Brain Research Bulletin 79 (2009) 123–129
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Brain Research Bulletin
journal homepage: www.elsevier.com/locate/brainresbull
Antipsychotic and antidepressant co-treatment: Effects on transcripts of
inducible postsynaptic density genes possibly implicated in
Carmela Dell’Aversano, Carmine Tomasetti, Felice Iasevoli, Andrea de Bartolomeis∗
Laboratory of Molecular Psychiatry and Pharmacotherapeutics, Department of Neuroscience, Section of Psychiatry, University School of Medicine “Federico II”, Edificio 18,
Via Sergio Pansini 5, 80131 Naples, Italy
a r t i c l ei n f o
Received 20 October 2008
Received in revised form 11 January 2009
Accepted 12 January 2009
Available online 2 February 2009
a b s t r a c t
Selective serotonin reuptake inhibitors (SSRIs) and antipsychotics co-administration is a widely used
strategy to treat both psychotic depression and depressive symptoms in schizophrenia. Nonetheless,
the molecular mechanisms involved in the therapeutic benefits of antidepressant–antipsychotic com-
bination are still elusive. It has been suggested that co-administration of SSRIs and antipsychotics may
result in molecular changes different from their individual effects. In the present study, we evaluated
the acute effects of two SSRIs, citalopram and escitalopram, alone or in combination with haloperi-
dol, on the expression of Homer1a together with its splice variant ania-3, and p11, two genes linked
respectively to dopaminergic and serotonergic neurotransmission and involved in synaptic plasticity.
Homer1a and ania-3 were induced in the striatum by haloperidol, alone and in combination with SSRIs,
but not by SSRIs only. Haloperidol+citalopram co-administration induced a stronger Homer1a expres-
sion than haloperidol alone in the ventrolateral caudate-putamen. No signal was detected for p11 in
striatum, while there were no significant differences among treatments in cortical subregions. Homer1a
was significantly down-regulated in the parietal cortex by all treatments. These results demonstrated
citalopram may influence the impact by haloperidol on the dopaminergic neurotransmission. Moreover,
present findings confirm that Homer1a and ania-3 are strongly induced in striatum by haloperidol, while
they are not influenced by citalopram or escitalopram in this region. Oppositely, in the cortex the two
transcripts are modulated by both haloperidol and SSRIs, suggesting a possible role of both dopamine
and serotonin in their cortical regulation.
© 2009 Elsevier Inc. All rights reserved.
Several studies demonstrated that the combination of antipsy-
effective for treating both psychotic-like symptoms in depression
and depressive symptoms of schizophrenia (for review see ).
Despite the increasing evidence of an integrative approach to the
pathophysiology of schizophrenia, which combines different neu-
rotransmitters systems (for review see ), and the relatively fre-
Abbreviations: APDs, antipsychotic drugs; SSRIs, selective serotonin reuptake
D2 receptors; LSD, lysergic acid diethylamide; ROIs, regions of interest; OD, optical
density; ANOVA, analysis of variance.
∗Corresponding author. Tel.: +39 081 7463673; fax: +39 081 7462378.
E-mail addresses: firstname.lastname@example.org (C. Dell’Aversano),
email@example.com (C. Tomasetti), felix firstname.lastname@example.org (F. Iasevoli),
email@example.com (A. de Bartolomeis).
quent use of antipsychotics and antidepressants co-administration
in clinical practice, there are few preclinical studies exploring this
combination on brain molecular signalling. This prompted us to
investigate the effects of antidepressant–antipsychotic combina-
tion on the expression of specific inducible genes, such as Homer1a,
its splice variant ania-3, and p11, that have been suggested to be
respectively implicated in the pathophysiology of schizophrenia
and depression as well as in the putative therapeutic action of
antipsychotics and antidepressants [11,12,34,40,43].
SSRIs inhibit the reuptake of 5-hydroxytriptamine (5-HT) by
blocking the serotonin transporter (SERT), leading to increased
through a prevalent dopamine D2 receptor (D2R) antagonism 
and, when acutely administered, induce a significant increase in
dopamine release [22,27]. Recent studies showed that the com-
bined administration of SSRIs and antipsychotics might result in
biochemical and molecular changes different from their individual
0361-9230/$ – see front matter © 2009 Elsevier Inc. All rights reserved.
