PERIODICUM BIOLOGORUM UDC 57:61

VOL. 113, No 1, 29–41, 2011 CODEN PDBIAD

ISSN 0031-5362

Review

Serotonin

Abstract
DOROTEA MÜCK-[ELER
NELA PIVAC Serotonin is a monoamine that could be found in plans, animals and hu-
man body. The homeostasis of serotonin is maintained by the series of inter-
Division of Molecular Medicine, dependent processes that include synthesis, storage, transport and removal/
Ru|er Bo{kovi} Institute, Bijeni~ka 54, 10000 degradation. In the human body serotonin is synthesized in two independ-
Zagreb, Croatia
ent compartments that are separated by brain-blood barrier. The majority of
Correspondence: serotonin is synthesized in enterochromaffin cells of the gastrointestinal
Dorotea Mück-[eler tract, released in the blood stream and stored in blood platelets. About 5% of
Laboratory for Molecular Neuropsychiatry serotonin is synthesized in the brain within serotonergic neurons. As a neu-
Division of Molecular Medicine
rotransmitter serotonin plays an important role in the regulation of physio-
Ru|er Bo{kovi} Institute
Bijeni~ka 54, 10000 Zagreb logical functions like body temperature, sleep, vomiting, sexuality, appetite,
E-mail: [email protected] behaviour and cognitive functions such as learning and memory. The dys-
function of the serotonergic system has been implicated in the aetiology of a
Abbreviations: variety of psychiatric (depression, schizophrenia, alcoholism) and neurolog-
alpha-MTrp;
alpha-methyl tryptophan;
ical (migraine, Alzheimer’s disease, epilepsy) disorders. Recent genetic asso-
AD, Alzheimer’s disease; ciation studies of the neuropsychiatric disorders have focused on functional
ADHD attention-deficit/hyperactivity disorder; polymorphisms i.e. DNA sequence variations that alter the expression and/
BBB, blood-brain barrier; or functioning of the gene product in the loci encoding different genes.
CSF cerebrospinal fluid; Some of them are genes for tryptophan hydroxylase, serotonin transporter
MAO, monoamine oxidase; and serotonergic receptors.
PTSD, posttraumatic stress disorder;
5-HIAA, 5-hydroxyindoleacetic acid;
5-HTT, serotonin transporter; THE BEGINNINGS
TPH, tryptophan hydroxylase

S erotonin (5-hydroxytryptamine, 5-HT) was discovered 60 years ago

in blood, peripheral tissues and central nervous system (1). It was
first identified as a vasoconstrictor substance that is released from plate-
lets during the coagulation of blood, and later as a monoamine neuro-
transmitter in the brain. It has been established that gastrointestinal
tract, blood platelets and brain were the main locations of serotonin in
the mammal’s body. In addition, serotonin could be also found in plants
(bananas, walnuts, tomatoes, hickories, pineapples), mushrooms, octo-
puses, and in poison of insects (spiders, scorpions, wasps).

Synthesis and metabolism

Serotonin is a tryptamine that consists of an indole ring with a hydro-
xide group on the fifth C atom, and a carboxyl-amide side chain (Figure 1).
The main precursor of serotonin is the essential amino acid L-try-
ptophan that must be provided by food. L-tryptophan and the other
precursor, 5-hydroxytryptophan, are transported from blood to brain by
the active carrier system located in the blood-brain barrier (BBB). It is
believed that serotonin, due to its chemical properties, does not cross
BBB, but new evidence (2) suggests that serotonin might cross endo-
Received February 22, 2011. thelial cells of the BBB using serotonin transporter. The serotonin syn-
thesis occurs in a two-step enzymatic procedure (Figure 2). The first
Dorotea Mück-[eler and Nela Pivac Serotonin

spinal fluid (CSF) and urine. The flavine-containing

mitochondrial enzyme monoamine oxidase (MAO) is
the most important enzyme for degradation of serotonin.
This process has two steps: first step is a degradation of
serotonin into 5-hydroxyindole acetaldehyde, and the
Figure 1. The chemical structure of serotonin or 3-(2-aminoet- second one is degradation through aldehyde dehydro-
hyl)-5-hydroxyindole. genase regulated conversion into 5-hydroxyinoleacetic
acid (5-HIAA) as the main metabolite of serotonin.
and rate-limited step is hydroxylation of the tryptophan In the human body, serotonin is synthesized and lo-
to 5-hydroxytryptophan. This reaction is catalyzed by cated in two compartments that are separated by BBB.
tryptophan hydroxylase, a specific enzyme located only The first compartment, called »peripheral« compartment,
in the serotonergic neurons (3). The 5-hydroxytrypto- contains the majority (about 95%) of serotonin in the
phan is decarboxylated by a nonspecific enzyme, aro- body. Peripheral serotonin is synthesized in enterochro-
matic amino acid decarboxylase, into serotonin. Seroto- maffin cells of the gastrointestinal tract. The second, i.e.
nin levels could be determined in the brain and various »central« compartment of serotonin is the central nervous
body fluids including serum/plasma, platelets, cerebro- system that synthesizes serotonin within serotonergic
neurons. Recent studies (3, 4) revealed that tryptophan
hydroxylase exists in two isoforms with different location
within the body of mammals (Table 2). Tryptophan hy-
droxylase type 1 (TPH1) is responsible for the synthesis
of the peripheral serotonin (4), while tryptophan hy-
droxylase type 2 (TPH2) is the predominant isoform in
the brain.

