journal of prosthodontic research 58 (2014) 217222

Available online at www.sciencedirect.com

ScienceDirect
journal homepage: www.elsevier.com/locate/jpor

Original article

Comparison of platelet serotonin transporter

activity in subjects with severe sleep bruxism
and control
Hajime Minakuchi DDS, PhD a, Chiharu Sogawa PhD b,
Emilio Satoshi Hara DDS a, Haruna Miki DDS a,
Kenji Maekawa DDS, PhD a, Norio Sogawa DDS, PhD b,
Shigeo Kitayama DDS, PhD b, Yoshizo Matsuka DDS, PhD c,
Glenn T. Clark DDS, MS d, Takuo Kuboki DDS, PhD a,*
a

Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine,
Dentistry and Pharmaceutical Sciences, Okayama, Japan
b
Department of Dental Pharmacology, Okayama University Graduate School of Medicine, Dentistry and
Pharmaceutical Sciences, Okayama, Japan
c
Department of Fixed Prosthodontics, Institute of Health Biosciences Graduate School, The University of Tokushima,
Tokushima, Japan
d
Advanced Program in Orofacial Pain and Oral Medicine, Ostrow School of Dentistry, University of Southern
California, USA

article info

abstract

Article history:

Purpose: The aim of this study was to evaluate the correlation between sleep bruxism (SB)

Received 9 October 2013

frequency and serotonin transporter (SERT)-driven serotonin (5-HT)-uptake in platelets.

Received in revised form

Methods: Subjects were dental trainee residents and faculty members of Okayama Univer-

9 May 2014

sity Hospital who were aware of having severe or no SB. SB frequency was assessed for 3-

Accepted 19 June 2014

consecutive nights by a self-contained electromyographic detector/analyzer, which indi-

Available online 7 August 2014

cated individual SB levels as one of four grades (score 0, 1, 2 and 3). Subjects were classified

Keywords:

SB for scores 2 or 3. Those subjects whose scores fluctuated from 0 to 3 during the 3 nights

Sleep bruxism

were omitted from further analysis. Fasting peripheral venous blood samples were collected

Human serotonin transporter

in the morning following the final SB assessment. Amounts of SERTs proteins collected from

as normal control (NC) when SB scores indicated only 0 or 1 during the 3 nights, or as severe

(hSERT)

peripheral platelets were quantified using ELISA, and SERTs transport activity was assessed

Uptake ability

by uptake assay using [3H]-5-HT.

Electromyography (EMG)

Results: Thirteen severe SB subjects and 7 NC subjects were eligible. Gender distribution,
mean age, 5-HT concentration and total amounts of SERT protein in platelets showed no
significant differences between NC and severe SB ( p = 0.85: Chi-squared test; p = 0.64, 0.26,

* Corresponding author at: Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of
Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8525, Japan. Tel.: +81 86 235 6682;
fax: +81 86 235 6684.
E-mail address: kuboki@md.okayama-u.ac.jp (T. Kuboki).
http://dx.doi.org/10.1016/j.jpor.2014.06.003
1883-1958/# 2014 Japan Prosthodontic Society. Published by Elsevier Ireland. All rights reserved.

218

journal of prosthodontic research 58 (2014) 217222

0.46: t-test). However, [3H]-5-HT uptake by platelets was significantly greater in NC compared
to severe SB subjects (12.79  1.97, 8.27  1.91 fmol/105 platelets/min, p < 0.001, t-test).
Conclusion: The results of this pilot study suggest a possible correlation between peripheral
platelet serotonin transporter uptake ability and SB severity.
# 2014 Japan Prosthodontic Society. Published by Elsevier Ireland. All rights reserved.

1.

