Effects of Bisphenol A and Learning on the Distribution of GABAAα1 Receptors in the Rat Hippocampus and Prefrontal Cortex
Bisphenol-A (BPA) is a widely distributed chemical having mixed estrogen agonist/antagonist properties. We investigated the effects of introduction of BPA and passive avoidance learning on the distribution of GABAAα1 receptors in the rat prefrontal cortex and hippocampus. BPA (5 and 50 mg/kg·day)...
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Інститут фізіології ім. О.О. Богомольця НАН України
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irk-123456789-1481462019-02-18T01:24:29Z Effects of Bisphenol A and Learning on the Distribution of GABAAα1 Receptors in the Rat Hippocampus and Prefrontal Cortex Taherianfard, M. Taci, A.A. Bisphenol-A (BPA) is a widely distributed chemical having mixed estrogen agonist/antagonist properties. We investigated the effects of introduction of BPA and passive avoidance learning on the distribution of GABAAα1 receptors in the rat prefrontal cortex and hippocampus. BPA (5 and 50 mg/kg·day) was introduced by oral intake for 15 days; learning and memory were tested in a shuttle-box. The distributions of GABAAα1 receptors were investigated by an immunohistochemical procedure. The BPA treatment significantly decreased the density of GABAAα1 receptors in the prefrontal cortex and hippocampus. The distribution of these receptors was significantly denser in BPA-exposed rats subjected to learning than that in rats without learning. Thus, BPA treatment leads to down-regulation of GABAAα1 receptors in the prefrontal cortex and hippocampus. Learning a passive avoidance reaction provides upregulation of such receptors in these brain structures. Бісфенол А (BPA) – це широко розповсюджений хімікат, що має змішані властивості агоніста/антагоніста естрогенів. Ми досліджували впливи введення BPA та навчання реакції пасивного уникання на розподіл ГАМКAα1-рецепторів у префронтальній корі та гіпокампі щурів. BPA (5 або 50 мг/кг на добу) вводився перорально протягом 15 діб. Результати навчання та формування пам’яті тестували в човниковій камері. Розподіл ГАМКAα1-рецепторів досліджували з використанням імуногістохімічної методики. Введення BPA істотно зменшувало кількість ГАМКAα1-рецепторів у префронтальній корі та полі CA1 гіпокампа. Розподіл цих рецепторів був значно щільнішим у щурів, котрим уводили BPA та піддавали навчанню, ніж у тварин, яким навчання не проводили. Таким чином, уведення BPA призводить до негативної регуляції системи ГАМКAα1-рецепторів у префронтальній корі та гіпокампі, тоді як навчання пасивній реакції уникання забезпечує позитивну регуляцію даної системи в згаданих мозкових структурах. 2015 Article Effects of Bisphenol A and Learning on the Distribution of GABAAα1 Receptors in the Rat Hippocampus and Prefrontal Cortex / M. Taherianfard, A. A. Taci // Нейрофизиология. — 2015. — Т. 47, № 1. — С. 31-37. — Бібліогр.: 26 назв. — англ. 0028-2561 http://dspace.nbuv.gov.ua/handle/123456789/148146 612.825:591.181:577.171 en Нейрофизиология Інститут фізіології ім. О.О. Богомольця НАН України |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine |
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English |
| description |
Bisphenol-A (BPA) is a widely distributed chemical having mixed estrogen agonist/antagonist
properties. We investigated the effects of introduction of BPA and passive avoidance learning
on the distribution of GABAAα1 receptors in the rat prefrontal cortex and hippocampus.