Serotonergic receptors
The complex functions of serotonergic system would
be impossible without a large number of serotonergic re-
ceptors (5). Serotonergic receptors are classified in seven
different groups or »families« called 5-HT1, 5-HT2,
5-HT3, 5-HT4, 5-HT5, 5-HT6, 5-HT7, and several
subtypes (Table 1) that differ in terms of structure, ac-
tion, and location. Serotonergic receptors are distributed
on the presynaptic and postsynaptic neurons in the cen-
tral nervous system and on the different peripheral cells
and organs (Table 1). The majority of serotonin receptors
are G protein-coupled receptors. The exception is 5-HT3
receptor that belongs to the ligand-gated ion channel re-
ceptors. Serotonergic receptors activate an intracellular
second messenger (cAMP, IP3, DAG) cascade and pro-
duce an excitatory or inhibitory response. Serotonin re-
ceptors are very important sites of action for different
classes of psychotropic drugs, like antidepressant drugs
(5), atypical antipsychotic drugs (olanzapine, risperidone)
Figure 2. Synthesis and degradation of serotonin. and psychoactive compounds (LSD, DMT).

TABLE 1
The serotonergic receptors.

Type Subtype Distribution Intracellular response

5-HT-1 1A, 1B, 1D, 1E, 1F CNS, blood vessels Inhibitory
5-HT-2 2A, 2B, 2C CNS, platelets, blood vessels, smooth muscle Excitatory
5-HT-3 3A, 3B CNS, GI tract Excitatory
5-HT-4 CNS Excitatory
5-HT-5 CNS Inhibitory
5-HT-6 CNS Excitatory
5-HT-7 CNS, GI tract, blood vessels Excitatory

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Serotonin Dorotea Mück-[eler and Nela Pivac

Serotonin in the central nervous system ulated by TPH1 (4). From gut serotonin is released in the
Serotonergic neurons are widely distributed through- blood stream and than stored mostly in blood platelets.
out the mammalian brain and serotonergic system is the The other peripheral cells that contain serotonin are
largest single system in the brain. The nine groups of macrophages and mast cells. Peripheral serotonin is me-
serotonergic cell bodies are located mainly in the area of tabolized in the liver by a MAO-A to 5-HIAA. The
brain stem raphe nuclei. Serotonergic nerve terminals 5-HIAA is filtrated and excreted by the kidney. The vast
could be found in nearly all other regions of the central increase in urine excretion of 5-HIAA was found in
nervous system. The widespread distribution of the ra- carcinoid syndrome, due to the pronounced production
phe projections suggests a highly collateralized axon sys- of serotonin by carcinoid cells.
tem (6). The communication of serotonergic system with In humans a direct association between neurotrans-
other important neurotransmitter systems like catechola- mitters in the brain and those excreted in the urine is not
minergic system (7) is well established, although the yet defined. New evidence suggests (2) that neurotrans-
mechanisms of interaction are not yet completely under- mitters excretion in the urine might be used as possible
stood. Significant amounts of data have demonstrated biomarkers of the central nervous system activity. The
that these interactions are very important in the mecha- study in rats treated with 5-hydroxytryptophan has shown
nisms of action of antidepressant and anxiolytic drugs. simultaneous changes in the activity of brain seroto-
nergic system and urinary serotonin levels.
Serotonin is implicated in many physiological (body
temperature, sleep, vomiting, sexuality, appetite), behav- Serotonin has an important role in the vascular biol-
ioural (aggression, mood) and cognitive (learning, mem- ogy. It is involved in the control of vascular resistance,
ory) functions (8). In addition, serotonin has an impor- blood pressure, haemostasis and platelet function (11).
tant role in the growth of the central nervous system One of the most important functions of the peripheral se-
during development. It plays a critical role as a growth rotonin is the promotion of platelet aggregation and
factor in the immature brain, directing both proliferation blood clotting. Activated 5-HT-2A receptors on platelet
and maturation. This is supported by the higher seroto- membrane also stimulate platelet activation and aggre-
nin turnover rate in the immature mammalian brain gation.
than at any other time in life. Recent data (9) suggested
that an overload of serotonin during cortical develop- Blood platelets and serotonergic
ment could induce abnormal distribution and incorrect neurons
positioning of cortical interneurons. The function of central serotonin in mood, state of
There are several methods for the determination of se- mind, and behaviour, as well as its role in cognition and
rotonin synthesis rate in vivo: a) pharmacological ma- memory are very difficult to establish. Literature data
nipulation, i.e. after the administration of compound suggest that blood platelets can be used as an easy obtain-
that inhibits enzyme aromatic acid decarboxylase like able peripheral model for the some processes in the cen-
NSD-1015, b) the use of radiolabel tryptophan, c) the tral serotonergic neurons (12–14) (Table 2). The kinetic
use of radiolabel alpha-methyl tryptophan (alpha-MTrp) and pharmacological characteristics of the active trans-
as an analogue of tryptophan. The limitation of the port of serotonin from plasma to platelets are similar to
pharmacological methods is that the effect of the tested the reuptake of serotonin from synaptic cleft into pre-
compound on the serotonin synthesis could be in part in- synaptic neurons. In addition, platelet MAO type B ac-
fluenced by the pre-pharmacological manipulation it- tivity corresponds to MAO-B activity in presynaptic part
self. Radiolabel tryptophan is an essential amino acid in- of neurons. There are also 5-HT2A receptors (14), a2-adre-
corporated in proteins, while radiolabel tryptophan me-
tabolites, like serotonin and 5-HIAA, are lost very rap-
idly from the brain. The use of alpha-MTrp labelled with TABLE 2
3H or 14C and the determination of serotonin synthesis Similarities and differences between blood platelets and
by an autoradiographic method (10) permits the mea- serotonergic synaptosomes.
surement of serotonin synthesis in the rat brain with high
Brain serotonergic neuron Blood platelets
anatomical resolution and without any pharmacological
pre-treatment. The disadvantages of this method are the Similarities
need for special equipment and a long procedure. Serotonin stored in dense bodies or vesicles
The alteration of the serotonergic system has been re- Active transport (uptake) of serotonin
lated with the aetiology of different neurological (mi- Binding sites for 3H-paroxetine, 3H-imipramine
graine, Alzheimer’s disease, epilepsy) and psychiatric Receptors: 5-HT2A and a2-adrenergic
(depression, schizophrenia, mood disorders, alcoholism,
Monoamine oxidase type B
ADHD, PTSD) disorders.
Differences
Peripheral serotonin Serotonin synthesis No synthesis
Peripheral serotonin is synthesized in enterochroma- Function: Function: aggregation,
ffin cells of the gastrointestinal tract. The synthesis is reg- Neurotransmission vasoactive compound

