of Health,. Bethesda,. Maryland. 20205. ABSTRACT. Daily changes in pineal ... photoperiodic control of seasonal reproductive cycles in the ferret. (Thorpe and.
BIOLOGY
OF REPRODUCFION
Diurnal
24, 778-783
Changes
(1981)
in Pineal
Melatonin
Relationship
Content
in Four
Species:
to Photoperiodism
B. GOLDMAN,’ V. HALL, C. HOLLISTER, P. ROYCHOUDUURY, S. YELLON and Department University
Rodent
of Bio behavioral of Storrs, Connecticut
S. REPPERT, L. TAMARKIN2 Sciences, 06268
and National
Institute
National
of Child
Institutes
Health
of Health,
and
Human
Bethesda,
Development,
Maryland
20205
ABSTRACT
changes
in pineal melatonin content were examined in four rodent species (rat, Syrian Turkish hamster, and Siberian hamster). All species had elevated pineal melatonin levels during the dark period of a lighting cycle with a long photoperiod of 16 h of light per day, and no obvious differences were observed between photoperiodic and nonphotoperiodic species. Pineal melatonin levels of Siberian hamsters maintained in either a short (10 h of light per day) or a long photoperiod were elevated for most of the dark period, so the duration of elevated levels of pineal melatonin was longer in a short photoperiod than in a long photoperiod. Treatment of pinealectomized Syrian hamsters with melatonin during the time of the night when pineal melatonin content would be elevated induced gonadal regression, while pinealectomized rats failed to respond to exogenous melatonin. Daily hamster,
INTRODUCTION
tonin
Diurnal rhythms concentrations
number
of
in
species,
of
serum and pineal have been reported
and
in
the
rat
melain a
changes
in
pineal melatonin concentrations have been shown to be reflected in the circulation (Rollag and Niswender, 1976; Reppert et al., 1979; Wilkinson et al., 1977; Panke et al., 1979). Pineal factor
melatonin in the
has
been
implicated
photoperiodic
reproductive
cycles
in
the
ferret
(Thorpe weasel hamster
et al.,
1974;
Tamarkin
1976),
and
Turek
et al.,
the
Siberian
1978). In a relatively the laboratory rat, much
less
duction
et al.,
Accepted
January
Received
September
hamster
role 1976).
in regulating Therefore,
compare
profile
tained
in
the
rat
and (Rust (Reiter
of
with
Siberian
a series
lighting
day. focus
of
administer melatonin ly nonphotoperiodic
et al.,
exogenous daily
species, to have a repro-
of
rats
with
study
were
treated
in the Syrian at
Pineal
Melatonin
All
melatonin hamsters
778
animals
AND
to
with
in a regimen
melatonin
MATERIALS
was
of
a relativerespond to that
Syrian hamster. hamsters were night
at
corresponding to the peak in pineal content. The effect of this treatment reproductive system was examined.
2, 1981. 30, 1980. Present address: Worcester Foundation for Experimental Biology, 222 Maple Ave., Shrewsbury, MA 01545. 2 Reprint requests: Dr. Lawrence Tamarkin, Bldg. 6, Rm. 136, IRP, NICHD, NIH, Bethesda, MD 20205.
main-
schedule
whether would
of melatonin
gonadal atrophy pinealectomized
injected
it was
this
to test species
melatonin;
injections
induces Finally,
hamsters
a photoinhibitory
10 h of light per The second
(Hoffmann,
nonphotoperiodic melatonin appears
significant
(Turek
1975;
melatonin
of seasonal
Herbert, 1976), the short-tailed and Meyer, 1969), the Syrian
to
pattern of Siberian hamsters maintained in a photostimulatory lighting schedule of 16 h of light per day was compared with the pineal
as a key
control
interest
photoperiodic rodents to determine if differences exist in the pineal melatonin rhythm between photoperiodic and nonphotoperiodic species. In addition, the daily pmneal melatonin
a
time
melatonin on the
METHODS
Rhythms used
content (Mesocricetus
for
were
measurements
sexually auratus)
of
mature. were
pineal Syrian purchased
PINEAL
from Turkish hamsters tained
Engle Laboratory Animals hamsters (Mesocricetus from
(Phodopus our
own
sun gorus laboratory
Rats were of the Purdue-Wistar tained from a breeding colony
MELATONIN
(Farmersburg,
AND
IN).
