SCN) (38, 48, 57). Lesions of the SCN abolish circadian
rhythmicity (61). In condition of constant darkness (DD), the circadian
clock free runs with its own period, different from but close to 24 h.
The daily light-dark cycle (LD) is the main synchronizer of the
circadian clock, and photic information entrains the pacemaker to a
period of exactly 24 h by eliciting the appropriate phase shift every
day (46). Besides this pathway, free-running rhythms can also be
affected by nonphotic stimuli, such as drug treatment (8, 18), food
restriction (15, 60), or locomotor activity (42).
The SCN are also involved in the generation of certain endocrine
rhythms, such as the melatonin rhythm. The lesion of the SCN abolishes
the rhythm of N-acetyltransferase
activity, the rate-limiting enzyme of melatonin synthesis, within the
pineal gland (29). Melatonin is a hormone produced by the pineal gland only during the night, and the duration of its secretion is
proportional to the duration of the night (25). Melatonin was first
studied as a conveyor of photoperiodic information to the brain (review in Refs. 4, 44), allowing seasonal adaptation of various physiological
functions (breeding, molt, hibernation, etc.). However, because
melatonin synthesis is rhythmic, it also provides day/night information
to the brain, and melatonin can act on the expression of circadian
rhythms (2). In rats, daily acute injection of melatonin can entrain
the locomotor rhythm of free-running animals (50). Melatonin is also
known to accelerate the reentrainment of circadian rhythms in rats
subjected to a shift in the LD cycle (49). These effects require the
integrity of the SCN (13). In vitro, melatonin can modify the
electrical activity of SCN neurons (58) and also phase shift the firing
rate of SCN neurons in brain slices (37). In Syrian and Siberian
hamsters, melatonin infusion can entrain the running-wheel activity of
animals maintained in constant darkness (28). Recently, membrane-bound
receptors of melatonin have been characterized in the SCN of mammals
(review in Refs. 34, 41). Melatonin has therefore been proposed to act
as an internal Zeitgeber regulating the expression of circadian rhythms
(2).
The development of synthetic analogs for hormones provides
physiological tools to understand the actions of these hormones and
opens the field of therapeutical approaches. Among the synthesized melatonin analogs, S20098 has specific agonist properties. It has a
high specific binding affinity for melatonin binding sites (69). Like
melatonin, S20098 downregulates melatonin receptor density (24, 35). It
can also entrain the rhythms of free-running rats when administered in
the late subjective day (9), and it affects the reentrainment of rat
after a phase shift of the LD cycle (52). The action of S20098 is dose
dependent (33) and also requires the integrity of the SCN (51). In
mouse and hamster, single doses of S20098 can phase shift the activity
rhythms (64). In vitro, the firing rate of SCN neurons in brain slices can be affected in a similar manner by melatonin and S20098 (20). In
vivo, both S20098 and melatonin given intraperitoneally are able to
suppress the firing rates of SCN cells in a similar dose-dependent manner, but the effects of S20098 are longer lasting (68).
To this date, however, all in vivo studies have been based on bolus
administration of melatonin or S20098. This imposed a handling of the
animals, which could have interfered with the results (50).
Furthermore, the duration of the melatonin peak could not be
controlled, although this duration provides an essential information in
photoperiodic animals. The effects of the duration of administration on
the expression of circadian rhythms are still unknown. To address these
points, we have used a chronic infusion device, providing for
continuous drug infusion of controlled duration (and dose) without
handling the animals. We could then follow rats over several months to
test the effects of periodic (daily) infusions of melatonin or S20098
of variable duration or pattern on the circadian rhythms.
Adult male Long-Evans rats were purchased from a commercial supplier
(Janvier, France). Before experimentation, animals (initial body mass
~200 g) were adapted to laboratory conditions for at least 2 wk (LD
12:12, lights on from 0700 to 1900, temperature 22 ± 1°C).
Throughout the experiments, the animals received food pellets and tap
water ad libitum.
Surgical Procedures
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
For the infusion, cannulation was performed as previously described (28, 45). Briefly, animals were anesthetized with Equithesin, and a cannula was introduced under the skin of the neck. The distal end of the cannula was placed on a swivel fixed to a bar hung from the top of the cage. The swivel was connected to a syringe carried by a pump (Harvard Apparatus). The pump was controlled by an electronic timer. The syringe was refilled weekly.
Simultaneously with cannulation, animals were implanted intraperitoneally with Mini-Mitter telemetry devices (Mini-Mitter, Sunriver, OR), to record body temperature and general activity every 5 min (Dataquest III acquisition system, Data Sciences, MN). Each cage was also equipped with a running-wheel that closed a microswitch on each turn (turns were counted every 5 min, Dataquest III).