Introduction

Sleep bruxism (SB) is classified under the subgroup of sleeprelated movement disorders, and at sometime in their lives,
the majority of people (8590%) experience mild or moderate
symptoms thought to be a direct result of SB [1]. In severe
cases, SB can cause dramatic tooth wear, which sometimes is
associated with dentin hypersensitivity and tooth mobility, as
well as a low prognosis of dental prostheses [2]. However,
current management approaches available for SB are largely
symptomatic therapies such as oral appliances and contingent counter-stimulation devices and are not considered to be
curative. Therefore, a deeper understanding of the molecular
mechanisms involved in SB arousals would lead to the
development of new therapies for management of SB.
Recently, the central nervous system (CNS) has been
hypothesized to play a role in the etiology of SB, since several
clinical case reports have shown that SB frequency is
alleviated and/or aggravated by administration of medications
that regulate monoamine levels at the CNS. Multiple case
reports have also assumed that SB events increased after
selective serotonin reuptake inhibitors (SSRIs) intake [3,4].
SSRIs are known to bind directly to serotonin transporter
(SERT), which regulates pre-synaptic 5-HT levels by reuptaking and transporting 5-HT. Consequently, SSRIs can
indirectly lead to increases in the serotonin (5-HT) concentration at the synaptic cleft. Interestingly, Kishi [5] and
Sabuncuoglu et al. [6] reported that administration of a
selective 5-HT1A receptor agonist (tandospirone and buspirone, respectively) suppressed SSRI-induced SB activity in
human patients. This clinical finding is based on the fact that
the 5-HT1A receptors are located pre-synaptically and functions as a 5-HT auto-receptor; therefore, it negatively regulates
the 5-HT nerve exocytosis process.
Additionally, 5-HT neurons have been reported to induce
excitatory effect on the post-synaptic firing-threshold of
motor nerves [7]. Inoue and colleagues examined the mechanisms by which 5-HT altered the post-synaptic firing threshold
using the rat trigeminal motor nucleus [8]. They showed that
5-HT induces a dose-dependent attenuation of the mediumduration after-hyperpolarization (mAHP) amplitude through
cAMP-dependent activation of protein kinase A (PKA). Based
on this fact, they concluded that 5-HT could increase the firing
output in jaw-closing motoneurons. Furthermore, the dorsal
raphe nucleus, which contains high levels of serotonin
receptors, is in close proximity to the trigeminal motor
nucleus; thus, there could be a strong potential for 5-HT
activation via volume transition between these nuclei. We
therefore, hypothesized that serotonergic nerve functions
could possibly be related to SB frequency; more specifically,

that the concentration of 5-HT in the presynaptic terminal

could in part regulate diurnal/nocturnal activities of trigeminal motor nerve and muscle hyperactivities (SB).
SERTs are located mainly in peripheral platelets and in the
brain [9] and are encoded by a single gene located in the
chromosomal region [10], and their amino acid sequences
are almost identical except for a difference in post-translational modifications [11]. Nevertheless, direct and accurate
investigation of alterations in 5-HT at the synapse is
problematic; therefore, we utilized a peripheral platelet model
which has been regarded to be comparable to central 5-HT
function [12,13].
Based on our hypothesis mentioned above, we examined
the peripheral platelet SERT function as a possible indicator of
the 5-HT concentration in the peripheral platelets and verified
a possible association with SB frequency (high frequent
bruxism and normal range subjects) in healthy young adults.

2.

Material and methods

2.1.

Study subjects

Subjects were recruited among the resident students of

Okayama University Hospital in 2010. Those subjects who
(1) were receiving orthodontic treatments, (2) had taken
psychotropic medication within the past 6 months, (3) used
an oral appliance within the past 6 months and (4) presented
cutaneous diseases (i.e., atopic dermatitis) were excluded. The
initial screening criterion was self-awareness of SB activities
by oral interview. In order to compare subjects with high SB
levels and normal controls, as a first step, the ambiguity
awareness of sever SB or non-SB subjects were rejected to
participate this study. In response, eligible candidates were
informed about the study objectives and asked to write the
informed consent form. Prior to the beginning of the study,
approval of the Independent Ethics Committee of Okayama
University Graduate school of Medicine, Dentistry and
Pharmaceutical Science was obtained (No. 967).

2.2.

Measurements of SB frequency

The candidate subjects were then asked to have their SB

frequency recorded by means of an electromyography (EMG)containing detection device (BiteStrip1, Up2dent, Germany),
which is composed of electromyography electrodes and an
amplifier to acquire masticatory muscle signals, a central
processing unit with real-time software that detects and
analyzes the EMG patterns. This device has been already
validated in comparison with polysomnography [14,15], and it
counts the number of masseter muscle hyperactivities as the