brandti) and Siberian cam pbelli) were obbreeding
strain
colonies.
and
were
ob-
in the laboratory of Dr. V. H. Denenberg, University of Connecticut. All animals were fed Wayne Lab Blox ad libitum. They were all maintained in the same animal room for 2 weeks prior to sacrifice. The room was maintained on a 16L:8D schedule (lights on from 0300-1900 h) and at a temperature of 22 ± 1#{176}C.In addition to the standard illumination, a red light was kept on continuously to facilitate the collection of pineal glands during the night. Red light does not interfere with the production of melatonin in the pineal (Tamarkin et al., 1979) or with the photoperiodic regulation of reproduction in the Syrian hamster (Tamarkin et al., 1977a,b). A second experiment investigated the daily pineal melatonin profile of Siberian hamsters maintained on a long photoperiod of 16L:8D or a short photoperiod of 1OL:14D (lights on from 0500-1500 h). Siberian hamsters were maintained in 1OL14D for 1 month prior to experimental use. As in the long photoperiod room, the short photoperiod room had a red light on continuously.
Pineal
Melatonin
Assay
Animals were sacrificed by decapitation. Pineals were removed within 2 mm after death and were immediately frozen in vials kept at -20#{176} C. Melatonin was measured by radioimmunoassay as previously described (Tamarkin et al., 1979).
Pinealectomies Adult rats and Syrian mized as described earlier They were allowed 2-7 operation before injections
PHOTOPERIODISM
Melatonin
The ment from tained 2000
Injections:
Injections:
Adult
Syrian
and
male
0700 h. At ectomized. pinealectomized
were
obtained
were pinealhalf of the unoperated
animals were moved to a room which was kept on a 1OL:14D cycle with the light phase at 1900-0500 h. On the following day animals in both photoperiods began receiving daily treatments with melatonin. Melatonin was administered 3 times daily at doses of I or 5 g per injection. The injections were administered at 1000, 1300, and 1600 h each day. The timing of these injections with respect to the two lighting regimens was such that they occurred at approximately the same circadian time in both the long-day and short-day animals, as assessed by time of locomotor activity onset. These times also correspond approximately to the times of peak pineal melatonin contents on the respective photoperiods (Tamarkin et al., 1979). Melatonin was dissolved in safflower oil and each animal received 0.02 ml solution at each injection. Controls received oil only. After 10 weeks of treatment the males were sacrificed and the testes were weighed. Females were checked daily for vaginal signs of ovulatory cycles throughout the experiment. Completeness of pinealectomy was checked at autopsy and two animals with pineal remnants were discarded.
RESULTS
Rats
Melatonin
All
four
diurnal (Fig.
Content species
rhythm 1). In the
content lights-off
began and
showed
in Syrian to peaked
sample was obtained. Serum was obtained gation after allowing the blood samples night at 4#{176}C. The serum was assayed for by using the rat radioimmunoassay kits NIAMDD.
