239

Send Orders for Reprints to reprints@benthamscience.ae

Current Psychiatry Reviews, 2018, 14, 239-244

REVIEW ARTICLE
ISSN: 1573-4005
eISSN: 1875-6441

Biomarkers of Major Depression Related to Serotonin Receptors

BENTHAM
SCIENCE

Meysam Amidfar1, Lejla Colic2,3, Martin Walter2,4-6 and Yong-Ku Kim7,*

1
Fasa University of Medical Sciences, Fasa, Iran; 2Otto-von-Guericke University, Magdeburg, Germany; 3Leibniz
Institute for Neurobiology, Magdeburg, Germany; 4Center for Behavioral Brain Sciences, Magdeburg, Germany;
5
Department of Psychiatry and Psychotherapy, Eberhard-Karls-University, Tübingen, Germany; 6Max Planck Institute
for Biological Cybernetics Tübingen, Tübingen, Germany; 7Department of Psychiatry, College of Medicine, Korea
University, Seoul, South Korea

A R T I C L E H I S T O R Y

Received: July 13, 2018
Revised: September 12, 2018
Current Psychiatry Reviews
Abstract: Background: Developing group of recent findings demonstrate that serotonin receptors
play a significant pathophysiological role in major depressive disorder (MDD).

Objective: This article will briefly review the literature concerning mechanisms of action, brain
distribution and localization of 5HT receptor subtypes and their changes in patients with MDD, as
reported via neuroimaging, postmortem and genetic studies.
Method: Postmortem brain researches, neuroimaging PET studies and genetic polymorphism studies
in suicide and depression were examined in order to explore the role of 5-HT receptor subtypes in
the neurobiology of major depression as possibly beneficial biomarkers for diagnosis and treatment
response in MDD.

Results: Reported significant association between Gene polymorphisms of 5-HT receptors including
5-HT1A, 5-HT1B, 5-HT3, 5HT4 and 5HT6 and diagnosis and treatment response in depression

Accepted: September 26, 2018
DOI:
10.2174/1573400514666181016115747

Keywords: Serotonin receptors, major depression, neuroimaging, postmortem brain, genetic investigations, 5-HT receptors.
suggests these serotonin receptor subtypes as important therapeutic and diagnostic markers for de-
pression. Neuroimaging studies by PET revealed a higher rostrally and lower caudally binding po-
tential of 5-HT1A receptor in the dorsal raphe nucleus in patients with suicidal depression, de-
creased potential binding of 5-HT1B receptor and elevated binding potential of cortical 5-HT2A
receptors. Postmortem studies reported an elevated abundance of 5-HT2A receptors in the prefrontal
cortex, altered mRNA encoding editing of 5-HT2C receptors in the prefrontal cortex and higher
levels of 5HT4 receptor binding in frontal cortex and caudate nucleus of depressed suicide victims.
Conclusion: 5-HT receptors including 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3, 5-HT4 and 5-
HT6 are involved in the neurobiology of major depression and might be beneficial biomarkers for
diagnosis and treatment response in MDD and will help the development of future treatments.

1. INTRODUCTION
depletion, reduced levels of 5-hydroxyindolacetic acid, a

Major depressive disorder (MDD) is a prevalent affective
disorder and one of the main causes of disability worldwide.
Its core symptoms include low mood and anhedonia (lack of
pleasure in activities that typically bring satisfaction and
enjoyment), which come together with an array of other
symptoms such as irritability, sadness, anergia, changes in
sleep and appetite, difficulties in concentrating, and suicidal
ideation [1, 2]. Enormous number of researches have re-
ported evidence related to abnormalities of the monoamine
serotonin in the pathogenesis and neurobiology of MDD:
clinical relapse in remitted depressed patients after tryptophan
*Address correspondence to this author at the Department of Psychiatry,
College of Medicine, Korea University, Seoul, South Korea; Tel: 82-31-
412-5140; E-mail: yongku@korea.edu
metabolite of serotonin, in the cerebrospinal fluid of patients
with suicidal depression, reduced brain and platelets trans-
porter binding sites in depressed subjects, the effectiveness
of selective serotonin reuptake inhibitors (SSRIs) in the
treatment of MDD and central and peripheral alterations of
serotonin receptor densities in depression and suicide [3-6].
The serotonergic neurons are grouped into two major divi-
sions of the raphe nuclei: the brainstem including cranial
nucleus containing the dorsal and median parts which project
mainly to the forebrain structures and take part in the regula-
tion of sleep, appetite, temperature and sexual behavior, and
the caudal nucleus containing the raphe pallidus, raphe mag-
nus, and raphe obscurus which projects to the brainstem nu-
clei and to the spinal cord and controls nociception and mo-
tor tone [7-11]. Importantly, medial and dorsal areas of the
raphe nuclei innervate brain areas that have been connected