journal of prosthodontic research 58 (2014) 217222

number of SB events that exceed the continuous 30%

maximum voluntary clenching and last more than 0.25 s.
This device was pre-set to measure for continuous 4.5 h
exactly, starting at 30 min activation and attachment on the
subjects cheek skin. Therefore, variations in sleeping period
would not affect the accumulated number of SB events in this
study sample of normal individuals. This device indicates the
total number of SB events in a 4-grade scale: 0 = fewer than 30
events; 1 = 3059 events; 2 = 6099 events, and 3 = more than
100 events. The participants were handed this device directly
and instructed on its usage using a mirror and an instruction
manual over 15 min by 2 pre-calibrated instructors. Subjects
were asked to measure individual SB frequency for three
consecutive nights at their home environment, and were
also requested to avoid alcohol and tobacco intake during
the experimental period.
Based on the 3-consecutive night SB score (03), subjects
were classified into severe bruxism (SB), normal control (NC)
groups and other. Subjects were classified as normal control
(NC) when SB scores indicated only 0 or 1 during the 3 nights,
or as severe SB for scores 2 or 3. Those subjects whose scores
fluctuated from 0 to 3 during the 3 nights were omitted from
further analysis.

2.3.
Measurement of platelet number, 5-HT content, total
amount of SERTs and 5-HT uptake
After final SB assessment, all subjects were asked to not take
breakfast because peripheral blood 5-HT concentration is
affected by blood nutrient component. Fasting peripheral
venous blood samples were collected only from the eligible
subjects (NC and severe SB) between 8:00 and 9:00 on the
morning into vacutainer CPT tubes (BD Vacutainer1 CPT with
sodium citrate, Becton, Dickinson and Company, San Jose, CA,
USA).
Platelet-rich plasma (PRP) was then prepared by centrifugation of blood samples at 1500  g for 15 min at room
temperature. Platelets and lymphocytes fraction were again
centrifuged at 100  g for 10 min to remove lymphocytes.
Platelets were then obtained in the supernatant. The platelets
fraction was precipitated by centrifugation at 3000  g for
15 min and suspended in 10 ml of Ca2+ free Krebs Hensleit
buffer (pH 7.4). The number of platelets per milliliter was
determined by flow cytometry (MACSQuant1 Analyzer,
Miltenyi Biotec, Bergisch Gladbach, Germany). Briefly, cells
were incubated with antibody against the platelet surface
marker CD42b (Biolegend, San Diego, CA, USA) for 30 min on
ice, and rinsed with phosphate buffer saline (PBS) containing
1% fetal bovine serum (FBS, Invitrogen, Carlsbad, CA, USA).
Cells were then centrifuged, re-suspended in PBS/FBS solution, and analyzed by flow cytometry.
For [3H] 5-HT uptake assay, aliquots of platelets were preincubated for 11 min at 37 8C. [3H] 5-HT (final concentration = 20 nM) was added, and the mixture was further
incubated for 2 min at 37 8C. Non-specific uptake was
measured in the presence of 100 mM paroxetine. Paroxetine
was added 5 min before starting incubation with [3H] 5-HT.
The uptake was terminated by addition of 5 ml ice-cold saline
solution, followed by vacuum filtration through a glass
microfiber (Whatmann GF/C), and washing four times with

219

ice-cold saline. The radioactivity retained on the filters was

measured by liquid scintillation counting.
The 5-HT concentration in platelets and total amount of
SERTs collected from peripheral platelets were quantified by
ELISA (Serotonin ELISA Kit, Genway Biotech Inc., San Diego,
CA, USA; ELISA KIT for Human SERT, USCN Life Science Inc.,
Wuhan, Hubei, China, respectively). ELISA assay and [3H] 5-HT
uptake assay were performed with duplicate samples and
platelet counting was performed by a single assay per
individual.

2.4.

Statistical analysis

Comparisons of demographic parameters between the SB and

NC groups were done by Chi-squared test and unpaired t-test
in order to evaluate group homogeneity. The mean 5-HT
concentration in platelets, total amount of SERT, total and
chiliad 5-HT uptakes of SERT were compared by unpaired ttest. The cut-off level for significance was set at alpha = 0.05.

3.

Results

3.1.

Subjects

Among the initial 39 applicants (28.0  4.02 yrs, male/female:

12/27), 13 subjects fulfilled the criteria of the SB group
(28.0  4.68 yrs, male/female: 5/8), and 7 subjects were eligible
for the NC group (30.2  5.61 yrs, male/female: 3/4). The SB
scores of the remaining 19 subjects fluctuated during the
assessment period, and thus not included in the analyses
(Fig. 1). Gender distribution, mean age showed no significant
differences between the SB and NC groups ( p = 0.85: Chisquared test; p = 0.64: t-test).