BPA (5 and 50 mg/kg·day) was introduced by oral intake for 15 days; learning and memory
were tested in a shuttle-box. The distributions of GABAAα1 receptors were investigated by
an immunohistochemical procedure. The BPA treatment significantly decreased the density
of GABAAα1 receptors in the prefrontal cortex and hippocampus. The distribution of these
receptors was significantly denser in BPA-exposed rats subjected to learning than that in rats
without learning. Thus, BPA treatment leads to down-regulation of GABAAα1 receptors in
the prefrontal cortex and hippocampus. Learning a passive avoidance reaction provides upregulation of such receptors in these brain structures. |
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Article |
| author |
Taherianfard, M. Taci, A.A. |
| spellingShingle |
Taherianfard, M. Taci, A.A. Effects of Bisphenol A and Learning on the Distribution of GABAAα1 Receptors in the Rat Hippocampus and Prefrontal Cortex Нейрофизиология |
| author_facet |
Taherianfard, M. Taci, A.A. |
| author_sort |
Taherianfard, M. |
| title |
Effects of Bisphenol A and Learning on the Distribution of GABAAα1 Receptors in the Rat Hippocampus and Prefrontal Cortex |
| title_short |
Effects of Bisphenol A and Learning on the Distribution of GABAAα1 Receptors in the Rat Hippocampus and Prefrontal Cortex |
| title_full |
Effects of Bisphenol A and Learning on the Distribution of GABAAα1 Receptors in the Rat Hippocampus and Prefrontal Cortex |
| title_fullStr |
Effects of Bisphenol A and Learning on the Distribution of GABAAα1 Receptors in the Rat Hippocampus and Prefrontal Cortex |
| title_full_unstemmed |
Effects of Bisphenol A and Learning on the Distribution of GABAAα1 Receptors in the Rat Hippocampus and Prefrontal Cortex |
| title_sort |
effects of bisphenol a and learning on the distribution of gabaaα1 receptors in the rat hippocampus and prefrontal cortex |
| publisher |
Інститут фізіології ім. О.О. Богомольця НАН України |
| publishDate |
2015 |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/148146 |
| citation_txt |
Effects of Bisphenol A and Learning on the Distribution of GABAAα1 Receptors in the Rat Hippocampus and Prefrontal Cortex / M. Taherianfard, A. A. Taci // Нейрофизиология. — 2015. — Т. 47, № 1. — С. 31-37. — Бібліогр.: 26 назв. — англ. |
| series |
Нейрофизиология |
| work_keys_str_mv |
AT taherianfardm effectsofbisphenolaandlearningonthedistributionofgabaaa1receptorsintherathippocampusandprefrontalcortex AT taciaa effectsofbisphenolaandlearningonthedistributionofgabaaa1receptorsintherathippocampusandprefrontalcortex |
| first_indexed |
2025-07-12T18:27:13Z |
| last_indexed |
2025-07-12T18:27:13Z |
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1837466742434037760 |
| fulltext |
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2015.—T. 47, № 1 31
UDC 612.825:591.181:577.171
M. TAHERIANFARD1 and A. A. TACI1
EFFECTS OF BISPHENOL A AND LEARNING ON THE DISTRIBUTION OF GABAAα1
RECEPTORS IN THE RAT HIPPOCAMPUS AND PREFRONTAL CORTEX
Received November 24, 2013.
Bisphenol-A (BPA) is a widely distributed chemical having mixed estrogen agonist/antagonist
properties. We investigated the effects of introduction of BPA and passive avoidance learning
on the distribution of GABAAα1 receptors in the rat prefrontal cortex and hippocampus.
BPA (5 and 50 mg/kg·day) was introduced by oral intake for 15 days; learning and memory
were tested in a shuttle-box. The distributions of GABAAα1 receptors were investigated by
an immunohistochemical procedure. The BPA treatment significantly decreased the density
of GABAAα1 receptors in the prefrontal cortex and hippocampus. The distribution of these
receptors was significantly denser in BPA-exposed rats subjected to learning than that in rats
without learning. Thus, BPA treatment leads to down-regulation of GABAAα1 receptors in
the prefrontal cortex and hippocampus. Learning a passive avoidance reaction provides up-
regulation of such receptors in these brain structures.
Keywords: bisphenol A (BPA), passive avoidance learning, GABAAα1 receptors, prefrontal
cortex, hippocampus, male rats.
1 Department of Physiology, School of Veterinary Medicine, Shiraz University,
Shiraz, Iran.
Correspondence should be addressed to M. Taherianfard
(e-mail: taherian@shirazu.ac.ir).
INTRODUCTION
At present, there are alarming reports regarding
the reproduction and health hazards of endocrine
disrupting chemicals in the environment [1].
Bisphenol A (BPA) is considered one of the most
common endocrine disruptors [2]. This compound is
extensively used in synthesis of a few types of plastics
and is present in a number of products used in industry
and everyday life. The molecule of BPA has two phenol
rings and possesses structural homology with a ring
of β-estradiol; BPA is suspected to bind to estrogen
receptors, to mimic estrogenic actions, and to exert
significant adverse effects on humans and animals [3].
GABA i s a ve ry impor t an t i nh ib i t o ry
neurotransmitter throughout the CNS that acts on
GABAA, GABAB, and GABAC receptors. GABAA
receptors mainly mediate fast inhibitory synaptic
transmission in the entire brain; this is why these
receptors are major targets for many pharmacological
agents, in particular synthetic and endogenous steroids
[4].