C. Dell’Aversano et al. / Brain Research Bulletin 79 (2009) 123–129
A growing body of evidence suggests that neuroplastic changes
may be implicated in the therapeutic effects of either class of
drugs and perhaps of their combination [20,31]. Indeed, it has been
observed that the expression of neurotrophic factors is enhanced
by the concomitant treatment with fluoxetine and olanzapine ,
while the subchronic administration of these two compounds sup-
presses the induction of two immediate-early genes (i.e., CREB and
c-fos) associated with long-lasting changes in the synapse .
synaptic plasticity. To test this hypothesis, we evaluated the effects
of acute administration of two SSRIs, citalopram and escitalopram,
alone or in combination with haloperidol, on the expression profile
of Homer1a, ania-3 and p11.
Homer1a and ania-3 are two Homer1 splice variants that are
induced in an immediate-early gene (IEG)-like fashion . Both
isoforms act as ‘dominant negatives’ by disrupting long Homers
constitutive clusters , resulting in a modification of synaptic
architecture . P11 gene encodes for S100A10 (p11), a member
of the S100 family of Ca2+-binding proteins that forms a permanent
heterotetrameric complex with the peripheral membrane-binding
protein annexin A2 and it has been recently shown to interact with
the serotonin 5-HT1Breceptor , regulating its localization at the
lated by typical and atypical antipsychotics, presumably according
to antipsychotics different dopaminergic profile [2,11,34,42]. A
direct modulation of Homer1a expression has been also reported
by direct and indirect dopamine agonists [2,46–48]. Moreover,
Homer1a and ania-3 have been recently shown to be induced
by compounds acting on serotonergic neurotransmission, such as
lysergic acid diethylamide (LSD) and antagonists at 5-HT recep-
tors [29,30]. A growing interest for these genes has recently arisen
from the observations of their involvement in motor and cogni-
tive behaviour as well as in synaptic plasticity processes. Moreover,
a role for Homer genes has been supposed in the pathophys-
iology of several behavioural disorders, such as schizophrenia
P11 has been reported to act as an inducible gene, and to
be directly related to serotonergic neurotransmission. It is up-
regulated in rodent brains by repeated antidepressant therapy (but
in an animal model of depression and in post-mortem brain of
depressed patients .
Citalopram and escitalopram were chosen because of their most
selective effect on 5-HT reuptake blockade among all the currently
available SSRIs, with escitalopram being approximately twice more
potent than citalopram [32,37]. Moreover, both drugs significantly
increase extracellular 5-HT, but not dopamine and noradrenaline
levels in rat prefrontal cortex [5,7,16,48].
2. Materials and methods
2.1. Animals and treatments
Male Sprague–Dawley rats (Charles-River Laboratories, Lecco, Italy) of approx-
imately 250g were housed in a temperature and humidity controlled colony room
and on the day of the experiment were randomly assigned to one of the six fol-
lowing groups: (1) saline solution 0.9% NaCl (SAL); (2) escitalopram 12mg/kg (ESC)
(Lundbeck Italia, Milan, Italy); (3) citalopram 14mg/kg (CIT) (Lundbeck Italia, Milan,
Italy); (4) haloperidol 0.8mg/kg (HAL) (Lusofarmaco, Milan, Italy); (5) HAL+ESC;
(6) HAL+CIT. All drugs were dissolved in a vehicle of physiological saline solution
(0.9% NaCl), which was used as a control. Drug doses were chosen based on previ-
ous animal studies in which molecular and behavioural effects predictive of either
antidepressive or antipsychotic activity were elicited [3,8,13,17,21,42]. All solutions
were suited to physiological pH value and injected intraperitoneally (i.p.) at a vol-
ume of 1ml/kg. The animals were killed by decapitation 90min after the treatment.
All procedures were conducted in accordance with the NIH Guide for Care and Use
of Laboratory Animals (NIH Publication N0. 85-23, revised 1996) and were approved
Fig. 1. Diagram of regions of interest (ROIs) quantitated on autoradiographic
film images in rat forebrain (section coordinates are approximately from Bregma
1.20–1.00mm). 1=cingulate cortex (Cg); 2=frontal cortex (FC); 3=parietal cortex
(PC); 4=dorsomedial caudate-putamen (CPDL); 5=dorsolateral caudate-putamen
(CPDM); 6=ventrolateral caudate-putamen (CPVM); 7=ventromedial caudate-
putamen (CPVL); 8=core of accumbens (AcCo); 9=shell of accumbens (AcSh).
Modified from Paxinos and Watson .
by local Animal Care and Use Committee. All efforts were made to minimize the
number of animals and their sufferance.