In all four species had decreased by
concentrations
the
were
maintained further
lights-on. decrease
(approximately 1 h after until doubling
In the occurred,
melatonin
at 4-5 h after in the began Syrian
the pineal to increase hamster, but
Siberian pineal
20-30-fold lights-off. This 4
h
after
of melatonin the pineal several-fold Syrian but
h after lights-off.
rat
achieved
time in all three species. The showed a significant rise in content within
content
pineal
increase at 5-6 and
pronounced
melatonin
hamster
In the Turkish hamster melatonin concentrations 1-2 h earlier than in peak
a
pineal
out the period of treatment. Food was provided as described above. Melatonin (Sigma) was dissolved in sesame oil. Injections were administered s.c. in a volume of 0.05 ml. The doses of melatonin were 2.5 Mg/injection in one group and 25 Mg/injection in a second group. Each animal was injected 3 times daily (at 0900, 1200, and 1500 h). Treatment was continued for 9 weeks. One week after the termination of injections, each rat was bled (1 ml) by cardiac puncture under ether anestesia at 1100-1300 h. The testes were then removed and weighed. Eight days after castration another blood by centrifuto clot overLU and FSH provided by
hamsters
this time most of the animals Five weeks after surgery males and all the
hamsters were pinealecto(Tamarkin et al., 1977a). days to recover from the were begun.
rats used for the melatonin injection experiwere adults of the Long-Evans strain, obtained Charles River Breeding Labs. They were mainon a 14L: 1OD cycle (lights on from 0600h) for 16 days prior to treatment and through-
Hamsters
female
from Engle Laboratory Animals, Farmersburg, IN. They were housed in the laboratory on a 16L:8D cycle with the light phase at 0700-2 300 h. To establish a more convenient daily schedule for the injection regimen, all animals underwent a gradual change in the phase of the lighting schedule. At approximately 2 week intervals the times of lights-on and lights-off were shifted 2 h later until a reversal of the photoperiod was obtained with the light phase at 1500-
Pineal Melatonin
779
lights-off content melatonin within
at the
same
hamster melatonin elevation) level was when occurred. content 1 h after
hamster no additional in the remaining species
a
GOLDMAN
780
ET AL.
600
800
-
SIBERIAN
HAMSTER
SyRIAN
600
HAMSTER
S00
400 C
L2
C 0.
C.
0
0
03
0.
z z
200
‘0 C)
C.
3000
z z
II
I-
4
-
Ui
600
RAT
TURRISH
2250
HAMSTER
400 500
200 750
0 I
I00
I
1200
00
I
1600
2000
2400
TIME
0400
0800
1200
TIME
FIG. 1. Diurnal fluctuations in pineal melatonin content in four species of rodents. All animals were maintained on a 16L:8D schedule with a dark period from 1900 to 0300 h. For Syrian hamsters each point represents the mean value for two animals (males). For the other species each point indicates the mean value for three to four animals (females).
FIG. 2. Daily profile of pineal melatonin in Siberian hamsters maintained in a long photoperiod of 16L: 8D with a dark period from 1900 to 0300 h or a short photoperiod of 1OL: 14D with a dark period from 1500 to 0500 h. Each point represents the mean SEM for four animals.
the
were
sacrificed pineal
what
melatonin
further
decrease
Comparison melatonin a
strated
that
of
pineal
content a short
daily
Siberian
short
resulted
the
or
showed
3 h after
by
of in
either
day
content
the
in a longer
period
melatonin
of
(Fig.
dark
pineal
of
of elevated
2).
Pineal
by 1800 but still
dark
the
levels
were
period
was
extended
baseline.
melatonin
in the short photoperiod, melatonin was maximally
hamsters hamsters
in the short photoperiod in the long photoperiod.
Comparison
a
difference
animals sacrificed had levels close
of the
pineal
melatonin
in
the
nocturnal
at 2300 h in the to baseline levels,
that
for
these
time
of
the
day
noted
to
pineal
and
melatonin
and the
for
should
be
of
increase
study
difficulties
account
it
populations
initial
first
collection
technical
However, two
the
in
In the no
were
profiles.
in
of
samples
all
differences
different
h in
basal
Effects
noted
animals
the
content
in
of Melatonin
Injections
injections
of melatonin
Daily testicular centrations 1).
those
so at 0300 elevated and
hamsters maintained experiments (Figs.
the
for
time elevated.
the
final was
de-
consis-
tent.