1875-6441/18 $58.00+.00 © 2018 Bentham Science Publishers

240 Current Psychiatry Reviews, 2018, Vol. 14, No. 4 Amidfar et al.

to the pathophysiology of MDD such as the hippocampus
(HC) and dorsolateral prefrontal cortex (DLPFC) [10]. Fu-
ture development of antidepressants that rely on activation or
deactivation of serotonin receptors can be achieved only
through identification of their characteristic brain localiza-
tion as well as their opposing roles on neuronal activity [12].
In the current study, we described the serotonin receptor sub-
types that their role in the pathophysiology of major depres-
sion has been identified including 5-HT1A, 5-HT1B,
5-HT2A, 5-HT2C, 5-HT3, 5-HT6 and 5-HT7 receptors.
Therefore, we did not mention the 5-HT receptor subtypes
that did not find available neuroimaging, brain postmortem
or genetic evidence about them and their involvement in the
neurobiology of major depression has not been elucidated
such as 5HT1D, 5HT1E or 5HT1F receptors. The focus
of this review is to provide a brief description of genetic,
neuroimaging and brain postmortem findings related to
serotonin receptor subtypes in major depression as well as
their mechanisms of action, brain distribution and neuronal
localization.

2. SUBTYPES OF 5-HT RECEPTORS AND
DEPRESSION: MECHANISMS OF ACTION, BRAIN
DISTRIBUTION AND NEURONAL LOCALIZATION
The impacts of serotonin are subserved by minimally 14
different members of 5-HT receptors including 13 individual
G-protein-coupled receptors (GPCRs) and one ligand-gated
ion channel (5-HT3 receptor) that are classified into 7 main
groups of 5-HT receptors on the bases of their structure and
operational features (5-HT1 to 5-HT7) [13, 14]. The implica-
tion of the 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3,5-
HT4, 5-HT6 and 5-HT7 receptors in depression has been
well documented [5]. Table 1 summarizes signaling path-
ways, neuronal location and brain distribution of 5-HT
receptors.
2.1. 5-HT1A Receptor
The five receptor subtypes (5-HT1A, 5-HT1B, 5-HT1D,
5-ht1E and 5-ht1F) of the 5-HT1 receptor family are linked
to the Gi/Go-protein coupling and act as inhibitory presynap-

Table 1. Signaling pathways, neuronal location, and brain distribution of serotonin receptor subtypes.

Receptor
Family Member
Signaling Pathway
Function
Neuronal Localization
Brain Distribution

↓cAMP

Gi/G0-protein cou- Somatic autorecep- midbrain raphe nuclei, hippocampus,
5-HT1A
G-protein coupled- Inhibitory

pled
tor/postsynaptic
septum, amygdala and corticolimbic areas

K+ current

nucleus accumbens, substantial nigra,

Gi/G0-protein cou- Terminal autorecep- basal ganglia, striatum, frontal cortex,
5-HT1B
↓cAMP
Inhibitory

pled
tor/postsynaptic
cingulate cortex, hippocampus, and
amygdala

5-HT2A
Gq11-protein coupled
↑PLC
Excitatory
Postsynaptic
neocortical areas

choroids plexus, the substantia nigra,

amygdala, thalamic nuclei, hippocampus,
5-HT2C
Gq11-protein coupled
↑PLC
Excitatory
Postsynaptic
anterior olfactory, cingulate and piriform
cortex, cerebral cortex, cerebellum and
endopiriform nuclei

entorhinal, frontal and cingulate cortices,

Ligand-gated Ion conductance hippocampus, amygdala, and caudate-
5-HT3
Excitatory
Postsynaptic

Na+/K+ channel
(K+, Na+, Ca2+)
putamen nuclei, dorsal motor nucleus of
the vagus nerve and the area postrema

hippocampal formation (CA1 and subicu-

lum), basal ganglia including globus pal-
lidus, substantia nigra, putamen, caudate
5-HT4
Gs-protein coupled
↑cAMP
Excitatory
Postsynaptic

nucleus, nucleus accumbens, neocortex,
some areas of the thalamus, raphe and
pontine nuclei

cortex, nucleus accumbens, striatum, olfac-

5-HT6
Gs-protein coupled
↑cAMP
Excitatory
Postsynaptic
tory tubercle, thalamus, cerebellum, hypo-
thalamus, amygdala and hippocampus

medial thalamic nuclei, cortical regions,

anterior thalamus,dentate gyrus,
5-HT7
Gs-protein coupled
↑cAMP
Excitatory
Postsynaptic
hypothalamus, anterior cingulate gyrus,
hippocampus, amygdala, and certain
brainstem nuclei