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Dorotea Mück-[eler and Nela Pivac Serotonin

nergic receptors (15) and binding sites for 3H-imiprami- elevated brain serotonin turnover is a consequence of in-
ne and 3H-paroxetine on the platelet membrane, which creased neuronal activity, enhanced vesicular leakage and
can be used as peripheral markers for the evaluation of subsequent intraneuronal metabolism or reduced brain
pharmacologic and kinetic characteristics of equivalent serotonin transporter availability.
central nervous receptors and binding sites on presynap- Platelet serotonin levels, platelet 5-HTT and platelet
tic or postsynaptic part of the serotonergic neurons in 5-HT2A receptors were also investigated in depression.
psychiatric and neurodegenerative disorders. The decreased (35) or unaltered (19, 36) platelet seroto-
Numerous studies have tested platelet serotonin con- nin levels were found in depressive patients as well as alte-
centrations in various psychiatric disorders. Altered pla- red number of platelet 5-HT2A receptors and the num-
telet serotonin concentrations were found in patients ber of platelet serotonin uptake sites (37).
with different psychiatric and neurological disorders like The majority of antidepressant drugs in current use,
major depression (16), subtype of major depression with act by affecting the neurotransmitters (serotonin, norad-
psychotic symptoms (17), bipolar disorder (18), schizo- renalin, and dopamine), their receptors and enzymes in-
phrenia (16, 19–21), postpartum depression (22), post- volved in their synthesis or degradation (38). However,
traumatic stress disorders (PTSD) with comorbid depre- the clinical improvement after antidepressant therapy is
ssion (23), PTSD with psychotic symptoms (24), alcohol- usually observed 2–3 weeks after the beginning of the
ism (25), attention-deficit/hyperactivity disorder (ADHD) treatment. It is believed that this therapeutic delay de-
with impulsive symptoms (26), migraine (27), and Alz- pends on the antidepressant-induced desensitization of
heimer’s disease (28, 29). serotonergic or noradrenergic receptors.

SEROTONIN AND NEUROPSYCHIATRIC Schizophrenia

DISORDERS Schizophrenia is a complex and multifactorial mental
Preclinical and clinical investigations suggest that se- disorder with the prevalence of 1% worldwide. The alter-
rotonin could be related to the aetiology and treatment of ations of the dopaminergic system and their receptors are
different neuropsychiatric disorders including depres- the basis for the »dopaminergic hypothesis« of schizo-
sion, schizophrenia, PTSD, alcoholism, ADHD and Alz- phrenia. Since this hypothesis is not able to explain the
heimer’s disease (AD). complex symptoms of disease and efficacy of atypical
antipsychotics, with a higher affinity for 5-HT2A than to
Depression D2 receptors, it is supposed that schizophrenia might be
associated with the dysfunction of other neurotransmit-
Depression is a severe and devastating mental disor-
ters systems like serotonergic system (39). In addition
der with a high prevalence worldwide, and with twice
serotonergic system regulates some physiological and be-
higher risk in women than in men. Although, the patho-
havioural functions that are disturbed in schizophrenia
genesis and treatment of depression were the topics of in-
(8). In line with this »serotonin hypothesis of schizo-
tensive preclinical and clinical research, the complex
phrenia« the alteration of serotonergic activity was found
neurobiological basis of depression is still unclear (30).
in the brain of schizophrenic patients, with the decreased
The first hypothesis of depression was established almost
serotonin neurotransmission in cortical regions, and in-
forty years ago (31). It postulated that depression is a
creased in the putamen, accumbens and pallidus. The
consequence of the low serotonin and/or noradrenalin
decreased or unaltered density of 5-HT2 receptors in
levels and the dysfunction in the central serotonergic,
frontal cortex (39), decreased density of 5-HT1A recep-
noradrenergic and dopaminergic systems. These neuro-
tors and unchanged 5-HT6 receptor binding (40) were
transmitters interact with each other and regulate mood,
also found in schizophrenic patients.
sleep, anhedonia, appetite, concentration and motiva-
tion, suicidal behaviour, cognitive and autonomic func- An increase in platelet serotonin concentration was
tions (8) that are frequently disturbed in depression. observed in schizophrenic patients with predominantly
chronic time course (41), with paranoid symptoms (19),
In following years numerous attempts were made to
positive symptoms (42) and in schizophrenic patients
identify the reproducible neurochemical alterations in
born in winter (20). Although there is no direct evidence
the nervous systems of patients with depression, but
that platelets serotonin concentration correlates with cen-
mostly with negative or inconsistent results. Concentra-
tral serotonin levels, an abnormal tomographic brain
tions of 5-HIAA, the major 5-HT metabolite, in CSF
scans were found in schizophrenic patients with high
have been extensively studied in depressed subjects. A
platelet serotonin levels (43).
significant reduction in CSF 5-HIAA was found in de-
pressed patients (32), but several other studies (33) were
not able to confirm the difference in 5-HIAA levels be- Posttraumatic stress disorder
tween depressed patients and healthy controls. Recent Posttraumatic stress disorder (PTSD) is a severe psy-
study (34) described elevated brain serotonin turnover chiatric and polygenetic disease that appears in some
rate in medication-free patients with depression, particu- people that survived the extremely dangerous traumatic
larly in those carrying the short form (s allele) of the gene life event like natural disasters, war or sexual abuse.
for serotonin transporter. However it was not clear if the PTSD could be associated with alterations in different