2.2. Tissue sectioning and in situ hybridization procedures
After the killing, the brains were removed, frozen on dry ice and stored at
−70◦C. Coronal sections of 12?m were cut on a cryostat, using the rat brain
atlas by Paxinos and Watson  as an anatomical reference (approximately from
hybridization. Section pre-treatment and oligonucleotide labelling procedures were
performed according to previously published protocols .
The Homer1a probe was a 48-base oligodeoxyribonucleotide complementary to
bases 2527–2575 of the rat Homer1a mRNA (GenBank Accession # U92079). The
ania-3 probe was a 48-bases oligodeoxyribonucleotide complementary to bases
1847–1894 of the rat ania-3 mRNA (GenBank Accession # AF030088). The p11 probe
was a 48-bases oligodeoxyribonucleotide complementary to bases 313–361 of the
were purchased from MWG Biotech (Firenze, Italy).
2.3. Image capture and statistical analysis
Hybridized sections were exposed to Kodak-Biomax MR Autoradiographic film
in a time range of 14–21 days to maximize signal-to-noise ratio. A slide contain-
ing known amounts of14C standards (American Radiolabeled Chemicals, St. Louis,
US) was co-exposed with the samples. The quantitation of the autoradiographic
signal was performed using a computerized image analysis system including: a
transparency film scanner Microtek ScanMaker 9800XL, an Apple iMac, and ImageJ
contained five animals. Each slide contained four adjacent sections of a single
animal. Analysis was carried out on digitized autoradiograms measuring mean
optical density (OD) within outlined regions of interest (ROIs) in correspondence
of subregions of the cortex, caudate-putamen and nucleus accumbens (Fig. 1).
Measurements of OD within ROIs were converted using a calibration curve based
on the standard scale co-exposed to the sections. A one-way analysis of vari-
ance (ANOVA) was used to analyse treatment effects. The Student–Newman–Keuls
post hoc test was used to determine the locus of effects in any significant
Results for each probe analyzed are detailed in Table 1. Sig-
nificant differences in Homer1a expression were detected among
C. Dell’Aversano et al. / Brain Research Bulletin 79 (2009) 123–129
mRNA levels of Homer 1a, ania-3 and p11 after acute treatments. Data are expressed as percentage of SAL relative dpm mean value±S.E.M and listed by brain region
analyzed along with the relative ANOVA values for each of the significant changes (p<0.05). FC=frontal cortex; PC=parietal cortex; DM=dorsomedial; DL=dorsolateral;
Probes ESC CITHAL HAL+ESC HAL+CIT
81.1 ± 5.6
94 ± 0.72
94.4 ± 2.6
81.6 ± 1*
96.07 ± 0.42
94.1 ± 2.9
94.8 ± 10.2
99.9 ± 9.2
81.9 ± 3.4*
96.2 ± 12.1
88.3 ± 5.9
96.5 ± 7.02
97.2 ± 7.08
82.5 ± 3.04*
93.9 ± 4.7
82.5 ± 2.6
84.1 ± 5.2
91.3 ± 2.8
77.5 ± 4.7*
86.3 ± 4.5
78.9 ± 5.4
87.4 ± 2.6
92.9 ± 3.8
73.4 ± 2.1*
85.5 ± 0.88
102.5 ± 2.5
81.1 ± 2.09
104.3 ± 2.2
103.5 ± 2.4
105 ± 2.7
103.2 ± 2.3
104.7 ± 1.7
106.4 ± 2.2
112.4 ± 1.9*
120.4 ± 6.7*
116.9 ± 2.3*
111.4 ± 2.3*
106.5 ± 1.4
115.9 ± 4.1*
119.5 ± 3.1*
107.9 ± 2.1
114.1 ± 3.57*
128.1 ± 7.55*
130.4 ± 1.9*
116.7 ± 2.1*
106.6 ± 2.5
113 ± 2.26
108.6 ± 3.2
114.8 ± 4.3
118.3 ± 1.3*
109.4 ± 3.03
115.5 ± 3.1*
114.6 ± 4.2
117.4 ± 3.9*
115.7 ± 1.08
98.5 ± 7.2
95.7 ± 3.5
97.1 ± 5.61
103.2 ± 1.9
99.6 ± 1.9
100.9 ± 3.4
102.6 ± 2.8
103.02 ± 2.86
