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Production of BDNF by Stimulation with Antidepressant-related Substances


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It is well known that downregulation of BDNF is involved in the pathophysiology of brain diseases including mental disorders such as depression. BDNF has many roles in brain neuronal function and its expression is influenced by neuronal activity stimulated by serotonin, noradrenaline, dopamine, and glutamatergic systems. It is possible that upregulation of BDNF via neuronal stimulation is critical for protection against functional damage to the brain which contributes to the pathophysiology of brain diseases. Interestingly, many chemicals, including agonists or antagonists for specific neurotransmitter receptors, increase BDNF levels in specific brain regions, resulting in a protective effect against neuronal damage. In the present review, we provide a broad overview of the recent issues concerning the relationship between BDNF production and chemicals including antidepressants.
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Production of BDNF by Stimulation with Antidepressant-related Substances
Tadahiro Numakawa
, Shuichi Chiba
, Misty Richards
, Chisato Wakabayashi
, Naoki Adachi
, Hiroshi
Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo,
187-8502, Japan
Core Research for Evolutional Science and Technology Program (CREST), Japan Science and Technology Agency (JST), Saitama, 332-0012,
Albany Medical College, Albany, NY 12208, USA
It is well known that downregulation of BDNF is involved in the pathophysiology of brain diseases including mental
disorders such as depression. BDNF has many roles in brain neuronal function and its expression is influenced by
neuronal activity stimulated by serotonin, noradrenaline, dopamine, and glutamatergic systems. It is possible that
upregulation of BDNF via neuronal stimulation is critical for protection against functional damage to the brain which
contributes to the pathophysiology of brain diseases. Interestingly, many chemicals, including agonists or antagonists
for specific neurotransmitter receptors, increase BDNF levels in specific brain regions, resulting in a protective eect
against neuronal damage. In the present review, we provide a broad overview of the recent issues concerning the
relationship between BDNF production and chemicals including antidepressants.
Keywords: BDNF, glutamate, dopamine, depression, antidepressant
Journal of Biological Medicine 2011:1(3) 1-10
©2011 BioMed Best Ltd. All rights reserved.
Since the discovery of antidepressive property of
isoniazid and iproniazid in addition to anti-tuberculosis
property in the early 1950s[1], the ecacy of innu-
merable substances and chemicals have been investi-
gated. This lead to the development of safer and more
powerful antidepressants, such as selective-serotonin
reuptake inhibitors (SSRI) and serotonin-noradrenalin
reuptake inhibitors (SNRI). While SSRIs and SNRIs
have significantly improved treatment options for some
patients, a substantial proportion of individuals do
Corresponding author
Email address: (Tadahiro Numakawa)
Department of Mental Disorder Research, National Institute of
Neuroscience, National Center of Neurology and Psychiatry, 4-1-1,
Ogawa-Higashi, Kodaira, Tokyo, 187-8502, Japan
Tel: +81-42-341-2711 ext. (5132), Fax: +81-42-346-1744
not experience improvement by the current first-line
therapies[2]. Taken together, additional research to
discover more ecacious drug candidates that utilize
novel brain mechanisms should be continued.
Researchers have found that most antidepressive
eects are achieved via stimulation of neurotrophic
factors[3]. This has been clearly demonstrated in
the upregulation of brain-deprived neurotrophic fac-
tor (BDNF), one of the critical neurotrophin family
proteins. Alterations in the expression/function of
BDNF have been implicated in the pathophysiology of
depression[4, 5]. BDNF exerts beneficial eects on neu-
ronal survival and synaptic plasticity through activation
of various intracellular signalings, including extracellu-
lar signal-regulated kinase (ERK), phosphoinositide 3-
kinase (PI3K)-Akt and phospholipase Cγ (PLCγ) path-
ways after stimulation of TrkB (high anity receptor
for BDNF)[6, 7], making BDNF upregulation in antide-
Tadahiro Numakawa et al. / Journal of Biological Medicine 2011:1(3) 1–10
pressive therapies an interesting issue.