Biomarkers of Major Depression Related to Serotonin Receptors
tic and postsynaptic receptors, where they inhibit adenylyl
cyclase and reduce adenosine monophosphate (cAMP) cell
levels [12, 13]. 5-HT1A receptors are also connected to
additional intracellular signal transduction mechanisms in-
cluding G-protein-coupled K+ channels and their activation
causes neuronal hyperpolarization by the opening of the
K+ channels [12, 13]. 5-HT1A receptors are located broadly
throughout the central nervous system (CNS), and are orga-
nized in two main groups, somatodendritic presynaptic auto-
receptors on the serotonin neurons of midbrain raphe nuclei
and postsynaptic heteroreceptors on the nonserotonergic neu-
rons of some structures of limbic system, specifically in the
hippocampus, septum, amygdala and corticolimbic areas
[15-19]. Activation of 5-HT1A autoreceptors by endogenous
serotonin or 5-HT1A agonists leads to opening of K+ chan-
nels and induces hyperpolarisation of the cell membrane,
resulting in reduced neuronal firing rate. This mechanism is
crucial for serotonergic self-regulation and maintaining of
the homeostasis via decrease of the serotonin release in most
brain regions, but particularly in dorsal raphe-innervated
regions [20-24]. Increased radioligand binding of an agonist
on to the inhibitory 5-HT1A autoreceptors has been detected
in the postmortem midbrain dorsal raphe (DR) nucleus of
depressive patients with suicide relative to healthy subjects
[25]. In addition, one positron emission tomography (PET)
study showed a higher binding potential of 5-HT1A receptor
and larger distribution of GG genotype of the 5-HT1A C-
1019G polymorphism in non-remitted MDD patients com-
pared with remitted ones [26]. The study indicated that both
markers may predict poorer response to antidepressant
treatment [26]. However, some PET data has indicated de-
creased 5-HT1A binding potential in the raphe and cortex in
MDD patients [27, 28]. 5-HT1A receptor cross-sectional
binding along the rostrocaudal axis of the dorsal raphe nu-
cleus (DRN) in patients with suicidal depression compared
with controls revealed higher rostral and lower caudal bind-
ing [29]. Association studies of the C (-1019) G 5-HT1A
promoter polymorphism in connection to major depression
and suicide have demonstrated that depressed patients carry
homozygous G (-1019) genotype twofold and suicide victims
fourfold versus controls, suggesting G (-1019) allele as a
predisposition toward the development of depression and
suicide [30]. In addition, one genome-wide linkage analysis
for MDD suggested HTR1A-1019G allele as a genetic risk
factor for MDD that might help in the progress of new anti-
depressants [31].

2.2. 5-HT1B Receptor

5-HT1B receptors have been found both pre- and post-
synaptically and their signal transduction is mediated by
negative coupling to adenylyl cyclase via intermediate G
protein type Gi or Go, and alternatively, is mediated through
mitogen-activated protein kinase (MAP-kinase) signaling
system [32]. 5-HT1B receptors are also dispersed all over the
CNS with maximum density in the nucleus accumbens, sub-
stantia nigra, basal ganglia, striatum, frontal cortex, cingulate
cortex, hippocampus, and amygdala [13, 32, 33]. 5-HT1B
receptors that as autoreceptors are located on axonal termi-
nals of 5-HT neurons locally regulate synthesis and release
of serotonin [13, 32, 33]. Postsynaptic 5-HT1B receptors or
heteroreceptors that are placed on axon terminals of nonsero-
Current Psychiatry Reviews, 2018, Vol. 14, No. 4 241
tonergic neurons predominantly in controlling centers of
motor skills such as basal ganglia, influence the release of
other neurotransmitters [13, 32, 33]. One longitudinal PET
study showed a significant reduction of binding potential of
the selective radioligand of 5-HT1B receptor in the dorsal
brainstem (DBS) after internet-based cognitive behavioral
therapy, which supports the implication of 5-HT1B receptor
in the effect of treatment with the psychological approach on
the biological response of MDD to treatment [34]. In addi-
tion, findings of another PET study suggest significantly
reduced the binding potential of 5-HT1B receptor in the ven-
tral striatum/ventral pallidum (VS/VP) area in MDD patients
compared to control subjects which might support the thera-
peutic rationale for investigation on 5-HT1B agonists as a
novel class of antidepressants [35]. Moreover, one genetic
association study found a significant association between the
human 5-HT1B receptor gene G861C locus and diagnosis of
a major depressive episode [36].
2.3. 5-HT2A Receptor

5-HT2A receptors, similar to the other members of the 5-
HT2 receptor family, are mostly linked to G protein type Gq
or G11 and enhance inositol phosphates and calcium concen-
tration of cytosol [13]. Expression of 5-HT2A receptors is in
all neocortical areas, in both interneurons and pyramidal
neurons [37]. It has been reported that depressive suicide
victims have augmented the amount of 5-HT 2 receptors in
their prefrontal cortex and amygdala compared to control
subjects, providing evidence for a hypothesis of the compen-
satory enhancement of 5-HT2 receptor in suicidal depression
[38]. Increased brain level of 5-HT2A receptors in suicidal
depressive patients has been referred to diminished serotonin
levels that result in the upregulation of receptors [39].
Shelton et al. (2009) found elevated 5-HT2A receptors in the
postmortem prefrontal cortex tissue from depressive subjects
compared to control group and this increase showed a corre-
lation with decreased protein kinase A (PKA) activity in the
depressed sample, suggesting that irregularities in 5-HT2A
receptors may be the result of abnormalities in PKA levels
[40]. Similarly, one PET study reported raised the binding
potential of 5-HT2A receptors in the cortex of medication-
free patients with depression [41]. Additionally, analysis of
the connection between antidepressant treatment response
and SNPs of serotonin 2A receptor (HTR2A) has revealed
a significant relationship between a variant of HTR2A
SNP rs7997012 and antidepressant response and remission
[42, 43].