101.9 ± 5.1
103.2 ± 3.1
92.8 ± 4.07
96.2 ± 3.7
99.7 ± 3.7
95.02 ± 5.3
95.6 ± 3.76
82.7 ± 4.2
83.5 ± 2.7*
86.8 ± 5.1
86.2 ± 5.5
87.2 ± 3.7
95.4 ± 8.5
88.3 ± 4.8
95.5 ± 7.06
102.01 ± 6.4
93.5 ± 3.03
96.6 ± 2.6
98.3 ± 2.5
99.02 ± 2.2
97.2 ± 2.4
96 ± 1.8
96.6 ± 1.7
97.4 ± 1.8
94.8 ± 1.8
113.8 ± 2.9*
121.9 ± 4.4*
118.3 ± 2.6*
112.03 ± 2.6*
97.9 ± 3.3
110.1 ± 2.2*
112.8 ± 2.2*
98.8 ± 3.7
104.4 ± 2.6
118.08 ± 3.3*
117.9 ± 3.2*
101.8 ± 3.02
99.8 ± 2.9
98.6 ± 2.7
98.5 ± 4.2
99.4 ± 5.6
115.04 ± 2*
112.5 ± 2.1
97.9 ± 6.3
97.4 ± 8.05
107.7 ± 2.5
106.08 ± 4.4
101.9 ± 5.09
102.8 ± 4
98.7 ± 5.09
97.9 ± 4.52
96.08 ± 2.86
95.1 ± 4.1
94.7 ± 0.76
97.3 ± 3.05
94.1 ± 5.2
104.8 ± 2.6
101.2 ± 1.03
107.1 ± 4.06
100.6 ± 1.4
97.1 ± 2.9
107.3 ± 1.3
92.1 ± 2.5
95.7 ± 2.8
91.7 ± 1.5
87.8 ± 3.7
99.5 ± 3.1
95.1 ± 6.5
98.5 ± 1.62
97.2 ± 4
90.8 ± 5.2
102.1 ± 2.02
*Significant differences from SAL at the Student–Neumann–Keuls (SNK) post hoc test.
treatment groups in all striatal subregions with the exception
of the nucleus accumbens shell (dorsomedial caudate-putamen,
CPDM: p=0.012; F(5;15)=4.39; dorsolateral caudate-putamen,
CPDL: p=0.0001; F(5;15)=12.76; ventromedial caudate-putamen,
CPVM: p=0.005; F(5;15)=5.29; ventrolateral caudate-putamen,
CPVL: p=0.0001; F(5;15)=20.31; core of the nucleus accumbens,
p>0.05; F(5;15)=2.24) (Fig. 3A and B). The post hoc test showed that
HAL significantly increased Homer1a expression (1) as compared
to SAL in all regions of the caudate-putamen, (2) as compared to
ESC and CIT in CPDL and CPVL, and (3) as compared to SAL in AcCo.
and CPVL as compared to SAL, ESC and CIT and (2) in AcCo as com-
pared to SAL. Finally, HAL+CIT significantly induced Homer1a (1) in
all regions of the caudate-putamen as compared to SAL, (2) in CPDL
as compared to ESC, CIT, HAL+ESC, (3) in CPVL as compared to all
the other treatments, (4) in CPVM as compared to ESC, and (5) in
AcCo as compared to SAL (Fig. 3A and B).
ANOVA test revealed significant differences in Homer1a expres-
sion among treatments in the outer layer of the parietal cortex
(PCo: p=0.002; F(5;17)=6.10) but not in the inner one (PCi: p>0.05,
F(5;17)=0.90), in the frontal cortex (outer layer, FCo: p>0.05;
F(5;17)=1.95; inner layer, FCi: p>0.05; F(5;17)=0.92), and in the cin-
gulate cortex (Cg: p>0.05; F(5;17)=0.41). The post hoc test showed
that Homer1a expression was significantly reduced in PCo by
all treatment groups as compared with SAL (Fig. 2 panel A and
Ania-3 showed a pattern of expression similar to Homer1a
(Fig. 2 panel B and Fig. 3D–F). The ANOVA test revealed signifi-
cant differences among treatments in all striatal subregions with
the exception of the nucleus accumbens shell (CPDM: p=0.001;
F(5;24)=6.25; CPDL: p=0.0001; F(5;24)=13.99; CPVM: p=0.003;
F(5;24)=4.885; CPVL: p=0.0001; F(5;24)=16.32; AcCo: p=0.033;
F(5;24)=2.91; AcSh: p>0.05; F(5;24)=1.31). Only a few differences
CPVM, HAL-treated group significantly induced ania-3 expression
as compared to all the other treatments; (2) in CPDL, a significant
ania-3 signal increase was induced by HAL as compared to SAL,
ESC, CIT and HAL+ESC; (3) HAL+CIT significantly induced ania-3
as compared to SAL, CIT and ESC in CPDL and CPVL but not in CPDM
and CPVM; (4) in AcCo, ania-3 was significantly induced by HAL as
compared to SAL (Fig. 3D and E).