After surgery, animals were transferred to individual cages. After 2 days of recovery they were infused daily with a vehicle solution (0.5% ethanol-Ringer) under the conditions to be used later for drug infusion. The animals were then maintained on LD 12:12 for at least 1 wk before being transferred to constant dim red light (DD, light intensity <1 lux).
Experimental Protocols
Twelve groups of animals were infused for various durations and with various doses, as follows (see Table 1).
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Single 1-h infusion. Four groups of
ten animals were infused for 1 h/day. They were infused with either
melatonin ( groups M-1h-50 and
M-1h-100) or S20098
( groups S-1h-50 and
S-1h-100). For each drug, two doses
were used: 50 ( groups M-1h-50 and
S-1h-50) and 100 µg/h
( groups M-1h-100 and
S-1h-100) (0.25 and 0.5 mg · kg
1 · h1,
respectively, at the beginning of the experiment).
Single 8-h infusion. Three groups were infused for 8 h/day with a dose of 50 µg/h. One group (group S-8h-50) was infused with S20098 (n = 10). The other two groups were infused with melatonin, and were either pinealectomized (group M-8h-50-Px, n = 6) or intact (group M-8h-50, n = 6).
Single 16-h infusion. Three groups were infused for 16 h/day. Two groups were infused with melatonin at doses of 50 and 100 µg/h [groups M-16h-50 (n = 10) and M-16h-100 (n = 9), respectively]. The third group was infused with S20098 at a dose of 50 µg/h ( group S-16h-50, n = 10).
Two 1-h infusions. Two groups were infused for 1 h twice a day. The first administration was from 0300 to 0400, the second from 1800 to 1900. In such a "skeleton" type infusion, the two signals corresponded to the extremities of the 16-h infusion. Animals were infused with a dose of 100 µg/h of either melatonin (group M-2×1h-100, n = 10) or S20098 ( group S-2×1h-100, n = 9).
After several weeks of infusion, the drugs were replaced by vehicle infusion to allow animals to free run again. The overall duration of experiments varied between 4 and 5 mo.
Graphical Representation
To facilitate the understanding of such long-term experiments, a similar presentation was used for all three variables studied, i.e., body temperature, general activity, and running-wheel activity (Fig. 1). Sampling period, 5 min, was the same for the three variables.
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Because of the very long duration of the experiments, decline of the battery voltage of radiotransmitters was not uncommon, leading to a downward drift of the recorded body temperature that could reach up to 1°C over the whole experiment (~0.006°C/day). To compensate for this, the daily average of body temperature (µTb) was calculated. A correction was then applied to all data to make µTb arbitrarily equal to a constant value, here 37.5°C (Kirsch, unpublished observations). Corrected body temperature data are represented on a linear scale ranging from 36.5 to 39.5°C.
For general and running-wheel activity, data are presented on a logarithmic scale, ranging from 1 to 1,000 counts/5 min.
On the graphs, the infusion time is represented by a gray pattern with a width corresponding to the duration of infusion. The vehicle infusion is shown in light gray, whereas melatonin or S20098 infusion is shown in dark gray.
Data Analysis
Temperature data were fitted by nonlinear least-squares regression analysis to the following equation (cosinor)
![y = Y<SUB>0</SUB> + [a<SUB>0</SUB> ⋅ cos (2&pgr;(<IT>t</IT> − ϕ)/&tgr;)]](/content/vol277/issue3/fulltext/R812/img001.gif)
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, and 
were the four
parameters to be determined. Y0
was the mean temperature, a0 was
the amplitude of temperature rhythm, was the acrophase, was the
circadian period, and t was the
standard local time.
The cosinor analysis was performed on the data of at least 7 consecutive days for each animal. For the groups that received a single
daily infusion, the data of body temperature were divided into five
different stages (Fig. 2): exposure to LD
conditions (stage
1), free-running conditions with
vehicle infusion (stage 2), the period of melatonin or
S20098 infusion preceding detectable entrainment
(stage
3), the entrainment of the rhythm
(stage
4), and the free-running rhythm
after withdrawal of melatonin or S20098 (stage
5). For the two groups infused two
times in 1 h, an additional stage
(stage
3') was included between
stages
3 (free run) and 4 (entrainment) (see Figs. 9-11).
Because of technical mishaps during long-term recording, it was not
possible to apply the regression analysis to all the stages in some
animals, which explains why some values are missing on the figures. On
the figures, error bars around each individual value represent the SE
of the parameter as estimated by the curve-fitting procedure.
