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Circadian pattern of plasma melatonin concentrations in the marmoset monkey (Callithrix jacchus).

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American Journal of Primatology 17:73-79 (1989)
BRIEF REPORTS
Circadian Pattern of Plasma Melatonin Concentrations in
the Marmoset Monkey (Callithrixjacchus)
G.E. WEBLEY', D.H. ABBOTT', L.M. GEORGE1,J.P. HEAR", AND H. MEHL2
'MRCIAFRC Comparative Physiology Research Group, Institute of Zoology, London;
ZInstitute of Hormone and Fertility Research, Hamburg, Federal Republic of Germany
This study describes the concentrations of melatonin in plasma samples
taken from marmoset monkeys (Cullithrix jucchus) every 4 h over three
24-h periods. A circadian pattern of secretion was apparent, with higher
levels recorded a t night (20.00-08.00 h) than during the day (08.00-20.00
h) and a peak concentration at 20.00 h. There was a significant difference
in the mean day and night concentrations (32.5 2 4.5 pg/ml versus 49.0 k
6.9 pg/ml, respectively) with individual concentrations ranging between
<lo-60 pglml in the day and 15-200 pg/ml a t night. Circadian plasma
melatonin concentrations were similar over the three 24-h periods, in male
(n = 3) and female (n = 3) monkeys, and in dominant (cyclic, n = 5 ) and
subordinate (acyclic, n = 4) females. The results show a less pronounced
circadian profile in the marmoset than is seen in the human but a similar
profile to that in the seasonally breeding rhesus monkey.
Key words: marmoset monkey, melatonin, social status
INTRODUCTION
In all animals so far investigated the pineal hormone melatonin follows a
circadian pattern of secretion [Tamarkin et al., 19851. In seasonally breeding
species such as the sheep this circadian pattern of melatonin is believed to mediate
the influence of seasonal changes in photoperiod on reproductive cyclicity, acting
on the luteinizing hormone-releasing hormone (LHRH) pulse generator [Bittman
et al., 19851 through two neuroendocrine mechanisms. One mechanism involves a
change in sensitivity to the negative feedback action of estradiol [Bittman et al.,
1983; Legan et al., 19771, while the other is independent of sex steroids and
involves the endogenous opioid peptides [Yang et al., 19881. Among primates, the
role of melatonin is less established, but the human shows a clear circadian pattern
in melatonin concentrations [Arendt, 1985; Webley et al., 1985; Webley &
Leidenberger, 19861. The rhesus monkey, a strict seasonal breeder, also exhibits a
Received for publication June 23, 1988; revision accepted September 21, 1988.
Address reprint requests to Dr. G.E. Webley, Institute of Zoology, Regent's Park, London NW14RY, UK.
0 1989 Alan R. Liss, Inc.
74 I WebIey et ai.
circadian change in plasma [Jenkin et al., 19801 and cerebrospinal fluid [Reppert
et al., 19791 concentrations.
The objectives of the present study were to establish whether there is a
circadian pattern of melatonin in the marmoset monkey, a primate species that
breeds throughout the year both in captivity and in the wild [Hearn, 1983;
Stevenson, 19781; to establish the physiological levels of circulating melatonin;
and to examine any gross changes in the circadian pattern of melatonin in
dominant (cyclic) compared with subordinate (acyclic)female monkeys.
MATERIALS AND METHODS
Animals
Adult male and female marmoset monkeys (Callithrixjacchus) were from the
self-sustaining breeding colony maintained a t the Institute of Zoology as described
previously [Hearn, 19831. The monkeys were housed either as breeding family
groups or groups of unrelated adults (social groups). When females are housed in
social groups one will become dominant and continue to have regular ovarian
cycles whereas the other females become subordinate and acyclic [Abbott & Hearn,
1978; Abbott et al., 19881.
Blood samples were taken from the femoral vein without sedation, as described
previously [Hearn, 19773, every 4 h over 24 h starting at 08.00 h. A preliminary
study was carried out in May 1987 with three female and three male marmosets.
In a subsequent study five dominant and four subordinate female marmosets were
sampled over two 24-h periods, 2 weeks apart, on June 30lJuly 1 and July 14/15
1987. In the first of these two 24-h periods, two of the dominant females were in the
luteal phase and three were in the follicular phase-this was reversed during the
second 24-h study. The male and female marmosets studied in May were maintained under conditions of natural light, supplemented with artificial light from
08.00 t o 20.00 h (dark phase from 20.00 h to 06.00 h). In the study of dominant and
subordinate females, the animals were solely maintained under conditions of
artificial light with a dark phase from 20.00 h to 08.00 h. In all studies the blood
samples collected during the dark phase were taken under dim red light during the
1min required to obtain the sample.