3.2.
Comparison of SERT between severe SB and control
subjects
The mean 5-HT concentration in platelets of SB and normal
control group was 661.2  303.9 ng/109 platelets and
467.7  345.2 ng/109 platelets respectively, with no significant
difference between the two groups ( p = 0.26, t-test) (Fig. 2A).
And, total amount of SERTs per 106 platelets were
1840.9  536.0 in SB and 1663.0  420.9 in NC group respectively. These showed no statistical significance between
these groups ( p = 0.46: t-test) (Fig. 2B).
However, the [3H] 5-HT uptake of total and chiliad SERT
were significantly greater in subjects with NC group than
in those with SB group (12.79  1.97, 8.27  1.91 fmol/105
platelets/min, p < 0.001, 8.05  2.14, 5.08  2.47 fmol/ng SERT
protein/min, p = 0.02, t-test) (Fig. 3A and B).

4.

Discussion

This study showed that the [3H] 5-HT uptake level through
SERT in the NC group was significantly greater than that in the
SB group in peripheral platelets. These results suggest that
SERT function analysis may provide a novel insight into the
risk for SB, and that the difference of SERT activity in

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journal of prosthodontic research 58 (2014) 217222

Screening process
Eligible 39 subjects (male/female: 12/27, mean age 28.0+/-4.02 yrs)
BiteStrip assessment
(Score 0, 1, 2 and 3, 3-consecutive nights)
Severe SB group

Moderate SB subjects

Normal control group

13 subjects (male/female: 5/8,

mean age 28.0+/-4.68 yrs)

19 subjects
(male/female: 4/15)

7 subjects (male/female: 3/4,

mean age 30.2+/-5.61 yrs)

Fig. 1 Procedure of sampling.

largely reflects platelet 5-HT content [1719]. Thus, the blood

5-HT concentration measured on day 7 was compared to the
baseline level and its reduction was used as an index of the
degree of 5-HT reuptake inhibition. These data would possibly
support the validation to measure the peripheral SERT
activities as an indirect simulation of the CNS; however, it
has not been completely validated yet. Thus, this is a notable
weak point of this study.
In this study, we measured the 5-HT uptake level in
the platelets and the 5-HT concentration in platelets.
The results indicated that the 5-HT uptake level through
SERTs in the SB group was significantly lower than that in the
NC group in peripheral platelets. This result was consistent
with our hypothesis and could partially explain the mechanism involved in SSRI-mediated aggravation of SB events in
previous case reports. The attenuation of 5-HT reuptake in
the platelets may cause a reduction of the whole-blood and
internal 5-HT concentration in platelets. The 5-HT concentrations in platelets did not show any significant difference
between the two SB groups. The previously reported 5-HT

peripheral platelets between NC and SB individuals may help

to elucidate the pathogenesis of SB severity, although further
investigation is still necessary to validate and confirm the
present findings. Currently, the valid diagnosis of SB is
performed by polysomnography assessment that usually
burdens the subjects due to multiple electrodes and cables
throughout their sleeping period. Thus, the discovery of a
novel SB related mediator would be an important contribution
for development of this research field.
In this study we examined peripheral platelet SERT
function, due to the unfeasibility in performing assessment
of SERT activity in the CNS, and it has been reported to
resemble and reflect central serotonergic function and is
widely used as an indicator of the central 5-HT metabolism
[12,13]. Additionally, Blier showed supportive results for this
platelet model, in that the oral administration of paroxetine
20 mg/day for seven days significantly reduced the wholeblood 5-HT level in a range of 4596% in healthy subjects [16].
As a very large proportion (9095%) of blood 5-HT is
sequestrated in the platelets, whole-blood 5-HT content

Platelet 5-HT concentration

Total amount of SERT

(106 platelets)

(ng/10 9 platelets)

2500

1000
2000
800
1500
600
1000

400

500

200

Severe
bruxism
group

Normal
control
group

p=0.26
(t-test )

Severe
bruxism
group

Normal
control
group

p=0.46
(t-test )

Fig. 2 Result of 5-HT concentration in platelets (A) and total amount of SERTs per 106 platelets (B). There was no significant
difference in plasma 5-HT concentration between severe and normal control groups ( p = 0.26: t-test). Total amount of SERTs
per 106 platelets showed no significant difference between severe and SB and normal control groups ( p = 0.46: t-test).

journal of prosthodontic research 58 (2014) 217222

[3H] 5-HT uptake

14

[3H] 5-HT uptake per 103 pg SERTs

fmol/1ng SERT protein/ min

10

12
fmol/ 10 5 platelets/ min

221

10
8
6
4

8
6
4
2

2
0

Severe
bruxism
group

Normal
control
group

Severe
bruxism
group

p<0.001 (t-test )

