Serotonin is also known as 5-hydroxytrytamine (5-HT) is
widely distributed in plant and animal tissues, venoms and stings. It is a
monoamine neurotransmitter synthesize in serotonergic neurons in the central
nervous system and enterochromaffin in the gastrointestinal tract in humans and
animals. This neurotransmitter like the other is found both periphery and
brain. The neurochemical mechanisms that regulate 5-HT transmission such as
synthesis and activation are generally the same either in the brain or
Precursor of serotonin is from tryptophan,
one of the essential amino acid in the body. Tryptophan containing food such as
poultry meats, milk, and other high-protein foods,
tryptophan is released from these proteins and enters the circulation.
Tryptophan is taken up b mast cell in intestinal tract and metabolized into
serotonin. A lesser, but equally important amount is taken up by the brain through
an active, energy-requiring transporter pump, large neutral amino acids (LNAA).
This transporter also take up other LNAA’s thus when a person taking large
amounts of protein, less tryptophan will carried out to the brain. While when a
person eating high carbohydrate-low protein meal, the amount of tryptophan
entering the brain will be significantly increased compared with the normal
situation (John W. C., 2001).
Tryptophan is converted into
5-hydroxytryptohan by tryptophan hydroxylase then converted into serotonin of
5-hydroxytryptamine by aromatic L-amino acid
synthesis of serotonin, this free amine is stored or is rapidly inactivated by
usually by oxidation catalyzed by the enzyme monoamine oxidase (MAO). Serotonin
is the precursor of melatonin synthesis. The synthesis of melatonin occurs in
pineal gland and retina. Serotonin regulates functions in the body
like mood, sleep, appetite, temperature regulation, perception of pain
regulation of blood pressure and vomiting. Serotonin is said to have relation
in depression, anxiety and migraine.
has no clinical applications as drug. But the receptor subtype selective
agonist proves to be values. There are several types of serotonin receptor
subtype that already identified. Each of this receptor subtypes are distributed
in different area in brain and gastrointestinal tract. Example of serotonin
agonists are buspirone, nonbenzodiazepine anxiolytic and dexfenfluramine as
appetite suppressant. Not even that, sumatripan and its congeners are agonists
effective in treatment of acute migraine and cluster headache. While to inhibit
the bad effect of inducing serotonin receptors like vomiting, a serotonin
antagonist like ondansetron is used. Melatonin is been studied for
several functions in the body including contraception, protection against
endogenous oxidants, prevention of aging and treatment for depression, HIV
infection and variety of cancer. Melatonin is most often administered to induce
sleep and to prevent jet lag. Both
in vitro studies and in vivo studies have shown that melatonin is a
potent scavenger of the highly toxic hydroxyl radical and other
oxygen-centered radicals, suggesting that it has actions not
mediated by receptors. In one study, melatonin seemed to be more
effective than other known antioxidants (e.g., mannitol,
glutathione, and vitamin E) in protecting against oxidative damage.
But the antioxidant effect is concentration dependant. It needs higher
concentration of melatonin than peak nighttime serum concentration. Melatonin
secretion does not change during the menstrual cycle in normal
women. Similarly, substantial increases in serum estradiol
concentrations do not alter melatonin secretion in infertile women
with normal cycles (Amnon B., 1997).
affective disorder during season change in temperate countries
Season is different in tropical countries and temperate countries. In
temperate countries, the changes in season are influence by the changing of
amount of sunlight. People in temperate and polar region experience four
distinguish season that are spring, summer, autumn (fall),
Northern part of the world experiences opposite season as in south part. This
changing of season usually accompanied by seasonal affective disorder (SAD),
one of the common conditions in temperate countries. It occurs especially starting from September or October and
ending in April or May (Sabra L. K. W. et al., 2006). This SAD is affecting 1-3% of adults in temperate climates and more prevalent in women (Magnusson
A. et al., 2003).
According to Jacobs
G.D. (2004), mood and energy in winter are poorest during winter. This led to
theory that lack of exposure to sunlight affects the population as a whole and
may be contributing to an overall increase in mood disorders in the general
population. The supplementary light in winter might have widespread benefit for
those individuals who are "normal" but are more vulnerable to
seasonal depressive symptom. Symptoms of SAD include irritability, sadness, anxiety,
increased appetite and a craving for carbohydrate, weight gain, decreased
activity and a need for more sleep, drowsiness during the daytime, and problems
with work and relationships (Miller
The severity of depressive or bipolar
disorder is vary to each people according to Partonen T (1998). He also stated that at first, SAD was related to
abnormal melatonin metabolism but later findings did not support this.