32 Period biol, Vol 113, No 1, 2011.

Serotonin Dorotea Mück-[eler and Nela Pivac

neuroendocrine (44) and neurotransmitter (45) systems. in male and female alcoholic patients, independently on
Despite the intensive neurobiological research, the role the presence of comorbid psychiatric disorders (60).
of serotonin in the pathophysiology of PTSD is still un- It has been shown that prolactin or cortisol response
clear. Some studies (46) suggested altered serotonergic to administration of serotonergic drugs like fenflurami-
function in PTSD that might contribute to cognitive dis- ne, m-clorophenylpiperazine, 6-chloro-2-1-piperazinyl-
turbances, depressive symptoms and many physiological pyrazine, and adrenocorticotropic hormone (ACTH) re-
and pathological behaviours, such as aggression, that fre- sponse to m-chlorophenylpiperazine, was lower in alco-
quently arises in PTSD. holics than in non-alcoholic patients (61), suggesting
It is believed that serotonergic neurons from dorsal also altered central serotonergic function in alcoholism.
nuclei raphe with nerve terminals in hippocampus and
amygdala are responsible for anxiogenic response to stress ADHD
via 5-HT2A receptors, while neurons from median ra- Serotonin dysfunction has been implicated also in
phe have anxyolitic effect achieved through 5-HT1A re- ADHD, although the primary neurotransmitter that is
ceptors. However, a positron emission tomography study altered in ADHD is dopamine, and to a lesser extent,
(47) did not find altered 5-HT1A receptors binding in noradrenalin (62). However, besides the classical charac-
patients with PTSD compared to healthy subjects. Indi- teristics symptoms of ADHD (such as hyperactivity, inat-
rect peripheral evidences for the altered efficacy of sero- tention and impulsivity), aggression, as well as distur-
tonergic system in PTSD are decreased serum serotonin bances in the cognition, are also frequent in ADHD.
concentration and altered number of platelet serotonin These findings confirmed also the role of serotonin in
transporters (48). Platelet serotonin concentration was ADHD (63). The concentration of serotonin was found to
higher in PTSD veterans with psychotic subtype of PTSD be lower in ADHD (64), or unaltered in ADHD (26).
compared to platelet serotonin concentration in non- Since ADHD is a multifactorial and clinically heteroge-
-psychotic war veterans or in healthy controls (24). Since neous psychiatric disorder, platelet serotonin concentra-
platelet serotonin concentrations correlated with the se- tion was found to be increased in children with ADHD
verity of delusions, the core psychotic symptoms, these with pronounced impulsive symptoms (26) suggesting
data confirmed that platelet serotonin concentration might that higher platelet serotonin concentration in impulsive
be used as a trait marker of psychotic symptoms in PTSD. compared to non-impulsive children with ADHD might
be used as a possible trait marker of impulsivity in ADHD.
Alcoholism The impulsivity is associated with serotonin function in
non-clinical sample (65). There is a significant correla-
Literature data suggest that alcohol dependence and tion between impulsivity and lower serotonergic func-
alcohol abuse could be associated with the disturbance in tion (66). On the other hand, the opposite data exist, and
serotonergic system (49). The role of serotonin in alco- therefore impulsivity has been associated also with the
holism is based on the data showing alterations in mea- increased serotonergic functioning (67) in children and
sures of the serotonergic function in the brain, as well as adolescents.
in CSF, blood precursor availability, uptake of serotonin
in blood platelets and challenge studies.
Alzheimer’s disease
Post-mortem brain analyses have found reduced sero- Alzheimer’s disease (AD) is a neurodegenerative dis-
tonin transporter binding in the hippocampus (50) or in order characterized with a progressive loss of cognitive
dorsal striatum (51), and decreased density of 5-HT1A functions such as learning and memory. The aetiology
receptors (52) in patients with alcoholism compared to and pathophysiology of AD is still unclear. The neuro-
non-alcoholic controls. Reduce activity of serotonergic biological alterations in AD include accumulations of
transporter in the brain of abstinent alcoholics was con- amyloid plagues outside and neurofibrillary tangles in-
firmed in vivo using SPECT (53). The values of 5-HIAA side neurons and the dysfunctions of cholinergic, cate-
concentration in CSF are in line with central seroto- cholaminergic and serotonergic systems. The decrease in
nergic disturbances in patients with alcoholism. Low the brain concentration of serotonin and 5-HIAA was
levels of 5-HIAA in CSF were found in early-onset alco- found in AD (68). The loss of presynaptic somatoden-
holics (54), in abstinent alcoholics (55) and in alcoholic dritic 5-HT1A autoreceptors and postsynaptic 5-HT1A
impulsive offenders (56). heteroreceptors (68), and 5-HT2 receptors in cerebral
Decreased plasma tryptophan levels and low seroto- cortex (69), were also found in patients with AD. It seems
nin precursor availability suggest impaired serotonin syn- that the development of behavioural and psychological
thesis in alcoholism (49). The results on the blood plate- symptoms in AD (70) is related to the genetic variants of
lets serotonin transporter activity in patients with alco- 5-HT2A and 5-HT2C receptors. In addition, daily living
holism are inconsistent. Lower (57), increased (58), or un- and functioning was improved in patients with AD trea-
altered (59) serotonin uptake into platelets were found in ted with combination of rivastigmine and selective sero-
alcoholics when compared to healthy controls. Alcohol- tonin reuptake inhibitor, fluoxetine.
ism-induced fall of serotonin transporter activity has been The reduced serotonin concentration in platelets (29),
related to a decreased platelet serotonin content observed CSF (71) and brain (72) of patients with AD would sug-