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Phase-angle differences (
) were estimated in two ways, according to
the rhythm studied. For temperature, when a period not significantly
different from 24 h was determined by cosinor analysis, a period of
exactly 24 h was imposed to calculate with a higher accuracy the
acrophase of the temperature rhythm ('). For wheel running,
daily onset (DO) was estimated by eye fitting over at least 10 consecutive days. Phase angle was given by the difference between the
onset of infusion time and the phase index (' or DO).
Student's t-test was used for
comparisons of the calculated s for various stages within a given
group. One-way ANOVA followed post hoc by Duncan's multiple-range test
was used for phase-angle comparisons between groups. In both cases,
dispersion within individuals (i.e., around regression line) was
assumed to be much lower than dispersion between individuals and was
therefore ignored. Values are given as means ± SE between animals.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Three types of responses to the treatment were observed: true entrainment, transient entrainment, or no response (Table 1). True entrainment was characterized by a synchronization of the rhythms as long as melatonin or S20098 was administered. When true entrainment occurred, the three physiological variables (body temperature, running-wheel, and general activity) showed the same response (Fig. 1). Transient entrainment was characterized by a synchronization of the rhythms for a few days up to 2 wk, after which the animals free ran until melatonin or S20098 was withdrawn (see Fig. 8). Finally, some animals did not respond to the treatment and free ran throughout the experiment.
Effects of 1-h Infusion
In group M-1h-50 (Fig. 2, A and B), when the animals were transferred to DD (stage 2) a classical free run of the rhythms was observed, with a period close to 24 h but significantly different from that of LD conditions (stage 1) (24.15 ± 0.03 h in stage 2 vs. 23.98 ± 0.01 h in stage 1, P < 0.05). The first days of melatonin infusion (stage 3) did not affect the period, which remained constant (24.15 ± 0.05 h). Thereafter, the infusion led to an entrainment in 9 out of the 10 animals; only one did not synchronize (Fig. 2B, stage 4). In one of these nine animals however, entrainment was only observed during a few days, after which the animal free ran again with a period similar to that measured after replacement of melatonin by a saline solution. In stage 5 (Fig. 2B), the free-running period with vehicle infusion was longer than that determined in stage 2 (24.32 ± 0.03 h in stage 5 vs. 24.15 ± 0.03 h in stage 2, P < 0.05).In group S-1h-50 (Fig. 2C), the animals showed a clear free run in DD (24.27 ± 0.03 h in stage 2 vs. 24.00 ± 0.02 h in stage 1, P < 0.05). At this dose the infusion of S20098 for 1 h was not able to entrain the rhythms that kept free running (Fig. 2C, stages 3 and 4). Only in one animal was a transient entrainment observed during a few days. In the last stage and similar to group M-1h-50, animals continued to free run during vehicle infusion with a period significantly longer than in stage 2 (24.41 ± 0.04 h in stage 5 vs. 24.27 ± 0.03 h in stage 2, P < 0.05).
In group
M-1h-100 (Fig.
3B),
after the free run observed in DD
(stage
2), the first days of melatonin
administration did not modify the period of the rhythms. One-hour
infusion of melatonin at a dose of 100 µg/h clearly resulted in a
true entrainment of the rhythms in all animals, which was sustained as
long as melatonin was present (stage
4). The return to a free-running
condition (vehicle infusion in stage
5) was characterized by a
significant lengthening of the period compared with
stage
2 (24.36 ± 0.02 h in
stage
5 vs. 24.14 ± 0.03 h in
stage
2, P < 0.05).
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In group S-1h-100 (Fig. 3, A and C) the first days of S20098 infusion (stage 3) induced a significant lengthening of the period compared with the free run with saline infusion (24.24 ± 0.04 h in stage 3 vs. 24.13 ± 0.02 h in stage 2, P < 0.05). After this transient change in the period, and as in group M-1h-100, the infusion of S20098 at a dose of 100 µg/h was able to entrain the rhythms of all the animals (stage 4) as long as S20098 was administered. Again, the vehicle infusion in the last stage led to a free run of the rhythms with a period slightly longer than in stage 2 (24.25 ± 0.05 h in stage 5 vs. 24.13 ± 0.02 h in stage 2, P = 0.06).
Effects of 8-h Infusion
In group M-8h-50 (Fig. 4B), the daily 8-h infusion of melatonin induced in the first days (stage 3) a slight, nonsignificant lengthening of the period compared with vehicle infusion (24.47 ± 0.08 h in stage 3 vs. 24.34 ± 0.02 h in stage 2, NS). This was followed by an entrainment of the rhythms of all the animals tested (stage 4). A vehicle infusion (stage 5) allowed the animals to free run again, with a period (24.38 ± 0.04 h) similar to that measured in stage 2.