As was reported, in vitro GABA release in
medial hyperstriatum ventral slices of the chick
brain increased following training [5]. The affinity
of GABAA receptors in different brain regions
demonstrates rather significant specificity. Using
molecular biological techniques allowed researchers to
reveal that a single amino acid residue is responsible
for such profound difference in the affinity and
functions of these receptors. The presence of a
histidine residue at position 101 of the primary amino
acid sequence of the α subunit produces subunit α1
characterized by high-affinity binding to diazepam [6].
GABAA receptors containing α1 subunit are specific
for fast synaptic inhibition in hippocampal CA1
pyramidal cells [7]. These (α1 subunit-containing)
GABAA receptors play an important role in modulation
of memory acquisition [8]. Some studies indicated the
presence of GABAA receptors in brain regions such
as the prefrontal cortex and hippocampus, i.e., the
regions especially important for learning and memory
[9, 10].
Choi et al. [11] reported that BPA can significantly
influence GABAA receptors. However, BPA is not
likely to act directly on the GABA binding sites of
GABAA receptors and to open Cl
– channels; it did
not induce any GABAA receptor-mediated currents in
dorsal root ganglion neurons where functional GABA
receptors are expressed. Instead, BPA might bind
to some modulatory sites located in the vicinity of
GABAA receptor-Cl
– channel complexes and in such a
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2015.—T. 47, № 132
M. TAHERIANFARD and A. A. TACI
way affect the GABAA receptor function [11].
There are many publications on the effects of
GABAA receptor agonists and antagonists on the
learning process in all technical conditions. There are,
however, few studies on the influence of learning on
the distribution of GABAA receptors. Xenoestrogens,
such as BPA, can modulate learning and memory
formation. Several studies showed that exposures to
BPA in prenatal/neonatal stages or in adult animals
induce significant impairment of learning and memory
[1, 11, 12]. At the same time, the effect of BPA on
GABAA receptor distribution in certain brain areas has
not been examined until now. The aim of our study
was to investigate the interaction of BPA treatment
with the effect of passive avoidance learning on the
distribution of GABAAα1 receptors in the prefrontal
cortex and CA1 region of the hippocampus in rats.
METHODS
Thirty male Sprague-Dawley rats weighing 200-220 g
were used. The animals were housed under a 12/12 h
light/dark cycle (light on at 6 a.m.) and controlled
temperature (20 ± 4°C) conditions. Food and water
were available ad libitum.
The rats were randomly divided into six equal
groups (n = 5 in each). Three groups were not sub-
jected to avoidance learning. Among them, group
1 received the solvent (sesame oil), while groups 2
and 3 were treated with 5 and 50 mg/kg × day BPA,
respectively; BPA and sesame oil were applied by oral
gavages for 15 days [12]. BPA was purchased from
Sigma-Aldrich (USA) and dissolved in sesame oil.
Groups 4-6 were trained in the shuttle box and also re-
ceived pure sesame oil or BPA dissolved in oil (5 and
50 mg/kg × day, respectively). The learning test was
done after 15 days of oral gavages.
Shuttle Box. A two-way shuttle-box with acrylic
walls and steel floor bars was used. The box, 44×20×19
cm, was bisected by a vertical partition into light and
dark compartments. The partition had an opening in its
middle, which allowed the animal to move freely from
one compartment to another. In the light compartment,
the animal was safe, while in the dark compartment it
could receive a 1-sec-long foot shock (0.6 mA) with a
latent period of 1.0 sec.
Behavioral Procedure. On the first day, all ani-
mals were individually subjected to 2-min-long adap-
tation to the shuttle box, in which the rat could explore
the light compartment and was allowed to move about
freely. Within this stage, the rats preferred the dark
compartment. If the rat did not move to this compart-
ment in 120 sec, it was removed from the study. This
adaptation was repeated 30 min later. On the second
day, the rats were placed in the light compartment of
the box and, 1.0 sec after entering the dark compart-
ment, received a 0.6 mA foot shock. The latency of
coming to the light compartment demonstrated by the
rat this day was considered an initial latency. On the
third day, the procedure was similar to that on the sec-
ond day; this day was considered a learning day. On
the fourth day (memory consolidation), the procedure
was similar to that on the learning day but without a
foot shock. On the fifth day (memory retention), the
procedure was similar to that on the fourth day. The
rats were considered completely learned if they did
not move to the dark compartment within a 120 sec
interval during the third, fourth, and fifth days of the
experiment.
