Open Journal of Psychiatry, 2011, 1, 33-39 OJPsych
doi:10.4236/ojpsych.2011.12006 Published Online July 2011 (
Published Onl ine July 2011 in SciRes.
Dopamine receptor D3R and D4R mRNA levels in peripheral
lymphocytes in patients with schizophrenia correlate with
severity of illness
Mitsuhiko Kawano1, Ken Sawada1,2,3*, Emi Tsuru4, Makoto Nishihara5, Kunio Ka to6,
William G. Honer3, Shinji Shimodera1, 7
1Department of Neuropsychiatry, Kochi Medical School, Kochi, Japan;
2Department of Psychiatry, Geiyo Hospital, Kochi, Japan;
3Department of Psychiatry, University of British Columbia, Vancouver, Canada;
4Division of Laboratory Animal Science, Kochi University, Kochi, Japan;
5Multidisciplinary Pain Centre, Aichi Medical University, Aichi, Japan;
6Morinomidori Mental Clinic, Yokohama, Jap an;
7Orygen Research Center, University of Melbourne, Australia.
E-mail: *
Received 16 May 2011; revised 20 June 2011; accepted 29 June 2011.
Schizophrenia is a disease that affects many areas of
the brain. The dopamine hypothesis is one of the
most widely -accepted ideas in the pathophysiology of
schizophrenia. Besides alterations in the dopaminer-
gic system in the central nervous system, there have
been several reports of changes in dopaminergic sys-
tems in the peripheral blood of schizophrenic pa-
tients. Several reports have shown that dopamine
receptor expression by lymphocytes is altered in pa-
tients with schizophrenia, but the results have been
conflicting. We therefore re-assessed D3R and D4R
mRNA levels in 11 patients with schizop hrenia and 12
healthy subjects and correlated levels with severity of
symptoms. D3R and D4R expression in lymphocytes
and granulocytes was measured by quantitative
RT-PCR and the severity of symptoms and cognitive
impairment were assessed using the PANSS and
BACS-J. There were no significant differences in
mean D3R or D4R mRNA levels in lymphocytes from
schizophrenic patients and controls and no signifi-
cant difference in mean D4R mRNA levels in granu-
locytes (D3R mRNA undetectable). In patients with
schizophrenia, D3R expression was inversely corre-
lated with the total PANSS score (r = 0.768, p = 0.009),
while D4R expression was positively correlated with
working memory scales (r = 0.895, p = 0.001). I n con-
clusion, these results imply that lymphocy te D3R a nd
D4R are involved in the mechanisms of the disorder
and could be used as target markers in the treatment
of schizophrenia.
Keywords: Dopamine receptor D3R; Dopamine
receptor D4R; Schizophrenia; RT-PCR; Lymphocyte;
Cognitive function
Schizophrenia is a disease that affects diverse brain re-
gions, causing patients to show a variety of clinical ma-
nifestations, such as psychopathologies and cogni- tive
deficits [1]. Intensive study for more than 30 years has
led to the proposal that alteration of dopaminergic neu-
rotransmission is implicated in the pathophysiology of
schizophrenia [2,3]. The dopamine hypothesis of schi-
zophrenia postulates that excessive dopaminergic neuro-
transmission in the limbic cortex is responsible for posi-
tive symptoms, such as hallucinations and delusions,
while limited dopaminergic activity in the frontal cortex
results in negative symptoms, such as avolition and an-
hednia, a nd in cogni t ive dysfunc tion [4].
Dopamine, a major neurotransmitter in the central
nervous system (CNS), regulates motor coordination,
cognition, mood, and reward, and acts on the endocrine
and cardiovascular systems. The dopamine receptor
family consists of five seven-transmembrane domain G
protein-coupled receptors termed D1R to D5R [5,6],
which are classified into the two groups of D1-like re-
ceptors (D1R and D5R) and D2-like receptors (D2R,
D3R, and D4R). D2-like receptors have attracted phar-
macological interest for the design of antipsychotics,
M. Kawano et al. / Open Journal of Psychiatry 1 (2011) 33-39
Copyright © 2011 SciRes. OJPsych
because the therapeutic benefits of these medications are
reported to be associated with their antagonistic action
on D2-like receptors in the brain. D3R is highly ex-
pressed in areas of the limbic cortex, such as the nucleus
accumbens and islands of Calleja, and moderately ex-
pressed in the striatum and dentate gyrus [7-9], while
D4R mRNA is expressed in the prefrontal and temporal
cortex and hippocampus [8,10-13]. A postmortem study
showed that D3 mRNA levels are selectively decreased
in the parietal cortex and motor cortex of schizophrenic
patients [14], and a focal decrease in D3R and D4R
mRNA levels in the orbitofrontal cortex has been re-
ported [11].