Hypothesis of brain serotonin function support the hypothesis of disturbed
activity in SAD patient. While according to Yang H.D. (1997), mania
attack is significantly higher in spring and summer (71.4%) than in fall and
winter (28.6%) while depressive attack is higher in fall and winter (63.4%)
than in spring and summer (36.6%), which shows there are clear relations
between affective disorder attack and seasonal change, and support the
circadian rhythm-melatonin hypothesis. Yang H.D. also suggests that there are
not gender differences between mania attack and depressive attack and seasonal
A et al. (2003) stated that the role
of circadian rhythms in SAD needs to be clarified. The phase-delay hypothesis
holds that SAD patients' circadian rhythms are delayed relative to the
sleep/wake or rest/activity cycle. This hypothesis predicts that the symptoms
of SAD will improve if the circadian rhythms can be phase-advanced. The retinal
hyposensitivity hypothesis for SAD support by the retina sensitivity was
significantly lower) in SAD patients compared with normal control subjects
conducted by Marc H. et al. (2004), but the
explanation for lower rod photoreceptor sensitivity in SAD is not known. They
also proposed that brain neurotransmitter dysregulation may be at the origin of
both the mood disorder
and retinal sensitivity change.
Despite of ugly
effect of SAD, the symptoms also promoted healthier pregnancies and gave rise
to enhanced female–male pair-bonding which improved the survival chances of
both mothers and babies. Hypomania in spring and summer also served to increase
the likelihood of procreation at the optimal time of year. But recurrent winter
depression can become a reproductive disadvantage (Eagles J.M.,
Selective serotonin reuptake inhibitor or
SSRI like citalopram, fluoxetine and sertraline (BNF 51, 2006) are used in treatment
of depression. Number of SSRI been prescribe to adult Swedish reduce as
increase of 1°C from and more SSRIs were dispensed to men and women in Sweden
during relatively cool Julys during the period 1991–1998 (Hartig, T., et al. 2007). This shows that depression
will increase as temperature decrease. People are more depress in winter rather
than in summer. The involvement of serotonin cause the depression.
of serotonin with seasonal changes
Mood can be seasonal according to
temperature and season we experience. The amount of sunlight that enters into
our retina will enhance the “happy” neurotransmitter release, serotonin.
Serotonin is involved in mood, behaviour and affective disorder. Light can
induce synthesis of serotonin. It proved in Chanut E. et al. (2002) origin of serotonin, precursor of melatonin, in the
retina of adult rat, where no immunoreactivity for serotonin or tryptophan
hydroxylase had ever been detected. Tryptophan hydroxylase is the initial and
rate limiting enzymes in the biosynthesis of serotonin neurotransmitter. This
enzyme not only determines the amount of serotonin produced at any given time
but also involve in influence of functional status of the serotonin neuronal
system. For these reason, physiological conditions or pharmacological
treatments which modify tryptophan hydroxylase can have short or long term
effects on serotonin system
Melatonin is produced in pineal gland and
retina. Retinal circadian rhythms are driven by an intrinsic oscillator, using
chemical signals such as melatonin, secreted by photoreceptor cells. It is
proven in this experiment by Chanut E. et
al. (2002) that tryptophan hydroxylase substrate concentration was higher
in the dark period than in the light period, and formation of hydroxylated
compounds was increased. They confirmed the presence of tryptophan hydroxylase
mRNA in the rat retina by RT-PCR.