Tissue Preparation. In all groups, the rats were
anesthetized by sodium thiopental (120 mg/kg); after
transcardial perfusion with 10% formaldehyde, their
brains were removed, washed by normal saline, and
fixed for 72 h in 10% formaldehyde in 0.1 M phos-
phate buffer (PB, pH 7.4). Then, the brains were post-
fixed in 4% formaldehyde in 0.1 M PB. After paraffin
embeding, paraffin blocks were prepared. Five-µm-
thick sections were made and mounted on 25% L-ly-
sine-coated glass slides.
Immunohistochemical Study. The slide-mounted
sections were dried and subsequently stored in a –20°C
freezer until used for antibody labeling. After taken
from the freezer, these sections of the rat brain were
brought to room temperature, washed, and the neces-
sary areas of the section were outlined with a liquid-
repellent slide marker pen (to retain reagents on the
sections during the immunostaining procedure). The
sections were incubated overnight with primary anti-
bodies (99% preferring α1) against GABAAα1 recep-
tors (10–3 dilution). On the next day, the sections were
rinsed in PBS, incubated with secondary antibody (en-
vision), and washed in PBS. Finally, the sections were
rinsed in PBS three times for 10 min, reacted with a
cromogen (Dab), and, after rinsing in PBS, put in a
hemotoxilin solution for nucleus staining. Negative-
control sections were incubated with PBS in the ab-
sence of primary antibody, and no immunoreactivity
was detected. Figure 1 shows such negative control,
where there was no brown color due to the reaction to
primary antibody. After preparing digital images of the
slides, the distribution of GABAAα1 receptor was ana-
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2015.—T. 47, № 1 33
EFFECTS OF BISPHENOL A AND LEARNING ON THE DISTRIBUTION OF GABAAα1 RECEPTORS
lyzed using Image Analyzer (version 1.33). Three in-
dices characterizing the distribution of receptors (hue,
saturation, and intensity) were estimated. It should be
taken into account that the above indices (measured by
the program in pixels, i.e., arbitrary units) are reverse
values, meaning that the greater values of the indices
measured, the lower densities of GABA receptors, .
Statistical Analysis. Statistical analyses of the nu-
merical data were performed using SPSS (version
18). One-way ANOVA was used to evaluate between-
group differences. The data are shown below as mean
± s.e.m., and the differences were considered signifi-
cant at P < 0.05.
RESULTS
The treatment with BPA in doses of 5 and 50 mg/kg·day
during 15 days with no learning significantly decreased
the density of immunoreactive GABAAα1 receptors in
the prefrontal cortex and hippocampal CA1 region
in comparison with the sham group without learning
(Figs. 2-5). The indices of color intensity (i.e., the
reverse values) in slices of the prefrontal cortex in the
respective animal groups (2 and 3) were significantly
greater than the respective index in group 1
(P < 0.05 and P < 0.01). The situation in slices of
the hippocampus of the animals with no learning was
nearly the same (Fig. 4).
The density of GABAAα1 receptors in the prefrontal
cortex and hippocampus of animals subjected to suc-
cessful avoidance learning (groups 4-6) demonstrat-
ed the regularities rather similar to those in groups
with no learning (1-3). The densities of these recep-
tors after BPA treatment were noticeably smaller than
those in the sham learned group. At the same time,
all these characteristics were, in general, noticeably
greater than those in the respective groups but with no
learning.
The indices of color intensity in slices of the pre-
frontal cortex of BPA-treated groups 5 and 6 were sig-
nificantly greater (P < 0.05 and P < 0.01) than that in
group 4 (i.e., the number of GABAAα1 receptors was
smaller). At the same time, comparisons of groups
4 vs. 1, 5 vs. 2, and 6 vs. 3 showed that the above
indices in the learned groups (4-6) were significant-
ly smaller than in groups without learning (1-3; P <
А
B
1
*
*
**
**
##
#
#
0
20
40
60
80
100
120
140
2 3 4 5 6
F i g. 1. Photomicrographs of the negative control. A) Hippocampus;
B) prefrontal cortex. ×400.
Р и с. 1. Мікрофотографії негативного контролю.