For levels after
However,
3 h longer
of
crease
h for hamsters in at baseline levels
animals pineal
from Siberian in two separate
the
levels
at 1900 h for those in a long photoperiod. both groups of animals, pineal melatonin were elevated until 1 h after lights-on, which
or in
demon-
portion
at this
maximally
analysis
maintained
photoperiod
extending
was elevated photoperiod,
lights-on.
profile
hamsters long
a some-
±
weights of serum in pinealectomized
Serum
creased the
in Rats
gonadotropin
in all groups case
prior
differences groups.
were
to
failed LH
and male
to alter
FSH conrats (Table
concentrations
after
castration
removal
of
observed
in-
and, the
as was
testes,
between
no
treatment
rhythm in 16L:8D 1, 2) reveals profile;
second while
the study those
Effect
of
the
Late
Syrian
Melatonin
Portion
Dark
During
Phase
in
Hamsters
Pinealectomized melatonin
Administered
of the
per
hamsters injection
receiving (15
i.tg/day)
5
showed
j.zg
PINEAL
TABLE
1. Testis
weight
and
serum
MELATONIN
LU and
FSH
AND
PHOTOPERIODISM
concentrations
in pinealectomized
Serum
Treatment
Testis
OiIa Melatonin, Melatonin,
3846± 3641 3718
2.5 Mg/injection 25 Mg/injection
alnjections
administered
bM
3 times
complete
testicular
regression
on
long
short
Animals
and
receiving
yielded animals
± ±
154b
44±11
154 158
31 34
daily,
at 0900,
in almost
photoperiods
1 j.ig melatonin
per
testicular results
regression were obtained
.tg dose acyclic
of melatonin in 1OL:14D
16L:8D; 1OL:14D
the 1 zg and 4/7
intact untreated pinealectomized 14D. mized
±
1200,
As might
6/8
dose rendered 8/8 acyclic in 16L:8D. females females
have
and were
which
is
Turkish
and
species,
pineal
to
the
tions
h. Eight
934± 976 1108
subjects
in each
to those observed data). Also, a similar
weeks. The 5
relatively
105 99 325
± ±
group.
large
precise
to
did between
nonphotoperiodic It should
patterns
isons
minor
three of
these
of
to
presented
has hamsters,
(unpubrhythm in observed it
in
seems
the
content the
in
respectively
Therefore,
melatonin
The were
diurnal would
species
be
compar-
here. point
experiment was
period
condition.
might rhythms
be
studied It
to
the
only
under
remains
differences
in short
consider
is that
in
evaluating
pineal a
melatonin long
possible
between
of photoperiodic
ic species
been
differences obscure
important
first
females diurnal
Syrian
1980).
night.
animals
the
and
photo-
that
there
melatonin
nonphotoperiod-
photoperiod.
A clear
differ-
9 375C
161.
80
1OL140
onsets
and
and
225C
were
respect term
also
ma75(
with in
to differenand
Syrian
300C
B
dark
However,
appear
male
very the three
the
with
photoperiodic
species. be noted that
pineal
rhythm
elevated
differences
species
content.
differences the
the
all
was
peaks
melatonin
of enough
in
content
sex
the
in these
four had
was species,
In
portion
melatonin
total
which
content
latter
timing
the
no
pattern photoperiodic hamsters.
the
that
An
previous
al.,
et
acyclic in All four
pinealectocycling.
female
(Rollag
during
nonphotoperiodic
seemingly
among
and
the
times contents
melatonin
male
unlikely
from
at selected
pineal
females acyclic in
species, all the in this study
melatonin
Other
of case
a
the
respect
tiate
expected
Syrian
during
period.
1500
±
230±31 175 ± 21 232 ± 37
similar lished
the to
in pineal melatonin content levels occurring at night. The
had a melatonin to two of the
observed
and
110 56 130
melatonin
2/6 oil-treated acyclic in 1OL:
oil-treated had stopped
been
diurnal rhythms with the highest
only
±
hamsters
after 10 in females.
in a variety of species examined
species, similar
±
391 548
F SH (ng/ml) After castration
pineal
3).