In this review, we discuss the relationship be-
tween BDNF and two therapeutic interventions in-
volving monoamine (5-hydroxytriptamine:5-HT., no-
radrenalin:NA., and dopamine:DA) and glutamatergic
receptors, respectively. Recent studies have unraveled
the receptor subtype specific regulation of BDNF, which
may be helpful to determine first-line treatments such
as reuptake inhibitors for monoamines. Second, we
discuss the recent development of glutamatergic re-
ceptor antagonists, focusing on N-methyl D-aspartate
(NMDA), that demonstrate a faster antidepressant eect
than current first-line therapeutics.
The BDNF gene has at least eight 5’ exons (exon I-
VIII) each with a specific promoter, and one 3’ exon
(exon IX) encoding the entire open reading frame for
the BDNF protein in both humans and rodents ([8
10] and see Figure 1). Transcription is initiated at
each 5’ noncoding exon site spliced to the common
3’ exon IX. Exons I, VII and VIII of the human
BDNF (hBDNF) gene contain an in-frame ATG codon
from which translation can be started, which results
in the distinct pre-proBDNF proteins with longer N-
termini[10]. All BDNF transcripts are processed at two
alternative polyadenylation sites, which give rise to two
distinct populations of mRNA with either short or long
3’ untranslated regions (3’ UTRs)[11]. Thus, BDNF has
multiple mRNA variants.
Recent reports demonstrate that several mRNAs are
transcribed from the opposite strand of hBDNF. This
gene, named OSBDNF or antiBDNF, consists of at least
10 exons (exon 1-10) and has no potential open reading
frame. Exon 5 of antiBDNF overlaps with exon IX
of the BDNF coding exon, suggesting its function as
a natural antisense to BDNF mRNA[10, 12].
Activity-dependent transcription has been confirmed
in as many as 300 genes, which encode proteins that
play a role in the experience-dependent changes of
the nervous system[13]. Interestingly, BDNF mRNA
also increases following seizure[14, 15]. Visual in-
put increases BDNF mRNA in the rat visual cortex
whereas dark-reared or monocular-deprived rats ex-
hibit significant BDNF downregulation[16, 17]. Hip-
pocampal BDNF mRNA was increased by glutamater-
gic stimulation via NMDA and non-NMDA recep-
tors and decreased by GABA (γ-aminobutyric acid)
stimulation[1822]. Intracellular Ca
elevation via
glutamate receptors or voltage-gated Ca
channels also
contribute to increases in BDNF mRNA[20]. Binding of
cAMP-responsive element binding protein (CREB) to a
-response element (CRE) induces activity-
dependent transcription from promoter IV[23, 24]. In-
terestingly, CRE mutation knock-in mice showed im-
pairment of the sensory experience-dependent induction
of BDNF expression[25]. In addition, other regulators
including upstream stimulatory factors (USFs), Ca
responsive transcription factor (CaRF) and MeCP2
(methyl-CpG-binding protein 2, as a negative regu-
lator) were reported[2628] in addition to BHLHB2
(basic helix-loop-helix B2) and NF-κB (nuclear factor-
κB)[29, 30]. BDNF promoter I is also regulated by
neuronal activity. Furthermore, CREB, USFs, MEF2D
(myocyte enhancer factor 2D), and NF-κB are involved
in promoter I regulation[3133].
Using bacterial artificial chromosome (BAC) trans-
genic mice, Timmusk and colleagues investigated reg-
ulation of the hBDNF gene[34, 35]. They found sev-
eral cis-elements and transcription factors regulating
activity-dependent transcription of hBDNF promoters.
Although CREB binding to CRE in hBDNF promoter
IV is critical, USF binding to the upstream stimulatory
factor binding element (UBE) also influences transcrip-
tion from hBDNF promoter IV. Furthermore, ARNT2
(aryl hydrocarbon receptor nuclear translocator 2, a ba-
sic helix-loop-helix (bHLH)-PAS transcription factor)
and NPAS4 (neuronal PAS domain protein 4) binding
to a PasRE (bHLH-PAS transcription factor response
element) in promoter IV were required for transcription
from exon IV[34, 35]. ARNT2 and NPAS4 are also
crucial for activity-dependent transcription from the
hBDNF promoter I[34, 35].