Several studies have shown that dopamine receptor
mRNA and protein levels are correlated with the symp-
toms of schizophrenia. D3 polymorphism was found to
be associated with improvement of symptoms after 10
weeks’ treatment in first-episode drug-naïve schizophre-
nia [15]. Polymorphism of D4R was correlated with
working memory in a near-infrared spectroscopy study
[16], while an animal study suggested an association
between D4R and working memory [17].
The CNS and peripheral nervous system modulate pe-
ripheral immune cells by releasing neuropeptides and
neurotransmitters [18]. Lymphocytes themselves pro-
duce dopamine [19], and the expression of dopamine
receptors on lymphocytes has been confirmed by quanti-
fication of mRNA [20]. Dopamine is an important regu-
lator of T lymphocyte functions [21]. RT-PCR and im-
munostaining studies on lymphocytes showed no de-
tectable D2 mRNA, but detectable D3R and D4R mRNA
[22-24]. D3R and D4R mRNA levels in lymphocytes are
comparable to, but D2R and DR5R mRNA levels are
significantly lower than, those in the brain [20]. Several
studies have examined D3R or D4R mRNA levels in
lymphocytes and T cells in schizophrenia, but the results
have been conflicting. D3R mRNA levels have been
reported to be elevated in lymphocytes from schizoph-
renic patients, while D4R mRNA levels were found to be
unaltered [25]. D3R mRNA levels in lymphocytes from
drug naïve schizophrenia were found to be increased
compared to controls [26]. Another report found signifi-
cantly higher levels of D3R mRNA in T cells from schi-
zophrenics, and a significant reduction in D4R mRNA
levels in CD4 + T cells [27], while two other papers re-
ported no alteration in D3R mRNA levels in peripheral
blood in the acute first episode of schizophrenia [28] or
no difference in D3R and D4R protein levels in peri-
pheral leukocytes between schizophrenics and controls
[29]. Thus, it is not clear whether dopamine receptor
mRNA levels are altered in the peripheral blood of pa-
tients with schizophrenia.
To validate the use of D3R and D4R as peripheral
markers in schizophrenia, we reexamined whether there
was a change in dopamine receptor expression using the
real-time reverse transcriptase-polymerase chain reaction
(RT-PCR) to quantify levels of D3R and D4R mRNAs in
lymphocytes and granulocytes in the peripheral blood of
patients with schizophrenia. Furthermore, we investi-
gated correlations between dopamine receptor expres-
sion levels and clinical manifestations or scores in men-
tal state examination and cognitive function assessments.
We used the following hypotheses to plan this study.
1) In terms of mRNA expression in the peripheral
blood, D3R is increased and D4R decreased in patients
with schizophrenia compared to the control group.
2) The alteration in D3R and D4R levels is related to
the severity of the clinical manifestations and cognitive
dysfunct i on in pati e nts with sc hizophrenia.
2.1. Participants
Eleven patients (age 56 ± 12 years (mean ±SD), 8 males)
with schizophrenia diagnosed using DSM-IV and twelve
healthy controls (44 ± 12 years, 3 males) were enrolled
in this study. All of the participants provided written
informed consent for participation in this study. The pa-
tients with schizophrenia were evaluated using the Posi-
tive and Negative Syndrome Scale (PANSS) and the
Brief Assessment of Cognition in Schizophrenia
(BACS-J), which are composed of Verbal Memory, Digit
Sequencing, Token Motor Task, Verbal Fluency, Symbol
Coding task, and Tower of London. The patients were
treated with aripiprazole (n = 4), olanzapine (n = 2), pe-
rospirone (n = 2), haloperidol (n = 2), or fluphenazine
decanoate (n = 1). The doses of antipsychotics were cal-
culated as chlorpromazine-equivalent doses. The study
was approved by the Ethics Committee of Kochi Medi-
cal School.