Tyrosine hydroxylase gene expression can
also be stimulated by calcitriol that accumulates in the nuclei of adrenal
medullary cells. Adrenergic input to the pineal gland at night induces the
transcription of CREM gene. Partonen T. (1998) stated that CREM gene is either
subsensitive or supersensitive to induction, depending on the photoperiod of
the prior night. This memory of past photoperiod, either experience long dark
period as in winter or long day period as in summer, induced changes in
melatonin either inhibitory or stimulatory effects on bodily functions. Body
works by storing information that will be needed to control the body function. The
author also stated that the involvement of calcitriol in increase serotonin
levels because of inhibition of melatonin binding to nuclear retinoid Z
receptors. Serotonin production is also thought to depend on duration of light
exposure the previous summer.
inactivated usually by
oxidation catalyzed by the enzyme monoamine oxidase (MAO). Involvement of MAO
in inactivation of serotonin is important in serotonin level in body. One
experiment open field of Yakut ground squirrels (Citellus
undulatus) was done. The objective of this study is to study the changes of MAO
in brain with changes of season. The experiment was done by Semenova TP (2004)
showed that in summer, all parameters of exploratory activity in the open field
and holeboard test reached the values characteristic of summer animals very
rapidly, within a few days or (in some cases) even within the first 24 hours
after the arousal from hibernation in the middle of April. In autumn these
parameters decreased to their minimum values 1.5-2 months prior to hibernation.
He also found that activity of MAO A measured with serotonin as a substrate in
the hippocampus was 1.8 times higher than the activity of MAO A with respect to
noradrenaline. In contrast, in autumn the MAO A activity determined with
noradrenaline as a substrate was 2.5 times higher than the activity a MAO A
with respect to serotonin. This shows that seasonal features of the higher
nervous activity of hibernating animals depend on the balance between
serotonergic and noradrenergic systems in different periods of the annual
Changes of mood are apparent in winter in
temperate countries rather than in tropical countries. This is probably because
of changes of amount sunlight with changing of season. In winter, people in
temperate countries will experience short days and long nights with extreme
temperature. The different of climate may lead to depression. In winter,
turnover of serotonin is the lowest according to Lambert GW et al. (2002). It
also proven by them that the production of serotonin was directly related to
duration of sunlight and increase in synthesis with increase in luminosity.
In other research conducted by Ohshima K. et al. (1999), the
seasonal variations in serotonin immunoreactivity and ultrastructure of the secretory
rudimentary photoreceptor cells (SRPC) were studied in the pineal organ of the
Japanese grass lizard, Takydromus tachydromoides in relation to the
environmental temperature. The different in temperature from spring to summer
shows increase intensity of immunoreactivity and weaker as the temperature drop
in winter. They also stated that, the
SRPC of the lizard showed distinct seasonal variations in number and size of
the dense-cored vesicles correlated to the serotonin immunoreactivity. But, the
changes in size of the lysosomes and nucleoli of the SRPC were inversely
proportional to that of the dense-cored vesicles. Furthermore, the lysosomes
ingested some dense-cored vesicles after the autumn, and they coalesced to form
huge autophagosomes or residual bodies during the winter.
of melatonin with seasonal changes
produce from serotonin. Melatonin is abundance in dark period as compared to
day period. Melatonin is normally made at night and may be
considered to act as a signal of darkness to the body. In all life
forms so far studied it seems to act as a time signal for the
organisation of daily (circadian; sleep-wake) or seasonal rhythms,
or both. Melatonin seems to play an important part in setting the
correct timing of sleep-wake cycles in mammals in the perinatal
period and of subsequent pubertal development. When given to humans
it has rapid, transient, mild, sleep inducing effects, and it lowers
alertness, body temperature and performance during the three or four
hours after low doses have been given. Correctly timed, it is able to shift the
internal "body clock" both to later and earlier times and
so melatonin has a potential value as a treatment for problems with
sleep and other body functions that have been disordered by time
human pineal gland is augment only during long photoperiod. There is a partial
effect of photoperiod on melatonin secretion. This may result from living in an
artificial light environment or due to other nonphotic signals involved in
rhythm. Research by Rafael L. et al. (1998) proved that melatonin
production with changes of season indicated that day–night difference in pineal melatonin
levels was evident only in the long photoperiod (April–September) with
significantly higher melatonin
concentrations occurring at night (2200–1000 h). Nighttime values in the long
photoperiod were significantly higher than the nighttime values during the
short photoperiod (October–March). During winter or short photoperiod, they
suggest that a possible in phase delay in melatonin secretion.