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Dorotea Mück-[eler and Nela Pivac Serotonin

gest the decrease in serotonin synthesis. The main factors

that influence serotonin synthesis are plasma availability
of its precursor tryptophan and the activity of the rate-
-limiting enzyme TPH. Plasma level of tryptophan de-
pends on the dietary intake and feeding behaviour that
could be also changed in AD. In patients with AD low
tryptophan concentrations in serum (73), plasma (74) Tryptophan hydroxylase
and CSF (71) was found in some, but not all studies (75).
2+
The alterations in serotonergic and kynuramine path- O2, BH4, Fe
ways of tryptophan metabolism have been connected to H2O, BH2
pathophysiology of AD (76), suggesting that low plasma
tryptophan concentration in AD might be also a conse-
quence of the enhanced tryptophan degradation via the
kynuramine pathway (73). In addition, tryptophan de-
pletion in healthy volunteers (77) or in patients with
mild to moderate AD (78) induced changes in cognitive
performance.
Altered serotonin synthesis in AD (72) might be a Figure 3. Tryptophan hydroxylase catalyzes tryptophan to 5-hydroxy-
consequence of reduced TPH activity in particular brain tryptophan.
areas of patients with AD (79) or the lack of the TPH co-
factors tetrahydrobiopterin and folic acid. Since TPH ac-
tivity is sensitive to reactive oxygen species, the tetrahy- In humans, the genes for TPH1 (MIM *191060) and
drobiopterin deficiency could also impair serotonin syn- TPH2 (MIM *607478) are located on chromosomes 11
thesis through oxidative damage of TPH (80). at position 11p14-p15.3 and 12 (12q21), respectively. The
human TPH2 gene spans 97 kilobases (kb) and consists
A decreased platelet serotonin concentration observed of 11 exons. The sequence identity between two homolo-
in patients with AD in the late phase of disease (29), gous TPH is 71% (121). In TPH1 knockout mice the
might be related to the reduced serotonin active transport concentration of peripheral serotonin was reduced to 6%
through platelet membrane. This finding is in line with (blood), 1.5% (jejunum) and 0.1% (colon) as compared
the decrease in the maximum number (Vmax) of seroto- to serotonin concentration in wild type mice (3, 82).
nin transporters found in severely ill patients with AD However, genetically modified mice without TPH1 iso-
compared to both patients with mild AD and healthy form had normal serotonin concentration in hippocam-
controls (81). pus and frontal cortex (82), and similar development, ap-
pearance and behaviour as mice with TPH1 gene. Those
CANDIDATE GENES OF THE results suggested that serotonin synthesis in the brain de-
SEROTONERGIC SYSTEM pends mostly on the TPH2 isoform activity. Recently,
Savelieva et al. (3) reported the phenotypic evaluation of
Recent genetic association studies of the neuropsychi-
TPH2 knockout mice and double knockout mice with-
atric disorders have focused on functional polymorphi-
sms i.e. DNA sequence variations that alter the expres- out both TPH1 and TPH2 gene. They have found the
sion and/or functioning of the gene product in the loci pronounced decrease in serotonin levels in cortex, thala-
encoding different genes. Some of them are genes for mus/hypothalamus, olfactory bulb, cerebellum hippo-
TPH, serotonin transporter (5-HTT) and serotonin type campus, brainstem and striatum in both groups of kno-
1A (5-HT1A), 1B (5-HT1B), 2A (5HTR2A) receptors. ckout mice compared to wild type mice. The lowest
serotonin concentration was determined in double kno-
Tryptophan hydroxylase ckout mice without TPH1 and TPH2 gene. Although
genetically modified mice were similar in appearance, or
Tryptophan hydroxylase (EC 1.14.16.4) is a key en- histological analysis with no loss of the serotonergic cell
zyme in the synthesis of serotonin. It metabolizes the es- bodies in raphe nucleus, there were differences in the
sential amino acid L-tryptophan, by hydroxylation at the body weight, body size and percent of body fat in male,
position 5, to the serotonin precursor L-5-hydroxytryp- and percent of body fat in female double knockout mice
tophan (Figure 3.). The cofactors are O2 (dioxygen), BH4 compared to wild type mice (3). There were a few effects
/(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin/ and Fe2+. of TPH genotype on behaviour. Mutant mice had similar
TPH is a specific and selective enzyme that is only lo- exploratory behaviour and locomotor activity and sho-
cated in the serotonin producing cells like serotonergic wed increased anxiety-like behaviour (3).
neurons, pineal gland and enterocromaffine cells of the
gut. It exists in two isoforms (3), with different location Several studies analyzed the association between ge-
within the body of mammals (Table 3). One isoform is netic variants of the TPH in neuropsychiatric disorders
TPH1 that is responsible for the synthesis of the periph- and emotion-related personality traits, but with inconsis-
eral serotonin (4), while TPH2 is the predominant iso- tent results. Zhang et al. (83) reported that allele A of the
form in the brain. functional polymorphism G1463A at TPH2 gene could