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In group S-8h-50 (Fig. 4, A and C), the daily 8-h infusion of S20098 induced the same responses as melatonin. The initial days of S20098 increased the period slightly, but not significantly, compared with saline infusion (24.45 ± 0.06 h in stage 3 vs. 24.28 ± 0.06 h in stage 2, NS). S20098 was then able to entrain the rhythms of all the animals (stage 4). A clear free run was observed in the last stage (vehicle infusion), with a period (24.24 ± 0.06 h) close to that determined in stage 2.
The effect of pinealectomy was also tested with an 8-h infusion in
group M-8h-50-Px (Fig.
5). The results were similar to controls
with the same infusion pattern (group
M-8h-50). After the free run in
stage
2, the first days of melatonin
administration induced a lengthening of the period (24.32 ± 0.04 h
in stage
3 vs. 24.17 ± 0.05 h in
stage
2, P < 0.05). Then all animals presented a clear entrainment of their
rhythms (stage
4). After replacement of melatonin
by a vehicle infusion, they all free ran, with a slightly but not
significantly longer period than in
stage
2 (24.30 ± 0.04 h in
stage
5 vs. 24.17 ± 0.05 h in
stage
2, NS).
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Effects of 16-h Infusion
In group M-16h-50 (Fig. 6B), the animals free ran in DD conditions (stage 2). The infusion of melatonin at a dose of 50 µg/h induced in the first days (stage 3) a marked lengthening of the period (24.40 ± 0.05 h in stage 3 vs. 24.11 ± 0.06 h in stage 2, P < 0.05). This was observed for all animals except one that already had a long free-running period before melatonin. A 16-h infusion of melatonin was able to entrain the rhythms in only 5 out of the 10 animals. However, this entrainment was a true one. The other animals kept free running during the administration of melatonin and presented a period longer than 24 h during the entire experiment. In the last stage, all the animals infused with saline free ran with a period longer than before melatonin infusion (24.50 ± 0.06 h in stage 5 vs. 24.11 ± 0.06 h in stage 2, P < 0.05) but close to that of stage 3.
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In group S-16h-50 (Fig. 6, A and C), the free-running period determined in DD (stage 2) was lengthened within a few days of infusion of S20098 at a dose of 50 µg/h in the same fashion as in the melatonin group (group M-16h-50; 24.48 ± 0.07 h in stage 3 vs. 24.09 ± 0.03 h in stage 2, P < 0.05). This change was observed in all the animals infused. The 16-h infusion was able to induce a true entrainment in only four of the ten animals (stage 4). In three others, a transient entrainment lasting just a few days was observed (see Fig. 8A), after which they free ran again before the withdrawal of S20098 (individual periods: 24.43 ± 0.03, 24.18 ± 0.03, and 24.31 ± 0.04 h, respectively). The last three animals kept free running with a period close to that of stage 3. As in group M-16h-50, the last stage of saline infusion was characterized by a marked lengthening of the period compared with stage 2 (24.52 ± 0.05 h in stage 5 vs. 24.09 ± 0.03 h in stage 2, P < 0.05). Again, the period of stage 5 was close to that of stage 3.
In group
M-16h-100 (Fig.
7), the infusion of melatonin at a dose of
100 µg/h also induced in the first days (stage
3) an important change in the period of the rhythms,
compared with the free run with a saline infusion (24.48 ± 0.05 h
in stage
3 vs. 24.13 ± 0.03 h in
stage
2, P < 0.05). A true entrainment was only observed in three out of the
nine animals (stage
4). In two others, a transient entrainment was obtained for about 3 wk, after which the animals free
ran again (Fig.
8B). The
melatonin infusion did not entrain the rhythms in the last four
animals, which continued to free run with a period (24.15 ± 0.01 h)
close to that of stage
2. In the last stage (saline infusion)
the animals free ran with a period longer than in
stage
2 (24.33 ± 0.05 h in
stage
5 vs. 24.13 ± 0.03 h in
stage
2, P < 0.05). Only one animal kept a free-running period close to 24 h.
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Effects of Two 1-h Infusions
In group M-2×1h-100 (Figs. 9 and 10A), the two 1-h signals of melatonin (100 µg/h) were able to induce a true entrainment of the rhythms to a period of 24 h in all animals. In all cases, the animals synchronized their rhythms within the shortest time interval between the infusions (i.e., between 1800 and 0400; Fig. 9). After the free run observed in DD (stage 2), the entrainment could be reached in two different ways. In four of the ten animals (Figs. 9A and 10A), the melatonin infusions induced only a slight lengthening of the period in the first days (stage 3), when the temperature peak was in the longest time interval. However, when the end of the temperature peak reached the 18- to 19-h melatonin signal, a clear-cut change in the period of the rhythms was observed (stage 3'). This new period was maintained until the animals were entrained (stage 4). In the six other animals (Figs. 9B and 10A), the beginning of melatonin administration directly induced a shortening of the period, which became shorter than 24 h (stage 3') until entrainment occurred (stage 4). When saline was infused again (stage 5), the animals free ran with a period higher than 24 h, except in three animals that kept a free-running period close to 24 h.