L. et al. (1998) also found that day night difference is an age related. They
found that day–night difference was evident in young subjects (30–60 years),
but not in elderly subjects (61–84 years). Elderly subjects had lower total melatonin
levels (day and night values) although statistically not significant. Thus they
concluded that the production of melatonin is not decline with increase age and
no significant day–night difference in melatonin
(1997) suggested that there are two photoreceptive systems that are one involve
in melatonin secretion and other mediating conscious of perception light. This
is because he found that blind person with no papillary light reflexes and
no conscious visual perception has light-induced suppression of
melatonin secretion. This suggests that blind person cannot be affected by
changing of sunlight and mood with different season.
nocturnal biosynthesis of melatonin in the rat pineal depends on strongly
enhanced expression of the enzyme arylalkylamine N-acetyltransferase
(AA-NAT). During constant darkness like in winter
time, the amplitudes of AANAT and melatonin rhythms were significantly lower
(by 50-80%) than those found under the daily light-dark cycle (Zawilska JB et al., 2006). This indicates that
melatonin production in pineal gland and retina is regulated by both light and
the endogenous circadian clock. The rapid slowing of the rhythms under constant
darkness suggests that of these two regulatory factors, environmental light may
be the primary stimulus in the maintenance of the high amplitude melatonin
production in the turkey. Without much light also can lead to decrease
synthesis in melatonin.
Arylalkylamine N-acetyltransferase (AA-NAT) gene is one of the cAMP
inducible genes. Study by Spessert
R. et al. (2006) showed that all cAMP
inducible genes tend to display higher maximum
expression under short photoperiod than in long photoperiod. They suggested
that all cAMP-inducible genes are influenced by photoperiod and depend on the
cycle of darkness. Thus AANAT will cause more melatonin production in dark
period as compared in day period.
(AANAT) is important in production of melatonin. Adrenergic inputs to pineal
gland from suprachiasmatic nucleus (SCN)
stimule transcription of AANAT during darkness. This lead to activation of
pinealocyte adrenoceptors involves in cAMP-dependent stimulation of protein
kinase A (PKA). In Lydia E. et al.
(2004) study, they found that the nocturnal rise in AA-NAT depends on the
lighting conditions. As compared with light/dark (LD) 12:12, the delay between
dark onset and the nocturnal rise in AA-NAT is shortened under long
photoperiods and prolonged under short photoperiods. They suggested that
rapidity of nocturnal AA-NAT induction depends on cAMP inducibility of the
gene. Accordingly, cAMP produces a strong AA-NAT response in pineals obtained
from rats housed under long photoperiods and a weak AA-NAT response under short
photoperiods. Changes in AA-NAT inducibility are fully developed not earlier
than after seven cycles. This observation suggests that long-term changes in
the photoperiod are necessary to achieve full adjustment of cAMP inducibility
of the gene. A direct relationship was found between cAMP-dependent AA-NAT
inducibility and the pineal protein kinase A (PKA) activity. As compared to LD
12:12, PKA activity was increased under long photoperiod and decrease under
synthesized in diurnal or circadian rhythm and produce large at night. The
amount of light can affect the production of melatonin. The melatonin synthesis
is related with 14-3-3 proteins. It is a large family of proteins that exist
primarily as homo- and heterodimers within all eukaryotic cells. It has been
demonstrated that cAMP levels and PKA activity in melatonin-synthesizing cells
(pinealocytes and retinal photoreceptors) increase at night. Phosphorylated of
serotonin N-acetyltransferase (AANAT) by PKA will bind to 14-3-3 proteins. Thus
this formation will form complex and protects from proteolytic destruction. Not
even that, this complex will induce changes of the AANAT molecule resulting in
an increase of the enzyme activity; this in turn enhances melatonin production
by several folds. Light can cause intracellular cAMP decrease and
dephosphorylation of phosphorylated AANAT. It can also enhance dissociation of
pAANAT from 14-3-3 complex and turning off melatonin production (Rosiak J et al., 2006).
there is restriction of movement. Because of heavy snow, people cannot go out
and do normal activities. The effect of latitude and melatonin production is seen
in experiment by Kriya L. D. et al. (2007). They use sled dog because
of its nature that is elite athletes.