2.4. 5-HT2C Receptor

5-HT2C receptors have the same intracellular cascade
response like other subtypes of the 5-HT2 receptor category
[44]. 5-HT2C receptors are scattered throughout the CNS
with elevated density in the choroids plexus, the substantia
nigra, amygdala, thalamic nuclei, hippocampus, anterior ol-
factory, cingulate and piriform cortex, cerebral cortex, cere-
bellum and endopiriform nuclei [14, 45, 46]. 5-HT2C recep-
tors have been mostly located somatodendritically but in the
certain brain regions such as septum and interpeduncular
nucleus, they can also be found on axon terminals [47]. A
unique property of 5-HT2C receptors is altered editing of
242 Current Psychiatry Reviews, 2018, Vol. 14, No. 4
their mRNA transcript that could cause subtle changes in
encoding sequence and functionally related effects on the
mature receptor protein [48]. The mRNA encoding of 5-
HT2C receptors has shown altered editing in the prefrontal
cortex of suicidal depression subjects which might be an
indication of the aberrant operation of the receptor protein
[12, 49]. Moreover, a significant association was reported
between functional polymorphism 68G>C (Cys23Ser) of
serotonin receptor 2C and suicide susceptibility, particularly
in women [50]. An increased expression of 5HT2C receptors
protein has been found in the PFC of victims of suicide in
comparison with controls [51]. In addition, depressed suicide
victims showed prominent changes in the editing of 5-HT2C
mRNA in the prefrontal cortex [52]. Both studies are there-
fore suggestive of abnormal serotonin signaling and 5-HT2C
receptor regulation.
2.5. 5-HT3 Receptor

The 5-HT3 receptor is the only non-GPCR serotonin re-
ceptor and is a member of the Cys-loop ligand-gated ion
channel family. It is predominantly found on GABAergic
interneurons of cortex and hippocampus [14, 53, 54]. The 5-
HT3 receptor is completely different from other serotonin
receptors since it directly opens non-selective Ca2+, Na+ and
K+ ion channels, triggers rapid depolarization of neurons
and subsequently causes the release of neurotransmitters
[14]. 5-HT3 receptors are present in all places of the brain
with the uppermost densities inside forebrain including the
entorhinal, frontal and cingulate cortices, hippocampus,
amygdala, caudate-putamen and brainstem nuclei surround-
ing the chemoreceptor trigger zone including the nucleus
tractus solitaries, the dorsal motor nucleus of the vagus nerve
and the area postrema (there it regulates vomiting and recep-
tor antagonists likely lead to antiemetic effects) [46, 55-58].
Different areas of CNS, depending on the function of neu-
rons, show distinctive localization of postsynaptic 5-HT3
receptors [12]. For example, postsynaptic sites in the den-
drites of the hippocampus and presynaptic nerve endings in
amygdala show most abundant immunoreactivity of 5-HT3
receptor [59]. It has been demonstrated that combination of
both risk polymorphisms of BDNF (Val66Met) and sero-
tonin receptor gene 3A (HTR3A) (in both the CC genotype)
in interaction with experience of early life stress have com-
pounded influences on the vulnerability for depression via
emotional and arousal brain networks [60]. Furthermore con-
trol subjects with both HTR3A CC genotype and early life
stress exposure display increased depressed mood and sig-
nificant reductions of grey matter (GM) volume in hippo-
campal structures, which spread to the frontal regions rela-
tive to subjects with CT or TT genotypes [61], which again
suggest certain genetic predispositions in serotonin system to
mood changes and development of MDD.
2.6. 5-HT4 Receptor

5-HT4 receptors are attached preferentially to Gs and
stimulation of adenylate cyclase and their activation is asso-
ciated with the promotion of cAMP formation [46, 62]. 5-
HT4 receptors are distributed principally in the hippocampal
region (CA1 and subiculum) and in the basal ganglia includ-
ing putamen, globus pallidus, caudate nucleus, nucleus ac-
Amidfar et al.
cumbens, substantia nigra and to a lower degree in the neo-
cortex, some areas of the thalamus, raphe and pontine nuclei
[63]. Location of the 5-HT4 receptors is somatodendritically
on axon terminals in globus pallidus and substantia nigra and
in the caudate and putamen [64]. Depressed suicide victims
have shown significantly higher levels of 5HT4 receptor
binding, as well as higher levels of its second messenger
cAMP in the caudate nucleus and frontal cortex as compared
to the control group [65]. Moreover, there was a significant
association between polymorphisms of serotonin 4 receptor
gene (HTR4) and major depressive disorder [66].
2.7. 5-HT6 Receptor