F i g. 2. Effects of BPA and avoidance learning on the GABAAα1
receptor distribution in the prefrontal cortex of male rats. Vertical
scale) Color intensity, arbitrary units (pixels). 1-6) Experimental
animal groups; 1-3, without learning, 4-6, with learning. 1 and 4)
Sham groups; 2 and 5) treated with 5 mg/kg∙day BPA; 3 and 6)
treated with 50 mg/kg∙day BPA. It should be taken into account
that the measured index of color intensity is reverse with respect
to the density of GABAAα1 receptors (the greater index, the smaller
number of the receptors). One and two asterisks show significant
differences from sham groups with P < 0.05 and P < 0.01. One and
two crosses show the analogous differences between groups 3 vs.
2 and 6 vs. 5. One and two # signs show significant differences in
comparing groups 4 vs. 1, 5 vs. 2, and 6 vs. 3.
Р и с. 2. Впливи бісфенолу А (BPA) та навчання реакції
уникання на розподіл ГАМКAα1-рецепторів у префронтальній
корі самців щурів.
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2015.—T. 47, № 134
M. TAHERIANFARD and A. A. TACI
А
B
1
1
2
2
3
3
Sham BPA (5 mg/kg·day) BPA (50 mg/kg·day)
F i g. 3. Photomicrographs of immunostaining of GABAAα1 receptors in the prefrontal cortex of rats of the experimental groups without
learning (A) and with learning (B). 1) Sham groups; 2) BPA, 5 mg/kg∙day, and 3) BPA, 50 mg/kg∙day. ×400.
Р и с. 3. Мікрофотографії імунозабарвлення ГАМКAα1-рецепторів у префронтальній корі щурів різних експериментальних груп,
підданих навчанню (А) та без навчання (В).
1
0
20
40
60
80
100
120
140
2 3 4 5 6
F i g. 4. Effects of BPA and avoidance learning on the GABAAα1
receptor distribution in the CA1 region of the hippocampus.
Designations are the same as in Fig. 2.
Р и с. 4. Впливи бісфенолу А (BPA) та навчання реакції уникання
на розподіл ГАМКAα1-рецепторів у полі CA1 гіпокампа.
cortex and hippocampus of male rats, while learning
passive avoidance leads to up-regulation of these re-
ceptors in the above-mentioned brain structures. A
combination of BPA treatment and avoidance learning
leads to down-regulation of GABAAα1 receptors in the
prefrontal cortex and CA1 region of hippocampus, but
the effect is more moderate than that in animals with-
out learning.
DISCUSSION
Previous studies were focused on the estrogenic
action of BPA; so, the main effect of BPA was
considered related to its action on reproductive tissues
[13]. Nonetheless, in addition to the effects on the
above tissues, BPA is likely to significantly alter
morphological and functional properties of neuronal
cells in the CNS. In particular, BPA was shown to
inhibit estradiol-induced hippocampal synaptogenesis
[14].
In our study, BPA decreased the number of
immunoreactive GABAAα1 receptors in the prefrontal
cortex and CA1 hippocampus region in the rat brain.
0.01, P < 0.01, and P < 0.05, respectively). The pat-
tern of the corresponding differences for the hippo-
campus was rather similar, but in this case the differ-
ences for groups 5 vs. 2 and 6 vs. 3 did not reach the
significance level.
Therefore, the treatment with BPA induces down-
regulation of GABAAα1 receptors in the prefrontal
** **
***
##
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2015.—T. 47, № 1 35
EFFECTS OF BISPHENOL A AND LEARNING ON THE DISTRIBUTION OF GABAAα1 RECEPTORS
Aoshima et al. [15] reported that BPA exerted complex
effects on GABAA receptor-mediated responses. This
agent in low amounts potentiated the responses in
the presence of GABA low concentrations, while
high concentrations of BPA inhibited such reactions.
Neurosteroids can affect gene expression of GABAA
receptor subunits, modifying, in such a way, GABAA
receptor distribution [16]. Progesterone and 3α-OH-5α
pregnan-20-one decreased the α1 subunit mRNA levels
in the CA2, CA3 subfields, and dentate gyrus of the
hippocampus in animals pretreated with estradiol [16].
Akk et al. [17] reported that agonistic effects of
neurosteroids on GABAA receptors depend on an open
vs. closed state of GABAA receptors. Neurosteroids, in
particular (3α, 5α, 17β)- 3-OH-18-norendrostane, in-
creased the GABAA receptor number in the case of the
open state of these receptors but decreased this value
in the closed state of such receptors. According to our
results, it seems that BPA manifests antagonistic ef-
fects with respect to neurosteroids, since exposure to
this agent decreases the GABAA receptor density in
the rat prefrontal cortex and CA1 hippocampal region.