2.2. Sample Processing
Peripheral blood, collected between 10:00 a.m. and noon,
was layered on Monopoly Separation Solution (DS
Pharma Biomedical) and separated into lymphocytes and
granulocytes according to the manufacture’s instructions.
2.3. RT-PCR
For RT-PCR analysis, total RNA was isolated using
TRIzol (Invitrogen). Total RNA (0.5 μg) was reverse
transcribed using Primescript reverse transcriptase (Ta-
KaRa) and random 6-mers and oligo dT primer (TaKaRa)
according to the manufacturer’s instructions. The result-
ing complementary DNA fragments were amplified us-
ing Fast Start Universal Probe Master Mix (ROX refer-
ence dye) (Roche) according to the manufacturer’s in
structions. Reactions were run using an ABI PRISM
M. Kawano et al. / Open Journal of Psychiatry 1 (2011) 33-39
Copyright © 2011 SciRes. OJPsych
7000 Sequence Detection System (Applied Biosystems)
under the following conditions : 50 ˚C for 2 min, 95˚C for
10 min, followed by 42 cycles of 95˚C for 15 s and 60˚C
for 1 min. Primers and probes were designed using the
Universal Probe Library Assay program
dex.jsp). The primers and the probe for
-actin mRNA
was purchased from Roche. The RT-PCR data were
normalized to those for the housekeeping gene
Relative mRNA expression was calculated using the
2.4. Statistical analysis
All statistical calculations were performed using the
SPSS statistical package version 11.0. To examine the
difference in age and sex between the groups, the chi-
square analysis was used for sex and the Mann-Whitney
test for age. We performed the Multivariate Generalized
Linear Models to evaluate whether age and sex affected
dopamine receptor mRNA levels. To compare differenc-
es in D3R and D4R mRNA levels between patients and
controls, we used the Mann-Whitney test. To excl ud e the
influence of possible confounders on dopamine receptor
mRNA levels, we performed the Spearman test to de-
termine whether there was a correlation between mRNA
levels and age, dose of antipsychotics, or duration of the
illness. Furthermore, because of the non-continuous na-
ture of the PANSS and BACS-J data, we analyzed cor-
relations between D3R and D4R mRNA levels and the
PANSS and subscales of the BACS-J using the Spear-
man test. A Bonferroni-correction was applied to correct
for multiple comparisons. We considered statistical sig-
nificant in multiple comparisons as p < 0.013 (compar-
ing granulocyte D4R mRNA and lymphocyte D3R and
D4R mRNA levels, 3 comparisons) or p < 0.00278
(comparing D3R and D4R mRNA levels and subscales
of BACS-J, 18 comparisons).
The average duration of illness in the patient group was
25.2 years. The patients had a total PANSS score of 83.6
± 13.8 (Table 1). The control group and patient group
had a different mean age and percentage of each sex (age:
p = 0.028, sex: p = 0.041). However, D3R and D4R
mRNA levels in lymphocytes or D4R mRNA levels
(D3R mRNA levels were undetectable) in granulocytes
measured by real-time RT-PCR were not influenced by
age or sex (age: Wilks’s lambda F = 3.95, df = 4, 27, p =
0.22, sex: Wilks’s lambda F = 42.57, df = 4, 13, p =
D2R, D3R, and D4R mRNA levels were measured in
granulocytes and lymphocytes, but D2R mRNA levels in
lymphocytes and granulocytes and D3R mRNA levels in
Tab le 1. Demographic and clinical characteristics of the pa-
tients and normal controls.
Schizophrenia Control
Sex (M:F) 8:3 3:9
Age 54.2 ± 10.7 43 .8 ± 12.0
Duration of illness 25.2 ± 15.3 (n = 11 )
PANSS total 83.6 ± 13.8
BACS-verbal memory –1.55 ± 0.96
BACS-working memory –1.24 ± 1.29
BACS-motor speed –3.87 ± 2.87 (n = 10)
BACS-verbal fluency –1.23 ± 1.75
BACS-attention –3.14 ± 1.91
BACS-executive –1.59 ± 2.04
BACS-composite –2.10 ± 1.45
Lymphocyte D3 0.52 ± 0.26 ( n = 9) 0.63 ± 0.27
Lymphocyte D4 0.49 ± 0.09 0 .51 ± 0.11
Granulocyte D4 0.44 ± 0.18 0.44 ± 0.12
granulocytes were very low and we therefore did not
analyze these further. The analysis showed that there
was no statistically significant difference between pa-
tients and controls in terms of lymphocyte D3R levels (p
= 0.286), lymphocyte D4R levels (p = 0.477), or granu-
locyte D4R levels (p = 0.792) (Figure 1).