They study both effect of exercise and non exercise dogs from 2 distinct latitudes.
Melatonin production was prolonged in high latitude dogs (65° N) as compared
with lower latitude dogs (45° N). This suggests that as latitude goes higher,
the season changes are more apparent. Melatonin secretion is increase as the
amount of sunlight is reduced. They also stated that melatonin production
increase in winter as compared to in summer. As for exercise, there is
reduction in winter melatonin levels at both latitudes. Adaptation to season
can also affect the melatonin production. They also found out that sled dogs in
Alaska had lower melatonin
levels than sled dogs in New York. This probably because sled dog in Alaska
experience colder temperature as compared to sled dog in New York. The low
melatonin mechanism is not well understood.
antioxidant defenses, hemostasis and glucose regulation are depend on melatonin
signal for circadian organization. Melatonin also proved to stabilizes and
strengthen coupling of circadian rhythms, especially of core temperature and
sleep-wake rhythms (Bruno C. et al., 2005). Melatonin is also important in gonadal activity. The
circadian disturbances related to production are probably subsequent to the
seasonal change. Both spermatogenesis and folliculogenesis are also proved to
be influence by melatonin. According to Partonen T. (1999), the exposure to bright light may be useful in
treatment of infertility in couples with abnormal melatonin metabolism.
of animal has their own mechanism to coordinate changing of season. As for
example animal at nontropical region will hibernate to restore its own body
temperature. They adapt to photoperiod to coordinate changes in behaviour and
physiology. Rodents shows increased in aggression in short, “winter like” as
compare to “summer-like” day length. They result from Aaron M. J. et al. (2002) showed that short-day
hamsters underwent gonadal regression and displayed increased aggression
compared with long-day animals. Melatonin
treatment also increased aggression compared with control hamsters without
affecting circulating testosterone. Collectively, the results of the present
study demonstrate that exposure to short days or short day-like patterns of melatonin
increase aggression in male Syrian hamsters. In addition, these results suggest
that photoperiodic changes
in aggression provide an important, ecologically relevant model with which to
study the neuroendocrine mechanisms underlying aggression in rodents
influences lots of body function. It can regulates the timing of seasonal
cycles in reproduction, energy metabolism and other seasonal
characteristics, and the effects are transduced through changes
in the duration of nocturnal melatonin
secretion from the pineal gland. Summer like physiology (short daily melatonin
signal) and winter like physiology (long melatonin signal) cause signal in
specific target in the brain and pituitary gland, each governing a different
component of the seasonal
adaptation. The pars tuberalis (PT) of the pituitary regulates prolactin
release and provides a tractable model system to investigate the molecular
decoding mechanism. In the PT, melatonin
onset at dusk activates cryptochrone (Cry1) gene expression and melatonin
offset at dawn activates period (Per1) gene expression (Amanda J. F. C. et al., 2003), thus the Cry/Per
interval varies directly with nightlength, and inverse to daylength (Gerald A. Lincoln, 2006). The author proposed
that photoperiod-induced changes
level of CRY/PER protein heterodimer formation thus under long days, prolactin
secretion is stimulated.
Serotonin is a neurotransmitter that release from brain and
gastrointestinal tract is related with light exposure. Serotonin regulates functions in the body like
mood, sleep, appetite, temperature regulation, perception of pain regulation of
blood pressure and vomiting. Melatonin is a serotonin derivative is not
a neurotransmitter and it is secreted from pineal gland and retina. Melatonin
has diurnal and circadian rhythm. Melatonin is been studied for several
functions in the body including contraception, protection against endogenous
oxidants, prevention of aging and treatment for depression, HIV infection and
variety of cancer. Melatonin is most often administered to induce sleep and to
prevent jet lag. Melatonin secretion is increase in dark period while serotonin
is increase in day period. Serotonin and melatonin is related in seasonal
changes. Depression of serotonin release in winter will lead to a condition
name seasonal affective disorder (SAD). Amount of photoperiod through out the
season affect the production of serotonin and melatonin. Serotonin is said to have relation in depression,
anxiety and migraine.
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