BPA having two hydroxyl residues provides only non-
competitive inhibition of GABAA receptors composed
of α1 and β1 subunits [15]. As was mentioned above,
exposure to BPA decreases the number of GABAAα1 re-
ceptors in the cerebral structures examined.
As our experiments demonstrated, BPA in both
doses significantly decreased the density of these
receptors, but the respective decreases were noticeably
lower in the groups trained for the avoidance reaction.
The corresponding effects of BPA treatment combined
with learning are rather similar in the prefrontal cortex
and hippocampus but, at the same time, such effects
demonstrate some specificity.
Several studies in humans and rodents demonstrated
tha t the pref ronta l and c ingula te cor t ices ,
hippocampus, striatum, amygdalar complex, and
thalamus are involved in the formation of depression-
like behaviors [18-20]. Shifts in the GABA system
in these brain structures are probably significantly
responsible for such behavioral modifications [19].
There are strains of mice that posses an amino acid
mutation in specific transmembrane regions of GABAA
receptors having α1 subunits [21, 22]. Berry et al. [23]
demonstrated that mice with the GABAA receptor α1
subunit mutation swim less intensely in both spatial
and nonspatial Morris water maze tests, compared
to the control. Overall, it appears that α1 subunits
of GABAA receptors may play a crucial role in the
performance of the above types of tests in mice. Stagg
et al. [24] found that the responsiveness of the GABA
system to modulation strongly correlates with motor
learning, and this is suggestive for a possible relevance
F i g. 5. Photomicrographs of immunostaining of GABAAα1 receptors in the CA1 hippocampal region of rats of different experimental
groups. Designations are similar to those in Fig. 3.
Р и с. 5. Мікрофотографії імунозабарвлення ГАМКAα1-рецепторів у полі CA1 гіпокампа щурів різних експериментальних груп.
А
B
1
1
2
2
3
3
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2015.—T. 47, № 136
M. TAHERIANFARD and A. A. TACI
of GABA to LTP-like synaptic plasticity in motor
learning of humans. Zheng et al. [25] demonstrated
that both protein and mRNA of the GABAA receptor
α1 subunit in the hippocampus and prefrontal
cortex were affected by acute restraint stress. These
authors suggested that GABAA receptors could play
a considerable role in the regulation of learning and
memory. Lech et al. [26] showed that the GABAA
receptor α1 subunit is upregulated in the locus of
cortical layer IV underwent to learning-induced plastic
changes. This subunit of GABAA receptors reacts
with a delay to the process occurring in the cortex
during plasticity modifications induced by associative
learning, since the changes in mRNA expression do
not appear during or immediately after the training
period. Several studies showed that treatment with
BPA impaired learning and memory in different tests.
According to the results of our study, it seems that
learning and memory impairment induced by exposure
to BPA may be induced by changes in the GABAAα1
receptor expression and distribution in crucial brain
areas (such as the CA1 region of the hippocampus and
prefrontal cortex).
Acknowledgments. This study was financially supported by
the Iran National Science Foundation (INSF).
The authors are thankful to Dr. S. Dehghani Najvani,
Professor of the Shiraz University, for valuable assistance in
the preparation of the manuscript.
The study was carried out in accordance with the statements
of the Council Directive regarding the protection of animals
used for experimental and other scientific purposes (86/609/
EEC, 1986, Strasbourg) and respective regulations of the Ethics
Committee of the Shiraz University.
The authors, M. Taherianfard and A. A. Taci, confirm that
the research and publication of the results were not associated
with any conflicts regarding commercial or financial relations,
relations with organizations and/or individuals who may have
been related to the study, and interrelations of co-authors of
the article.
М. Тахеріанфард1, А. А. Тасі1
ВПЛИВИ БІСФЕНОЛУ А ТА НАВЧАННЯ УНИКАННЮ
НА РОЗПОДІЛ ГАМКAα1-РЕЦЕПТОРІВ У ГІПОКАМПІ ТА
ПРЕФРОНТАЛЬНІЙ КОРІ ЩУРІВ
1 Коледж ветеринарної медицини Шіразького університету
(Іран).
Р е з ю м е
Бісфенол А (BPA) – це широко розповсюджений хімікат, що
має змішані властивості агоніста/антагоніста естрогенів.