To exclude the effects of antipsychotics and duration
of the illness, we analyzed correlations between receptor
mRNA levels and dose of antipsychotics or duration of
illness, and found no statistically significant correlation
with lymphocyte D3R mRNA levels (antipsychotics: p =
0.795, duration: p = 0.100), lymphocyte D4R mRNA
levels (antipsychotics: p = 0.985, duration: p = 0.464) or
granulocyte D4R mRNA levels (antipsychotics: p =
0.253, duration: p = 0.136). Lymphocyte D3R mRNA or
lymphocyte or granulocyte D4R mRNA levels were also
not significantly correlated with duration of the illness.
Next, to examine the relevance of dopamine receptor
mRNA levels to clinical factors, we examined correla-
tions between dopamine receptor mRNA levels and the
PANSS and BACS-J scores. Although the correlation
between lymphocyte D3R mRNA levels and the PANSS
subscales did not reach statistical significance, lympho-
cyte D3R mRNA levels and total PANSS score showed a
statistically significant inverse relationship (Spearman, r
= 0.768, p = 0.009). Lymphocyte D4R mRNA levels and
the score on the working memory subscale of the
BACS-J also showed a strong positive correlation
(Spearman, r = 0.895, p = 0.001) (Figure 2).
M. Kawano et al. / Open Journal of Psychiatry 1 (2011) 33-39
Copyright © 2011 SciRes. OJPsych
Although we successfully quantified levels of mRNAs
Figure 1. D3R and D4R mRNA levels in lymphocytes and
D4R mRNA le vels in granulocytes. The y-axis shows the re la-
tive expression level. Sch: schizophrenia, Con: Control
for lymphocyte D3R and D4R and granulocyte D4R,
there were no statistically significant differences in the
levels of these receptor mRNAs in patients with schi-
zophrenia and controls. Consequently, this study failed
to replicate the previous results of either elevated D3R
mRNA levels [25] or reduced D4R levels in lympho-
cytes [27]. However, among the patients with schizoph-
renia, lymphocyte D3R mRNA levels showed a negative
correlation with the total PANSS score. In addition, there
was a strong correlation between lymphocyte D4R
mRNA levels and the score for working memory.
Several studies have indicated that D3 R mRNA levels
correlate with the clinical assessment. A study showed a
negative correlation between D3R mRNA levels in
lymphocytes and the personality trait of persistence in
the normal population [28]. The Ser9Gly polymorphism
of D3R is associated with severity of symptoms of the
first-episode of schizophrenia in drug-naive patients [15].
Lower levels of lymphocyte D3R protein in schizophre-
nia correlated with a higher hebephrenic subscale score
of the BPRS [29]. Consistent with this last report, our
results showed that the severity of psychotic symptoms
in patients with schizophrenia correlated with lower
lymphocyte D3R mRNA levels. However, our results
conflict with the increase in lymphocyte D3R mRNA
levels reported in patien ts with schizophrenia, taken as a
whole, compared to healthy controls [25]. As the patients
we recruited were relatively chronic and showed higher
symptom scores, it is possible that D3R mRNA levels
may have been reduced.
In addition to the correlation with D3R, this study
demonstrated that lymphocyte D4R mRNA levels
showed a strong positive correlation with the scale of
working memory, a subscale on the BACS-J.