There are many reports concerning the relationship
between BDNF and 5-HT. The possible role of 5-HT
in the regulation of BDNF expression in vivo has been
examined for more than a decade. In 1995, Nibuya et
al.[36] reported an increase in BDNF mRNA levels in
rat hippocampus after chronic, but not acute, adminis-
tration with sertraline (SSRI). Many follow-up studies
corroborated this finding, demonstrating BDNF mRNA
and/or protein upregulation in the hippocampus and/or
frontal cortex after chronic administration with SSRIs.
At this point, the positive eect of sertraline[37, 38],
paroxetine[39], and fluoxetine[37, 38, 40] on BDNF
levels was confirmed. Interestingly, the bi-phasic dy-
namics of BDNF mRNA expression after SSRI expo-
sure were reported. Coppell et al.[38] demonstrated the
Tadahiro Numakawa et al. / Journal of Biological Medicine 2011:1(3) 1–10
Figure 1. Structure of human BDNF gene. Each segment of BDNF mRNA contains an alternative 5’ noncoding exon spliced to the common
exon IX that encodes the pre-proBDNF protein. ATG (*) indicates the possible start positions for translation and TAG is the stop codon. We
referred to the description by [810].
downregulation (at 4 hours) and corresponding upregu-
lation of BDNF (at 24 hours) after the last injection of
repeated 2-week fluoxetine administration in rats. This
bi-phasic regulation may be attributed to transcriptional
selection of exons of the BDNF gene[41].
Compared to studies investigating the eect of SSRI
administration on BDNF regulation, research on the
involvement of 5-HT receptors on the regulation of
BDNF expression remains scarce. One pioneering study
conducted by Vaidya et al.[42] investigated 5-HT recep-
tors and BDNF expression, finding an increase in BDNF
mRNA in rat parietal cortex after systemic adminis-
tration of 4-iodo-2,5-dimethoxyphenylisopropylamine
(an agonist for the 5-HT
receptor). However, it
was later found that 8-hydroxy-2-(di-n-propylamino)
tetralin (8-OH-DPAT, an agonist for 5-HT
significantly decreased BDNF mRNA in the dentate
gyrus of euthyroid rats following chronic treatment
with T3 (thyroid hormone;[43]). Chronic treatment
with S32006 (5-HT
receptor antagonist) increases
BDNF mRNA and consequently produces antidepres-
sant/anxiolytic properties[44]. Recently, it was dis-
covered that agomelatine, a melatonergic receptor ag-
onist and 5-HT
receptor antagonist, stimulates BDNF
mRNA expression in hippocampal tissue as well as
adult neurogenesis[45]. These studies suggest a regula-
tory role for 5-HT-stimulated BDNF production, though
further studies are required to elucidate therapeutic
mechanisms of SSRIs in the brain.
Properties of noradrenergic (NA) neurotransmission
in the regulation of BDNF expression have been discov-
ered using NA reuptake inhibitors such as desipramine.
In early studies, increases in rat hippocampal BDNF
mRNA were found after chronic (21-days) treatment
with desipramine[36]. The upregulation of BDNF by
desipramine was also demonstrated in wild-type mice,
but not in CREB deficient mice, suggesting involvement
of CREB signaling in BDNF production[46]. Dias
et al.[47] corroborated these findings, discovering ele-
vated mRNA transcripts containing exon IV (was exon
III) of the BDNF gene in rat cerebral cortex and amyg-
dala after administration of desipramine for 21 days.
Recent studies have found a neuroprotective role
for adrenergic receptor agonists/antagonists in addition
to discovering their influence on BDNF transcription.