DISCUSSION
rat,
643
7 7
melatonin.
Before castration
all cases
half begun
had rendered and 6/8 animals
None of the five females in 16L:8D
studies rodent
Serum
After castration
(Fig. injection
variable results; approximately on each photoperiod had
show Parallel
±
with
injected
H (ng/ml)
Before castration
(mg)
rats
SEM.
±
both
wt
781
the
hamsters
were used in this study while females were used in the three remaining species. However, pineals were also obtained from a few male Turkish
lit_i____ Ph,,, OIl
PIn,, 1M9 N
PIn,, Sjig N
I
___
Intact No tr.stm.nt
FIG. 3. Testes weights in Syrian hamsters injected 3 times nightly with melatonin or vehicle. Injections were administered at a time corresponding approximately to the time of elevated pineal melatonin content in untreated hamsters. Animals were exposed to long or short photoperiods.
GOLDMAN
782
ence in the in Siberian short
pineal melatonin rhythm was noted hamsters maintained in a long or a
photoperiod. In the first experiment
which
had
elevated
times
of
sampling
from
the
three
experiment, demonstrated the
day
of
pineal
ent
the
of
in
hamsters, period of
elevated
levels
Syrian
differ-
than
that
hamsters, failed
when
to
animals (Tamarkin
previous study phase-shift
previ-
where
the
show
any
were
exposed
et
al.,
the
circadian
1979).
with Syrian hamsters, occurred in peak levels
cycle
in
which
et al., 1979; pinealectomized phase,
Tamarkin animals gonadal
regression
long-day
and
studies
melatonin
gonadal injections
regression when in pineal-intact
middle 1979b). melatonin
of the dark Still other injections
light phase. neither time
phase studies are
daily.
there and
may be an interaction endogenous melatonin
photoperiod
hamsters
demonstrates levels of
pineal
photoperiod. species the
et
that the melatonin
These length
pineal critical
melatonin information
length
for
the
al.,
Siberian
1979).
duration is longer
elevated a short
in that of
for this elevated
provide the animal about environmental
regulation
of
seasonal
and
count
clearly of
data suggest of the period may
The
hamsters
with day-
reproduc-
for
It has species,
been the
mouse,
reported Syrian
Syrian
1979).
Constant-release (Hoffmann, that
1976)
daily
data). species,
the
in the
the
and
Two ferret
weasel
(Rust
also showed dramatic to exogenous melatonin. present study is the first
pinealectomized
of
melatonin hamsters
were during
day
as to
in
hamsters
melatonin
al.,
et al.,
per
systems
of
likely
in
with
over
which of
to be
responsive
time
of the Syrian
However,
in a
observed
that
inducing hamsters a period
present
gonadal when of
may results
report that
course
short-day
exposure
previous
indicated
photoperiodic
sensitivity.
duration
1979). in
of the
the
This the
we
day
conclusion,
1975)
to
physiological hamsters have given 3 times
in
was effective in pinealectomized 3 times
In
which
phase
to
experiment
agreement in
interval.
al.,
to concen-
the
differences
a 6-h
level et
in exposure
Thus, the 6-h duration a critical feature.
that the
possible that the of melatonin
above
(Tamarkin
present
(Goldman
it remains of administration
correspond
pineal
the
hypothesis
melatonin
mask
over
animals, Bittman,
increase
in pinealectomized melatonin injections to
given
and
administered that
so
per
gonadal
1969),
injections
range
melatonin regression
Herbert,
in
the
resulted
ac-
was equally effecshort-day pinealecobservation would
might
enough
preliminary
photoand
here far
peak
in pineal-intact and Goldman, additional
employed
happens
have
pinealectomized et al., 1979;
days
to
Our studies employed
of melaton-
(Thorpe
short-tailed
trations
Siberian we
injections atrophy (Yellon
the to a
al.,
short
Nevertheless, and mode
doses
might of responsive-
mentioned,
sensitivity
the The
melatonin
interaction
contradict
to
1979).
et
of
regression
induce testicular of this species
and
while 1975).