34 Period biol, Vol 113, No 1, 2011.

Serotonin Dorotea Mück-[eler and Nela Pivac

TABLE 3 Serotonin Transporter-Linked

Two tryptophan hydroxylase isoforms, their location Polymorphic Region
and function of the corresponding central or peripheral
serotonin. The serotonin transporter (5-HTT) is an important
protein responsible for the active transport of serotonin
Tryptophan hydroxylase isoform into neurons, enterochromaffin cells and platelets. In the
brain 5-HTT is localized in membrane of presynaptic
TPH1 TPH2
nerve terminals and in dendritic arbors close to seroto-
Location ninergic cell bodies. 5-HTT regulates serotonin levels in
Peripheral tissue Brain the synaptic cleft following neuronal stimulation, and
Serotonin functions consequently the magnitude and duration of its effect on
Migraine Migraine postsynaptic serotonergic receptors. It terminates the ac-
tion of serotonin by rapid reuptake of released serotonin
Vasoconstriction Sleep from synaptic cleft into presynaptic neuron by means of
Haemostasis Behaviour an active transport process that depends upon maintenance
Immune system Mood of ion gradients across the cell membrane by Na+-K+-
Intestinal motility Food intake and body weight –ATPase (90). The in vitro and in vivo (91) studies have
shown that 5-HTT is not only a protein with important
Melatonin synthesis Neuropsychiatric disorders
role in the homeostatic regulation of the serotonergic
function, but also a site of action for several classes of an-
tidepressant drugs including classical tricycle compounds
be related to the low TPH2 activity and consequently to
and novel selective serotonin reuptake inhibitors (91).
the impaired brain serotonin synthesis in depressed pa-
tients. Their suggestion that 1463A allele could be a risk Among a number of genes involved in the synthesis of
factor for unipolar major depression were not confirmed protein related to metabolism and function of serotoner-
in the larger number of patients of the West European gic system, gene encoding the 5-HTT (SLC6A4) is the
most extensively investigated. The 5-HTT gene (OMIM
Caucasian origin with affective disorders (84), or in Chi-
*182138) is located on chromosome 17 at position 17q11.1-
nese population with unipolar depression (85). Recent, -17q12 and consisted of fifteen axons encoding a protein
haplotype analysis of the eight polymorphisms: rs4448731 of 630 amino acids with 12 transmembrane domains (90,
(intergenic), rs4565946 (intron 2), rs11179000 (intron 4), 92). The most studied variants in the 5-HTT gene are the
rs7955501 (intron 5), rs10506645 (intron 7), rs4760820 serotonin transporter-linked polymorphic region (5-HTT
(intron 8), rs1487275 (intron 8) and rs10879357 (intron gene-linked polymorphic region, 5-HTTLPR; rs795541)
8) of the human TPH2 (86) has shown no association and a functional variable number of tandem repeats
between TPH2 polymorphisms and bipolar depression (VNTR) polymorphism in intron 2. 5HTTLPR is a re-
and suicidal behaviour in Brazilian population. There petitive element of varying length in the 5’ flanking re-
were also no significant differences in genotype or allele gion located ~1.4kb upstream of the transcription start
frequencies of the TPH2 -703G/T polymorphism be- site that modulates transcriptional activity of human 5-
tween bipolar patients and healthy subjects of the Ko- -HTT (90). A deletion/insertion in the 5-HTTLPR cre-
rean origin (87). The meta-analysis of TPH1 and TPH2 ates two alleles (each of 20 to 23 bp): short or S allele and
long or L allele made up of fourteen and sixteen repeated
gene variants in the large number of subjects with ADHD
elements, respectively. Some studies have found that long
from four independent European Caucasian samples allele results in higher serotonin transporter mRNA tran-
have shown no consistent evidence for common genetic scription in human cell lines. The uptake of serotonin is
variants in the TPH1 and TPH2 regions in ADHD (88). two-fold higher in cells containing the homozygous L/L
It has been hypothesized that smaller volumes of the form of the SLC6A4 than either the L/S or S/S forms. On
amygdala and hippocampus are related to the presence the other hand, S allele is associated with reduced trans-
criptional efficiency and decreased 5-HT expression and
of the T allele of the TPH2 (rs4570625; G-703T) poly-
uptake (92).
morphism in Japanese subjects. This was the first study
that compared personality traits (harm avoidance, re- It has been suggested that this 5-HTTLPR polymor-
ward dependence, novelty seeking, persistence, self di- phism alters the promoter activity and consequently se-
rectedness, cooperativeness, self-transcendence) assessed rotonergic functions (93). In this respect, a significantly
with the Temperamental and Character Inventory (89), higher maximal number (Bmax) of platelet serotonin
uptake sites was found in subjects carrying the L/L geno-
with the volume of amygdala and hippocampus (deter-
type as compared with Bmax of platelet serotonin uptake
mined using magnetic resonance imaging) in T allele sites in individuals with L/S or S/S genotype (94). Addi-
carriers and GG individuals. The results suggested that tionally, the uptake of serotonin is approximately two-
regional brain volume could be a brain structural inter- -fold higher in cells containing the homozygous L/L
mediate phenotype between genetic variations in THP2, form of the 5-HTT, while S allele is related to reduced
i.e. between serotonin synthesis and personality traits re- transcriptional efficiency and therefore decreased seroto-
lated to mood or anxiety disorders (89). nin uptake (92). Volumetric neuroimaging studies have