Normal
control
group

p=0.02 (t-test )

Fig. 3 Result of [3H] 5-HT uptake of total (A) and per 103 pg SERTs (B). [3H] 5-HT uptake of total SERT was significantly greater
in subjects with normal control group than in those with severe SB (12.79 W 1.97, 8.27 W 1.91 fmol/105 platelets/min,
p < 0.001, t-test). [3H] 5-HT uptake of per 103 pg SERTs was also significantly greater in subjects with normal control group
than in those with severe SB (8.05 W 2.14, 5.08 W 2.47 fmol/1 ng SERT protein/min, p = 0.02, t-test).

concentrations in platelets were 471 (361519) ng/109 platelets (median, interquartile range, n = 163), 467.2  38.5 ng/109
platelets (mean  SD) and 906.2  285.3 ng/109 platelets
(mean  SD, n = 30) in healthy control subjects [2022].
Thus, our results of 5-HT concentrations are within
normal range.
We also measured the total amount of platelet SERTs by
ELISA in the fractionated component. The total amount of
platelet SERTs did not show a significant difference between
the SB and NC groups. We cannot however ignore that SERTs
detected by ELISA could contain both intracellular and cell
surface expressed SERTs. The 5-HT transport activity and cell
surface expression of SERTs are regulated by various cellular
mechanisms including membrane trafficking, influenced by
post-translational modifications and transporter-associated
proteins. Furthermore, 5-HT transport activity is influenced by
the SERTs kinetic characteristics in addition to the regulation
of cell surface expression. In this study, we did not analyze the
correlation between numerical SB frequency and SERTs
kinetic characteristics (i.e. maximum velocity [Vmax] and
affinity constant [Km]) since convenient and extreme subjects
were adopted and outcome of SB assessment was not strictly
numerical, but ordinal variable. In the future, we will analyze
SERTs kinetic characteristics in addition to SERTs localization
in platelets, and examine the correlation between the
expression and maturation-associated aspects of SERT on
platelet plasma membrane and SB frequency.
The SB detection device used in this study was a wireless
and all-in-one type portable EMG; and the outcome of SB
frequency was not numeric but an ordinal variable ranging
from 0 to 4, which was also another weak point in this study.
Therefore, the accuracy of SB assessment could not be
satisfactorily high compared with ambulatory EMG or polysomnography assessment. Although this 4-grade assessment
system could apparently limit a precise detection of SB activity
compared to numerical values, it contributes to improve the
usability, miniaturization and decrease costs of this assessment. Furthermore, since we analyzed SB for 3 consecutive
nights, we could eliminate data of subjects with fluctuating

SB activity, which could potentially increase the reliability of

subject categorization.
In this study, measurement of the SERTs activity was under
assumption that the activities of both serotonergic and motor
nerves are identical. While the 5-HT nerve can be realistically
affected by several neurotransmitters in vivo, this point was
not considered in this study. Future research is necessary to
confirm these regulatory effects of 5-HT on motor nerve
activities and to carry out concomitant assessment of the
association between SERTs ability and SB frequency. Additionally, further investigation is needed to elucidate the
precise correlation between 5-HT uptake level and SB
frequency by means of continuous quantification.
Finally, the sampling process in the present study was
potentially biased since recruitment was based on a convenient sample. However, since the predictor variables such as
5-HT uptake level and amount of SERTs were completely
unknown during the sampling period, the sampling bias
effect should be extremely low. Collectively, these data will be
helpful in elucidating the pathophysiological mechanisms of
SB, and establish platelet serotonin uptake as a candidate
indicator of SB severity.

5.

Conclusion

This study demonstrated a significantly higher [3H] 5-HT

uptake level by SERTs in peripheral platelets of normal control
subjects compared to those of severe SB subjects. These
findings showed the supportive notion that demonstrates
our hypothesis on the association between SB frequency and
SERT activity.

Ethical approval
This experimental protocol was approved by the Ethical
committee of Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences (#224).

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journal of prosthodontic research 58 (2014) 217222

Source of funding
This research was supported by the Grant-In-Aids ((C)
#20592265, (B) #23390442) for Scientific Research from Ministry
of Education, Science and Culture, Japan.

Competing interests
The authors declare that they have no competing interests.

Acknowledgements
This research was supported by Grants-In-Aid ((C) #20592265,
(B) #23390442) for Scientific Research from the Ministry of
Education, Science and Culture of Japan.

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