(Tamarkin
1978),
single
unpublished
Meyer, responses The
following
which consisin pinealec-
implants
gonadal
hamster
periodic
injections regression
hamsters
observed in can males
of
grasshopper
implants, et al.,
to
that
exogenous pineal-intact
patterns
and (Goldman
3
suggested
between in
this
previously
exposure
present study indicate that rat also failed to respond
of melatonin induced te3ticular
induced
the
regression
with melatonin to respond (Turek
tomized also
photoperiodic
and
gonadal
results of the pinealectomized regimen tently
two
hamster
showed
treatment rat failed
that
been
study melatonin treatment tive in both long-day and tomized hamsters. This appear
tion.
hamsters are signifi-
is administered
it has
different
intact
As
melatonin
that
the
ness in respectively 1978).
(Tamarkin et al., have revealed that more effective in with intact hamsters the early part of the
variables
in
when
causing
in single during the
Thus, in pinealectomized of day nor photoperiod However,
earlier
in
administered hamsters
times
(Tamarkin
In
ineffective
compared during
When during in both
animals.
was
pinealectomized when administered
data on (Panke
occurred
short-day
cant
study
melatonin
et al., 1979). were injected
of pineal melatonin with a shift in the photoperiod, but the duration of elevated levels of pineal melatonin was similar in a long or a short present
pineal
release probably occurs, as judged from fluctuations in pineal melatonin content
this
second
is a distinctly
rhythm
photoperiod
at all
differed
The
response
change
In the a predictable
night,
Siberian the dark
This
melatonin
a short
the
period
melatonin
observed
hamsters, levels
species.
only with extending
melatonin.
remarkable to
during
extended
pineal
Siberian
melatonin
other
done that
pineal
ously
the
pineal
ET AL.
the
mammals
to exogenous
1.5
h.
not
be
are (Turek
reproductive are
in et
more
melatonin
PINEAL
compared
with
the
nonphotoperiodic consistent
reproductive In
in
diurnal
differences melatonin
tween
photoperiodic
and
respectively.
However,
dark
period
resulted
in
pineal
content
of
the
day
an
extended
melatonin
melatonin
was
regression
when
capable
melatonin
content
extending of
is increased
elevated exogenous
inducing to
during the phase during
the
hamsters
Finally, of
of be-
nonphotoperiodic
administered
mized Syrian hamsters the dark period-the
rhythms
period
levels.
no
observed
Siberian
gonadal pinealecto-
latter which
in this
PHOTOPERIODISM
of
addition,
were
for
AND
systems
species.
pineal species,
MELATONIN
part of pineal
Reiter,
gland. Ann. Rev. R. J., Vaughan,
783
Physiol. 35, 305-328. M. K., Blask, D. E. and
John-
son, L. Y. (1974). Melatonin: Its inhibition of pineal anti-gonadotrophic activity in male hamsters. Science 185, 1169-1171. Reppert, S. M., Perlow, M. J., Tamarkin, L. and Klein, D. C. (1979). A diurnal melatonin rhythm in primate cerebrospinal fluid. Endocrinology 104, 295-301. Rollag, M. and Niswender, G. (1976). Radioimmunoassay of serum concentrations of melatonin in sheep exposed to different lighting regimens. Endocrinology 98, 482-489. Rollag, M. D., Panke, E. S., Trakulrungsi, W., TrakuIrungsi, C. and Reiter, R. J. (1980). Quantification of daily melatonin synthesis in the hamster
pineal gland. Endocrinology
species.
106, 231-2
36.
Rust,
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