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In group S-2×1h-100, the sequenced infusions of S20098 also entrained the rhythms of all animals to a period of 24 h (Fig. 10B), and synchronization occurred within the shortest time interval. As in group M-2×1h-100, the entrainment was reached in two different ways. For 7 out of the 9 animals (Fig. 10B) and as depicted for melatonin, initial days of S20098 administration did not modify the period of the rhythm (stage 3). Then, once the end of the temperature peak had reached coincidence with the S20098 signal located from 1800 to 1900, the period increased (stage 3') until entrainment occurred (stage 4). In the other two animals, initial infusion of S20098 induced a transient entrainment for 2 or 3 wk (Fig. 10B), with the temperature peak within the longest time interval (i.e., between 0400 h and 1800 h, stage 3). Then the animals presented a shortening of the period (stage 3') until the entrainment was achieved (stage 4). On return to saline infusion, the animals free ran again, except for two of them.
Even though all animals infused with melatonin or S20098 were entrained in the shorter time interval, the activity and temperature peaks were not fully compressed in this 8-h interval. Both rhythms extended after the end of the second infusion signal.
Effects of Infusions on Phase Angle
All animals showed a negative phase angle with reference to the onset of infusion, the onset of running-wheel activity, and the temperature acrophase taking place after the infusion onset. Only two animals, infused with melatonin for 1 h at a dose of 50 µg/h, showed a positive phase angle for running-wheel onset, which occurred ~3 h before onset of infusion (temperature acrophase was observed more than an hour after infusion onset). However, the two rhythms used for the determination of phase angle showed different responses according to the infusions performed (Fig. 11).
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With a 1-h infusion, the phase angle for the acrophase of body
temperature rhythm was fairly constant, around 6 h after the infusion
onset (Fig. 11) irrespective of the drug infused (melatonin or S20098)
and the dose (50 or 100 µg/h). The same observation was done for the
phase angle of running-wheel onset, which occurred less than an hour
after the infusion onset (Fig.
12A).
The difference between these two phase-angles was ~5 h for these
experimental groups.
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With an 8-h infusion, the phase angle increased for both rhythms. Body temperature acrophase and running-wheel onset were delayed with respect to the onset of infusion by ~7-8 h for temperature and 2-3 h for running-wheel (Fig. 12B). This response was not modified by pinealectomy (group M-8h-50-Px) compared with intact animals (group M-8h-50). With the infusion of S20098 (group S-8h-50), the increase of the phase angles of the two rhythms was slightly higher than for melatonin, but a significant difference was observed only for the running-wheel onset (P < 0.05).
With a 16-h infusion, the phase angle of the rhythms increased further. The onset of running-wheel activity occurred ~6 h after the onset of infusion (Fig. 12C), compared with ~10 h for temperature acrophase. S20098 (group S-16h-50) induced a significantly higher delay of running-wheel onset than melatonin (group M-16h-50, P < 0.05).
With two 1-h infusions, the reference used was the signal applied from 1800 to 1900. For these two groups, responses were similar to those of the groups infused for 1 h with the same dose (groups M-1h-100 and S-1h-100). The onset of running-wheel activity occurred soon after the beginning of the infusion (low phase angle), and the difference between the two phase angles was ~5 h, as for the 1-h infusion.
The phase angles of the rhythms were strongly correlated with infusion
duration (Fig.
13A),
and the regression coefficients for the two rhythms were very similar.
Correspondingly, the phase angles of running-wheel onset and
temperature acrophase were strongly correlated (Fig.
13B).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Daily infusions of melatonin or S20098, for 1, 8, or 16 h or 2 × 1 h, entrained the circadian rhythms to 24 h. Rhythms of body temperature, running-wheel activity, and general activity were monitored simultaneously. Judging from visual inspection of the graphs, the entrainment patterns were fairly similar for these three variables, with the exception of the phase angle once entrainment was reached. This was also observed in a study using daily melatonin injections (10). Apart from differences in effects on phase angle, the following discussion will focus on the temperature rhythm, which lends itself to a more accurate analysis.