The 5-HT6 receptor is positively connected to the Gs-
sensitive AC5 isoform which induces production of cAMP
[67]. 5-HT6 receptors are postsynaptic receptors showing
greatest density in the cortex, olfactory tubercle, striatum,
nucleus accumbens and indicate moderate levels in the
thalamus, hippocampus, cerebellum, hypothalamus, and
amygdala [67]. Genetic association analysis studies did not
show meaningful variations in genotype or allele frequencies
of 5-HT6 receptor C267T polymorphism between controls
and MDD patients but revealed significantly better response
to treatment with antidepressants in MDD patients within the
heterozygote group (CT genotype) than those within homo-
zygote groups (CC+TT genotypes) [68, 69].
2.8. 5-HT7 Receptor

5-HT7 receptors are also joined to Gs and stimulate
cAMP synthesis by adenylate cyclase [70]. 5-HT7 receptors
are widely distributed in the brain with high expression in
anterior thalamus, medial thalamic nuclei, dentate gyrus,
cortical regions and with intermediate levels in the
amygdala, hypothalamus, hippocampus, anterior cingulate
gyrus and certain brainstem nuclei [46, 71, 72]. Their distri-
bution, therefore, reinforces the participation of this receptor
in emotional behavior, cognition and sensory processing [46,
71, 72]. Immunolocalisation and autoradiography studies
have suggested that 5-HT7 receptors have predominantly
somatodendritic localization [12]. Well established physio-
logical role of 5-HT7 receptors in the mechanism underlying
circadian rhythm regulation and sleep has been attributed
to their selective expression in the suprachiasmatic nucleus
[44, 73].
CONCLUSION

PET studies and brain postmortem findings about the
involvement of different serotonin receptor subtypes in ma-
jor depression. 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3,
5-HT4, 5-HT6 and 5-HT7 receptors are distributed in the
brain circuits of cognitive and emotional processing. Consid-
ering location and function of these receptors, it is thus not
surprising that they also play a critical role in the patho-
physiology of major depression.
Therefore, changes in, for example, binding potential or
postmortem expression levels can be used as biomarkers not
only for exploration of mechanistic causes of depression but
also for diagnosis and treatment course in MDD. Further on,
genetic variations in serotonin receptors were associated to
Biomarkers of Major Depression Related to Serotonin Receptors
treatment outcome and remission, which by itself can be
used for targeted stratification and faster detection of non-
responders. Nevertheless, comprehensive multi-center stud-
ies are needed to detect the most promising receptor candi-
date and following development of new treatment options.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
Lejla Colic, Martin Walter has received research support
from Janssen Pharmaceutical and HEEL Gmbh, not related
to this review. The authors declare no conflict of interest,
financial or otherwise.
ACKNOWLEDGEMENTS
Declared none.

REFERENCES

[1] Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia
LM. Neurobiology of depression. Neuron 2002; 34(1): 13-25.

[2] Willner P, Scheel-Krüger J, Belzung C. The neurobiology of de-
pression and antidepressant action. Neurosci Biobehav Rev 2013;
37(10): 2331-71.

[3] Owens MJ, Nemeroff CB. Role of serotonin in the pathophysiology
of depression: Focus on the serotonin transporter. Clinical chemis-
try 1994; 40(2): 288-95.

[4] Amidfar M, Kim Y-K, Colic L, et al. Increased levels of 5HT2A
receptor mRNA expression in peripheral blood mononuclear cells
of patients with major depression: Correlations with severity and
duration of illness. Nord J Psychiatry 2017; 71(4): 282-8.

[5] Amidfar M, Colic L, Walter M, Kim Y-K. In: Kim Y-K, Ed. Un-
derstanding depression. Singapore: Springer 2018; pp. 83-95.
[6] Mann JJ. Role of the serotonergic system in the pathogenesis of
major depression and suicidal behavior. Neuropsychopharmacology
1999; 21(S1): 9S.

[7] Berger M, Gray JA, Roth BL. The expanded biology of serotonin.
Annu Rev Med 2009; 60: 355-66.

[8] Hornung J-P. The human raphe nuclei and the serotonergic system.
J Chem Neuroanat 2003; 26(4): 331-43.

[9] Jacobs BL, Azmitia EC. Structure and function of the brain sero-
tonin system. Physiol Rev 1992; 72(1): 165-229.

[10] López-Figueroa AL, Norton CS, López-Figueroa MO, et al. Sero-
tonin 5-HT1A, 5-HT1B, and 5-HT2A receptor mRNA expression
in subjects with major depression, bipolar disorder, and schizo-
phrenia. Biol Psychiatry 2004; 55(3): 225-33.

[11] Mohammad‐Zadeh L, Moses L, Gwaltney-Brant S. Serotonin: A
review. J Vet Pharmacol Ther 2008; 31(3): 187-99.