Ми досліджували впливи введення BPA та навчання реакції
пасивного уникання на розподіл ГАМКAα1-рецепторів у пре-
фронтальній корі та гіпокампі щурів. BPA (5 або 50 мг/кг
на добу) вводився перорально протягом 15 діб. Результати
навчання та формування пам’яті тестували в човниковій ка-
мері. Розподіл ГАМКAα1-рецепторів досліджували з викорис-
танням імуногістохімічної методики. Введення BPA істотно
зменшувало кількість ГАМКAα1-рецепторів у префронталь-
ній корі та полі CA1 гіпокампа. Розподіл цих рецепторів був
значно щільнішим у щурів, котрим уводили BPA та підда-
вали навчанню, ніж у тварин, яким навчання не проводили.
Таким чином, уведення BPA призводить до негативної ре-
гуляції системи ГАМКAα1-рецепторів у префронтальній корі
та гіпокампі, тоді як навчання пасивній реакції уникання
забезпечує позитивну регуляцію даної системи в згаданих
мозкових структурах.
REFERENCES
1. K. Miyagawa, M. Narita, H. Akama, and T. Suzuki, “Memory
impairment associated with a dysfunction of the hippocampal
cholinergic system induced by prenatal and neonatal
exposures to bisphenol-A,” Neurosci. Lett., 418, No. 3, 236-
241 (2007). doi:S0304-3940(07)00125-5 [pii] 10.1016/j.
neulet.2007.01.088.
2. W. V. Welshons, S. C. Nagel, and F. S. V. Saal, “Large effects
from small exposures. III. Endocrine mechanisms mediating
Effects of bisphenol a at levels of human exposure,” Suppl.:
Endocrinol. Endocrine Disrupt. Chem., 147, No. 6, s56-s69
(2006). doi:DOI: 10.1210/en.2005-1159.
3. L. Corrieri, D. D. Seta, C. Virginie, and L. Fusani,
“Developmental exposure to xenoestrogen enhances spatial
learning in male rats,” Horm. Behav., 51, 620-625 (2007).
doi:10.1016/j.yhbeh.2007.03.002.
4. P. J. Whiting, “GABAA receptor subtype in the brain: a
paradigm for CNS drug discovery?” Drug. Discov., 8, 445-450
(2003).
5. B. J. McCabe, G. Horn, and K. M. Kendrick, “GABA, Taurine
and learning: release of amino acids from slices of chick brain
following filial imprinting,” Neuroscience, 105, No. 2, 317-
324 (2001). doi:S0306-4522 (01) 00186-5.
6. H. A. Wieland, H. Lüddens, and P. H. Seeburg, “A single
histidine in GABAA receptors is essential for benzodiazepine
agonist binding,” J. Biol. Chem., 267, 1426-1429 (1992).
7. G. A. Prenosil, M. S. Gasser, U. Rudolph, et al., “Specific
subtypes of GABAA receptors mediate phasic and tonic
forms of inhibition in hippocampal pyramidal neurons,”
J. Neurophysiol., 96, 846-857 (2006).doi:DOI:10.1152/
jn.01199.2006.
8. M. M. Savic, D. I. Obradovic, N. D. Ugresie, et al.,
“Bidirectional effects of benzodiazepine binding site ligands
on passive avoidance task: differential antagonism by
flumazenil and beta-CGt,” Behav. Brain Res., 158, 293-300
(2005).
9. D. L. Krebs-Kraft, M. G. Wheeler, and M. B. Parent, “The
memory-impairing effects of septal GABA receptor activation
involve GABAergic septo-hippocampal projection neurons,”
Learning Memory, 14, 833-841 (2007).doi:10.1101/lm.809407.
10. R. A. Rissman, R. Nocera, L. M. Fuller, et al., “Age-related
NEUROPHYSIOLOGY / НЕЙРОФИЗИОЛОГИЯ.—2015.—T. 47, № 1 37
EFFECTS OF BISPHENOL A AND LEARNING ON THE DISTRIBUTION OF GABAAα1 RECEPTORS
alterations in GABAA receptor subunits in the nonhuman
primate hippocampus,” Brain Res., 1073/1074, 120-130
(2006). doi:DOI: 10.1016/ J.brainres.2005.12.036.
11. I. S. Choi, J. H. Cho, E. J. Park, et al., “Multiple effects of
bisphenol A, an endocrine disrupter, on GABA(A) receptors
in acutely dissociated rat CA3 pyramidal neurons,” Neurosci.