The start of the ovarian cycle was controlled by administration of a single
intramuscular (i.m.) injection of 0.5 pg cloprostenol (Estrumate; ICI Pharmaceuticals Division, Maccclesfield, Cheshire) [Summers et al., 19851to synchronize the
cycles and to ensure that the dominant females were studied in the follicular and
luteal phases. The ovarian cycles were monitored by measurement of plasma
progesterone concentrations, 2 to 3 times per week, as the marmoset monkey does
not menstruate and vaginal smear cytology does not accurately reflect the stage of
the ovarian cycle [Hearn & Renfree, 19751.The ovarian cycle of the marmoset is 28
days with an 8- to 9-day follicular phase and a 19- to 20-day luteal phase [Harlow
et al., 19831.
Assays
Melatonin was measured using a direct tritiated radioimmunoassay as described previously [Webley et al., 19851. Plasma and serum samples gave similar
values in the assay (data not shown) demonstrating that there was no effect of the
concentration of heparin used (surface coating only) in taking the blood sample.
Plasma volumes of 100 p1, made up to 250-p1 sample volumes with assay buffer,
were assayed in duplicate. Plasma samples diluted in parallel to the standard
curve, a plasma pool, from male marmosets, assayed at volumes of 200 pl, 100 pl,
Melatonin in the Marmoset Monkey I 75
and 50 p1 gave values of 49,47.8, and 52 pglml, respectively. Recovery of melatonin
added to a plasma pool a t concentrations of 20 pg/ml and 40 pg/ml gave recoveries
of 101%to 111%.The assay had a sensitivity of 2.0 pg/ml and intra- and interassay
coefficients of variation of <6% and <16%, respectively.
Progesterone concentrations in marmoset plasma were measured using a
direct enzyme immunoassay as described previously [Hodges et al., 19881. The
sensitivity of the assay was 1.1 ng/ml, and intra- and interassay coefficients of
variation were <9% and <16%, respectively.
Analysis of Results
A log transformation of plasma melatonin concentrations was carried out to
increase linearity of the data and to reduce the heterogeneity of variance [Helwig
& Council, 1979; Sokal & Rohlf, 19811. Plasma melatonin values from the study in
May were subjected to a two-way analysis of variance for repeated measures. No
significant difference was found between the sexes so the data for both sexes were
combined and subjected to a one-way analysis of variance. Plasma melatonin
values in the June/July study were initially put through a nested three-way
analysis of variance with replication [Sokal & Rohlf, 19811. As no significant
difference was found between the days, the data were combined and subjected to a
two-way analysis for repeated measures to test for differences between females
over the 24-h period. For this analysis four outlying melatonin values of 140, 150,
170, and 205 pg/ml from three animals were excluded. These values greatly
exceeded the overall mean (L SD) of 32.0 k 29.7 pmol/liter and were identified by
an outlier test [Sokal & Rohlf, 19811. In all cases comparison of individual
transformed means were made post hoc using Duncan’s Multiple Range test
[Helwig & Council, 19791.
To determine whether there was any change in the total exposure to melatonin
over 24 h (melatonin index), as described previously in women [Webley &
Leidenberger, 19861, the area under the melatonin curve over 24 h was calculated,
using the nadir in melatonin concentrations as the baseline. The melatonin index
was compared between days and a t different stages in the cycle using Student’s
paired t test.
RESULTS
The plasma concentrations of melatonin in the marmoset monkey showed a
circadian pattern of secretion with significantly higher levels recorded during the
hours of darkness (F(6,35) = 2.59, P < .035). A peak concentration of 49.0 6.9
pg/ml (antilog of transformed mean ? SEM) was recorded a t 20.00 h. There was no
significant difference in the melatonin concentrations between males and females
(F(1,4) = 1.43, P < .3) so the data were combined and are illustrated in Figure 1.
The difference in the mean melatonin concentrations over 24 h was not marked,
changing by only 50%. There was, however, individual variation, which is also
evident from the circadian profiles of melatonin shown in Figure 2 for the
dominant and subordinate females. The melatonin concentrations recorded over
both May and June/July studies ranged between <10 and 60 pg/ml during the day
and 15 to 200 pg/ml during the night.
There was no significant difference in the plasma melatonin concentrations
between the two 24-h periods in June and July (F(1,2) = 00.31, P > .05), so the
data for both days were combined. There was also no difference in melatonin
concentrations between any of the three female groups: dominant females (follicular phase), dominant females (luteal phase) and acyclic subordinate females
(F(2,ll) = 00.02, P > .97). Combining all data from dominant and subordinate
*
76 I Webley et al.
1
0800
1
. .
12.00
ICKX)
-
m
1
2ooo 2400
W
ocoo
v
00
Time (h)
-40
z
B
i
A
2
Fig. 1. Concentrations of melatonin (mean ? confidence limits) in plasma samples taken every 4 h over 24 h
from three female and three male marmoset monkeys. The data are expressed as the antilog of the transformed
means with 95%confidence limits. *P < .05 vs. 12.00 and 08.00 h (day 2) (Duncan’s multiple range test). The
dark period ended at 06.00h, 2 h before the artificial lights were switched on, because of natural daylight
supplementation.