[12] Artigas F. Serotonin receptors involved in antidepressant effects.
Pharmacol Ther 2013; 137(1): 119-31.

[13] Hoyer D, Hannon JP, Martin GR. Molecular, pharmacological and
functional diversity of 5-HT receptors. Pharmacol Biochem Behav
2002; 71(4): 533-54.

[14] Barnes NM, Neumaier JF. Neuronal 5-HT receptors and SERT.
Tocris Biosci Sci Rev Ser 2011; 34: 1-16.
[15] Martinez D, Hwang D-R, Mawlawi O, et al. Differential occupancy
of somatodendritic and postsynaptic 5HT1A receptors by pindolol:
A dose-occupancy study with [11C] WAY 100635 and positron
emission tomography in humans. Neuropsychopharmacology 2001;
24(3): 209-29.

[16] Pazos A, Palacios J. Quantitative autoradiographic mapping of
serotonin receptors in the rat brain. I. Serotonin-1 receptors. Brain
Res 1985; 346(2): 205-30.

[17] Pompeiano M, Palacios J, Mengod G. Distribution and cellular
localization of mRNA coding for 5-HT1A receptor in the rat brain:
Correlation with receptor binding. J Neurosci 1992; 12(2): 440-53.
Current Psychiatry Reviews, 2018, Vol. 14, No. 4 243
[18] Sanabria-Bohórquez SM, Biver F, Damhaut P, Wikler D, Veraart
C, Goldman S. Quantification of 5-HT 1A receptors in human brain
using p-MPPF kinetic modelling and PET. Eur J Nucl Med Mol
Imaging 2002; 29(1): 76-81.

[19] Santana N, Bortolozzi A, Serrats J, Mengod G, Artigas F. Expres-
sion of serotonin1A and serotonin2A receptors in pyramidal and
GABAergic neurons of the rat prefrontal cortex. Cereb Cortex
2004; 14(10): 1100-9.

[20] Adell A, Carceller A, Artigas F. In vivo brain dialysis study of the
somatodendritic release of serotonin in the raphe nuclei of the rat:
Effects of 8-hydroxy-2- (di-n-propylamino) tetralin. J Neurochem
1993; 60(5): 1673-81.

[21] Casanovas J, Lesourd M, Artigas F. The effect of the selective 5-
HT1A agonists alnespirone (S-20499) and 8-OH-DPAT on ex-
tracellular 5-hydroxytryptamine in different regions of rat brain. Br
J Pharmacol 1997; 122(4): 733-41.

[22] Casanovas JM, Artigas F. Differential effects of ipsapirone on 5-
hydroxytryptamine release in the dorsal and median raphe neuronal
pathways. J Neurochem 1996; 67(5): 1945-52.

[23] Sprouse JS, Aghajanian GK. (-)-Propranolol blocks the inhibition
of serotonergic dorsal raphe cell firing by 5-HT1A selective ago-
nists. Eur J Pharmacol 1986; 128(3): 295-8.

[24] Sprouse JS, Aghajanian GK. Electrophysiological responses of
serotoninergic dorsal raphe neurons to 5‐HT1A and 5‐HT1B ago-
nists. Synapse 1987; 1(1): 3-9.

[25] Stockmeier CA, Shapiro LA, Dilley GE, Kolli TN, Friedman L,
Rajkowska G. Increase in serotonin-1A autoreceptors in the mid-
brain of suicide victims with major depression-postmortem evi-
dence for decreased serotonin activity. J Neurosci 1998; 18(18):
7394-401.

[26] Parsey RV, Olvet DM, Oquendo MA, Huang Y-Y, Ogden RT,
Mann JJ. Higher 5-HT 1A receptor binding potential during a ma-
jor depressive episode predicts poor treatment response: Prelimi-
nary data from a naturalistic study. Neuropsychopharmacology
2006; 31(8): 1745.

[27] Sargent PA, Kjaer KH, Bench CJ, et al. Brain serotonin1A
receptor binding measured by positron emission tomography with
[11C] WAY-100635: Effects of depression and antidepressant treat-
ment. Arch Gen Psychiatry 2000; 57(2): 174-80.

[28] Drevets WC, Frank E, Price JC, Kupfer DJ, Greer PJ, Mathis C.
Serotonin type-1A receptor imaging in depression. Nucl Med Biol
2000; 27(5): 499-507.

[29] Boldrini M, Underwood MD, Mann JJ, Arango V. Serotonin-1A
autoreceptor binding in the dorsal raphe nucleus of depressed sui-
cides. J Psychiatry Res 2008; 42(6): 433-42.

[30] Lemonde S, Turecki G, Bakish D, et al. Impaired repression at a 5-
hydroxytryptamine 1A receptor gene polymorphism associated
with major depression and suicide. J Neurosci 2003; 23(25): 8788-
99.

[31] Neff C, Abkevich V, Packer J, et al. Evidence for HTR1A and
LHPP as interacting genetic risk factors in major depression. Mol
Psychiatry 2009; 14(6): 621.