Methodological Aspects
Daily infusion of melatonin or S20098 with an indwelling cannula represents an efficient way to synchronize the free-running rhythms of rats maintained in dim red light. Compared with single daily injections, it circumvents the possible effects of handling, the physiological impact of which is still under debate (26, 62).Plasma concentrations of melatonin or S20098 attained during the infusions in the present study are still undetermined. We are presently trying to determine plasma melatonin concentrations in similar conditions, but it is difficult to take blood samples from animals connected to the infusion system, and even more so to follow them for several weeks. However, the doses used in this study were in the same range as those used in previous studies with daily subcutaneous or intramuscular injections (9, 12), i.e., ~1 mg/kg or less. Based on daily subcutaneous melatonin injections in rats, a dose-dependent study showed that all effective doses resulted in a marked increase of plasma melatonin that was sustained over several hours (12). Because of the high levels of plasma melatonin achieved, it was suggested that the effects of melatonin were pharmacological. In humans, plasma melatonin levels were also significantly increased for several hours after an oral administration (19). New systems of melatonin administration in humans (6, 31), through transmucosal patches or by oral controlled release, induced a melatonin peak sustained over several hours with relatively low amounts of melatonin (0.5 mg).
Similarly, a dose-dependent study with oral administration of S20098
showed a positive relationship between plasma concentration of S20098
and the efficiency of entrainment (33). Because S20098 was delivered
orally, the doses used were higher than those of the present study.
When delivered by peripheral injection (intramuscularly or
subcutaneously), S20098 at a dose of 1 mg/kg was as potent as melatonin
to induce entrainment (9, 54). In kinetic studies performed with bolus
subcutaneous administration of S20098 (1 mg/kg), a maximal
concentration of 154 ng/ml was reached 15 min later, and the drug could
be detected in the plasma up to 6 h after injection (Servier Co.,
unpublished data). Based on this data, pharmacokinetic simulations
showed that a 1-h infusion at 0.25 mg · kg1 · h1
would not reach a concentration high enough to entrain rhythms, i.e.,
50 ng/ml (33). However, this value of 50 ng/ml might be reached with
infusions of 0.5 mg · kg1 · h1
for 1 h or 0.25 mg · kg1 · h1
for 8 h. S20098 then remains at detectable levels in the plasma for
4-6 h after its administration. The active concentrations of
S20098 are the same by subcutaneous route as by oral route; the oral
doses have to be higher than subcutaneous doses to account for the
bioavailability of the drug. Taken together, these data suggest that
the most important factors to inducing entrainment are the peak
concentration of S20098 or melatonin and the corresponding minimal
duration of exposure.
S20098 vs. Melatonin
In humans, both compounds have an influence on the circadian rhythms (21, 30). Melatonin and S20098 share the same chronobiotic properties, and their practical impact for the treatment of disruption of the circadian rhythmicity might be particularly relevant (1).In the present study, melatonin and S20098 presented the same ability
to entrain the free-running rhythms. The only exception was the
infusion of S20098 at the lowest dose (50 µg/h = 0.25 mg · kg1 · h1)
for 1 h/day, which was unable to entrain the rhythms. However, melatonin infused at the same dose was not effective in all animals. Thus for both drugs a higher dose (100 µg/h = 0.5 mg · kg1 · h1)
was required to entrain the rhythms in all animals. With an 8-h
infusion both drugs were fully effective at 50 µg/h to induce an
entrainment. Nevertheless, the efficiency of infusions decreased with a
very long duration of administration (16 h), regardless of the dose and
drug. Because the efficiency of the treatment decreased as the duration
increased, the duration of presence in the organism must be taken into
account. However, our results demonstrate that it is possible to
entrain free-running animals even with a very long duration of infusion.
Phase Angle Between Zeitgeber and Entrained Rhythm
When administered by daily injection, both melatonin and S20098 induce entrainment only when the injection time coincides with the onset of activity (9, 51). If the injections start at any other time, the rhythms keep free running until this coincidence occurs. There is therefore a "window of sensitivity" at which the drugs are effective. Because rats free run with a period longer than 24 h, drugs must induce a daily phase advance of the pacemaker to achieve entrainment. The phase-response curve to a single injection of melatonin or S20098 supports this idea. Injections induce a phase advance of the free-running rhythms of rodents kept in constant darkness only around circadian time 10 and 11 (3, 64). Similar results were obtained in the present study with a daily 1-h infusion. Both melatonin and S20098 induced entrainment when the infusion coincided with the onset of activity, and did not alter the free-running period in the first week of infusion (stage 3).During an entrainment, when the period of the pacemaker is equal to the
period of the Zeitgeber, it is assumed that the pacemaker maintains a
constant phase relation () with the Zeitgeber, with some dependency
of on the photoperiod for light entrainment (46).