NA itself has neuroprotective properties, protecting
against neurotoxicity stimulated by amyloid beta in
vitro[48]. NA action is mediated through canonical
and β
adrenergic receptor-dependent intracellular
signaling in addition to the induction of NGF and BDNF
upregulation in cultured NT2 cells[48]. Stimulation
of BDNF production by NA and β-agonists was also
found in cultured astrocytes[49]. Repeated treatment
with amibegron (SR58611A, a β
agonist) decreased
immobility in the forced swim test, which suggest an-
tidepressive property of amibegron, and this substance
increased BDNF and CREB protein expression in rat
hippocampal tissue[50]. In addition, chronic treatment
with the α
-adrenoceptor antagonist dexefaroxan poten-
tiates the survival of postmitotic cells, and enhances
neurogenesis in the dentate gyrus of adult rat hippocam-
pal tissue[51]. Interestingly, dexefaroxan increased
BDNF immunoreactivity in the hippocampal neuropile
layer and in granule cells of the dentate gyrus[51].
Although the α-antagonism or β-agonism seem to be
involved in BDNF production, the behavioral eects
elicited by acute administration may be mediated by
adierent pathway. Zhang et al.[52] demonstrated
that the immobility reducing eect of desipramine in
the forced swimming test (FST) was mediated via α
adrenoreceptors, but not via β receptors. This discrep-
ancy may be useful for future research, as it is possible
that the immobility reducing eects of substances may
not necessarily predict the therapeutic eect of antide-
pressants via BDNF production.
Tadahiro Numakawa et al. / Journal of Biological Medicine 2011:1(3) 1–10
The dopaminergic (DA) system aects emotional
circuits in the brain including mood and reward-
punishment related behaviors. Mood and motivation are
largely controlled by the mesocortical and mesolimbic
pathways, which connect the ventral tegmental area
(VTA) to the prefrontal cortex (PFC), and the VTA
to the ventral striatum (including nucleus accumbens),
amygdala and hippocampus, respectively[53]. DA re-
ceptors are divided into two families; D1-like (D1
and D5) and D2-like (D2, D3 and D4) receptors[54].
D1-like receptors are coupled to the Gαs, and their
activation results in stimulation of adenylyl cyclase-
mediated signaling, while D2-like receptors bind Gαi
which inhibits adenylyl cyclase[54].
The dopaminergic system is a critical regulator of
BDNF expression. For example, repeated (29-days) ad-
ministration with the typical antipsychotic haloperidol
(D2 receptor antagonist) decreases BDNF protein levels
in the cerebral cortex and hippocampus[55]. Dawson
et al.[56] exploited the immunohistochemical approach,
revealing that a 3-day administration of haloperidol
results in downregulation of BDNF immunoreactivity in
PFC, hippocampus, amygdala and VTA of rats. In con-
trast, the atypical antipsychotic quetiapine (a dopamine,
serotonin and adrenergic receptor antagonist) increases
BDNF mRNA levels in hippocampal tissue of MK-
801-treated rats, which is a well-established model of
schizophrenia[57]. Forty-five-days of treatment with
olanzapine (atypical antipsychotic) also counteracts the
BDNF reduction caused by haloperidol[58].
Regulation of BDNF via both D1- and D2-like re-
ceptor signalings is also shown. Apomorphine, a
D1/D2 receptor agonist, increases BDNF mRNA levels
while protecting cultured mesencephalic DA neurons
against various stressors[59]. SKF38393, a D1 agonist,
upregulates BDNF mRNA levels in striatal neuronal
cultures[60]. Williams and Undieh[61] also showed that
24-h incubation with DA or SKF38393 enhances BDNF
protein expression in cortical, striatal, and hippocam-
pal acute slices. Importantly, a three day-treatment
with pramipexole or ropinirole (D3-preferential ago-
nists) protected primary mesencephalic cells from in-
jury secondary to 1-methyl-4-phenylpyridinium admin-
istration, and enhanced release of both BDNF and glial
cell line-derived neurotrophic factor (GDNF) into the
media[62]. Furthermore, pramipexole-treated medium
of astroglial cultures protected SH-SY5Y cells from cell
death caused by lactacystin, a proteasome inhibitor[63].