[32] Sari Y. Serotonin1B receptors: From protein to physiological func-
tion and behavior. Neurosci Biobehav Rev 2004; 28(6): 565-82.

[33] Castro ME, Pascual J, Romón T, Berciano J, Figols J, Pazos A. 5-
HT1B receptor binding in degenerative movement disorders. Brain
Res 1998; 790(1-2): 323-8.

[34] Tiger M, Rück C, Forsberg A, et al. Reduced 5-HT1B receptor
binding in the dorsal brain stem after cognitive behavioural therapy
of major depressive disorder. Psychiatry Res Neuroimaging 2014;
223(2): 164-70.

[35] Murrough JW, Henry S, Hu J, et al. Reduced ventral striatal/ventral
pallidal serotonin 1B receptor binding potential in major depressive
disorder. Psychopharmacology 2011; 213(2-3): 547-53.

[36] Huang Y-y, Oquendo MA, Friedman JMH, et al. Substance abuse
disorder and major depression are associated with the human 5-HT
1B receptor gene (HTR1B) G861C polymorphism. Neuropsycho-
pharmacology 2003; 28(1): 163.

[37] Burnet P, Eastwood S, Lacey K, Harrison P. The distribution of 5-
HT1A and 5-HT2A receptor mRNA in human brain. Brain Res
1995; 676(1): 157-68.

[38] Hrdina PD, Demeter E, Vu TB, Sótónyi P, Palkovits M. 5-HT
uptake sites and 5-HT2 receptors in brain of antidepressant-free
suicide victims/depressives: increase in 5-HT2 sites in cortex and
amygdala. Brain Res 1993; 614(1-2): 37-44.

244 Current Psychiatry Reviews, 2018, Vol. 14, No. 4
[39] Jans L, Riedel W, Markus C, Blokland A. Serotonergic vulnerabil-
ity and depression: Assumptions, experimental evidence and impli-
cations. Mol Psychiatry 2007; 12(6): 522.

[40] Shelton R, Sanders-Bush E, Manier D, Lewis D. Elevated 5-HT 2A
receptors in postmortem prefrontal cortex in major depression is
associated with reduced activity of protein kinase A. Neurosci
2009; 158(4): 1406-15.

[41] Bhagwagar Z, Hinz R, Taylor M, Fancy S, Cowen P, Grasby P.
Increased 5-HT 2A receptor binding in euthymic, medication-free
patients recovered from depression: A positron emission study with
[11C] MDL 100,907. Am J Psychiatry 2006; 163(9): 1580-7.

[42] Lucae S, Ising M, Horstmann S, Baune BT, et al. HTR2A gene
variation is involved in antidepressant treatment response. Eur
Neuropsychopharmacology 2010; 20(1): 65-8.

[43] McMahon FJ, Buervenich S, Charney D, et al. Variation in the
gene encoding the serotonin 2A receptor is associated with out-
come of antidepressant treatment. Am J Hum Genet 2006; 78(5):
804-14.

[44] Carr GV, Lucki I. The role of serotonin receptor subtypes in treat-
ing depression: A review of animal studies. Psychopharmacology
2011; 213(2-3): 265-87.

[45] Abramowski D, Rigo M, Duc D, Hoyer D, Staufenbiel M. Local-
ization of the 5-hydroxytryptamine2C receptor protein in human
and rat brain using specific antisera. Neuropharmacology 1995;
34(12): 1635-45.

[46] Hannon J, Hoyer D. Molecular biology of 5-HT receptors. Behav
Brain Res 2008; 195(1): 198-213.

[47] López-Giménez JF, Mengod G, Palacios JM, Vilaró MT. Regional
distribution and cellular localization of 5-HT2C receptor mRNA in
monkey brain: Comparison with [3H] mesulergine binding sites
and choline acetyltransferase mRNA. Synapse 2001; 42(1): 12-26.

[48] Berg KA, Clarke WP, Cunningham KA, Spampinato U. Fine-
tuning serotonin2c receptor function in the brain: Molecular and
functional implications. Neuropharmacology 2008; 55(6): 969-76.

[49] Gurevich I, Tamir H, Arango V, Dwork AJ, Mann JJ, Schmauss C.
Altered editing of serotonin 2C receptor pre-mRNA in the prefron-
tal cortex of depressed suicide victims. Neuron 2002; 34(3): 349-
56.

[50] Videtič A, Peternelj TT, Zupanc T, Balažic J, Komel R. Promoter
and functional polymorphisms of HTR2C and suicide victims.
Genes Brain Behav 2009; 8(5): 541-5.

[51] Pandey GN, Dwivedi Y, Ren X, et al. Regional distribution and
relative abundance of serotonin 2c receptors in human brain: Effect
of suicide. Neurochem Res 2006; 31(2): 167-76.

[52] Schmauss C. Serotonin 2C receptors: Suicide, serotonin, and run-
away RNA editing. Neuroscientist 2003; 9(4): 237-42.