Res., 59, No. 1, 8-17 (2007). doi:S0168-0102(07)00179-4 [pii]
10.1016/j.neures.2007.05.003.
12. C. R. Goncalves, R. W. Cunha, and D. M. Barros, “Effect of
prenatal and postnatal exposure to a low dose of bisphenol A on
behavior and memory in rats,” Environ. Toxicol. Pharmacol.,
30, 195-201 (2010). doi:DOI:10.1016/j.etap.2010.06.003.
13. C. Gupta, “Reproductive malformation of the male offspring
following maternal exposure to estrogenic chemicals,”
Proc. Natl. Acad. Sci. USA , 92 , 7749-7753 (2000).
doi:PMID:10806411.
14. N. J. MacLusky, T. Hajszan, and C. Leranth, “The
environmental estrogen bisphenol A inhibits estradiol-
induced hippocampal synaptogenesis,” Environ. Health
Perspect., 113, 675-679 (2005). doi:10.1289/ehp.7633.
15. H. Aoshima, S. J. Hossain, H. Imamura, and R. Shingai,
“Effects of bisphenol A and its derivatives on the response of
GABA(A) receptors expressed in Xenopus oocytes,” Biosci.
Biotechnol. Biochem., 65, No. 9, 2070-2077 (2001).
16. M. Orchinik, N. G. Weiland, and B. S. McEwen, “Chronic
exposure to stress levels of corticosterone alters GABAA
receptor subunit mRNA levels in rat hippocampus,” Mol. Brain
Res., 34, No. 1, 29-37 (1995).
17. G. Akk, J. R. Bracamontes, “Neuroactive steroids have
multiple actions to potentiate GABAA receptors,” J. Physiol.,
558, 59-74 (2004). doi:10.1113/jphysiol.2004.066571.
18. K. McFarlane and P. W. Kalivas, “The circuity mediating
cocaine-induced reinstatement of drug-seeking behavior,” J.
Neurosci., 21, 8655-8663 (2001).
19. P. Brambilla, J. Perez, F. Barale, et al., “GABAergic
dysfunction in mood disorders,” Mol. Psychiat., 8, No. 715,
721-737 (2003).
20. A. M. Farrar, L. Font, M. Pereira, et al., “Forebrain circuity
involved in effort-related choice: injections of the GABAA
agonist muscimol into ventral pallidum after response
allocation in food-seeking behavior,” Neuroscience, 152, 321-
330 (2008).
21. C. M. Borghese, D. F. Werner, N. Topf, et al., “An isoflurane-
and alcohol-insensit ive mutant GABAA receptor α1
subun i t w i th nea r-no rma l appa ren t a ff in i ty fo r
GABA: Characterization in heterologous systems and
product ion of knockin mice,” J. Pharmacol . Exp.
Therapeutic, 319, No. 1, 208-218 (2006). doi:10.1124/
jpet.106.104406.
22. J. M. Sonner, D. F. Werner, F. P. Elsen, et al., “Effect
of Isoflurane and other potent inhaled anesthetics on
minimum alveolar concentrat ion, learning, and the
righting reflex in mice engineered to express α1 γ-amino-
butyric acid type A receptors unresponsive to isoflurane,”
Anesthesiology, 106, No. 1, 107-113 (2007).
23. R. B. Berry, D. F. Werner, X. F. Wang, et al., “Mice with
targeted genetic reduction of GABAA receptor a1 subunits
display performance differences in Morris water maze
tasks,” Neurobiol. Learn Mem. , 90 , 580-583 (2008).
doi:10.1016/j.nlm.2008.06.004.
24. C. J. Stagg, V. Bachtiar, and H. Johansen-Berg, “The role of
GABA in human motor learning,” Curr. Biol., 21, 480-484
(2011). doi:DOI: 10.1016/j.cub.2011.01.069.
25. G. Zheng, X. Zhang, Y. Chen, et al., “Evidence for a role
of GABAA receptor in the acute resraint stress-induced
enhancement of spatial memory,” Brain Res., 1181, 61-73
(2007). doi:DOI: 10.1016/j.brainres.2007.08.077.
26. M. Lech, A. Skibinska, and M. Kossut, “Delayed upregulation
of GABAA alpha1 receptor subunit mRNA in somato-
sensory cortex of mice following learning-dependent
plasticity of cortical representations,” Mol. Brain Res., 96,
82-86 (2001). doi:10.1016/S0169-328X(01)00271-6.
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