Period biol, Vol 113, No 1, 2011. 35

Dorotea Mück-[eler and Nela Pivac Serotonin

shown that the S allele is associated with reduced grey pulsive disorder, the results of the lack of association be-
matter volume in the limbic system and disrupted amy- tween 5HTTLPR and platelet serotonin concentration
gdala-cingulate coupling (95). suggest that genotype-induced changes in 5-HTT tran-
scription and consequent changes in platelet serotonin
The intron 2 VNTR contains nine, 10, or 12 copies of concentration might be differently regulated in healthy
a sixteen- or seventeen-base pair repeat (96). A stronger subjects and psychiatric patients (107).
expression and greater enhancer activity was observed by
the 12-copy allele than by the 10-copy allele in the hind- The relationship between the changes in serotonin
brain of transgenic embryonic mice (97) and in embry- uptake and 5-HTT gene in patients with AD is inconsis-
onic stem cells (98) suggesting its functionality. Very poor tent. A study (108) failed to find the difference in the
linkage disequilibrium was found between 5HTTLPR allelic distribution on the deletion/insertion polymor-
and the intron 2 VNTR (99). phism of the 5-HTT gene between patients and controls.
In contrast, an association between long allele of the
A lot of studies conducted in healthy individuals and 5-HTT gene and development of aggressive behaviour
in patients with psychiatric and neurological disorders in AD was found (109).
suggested that 5-HTTLPR could be considered as a can-
didate gene for depression (99), mood disorders (100), al-
coholism, autism and stress related psychiatric disorders, Serotonin type 1A receptor
while other studies did not replicate these data (101). An Serotonegic receptor type 1A (5-HT1A) is one of the
association between early stressful life event (childhood most investigated and characterized serotonergic recep-
maltreatment, abuse, lack of social support) and increas- tors. The 5-HT1A receptors were found in a variety of
ing risk for the development of depression in subjects human brain regions (110). They are subdivided accord-
carrying short alleles was found (102). In addition, there ing to their location in a) presynaptic somatodendritic
is a growing body of literature suggesting the connection 5-HT1A autoreceptors located on cell bodies and den-
between stressful life events and occurrence of depression drites of serotonergic neurons in dorsal and median ra-
that may be dependent on variation at the 5-HTTLPR phe nuclei and b) 5-HT1A heteroreceptor positioned
locus of the 5-HTT (102). However, recent meta-analysis postsynaptically in the pyramidal cells and interneurons
(103) did not confirm that the 5-HTTLPR genotype and of cortico-limbic regions (hippocampus, cerebral cortex
stressful life events, alone or in combination, are risk fac- and lateral septum) that received serotonergic input from
tors for the development of depression in both male and the raphe nuclei (5). The activation of presynaptic 5-HT1A
female subjects. autoreceptors by serotonin or its agonists inhibits the fir-
Different findings related to the association between ing rate of the serotonergic neuron and reduces serotonin
5HTTLPR and psychiatric disorders might be induced synthesis, turnover and release (111) and thus affects the
by differences in population genetic structure and sub- serotonergic activity in projection areas. In addition,
structure between cases and controls, and to ancestry dif- 5-HT1A receptors have an important role in the neuro-
ferences corresponding to ethnic groups. There are signi- developmental processes such as synapse formation, neu-
ficant differences in the allele frequencies in 5-HTTLPR rite outgrowth and neuronal migration (112). Due to
between Caucasian and Asian populations, since S allele their wide distribution and multitude of functions, 5-
is found in 42% of Caucasians and in 79% of Asians -HT1A receptors are associated with aetiology and treat-
(104). In the large groups of healthy subjects from Croa- ment of mental disorders (113), especially major depres-
tia and the Russian federation (Russians, Bashkirs and sive disorder.
Tatars) there were significant ethnic differences in allele Post-mortem evaluation of the number and/or affinity
and genotype frequencies of the 5-HTTLPR (104). The- of 5-HT1A receptors in the brain of depressed patients
se finding might explain the contradictory results show- revealed different results among studies. Reduced 5-HT1A
ing the positive or negative or no association between ligand binding or receptor gene expression was found in
various psychiatric disorders, treatment outcomes and cortico-limbic regions of the suicide depressed victims
5-HTTLPR across different populations. with or without medication at the time of death (114).
The increase in 5-HT1A receptor binding (115) and
The association between 5HTTLPR and s platelet se-
negative results (116) were also reported. This lack of
rotonin concentration was also studied, but the findings
consistency between studies can be due to the variety of
were contradictory, showing positive, negative or a lack of
factors including sex, comorbidities (substance abuse, al-
association (105–107). The study including large groups
cohol dependence and other psychiatric diagnoses),
of healthy male and smaller groups of female Caucasian
post-mortem delay and to the different methods used for
subjects of Croatian origin, free of neuro-psychiatric dis-
the measurement of the 5-HT1A ligand binding. The
orders, showed also a lack of association between 5-
desensitization of presynaptic 5-HT1A autoreceptors,
-HTTLPR genotypes and platelet 5-HT concentration,
but not postynaptic receptors was observed after chronic
and failed to detect the functional relevance of the 5-
treatment with antidepressants like serotonin reuptake
-HTTLPR variants on platelet 5-HT concentration (107).
inhibitors and monoamine oxidase inhibitors.
Therefore, since a positive significant association be-
tween L/L and L/S genotypes and increased blood sero- The 5-HT1A receptor is coded by the HTR1A gene
tonin levels was detected in patients with obsessive-com- (OMIM *109760) located on chromosome 5 at position