[53] Morales M, Bloom FE. The 5-HT3 receptor is present in different
subpopulations of GABAergic neurons in the rat telencephalon. J
Neurosci 1997; 17(9): 3157-67.

[54] Puig MV, Santana N, Celada P, Mengod G, Artigas F. In vivo
excitation of GABA interneurons in the medial prefrontal cortex
through 5-HT3 receptors. Cereb Cortex 2004; 14(12): 1365-75.

[55] Barnes J, Barnes N, Costall B, Ironside J, Naylor R. Identification
and characterisation of 5-hydroxytryptamine3 recognition sites in
human brain tissue. J Neurochem 1989; 53(6): 1787-93.

[56] Laporte A, Kidd E, Verge D, Gozlan H, Hamon M. Autoradio-
graphic mapping of central 5-HT3 receptors. Central Peri 1992; 5:
157-87.

Amidfar et al.
[57] Pratt GD, Bowery NG, Kilpatrick GJ, et al. Consensus meeting
agrees distribution of 5-HT3 receptors in mammalian hindbrain.
Trends Pharmacol Sci 1990; 11(4): 135-7.

[58] Thompson AJ, R Lummis S. 5-HT3 receptors. Curr Pharm Des
2006; 12(28): 3615-30.

[59] Miquel MC, Emerit M, Nosjean A, et al. Differential subcellular
localization of the 5-HT3-As receptor subunit in the rat central
nervous system. Eur J Neurosci 2002; 15(3): 449-57.

[60] Gatt JM, Nemeroff CB, Schofield PR, et al. Early life stress com-
bined with serotonin 3A receptor and brain-derived neurotrophic
factor valine 66 to methionine genotypes impacts emotional brain
and arousal correlates of risk for depression. Biol Psychiatry 2010;
68(9): 818-24.

[61] Gatt JM, Williams LM, Schofield PR, et al. Impact of the HTR3A
gene with early life trauma on emotional brain networks and de-
pressed mood. Depress Anxiety 2010; 27(8): 752-9.

[62] Pauwels PJ. 5-HT receptors and their ligands. Neuropharmacology
2003; 1083: 38.

[63] Varnäs K, Halldin C, Pike VW, Hall H. Distribution of 5-HT4
receptors in the postmortem human brain-an autoradiographic
study using[125I] SB 207710. Eur Neuropsychopharmacol 2003;
13(4): 228-34.

[64] Vilaró MT, Cortés R, Gerald C, Branchek TA, Palacios JM, Men-
god G. Localization of 5-HT4 receptor mRNA in rat brain by in
situ hybridization histochemistry. Mol Brain Res 1996; 43(1-2):
356-60.

[65] Rosel P, Arranz B, Urretavizcaya M, Oros M, San L, Navarro MA.
Altered 5-HT2A and 5-HT4 postsynaptic receptors and their intra-
cellular signalling systems IP3 and cAMP in brains from depressed
violent suicide victims. Neuropsychobiology 2004; 49(4): 189-95.

[66] Ohtsuki T, Ishiguro H, Detera-Wadleigh S, et al. Association
between serotonin 4 receptor gene polymorphisms and bipolar
disorder in Japanese case-control samples and the NIMH Genetics
Initiative Bipolar Pedigrees. Mol Psychiatry 2002; 7(9): 954.

[67] Wesołowska A. Potential role of the 5-HT6 receptor in depression
and anxiety: An overview of preclinical data. Pharmacol Rep 2010;
62(4): 564-77.

[68] Hong C-J, Tsai S-J, Cheng C-Y, Liao W-Y, Song H-L, Lai H-C.
Brief clinical report: Association analysis of the 5-HT6 receptor
polymorphism (C267T) in mood disorders. Am J Med Genet B
Neuropsychiatry Genet 1999; 88(6): 601-2.

[69] Lee SH, Lee KJ, LeE HJ, Ham BJ, Ryu SH, Lee MS. Association
between the 5-HT6 receptor C267T polymorphism and response to
antidepressant treatment in major depressive disorder. Psychiatry
Clin Neurosci 2005; 59(2): 140-5.

[70] Neumaier J, Sexton T, Yracheta J, Diaz A, Brownfield M. Local-
ization of 5-HT7 receptors in rat brain by immunocytochemistry, in
situ hybridization, and agonist stimulated cFos expression. J Chem
Neuroanat 2001; 21(1): 63-73.

[71] Hedlund PB, Sutcliffe JG. Functional, molecular and pharmacol-
ogical advances in 5-HT7 receptor research. Trends Pharmacol Sci
2004; 25(9): 481-6.

[72] Varnäs K, Thomas DR, Tupala E, Tiihonen J, Hall H. Distribution
of 5-HT7 receptors in the human brain: a preliminary autoradio-
graphic study using [3H] SB-269970. Neurosci Lett 2004; 367(3):
313-6.

[73] Hedlund PB. The 5-HT 7 receptor and disorders of the nervous
system: An overview. Psychopharmacology 2009; 206(3): 345-54.