In the cortex, significant differences in ania-3 expression were
(FCo: p>0.05; F(5;24)=1.55; PCo: p>0.05; F(5;24)=1.38; Cg: p>0.05;
down-regulated by HAL+ESC compared to SAL and CIT. In PCi, a
C. Dell’Aversano et al. / Brain Research Bulletin 79 (2009) 123–129
Fig. 2. Autoradiographic film images of Homer 1a (panel A) and ania-3 (panel B) mRNA detected by means of in situ hybridization histochemistry (ISHH) in coronal brain
sections after acute treatment (n=5 rats in each group) with: saline solution 0.9% NaCl (SAL), escitalopram 12mg/kg (ESC), citalopram 14mg/kg (CIT), haloperidol 0.8mg/kg
(HAL), HAL+ESC or HAL+CIT.
to CIT was observed (Fig. 2 panel B and Fig. 3F).
P11 expression was negligible in the striatum while it was
detected in each subregion of the cortex analyzed (Fig. 4A and
B). Nonetheless, no significant differences among treatments were
observed at the ANOVA test in any cortical subregion (FCo: p>0.05;
F(5;23)=0.55; FCi: p>0.05; F(5;23)=2.23; PCo: p>0.05; F(5;23)=0.86;
PCi: p>0.05; F(5;23)=1.93; Cg: p>0.05; F(5;23)=0.92).
Fig. 3. Homer 1a and ania-3 mRNA levels after acute treatment. Panels A–C: Homer 1a mRNA levels in cortex, caudate-putamen and nucleus accumbens. Panels D–F: ania-3
mRNA levels in cortex, caudate-putamen and nucleus accumbens. Data are reported in relative dpm as mean±S.E.M. Student–Neumann–Keuls (SNK) post hoc test: *=vs.
C. Dell’Aversano et al. / Brain Research Bulletin 79 (2009) 123–129
Fig. 4. Panel A: autoradiographic film images of p11 mRNA detected by means of in situ hybridization histochemistry (ISHH) in coronal brain sections after acute treatment
(n=5 rats in each group) with: saline solution 0.9% NaCl (SAL), escitalopram 12mg/kg (ESC), citalopram 14mg/kg (CIT), haloperidol 0.8mg/kg (HAL), HAL+ESC or HAL+CIT.
Panel B: P11 mRNA levels after chronic treatment in cortex: frontal cortex (FC); intermediate cingulate cortex (Cg); parietal cortex (PC). Data are reported in relative dpm as
mean±S.E.M. Student–Neumann–Keuls (SNK) post hoc test: *=vs. SAL (p<0.05).
The major finding of the present study is that the acute
co-administration of haloperidol+citalopram induced a stronger
Homer1a expression than haloperidol and citalopram alone in the
ventrolateral subregion of caudate-putamen (CPVL). In the other
subregions of the striatum, Homer1a and ania-3 expression was
induced by haloperidol, alone or in combination with escitalopram
This result let us to hypothesize that haloperidol+citalopram
combination may perhaps stimulate different signalling pathways,
or induce synergistic pathways, as compared to that elicited by
these drugs when administered alone. This finding is consistent
with other reports in which the combination of an SSRI and
haloperidol induced different gene expression profiles compared
to those induced by their individual administration [9,10].
Moreover, present findings confirm our previous observa-
tions that both Homer1a and ania-3 are induced in the striatum
by compounds, such as haloperidol, which strongly impact the
dopaminergic neurotransmission, probably through a dopamine
D2 receptor-mediated mechanism [2,11,34,42]. On the other hand,
we showed that drugs that selectively impact the serotonin reup-
take, such as citalopram and escitalopram, have negligible effects
on Homer1a and ania-3. Although SSRIs, such as citalopram, have
been demonstrated to significantly increase serotonin levels in
striatal regions when acutely administered , it is possible to
hypothesize that the acute indirect agonism at serotonergic recep-
tors, induced by selective SERT blockade, may be not involved in
Homer1a and ania-3 expression, at least in striatal areas. These
findings are consistent with previous reports in which acute SSRIs
(citalopram and fluoxetine) administration had scarce or no effects
on the transcription of other immediate-early genes (i.e., c-fos)
in the striatum [18,26]. Therefore, since in previous works it has
been suggested that Homer1a may be induced in striatal areas by
drugs acting on dopaminergic neurotransmission [42,46], it could
be hypothesized that citalopram administration might potenti-
ate the impact of haloperidol on striatal dopaminergic systems,
synergistically increasing Homer1a expression. Indeed, citalopram
has been demonstrated to significantly increase striatal dopamine
release induced by haloperidol .