With daily injections of melatonin or S20098, the onset of activity is
linked to the time of injection (13, 50), and the phase angle is close
to zero. This was also the case in the present study with 1-h infusion.
However, we observed that the phase angle difference () depended on
the duration of infusion. The negative phase angle was increased as the
duration of infusion increased, both for the running-wheel activity and
temperature rhythms. Furthermore, the responses of the two rhythms to
the infusions were similar, resulting in a very stable temporal
relationship between the rhythms (Fig. 13A). As a consequence, these two
rhythms were strongly correlated (Fig.
13B). For all physiological
functions studied to date in rodents, the circadian rhythms are tightly
correlated. In rats, the phase relationship between temperature and
activity rhythms is independent of environmental lighting conditions
(53). In Syrian hamsters, the running-wheel activity and pineal
melatonin rhythms are well correlated, despite a great variability in
their phase relationship (22). In the present study, the variability of
the phase angle also increased with the duration of infusion (Fig. 11).
Some subtler variations in the temporal organization of the rhythms
might also exist. With the S20098 infusions of 8 or 16 h, running-wheel
activity onset seemed to be delayed with reference to melatonin
infusion, whereas temperature was apparently unaffected. This
observation might suggest an action of the drugs on the temporal
organization of the rhythms, but we had too few groups, and further
studies are required to confirm these observations. In a recent study,
the temporal relationship between general activity and body temperature
in rats could be altered by a pharmacological treatment; chronic
administration of antidepressant agents significantly delayed activity
rhythm without changing the timing of body temperature acrophase (43).
Transient Entrainment
Another difference between the infusion and injection protocols was that with an infusion a transient entrainment could be observed. In such a case, the animals were entrained only for a few days or few weeks, and started to free run again before the withdrawal of the drugs (Fig. 8). This was observed with the extreme infusion conditions, i.e., a short duration (1 h) with a low dose or a very long duration (16 h). Why the pacemaker escaped the entraining signal is still unknown.Effects on Free-Running Period Before Entrainment
In addition to the effects on phase angle, another response could be seen in stage 3. With an 8-h infusion, and more evidently with a 16-h infusion, drug administration induced a change in the free-running period in the first days. The period was
lengthened compared with saline infusion, suggesting that melatonin and
S20098 delayed the pacemaker day to day until entrainment (Fig.
14A). In other words, with a long duration of infusion, entrainment occurred
earlier than predicted by the model based on injections. Moreover, the
magnitude of the change in period (
) increased significantly with
infusion duration (Fig. 14B).
Strikingly, 16-h infusions did not entrain all animals, but still
increased the free-running period in all of them. These observations
cannot be explained on the basis of a "window of sensitivity,"
but rather suggest that the chronobiotic properties of melatonin and
S20098 infusions imply an active mechanism on the circadian clock.
|
The hypothesis of an active mechanism is reinforced by the results of skeleton infusions (groups M-2×1h-100 and S-2×1h-100). In these groups, the infusions of melatonin and S20098 induced entrainment after a stage (3') in which periods were either lengthened in a fraction of the animals or shortened in the others. However, all animals responded in such a way that, once entrained, their active phase was in the shorter time interval between the drug signals. This suggests that to achieve entrainment, drugs had to induce either a phase delay when the period had been shortened, or a phase advance when the period had been lengthened. Such a dual effect of melatonin has also been observed in two other studies. First, when submitted to a 5-h phase advance of the dark onset in LD conditions, rats daily injected at the new dark onset reentrained with a decreased latency, but some of them did it by phase delay, whereas the others did it by phase advance (49). Second, infusions of melatonin have been reported to entrain hamsters by inducing a phase advance with a free-running period longer than 24 h, and a phase delay with a period shorter than 24 h (28). These observations suggest that the drugs have opposite effects at a given time depending on the period before entrainment, which is quite difficult to explain in connection with the phase-response curve.
In addition, entrainment occurred at a time that was exactly opposite to that observed for skeleton photoperiod, where activity was localized in the longer time interval (46). However, the trailing peak, observed after the second infusion, has been previously reported in rats submitted to a skeleton photoperiod with an 8-h interval (59).