Fig. 2. Concentrations of melatonin (mean -C confidence limits) in plasma samples taken every 4 h over 24 h
from five dominant (cyclic) females and four subordinate (acyclic) female marmoset monkeys. The data are
expressed as the antilog of the transformed mean with 95%confidence limits. a, P < .05 vs b and c; b, P < .05
vs. a and c; c, P < .05 vs. a and b (Duncan’s multiple range test).
Melatonin in the Marmoset Monkey I 77
females gave a circadian pattern of plasma melatonin concentrations with significantly higher values recorded at 20.00 h than a t other times of day (F(6,64) =
4.29, P < .0011) (Fig. 2).
Calculation of the melatonin index for the individual 24-h profiles showed that
there was no significant difference in the values for the follicular (52 f. 14 pgday,
mean 2 SEM, n = 5,) and luteal phase (104 2 40 pg.day, n = 5) of the cycle in
dominant females and no significant difference between dominant (78 rt 22 pgday,
n = 10) and subordinate females (104 2 23, pg.day, n = 8).
DISCUSSION
This study describes a circadian pattern of melatonin in the marmoset monkey
with significantly higher plasma concentrations recorded a t night (20.00-08.00 h)
than during the day (08.00-20.00 h). The pattern is similar to that described in the
human [Arendt, 1985; Webley et al., 1985; Webley & Leidenberger, 19861 and
rhesus monkey [Jenkin et al., 19801 but differs in the timing of the peak
concentration: a peak melatonin level recorded a t 20.00 h in the marmoset
monkey, 04.00 h in the human [Webley et al., 19851 and 05.30 h in the rhesus
monkey [Jenkin et al., 19801. The earlier peak level in the marmoset may be
related to activity since the animals habitually enter their nestboxes to sleep a t
between 18.00 and 19.00 h. A relationship between the excretion pattern of
melatonin and the activity pattern has been described in the hamster [Korenman
et al., 19881.
A variation in concentrations of melatonin of up to twofold in the marmoset is
similar to that described in the rhesus monkey in which mean levels ranged from
115 to 368 pmolfliter [Jenkin et al., 19801. In contrast the difference in mean
daylnight levels was considerably greater in the human with an increase from
between 20 and 200 pmol/liter in the day to up to 850 pmol/liter a t night [Webley
et al., 1985; Webley & Leidenberger, 19861. The marmoset monkeys were exposed
to a similar light/dark cycle to that in their equatorial habitat.
We demonstrated previously the ability of melatonin to stimulate the secretion
of progesterone by the corpus luteum of the marmoset monkey when perfused in
vivo [Webley 8z Hearn, 1987; Hearn & Webley, 19871. The present study confirms
that the concentrations of melatonin tested were within the physiological range of
concentrations in the peripheral circulation. An association between elevated
melatonin levels and the luteal phase was suggested from our study of peripheral
melatonin concentrations in women [Webley & Leidenberger, 19861 in which there
was an increase in the circadian output (melatonin index) during the luteal phase
of the menstrual cycle. In the present study, it was not possible, from the number
of dominant animals investigated at any particular stage of the cycle, to establish
whether any such changes were occuring across the cycle in the marmoset.
Experiments are now underway in vivo to test the involvement of melatonin as
part of the luteotrophic complex in the marmoset and human.
The possibility that changes in the circadian pattern of melatonin might be
associated with the socially induced acyclicity in subordinate female marmosets
was not supported by our results. Earlier studies in our laboratory showed that the
immediate cause of acyclicity was suppressed pituitary LH secretion associated
with impaired GnRH secretion [Abbott, 1987, 19881. Two components of the
GnRH/LH suppression were identified, and these were similar to the mechanisms
controlling LH secretion during seasonal anoestrus in the sheep [Legan et al.,
1977; Yang et al., 19881. One is manifest as an increase in sensitivity to estradiol
negative feedback [Abbott, 19881, and the other is apparently independent of
ovarian negative feedback and involves the endogenous opioid peptides [Abbott, in
78 I Webley et al.
press]. In the sheep changes in the duration of the nocturnal elevation of melatonin
have been shown to mediate the influence of photoperiod on changes in the LH
secretion [Bittman & Karsch, 19841 by their actions on hypothalamic GnRH
secretion [Robinson et al., 19861. The results in the present study suggest that
normal changes in the circadian pattern of melatonin are not perturbed in the
acyclic, subordinate marmoset and thus appear to play no part in the social
suppression of GnRH/LH secretion.
CONCLUSIONS
1. The marmoset monkey shows a circadian pattern of plasma melatonin
concentrations.
2. Night concentrations of melatonin (mean 49.0 6.9 pg/ml) significantly
exceeded mean concentrations during the day (32.5 t 4.5 pg/ml).
3. There was no significant difference in plasma melatonin concentrations,
over the circadian profile, in dominant (cyclic) and subordinate (acyclic) female
marmoset monkeys.
*
ACKNOWLEDGMENTS
We thank Professor F.A. Leidenberger for his interest and support. The work
was funded by a joint MRC/AFRC programme grant (to J.P.H.).
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