36 Period biol, Vol 113, No 1, 2011.

Serotonin Dorotea Mück-[eler and Nela Pivac

5q11.2-q13. Recently, the 27 single nucleotide polymor- Animal studies suggested that 5-HT1B receptors ha-
phisms of the HTR1A gene were described (113). Among ve a role in aggressive behaviour related to alcoholism.
them the most investigated, and the most prevalent in Knockout mice showed increased alcohol intake and
normal human population is a functional polymorphism more propensities to aggressive behaviour, although ot-
C-1019G (rs6295), located within the promoter region of her studies (121) did not confirm the relationship be-
the gene. It has been shown that this polymorphism reg- tween 5-HT1B receptors and alcoholism. The 5-HT1B
ulates gene expression (117). Genetic studies suggested receptor gene has been postulated to play a modulatory
that the G allele of the C-1019G is associated with an in- role in alcohol consumption and alcohol dependence,
crease in presynaptic 5-HT1A receptor expression and and was considered as candidate gene for alcoholism
lowered expression of the postsynaptic 5-HT1A receptor.
(122).
These opposite effects could be related to two transcrip-
tion factors: epidermal autoregulatory factor-1 (Deaf-1 In humans 5-HT1B receptor is encoded by the gene
or NUDR) and Hes5 that are co-localized on both, pre- HTR1B (OMIM*182131) located on chromosome 6 wi-
synaptic and postsynaptic 5-HT1A receptors (117, 118). thin the region 6q13-q26 at position 6q14.1. Intronless
Deaf-1 is a repressor at somatodendritic 5-HT1A recep- HTR1B gene consists of a single exon, encoding a 390
tor, but enhances the transcription in non-serotonergic amino acid peptide (123). A number of polymorphisms
neurons that express postsynaptic 5-HT1A receptors. has been discovered in the coding sequence and sur-
Several studies investigated the association between rounding 5’ and 3’ untranslated regions. 5HTR1B gene is
C-1019G HT1A promoter polymorphism and regional an attractive candidate for studies of the genetic basis of
binding potential of two selective 5-HT1A antagonists ADHD (124). The most widely studied polymorphism
11C-WAY100635 or 18F-MPPF using Positron Emission of the HTR1B gene in and around the HTR1B locus is
Tomography (PET) in healthy subjects, but with incon- relatively common synonymous G861C polymorphism
sistent results (119). Concerning response to treatment, (124).
the C-1019G variant seems to be of primary interest in
antidepressant response: C allele carriers generally show Serotonin type 2A receptor
a better response to treatment, especially in Caucasian
samples (113). Serotonin type 2A receptor (5HT2A) is a G protein
coupled serotonergic receptor located on the membrane
Serotonin type 1B receptor of postsynaptic serotonergic neurons. High concentra-
tions of 5-HT2A receptors were found on the apical den-
Serotonergic receptors type 1B (5HT1B) were found drites of pyramidal cells in layer V in cortex (prefrontal,
to be rodent specific and similar to the human seroto- parietal, somatosensory), claustrum and basal ganglia (5).
nergic receptor type 1D (5-HT1D). Since these two ty- In the brain 5-HT2A receptors mediate hormone secre-
pes of 5-HT1 receptors share similar brain distribution, tion, mood and perception, and regulate different behav-
transductional features and function, it has been sug- iours. 5-HT2A receptors are highly expressed in blood
gested that they are species homologues with 97% overall
platelets, fibroblasts, and many cell types of the cardio-
sequence homology (5).
vascular system. Widely distributed peripheral 5-HT2A
Serotonergic receptors type 1B (5HT1B) are terminal receptors are involved in the platelet aggregation (14),
autoreceptors and postsynaptic heteroreceptors (5), lo- capillary permeability and vascular smooth muscles con-
cated in the central nervous system in the basal ganglia, traction. 5-HT2A receptors are molecular target for many
striatum, hippocampus and cortex. 5-HT1B receptors atypical antipsychotic drugs like olanzapine or risperidone.
were also found on the variety of vascular tissues includ-
ing cerebral arteries. The main function of autoreceptors The loci encoding the serotonin type 2A receptor
located on the nerve terminals is the control of serotonin (HTR2A) are located on the long arm of the chromo-
release, but they may act as terminal heteroreceptors con- some 13q14-q21 in man, and on chromosome 14 in the
trolling the release of other neurotransmitters like cate- mouse (125). The HTR2A gene consists of 3 exons sep-
cholamine and GABA (5). arated by 2 introns and spans over 20 kb (126). A num-
ber of polymorphisms encoding for HTR2A gene was
A recent study (120) has shown the co-localization
found, including A-1438G (rs6311), T102C (rs6313)
and interaction of 5-HT1B receptors and protein p11 at
the cell surface in vitro. The p11 knockout mice exhib- and His452Tyr (rs6314). Several genetic studies investi-
ited a depression-like phenotype and had reduced re- gated the association of HTR2A genetic variants and vul-
sponsiveness to 5HT1B receptor agonists and reduced nerability to psychiatric disorders like schizophrenia (127),
behavioural reactions to antidepressants. The decrease in suicide (128), panic disorder, alcoholism (129) and AD
brain p11 expression was found in the animal model of (130), with inconsistent and mostly negative results. Sev-
depression and in the brain tissue from depressed pa- eral studies reported that particular polymorphism in
tients, while an over expression in p11 and the increase in HTR2A gene may, to some extent, account for the differ-
5HT1B receptor function was observed in rodent brains ence in treatment response to risperidone (131), cloza-
after antidepressants or electroconvulsive therapy (120). pine (132) and antidepressants (133).

Period biol, Vol 113, No 1, 2011. 37

Dorotea Mück-[eler and Nela Pivac Serotonin

IN CONCLUSION 18. SAGUD M, PIVAC N, MUSTAPIC M, NEDIC G, MIHALJE-

VIC-PELES A, KRAMARIC M, JAKOVLJEVIC M, MUCK-SE-
Since serotonin discovery in the gastrointestinal tract LER D 2008 The influence of lamotrigine on platelet serotonin con-
centration in patients with bipolar depression. Psychopharmacology
(1), the comprehensive investigations enlarge its first role 197: 683–685
as a hormone to the neurotransmitter function in the 19. MUCK-SELER D, JAKOVLJEVIC M, DEANOVIC Z 1991 Pla-
central nervous system that has a myriad of central and telet serotonin in subtypes of schizophrenia and unipolar depres-
peripheral functions. However, serotonin has an impor- sion. Psychiatry Res 38: 105–113
tant role in the modulation the effects of other neuro- 20. MUCK-SELER D, PIVAC N, JAKOVLJEVIC M 1999 Sex differ-
ences, season of birth and platelet 5-HT levels in schizophrenic pa-
transmitters. In the words of Thomas Carew, a Yale re- tients. J Neural Transm 106: 337–347
searcher, »Serotonin is only one of the molecules in the 21. MUCK-SELER D, PIVAC N, JAKOVLJEVI] M, BRZOVI] Z
orchestra. But rather than being the trumpet or the cello 1999 Platelet 5-HT, plasma cortisol and dexamethasone suppression
player, it is the band leader who choreographs the output test in schizophrenic patients. Biol Psychiatry 45: 1433–1439
22. MAURER-SPUREJ E, PITTENDREIGH C, MISRI S 2006 Pla-
of the brain.« telet serotonin levels support depression scores for women with
postpartum depression. J Psychiatry Neurosci 32: 23–29
23. MUCK-SELER D, PIVAC N, JAKOVLJEVI] M, [AGUD M,
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