Many studies have demonstrated that D4R levels have
Figure 2. (a) Correlation plot of the total PANSS score versus
lymphocyte D3R mRNA levels; (b) Correlation plot of the
working memory score on the BACS-J versus lymphocyte
D4R mRNA le ve ls.
an important implication for working memory. A func-
tional imaging study showed that variation in the number
of allele repeats in D4R exon II is associated with work-
ing memory [16]. During working memory, gamma
aminobutyric acid GABAergic interneurons control the
activity of pyramidal neurons in the prefrontal cortex [30]
and disturbance of GABAergic inhibition results in im-
pairment of working memory [31]. Recently, a mechan-
ism in which the D4R is involved in working memory
was proposed. Electrophysiological and immunofluo-
rescence studies have shown that D4R activation leads
to depression of actin-based trafficking of α-amin o
-3-hydroxy-5-methyl-4-isoxazolepropionic acid recep-
tors and excitatory transmission in the GABAergic in-
terneurons of the prefrontal cortex [32] and D4R activ a-
M. Kawano et al. / Open Journal of Psychiatry 1 (2011) 33-39
Copyright © 2011 SciRes. OJPsych
tion controls the myosin-based transport of the GABAA
receptor in the prefrontal cortex [33]. Conversely, a re-
duction in the D4R in the cerebral cortex (prefrontal
cortex) might worsen working memory and the reduc-
tion might result in a decrease in lymphocyte D4R levels.
Since we did not perform the BACS-J on the control
group, it is not known whether these correlations also
apply to the normal population.
Previous studies have shown that lymphocytes in the
blood interact with the CNS through the blood-brain
barrier (BBB). In neurodegenerative disorders, such as
multiple sclerosis and Parkinson’s disease, lymphocytes
can cross the BBB to act on the CNS [34,35]. A micro-
array study showed that, of the 45 candidate genes rele-
vant to schizophrenia, 21 are expressed in both whole
blood and prefrontal cortex. Furthermore, the level of
expression of many genes, including those for which the
protein product is involved in exocytosis and neurogene-
sis, is not significantly different between whole blood
and prefrontal cortex [36]. Thus, the peripheral altera-
tions in schizophrenia possibly reflect impairment in the
CNS. The availability of an accessible tissue, such as the
blood, with an mRNA expression profile similar to that
of the CNS has the potential to advance research in
One confounding factor in this study was the
long-term treatment of the patients. Although it was
possible that antipsychotics might affect dopamine re-
ceptors in the peripheral blood, our results showed no
correlation between antipsycho tic medication and D3R
or D4R mRNA levels. A previous report also showed
that the type of antipsychotic does not affect D3R and
D4R mRNA levels [25]. Another study showed that pa-
tients treated with olanzapine for 16 days show no in-
crease in D3R mRNA levels [37]. In addition, duration
of illness was not correlated with dopamine receptor
expression in our study. To clearly determine whether
antipsychotics change the expression of dopamine re-
ceptors, animal experiments using antipsychotics and
psychomimetics are required.
There are several limitations to this study. Firstly, the
sample population was small and a large-scale study
is required to confirm the correlations. Secondly, we
measured mRNA levels, and not amounts of protein. The
levels and functions of D3R and D4R protein in peri-
pheral blood are not known, Flow cytometry would be
useful for double-staining studies on peripheral blood.
Thirdly, the lymphocyte population used consisted of B
lymphocytes, natural killer cells, an d T lymphocytes and
the next stage would be to separate these cell subtypes
and investigate D3R and D4R expression. Despite these
limitations, this study provides a preliminary insight into
the function of D3R and D4R in peripheral blood in pa-
tients with schizophrenia, which may have diagnostic
importance for evaluating the severity of symptoms of
and cognitive func tion .
In conclusion, this study found that D3R and D4R
mRNA levels in the peripheral blood in patients with
schizophrenia were unchanged compared to controls.
However, patients with a higher total score on the
PANSS had lower levels of lymphocyte D3R mRNA and
patients with a higher score in the digit sequencing task
(better working memory) on the BACS-J had higher
lymphocyte D4R mRNA levels. D3R and D4R mRNA in
peripheral lymphocyte can therefore be used as a meas-
ure of severity of schizophrenia. We also need to eva-
luate an appropriate cognitive function in a control group
to examine whether there is also a correlation with D4R
mRNA levels in the normal population. Measurement of
protein levels involving a large number of cases are
needed to confirm our results. Further work to replicate
and validate the correlation between lymphocyte D3R
and D4R levels and clinical manifestations should pro-
vide useful information for the assessment and manage-
ment of schizophrenia.
This research was partially supported by the Ministry of Education,
Science, Sports and Culture, Grant-in-Aid for 19591359 and Kochi
Medical School Alumni Association.
We thank Dr. Kaneda who kindly provided suggestions for analyz-
ing cognitive function.
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