Role of Pineal Gland: Sites of Action of Melatonin and S20098
In mammals, it is generally assumed that the pineal gland is not involved in the generation and maintenance of circadian rhythmicity (47, 63). Pinealectomized rats keep their ability to be entrained by daily injections of melatonin and S20098 and present the same phase angle difference as intact animals (51, 65). Here too, pinealectomy failed to modify either the ability of infusions to entrain the free-running rhythms or the phase angle for melatonin or S20098 (data not shown for S20098). Nevertheless, pinealectomy may modify the reentrainment of rats after a phase shift of the LD cycle (2). One week after pinealectomy, the rhythm of firing rate of SCN neurons in vitro is altered, as well as the daily rhythm of responsiveness to melatonin (56). Melatonin interferes with the metabolic activity of the SCN (14), and both melatonin and S20098 modulate the firing rate of SCN neurons in vivo (68) and in vitro (20, 36, 37). The action of melatonin or S20098 is thought to be mediated by high-affinity membrane-bound receptors, and two subtypes, the MEL1a and the MEL1b, are putative candidates (32, 54, 55). Although this is still controversial, melatonin might also activate an orphan nuclear receptor of the RZR/ROR family (5).Nevertheless, the sites of action of melatonin and S20098 implicated in the entrainment of the circadian pacemaker still remain an open question. Most of our animals free ran after drug treatment (stage 5) with a different period (generally longer) than before drug treatment (stage 2). Should these changes in free-running period represent a strong aftereffect of treatment, then chronic administration of melatonin or S20098 would directly affect the functioning of the circadian pacemaker. However, another explanation is possible. Light entrainment is known to induce an aftereffect, so that the free-running period in the first days of constant darkness (DD) is close to 24 h. The period gradually lengthens before stabilizing after at least 50 days in DD (46, 59). This state has been referred to as the "natural" or "most probable" state of the pacemaker (46). Although our experiment was not designed to check this point, it could be observed in group S-1h-50, in which the animals free ran throughout the experiment. In the groups in which entrainment occurred, the period in stage 5 was similar to the corresponding period in group S-1h-50. It could then be proposed that an animal released from melatonin or S20098 entrainment expresses faster its "natural" free-running period. This implies that melatonin or S20098 entrainment would have no aftereffects contrary to light. If so, melatonin or S20098 action on the circadian pacemaker might involve pathways other than light. These substances might also act at another level than the circadian pacemaker. In humans, exogenous administration of melatonin was able to entrain one, but not all, of the rhythms recorded (23, 70). For body temperature, contradictory results were obtained concerning the generation of the rhythm by the SCN (39), suggesting the implication of other brain structures.
In conclusion, melatonin and S20098 are very active compounds that can affect and entrain the circadian pacemaker of rodents. The entraining properties of melatonin and S20098 were similar and were not affected by infusion duration for 1- or 8-h infusions, whereas efficiency was decreased with a 16-h infusion. Once entrained, the phase angle between the onset of infusion and the rhythms (onset of activity or acrophase of body temperature) increased with the duration of infusion. Before entrainment, the free-running period increased with the duration of infusion, an effect that was not predictable from the phase-response curve. This suggests that the pattern of delivery of melatonin or S20098 influences the functioning of the circadian pacemaker. Thus the control of delivery might be important to obtain an optimal response in clinical applications.
Perspectives
The effects of melatonin or S20098, as for other nonphotic stimuli, such as drug treatment or food restriction, on the circadian clock might involve various pathways and brain structures. Changes in the serotonergic pathway alter the phase-shifting properties of nonphotic stimuli (17, 18). High concentrations (mM range) of melatonin inhibit serotonin reuptake in rat pineal glands in vitro (40) and in the hypothalamus (11). Such an effect on serotonergic terminals within the SCN might be involved. Melatonin, as well as S20098, also inhibits the firing rate of neurons of the intergeniculate leaflet of the thalamus (68), involved in the phase-shifting effects of certain nonphotic stimuli (16, 27, 67). Melatonin receptors are also present in the paraventricular nucleus of the thalamus (34), which receives SCN neuronal projections (66) and is supposed to belong to the main center for controlling motor behavior (7). Thus the characterization of melatonin sites of action should provide us with a better understanding of how melatonin gives time cues to the circadian pacemaker. When phase-shifts are imposed (shift-workers) or the organization of the rhythms is altered (aging), some benefits might then accrue from the chronobiotic properties of melatonin to improve the relation between the endogenous clock and the external environment.| |
ACKNOWLEDGEMENTS |
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The authors are specially grateful to S. Gourmelen and R. Brenklé for excellent technical assistance in the care of the animals and telemetry devices.
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FOOTNOTES |
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This work was supported by the Institut de Recherches Internationales Servier, France.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: B. Pitrosky, Neurobiologie des Fonctions Rythmiques et Saisonnières, UMR-CNRS 7518, Université Louis Pasteur, 12 Rue de l'Université, 67000 Strasbourg, France (E-mail: pitrosky{at}neurochem.u-strasbg.fr).
Received 17 December 1998; accepted in final form 21 May 1999.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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