Since ventrolateral striatum has been shown to participate in
neuronal networks controlling emotion and affective behaviour
, our observation that the combined haloperidol+citalopram
administration results in molecular changes dissimilar from that
induced by individual drugs might provide a preclinical tool to bet-
ter understand their combined effects in psychotic depression and
splice variants of Homer1 gene, Homer1a and ania-3, showed over-
all a similar pattern of expression, we found some differences (see
Section 3). The major difference between them is the response to
significantly induced as compared to all the other treatments and
a differential regulation with neuroanatomical specificity. How-
ever, the most conservative explanation could be a difference in the
signal-to-noise ratio between the two inducibile genes, where that
for Homer1a is higher than that for ania-3. Further investigations
ciation of haloperidol plus escitalopram did not enhance Homer1a
be explained by the different pharmacological and biochemical
characteristics of the S-enantiomer of citalopram as compared to
C. Dell’Aversano et al. / Brain Research Bulletin 79 (2009) 123–129
the racemic mixture [28,37]. It has been reported that escitalopram
is about twice more potent than citalopram in inhibiting serotonin
reuptake  and that citalopram acts on secondary molecular tar-
affinity than its S-enantiomer . Therefore, it is possible that the
differences between citalopram and escitalopram in Homer1a and
However, a more conservative explanation could be that the dose
of the racemic citalopram that we used contained a dose of the S-
enantiomer which was about half the dose of that administered to
the escitalopram-treated group. Moreover the effects of serotonin
reuptake inhibition on Homer1a expression could be dose-related
following a bi-phasic or inverted U-shaped dose–response curve
such that lower to moderate increases in 5-HT transmission might
yield effects that were not seen with higher levels. This could
involve the recruitment of different 5-HT receptor sub-types or
the activation of different feedback loops as extracellular 5-HT
ways. More studies would be required in order to investigate these
In this study, only minimal changes in cortical expression of
Homer1a and ania-3 were detected. This result is in agreement
with those from other studies that reported the lack of c-fos induc-
tion by antidepressant compounds in several cortical areas [26,38].
Recent evidence has been provided that serotonergic compounds
may elicit Homer1a and ania-3 expression in the cortex . In our
precedent work, we showed that antipsychotics with serotoner-
gic profile (i.e., aripiprazole) induced Homer1a in the cortex, while
haloperidol, which is virtually devoid of serotonergic action, did
not . The results of the present study may suggest that indirect
serotonergic agonism could be not involved in Homer1a induction
in the cortex. Taken together, these observations let us to hypothe-
size that antagonism at serotonergic receptors, rather than indirect
agonism, may be implicated in the induction of Homer1a expres-
sion in these regions. Further studies are needed to clarify this
The putative serotonergic gene p11 has been reported to be
induced by repeated antidepressant administration . Although
we showed basal p11 expression in the inner layers of the cor-
tex, gene expression was not enhanced by SSRIs, haloperidol or
SSRIs plus haloperidol. This finding is in contrast with previous
observations of increased p11 mRNA in cortical areas by chronic
imipramine and tranylcypromine , probably due to the very
different receptorial profile of these two antidepressants from
In conclusion, we have demonstrated: (1) the differential
effect upon gene expression of postsynaptic proteins by acute
antipsychotic–antidepressant co-administration compared to the
administration of each compound alone and (2) a brain region
specificity of this effect. However, since both depression and psy-
chosis need chronic antidepressant and antipsychotic treatments,
further studies are warranted to better explore the implication of
postsynaptic density proteins in the pathophysiology and treat-
ment of these disorders.
Conflict of interest
This study was partially supported by an unrestricted grant by
H. Lundbeck, Italy, who was not responsible for creation of the
study protocol, data analysis, data interpretation, or writing of the
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Differential effectsof adjunctive