Cabergoline (a D2 receptor agonist) also elevated con-
centrations of NGF, BDNF and GDNF in culture
Figure 2. Expression of BDNF was increased by chronic treatment
with cabergoline. Chronic treatment with cabergoline (0.5 μmol/kg
B.W., s.c., s.i.d. to rats) was applied to investigate the possible change
in expression of BDNF, p75 (low anity receptor for BDNF), and
TrkB. Hippocampal BDNF was upregulated by cabergoline, while
receptors (p75 and TrkB) were not changed. β-actin is a control.
(Please see [65] for detail).
medium from astrocytes[64]. Interestingly, we recently
found hippocampal BDNF upregulation following treat-
ment with cabergoline in rats[65]. In our system, it
was revealed that repeated administration of cabergo-
line for 14 days reduced both the immobility in the
FST as well as the latency of feeding behavior in the
novelty-suppressed feeding test, suggesting that the D2
receptor agonist has an antidepressant eect. Following
cabergoline treatment of rat hippocampal tissue, we
observed marked upregulation of BDNF and increased
activation of ERK1, one of the downstream molecules
of BDNF/TrkB signaling, with no change in BDNF
receptor levels (TrkB and p75) ([65] and see Figure 2).
DA receptor agonists have been proposed as an inter-
vention for treatment-refractory depression, and some
studies report its ecacy[6669]. Understanding the
mechanism behind the antidepressive properties of the
dopaminergic system may help to unravel the puzzling
pathology of depression.
BDNF and glutamate, an excitatory neurotransmitter,
work together in the central nervous system to aect
neuronal function. Many studies have found that BDNF
plays a critical role in glutamatergic neurotransmis-
Tadahiro Numakawa et al. / Journal of Biological Medicine 2011:1(3) 1–10
sion and synaptic plasticity[70]. For example, regu-
lation of NMDA and α-amino-3-hydroxy-5-methyl-4-
isoxazole propionic acid (AMPA) receptor subunits is
one important function of BDNF[71, 72]. Recently, we
have demonstrated BDNF-dependent upregulation of
synaptic proteins, including NR2A, possibly caused by
activation of ERK signaling[73]. It is well known that
BDNF enhances glutamatergic neurotransmission[74,
75]. Previously, we also reported that BDNF induces
release of glutamate in cultured neurons[76, 77]. In our
system, we demonstrated that PLCγ pathway activation,
an essential signaling pathway for BDNF-induced glu-
tamate release, is downregulated after chronic exposure
to glucocorticoids, which are stress hormones involved
in major depressive disorder[4, 78]. In turn, glutamate
stimulation upregulates BDNF expression. Simmons et
al.[79] reported that ampakine, a modulator of AMPA
glutamate receptors, has a positive impact on BDNF
expression in the mouse model of Huntington’s disease
(HD). In the HD mice (CAG140 mice, human exon
1 with about 140 repeats of the trinucleotide CAG
inserted into the huntingtin gene), the expression of
BDNF was lower relative to that of wild-type mice[79].
Importantly, ampakine application reversed the down-
regulation of BDNF and rescued synaptic plasticity and
memory in HD mice[79]. S18986, a modulator of
AMPA glutamate receptors, has a neuroprotective ef-
fect against excitotoxicity[80]. The neuroprotection by
S18986 in ibotenate-induced brain lesions of newborn
mice was blocked in the presence of inhibitors for ERK
and PI3K/Akt pathways, and in the presence of neu-
tralizing anti-BDNF antibody. Furthermore, neocortical
BDNF mRNA was increased by S18986 application,
suggesting a neuroprotective role for S18986-induced
BDNF synthesis[80].
Historically, much attention has been given to the
therapeutic potential of the glutamatergic system in
the regulation of depressive disorder[81]. Specifically,
preclinical studies have found antidepressant-like ef-
fects of NMDA receptor antagonists[8285]. Com-
petitive (2-amino-7-phosphonoheptanoic acid) and non-
competitive (dizocilpine [MK-801]) NMDA antago-
nists elicit antidepressant-like eects in the inescapable
stressed animal[82]. Clinical studies also indicate
potential for the antidepressant-like eect of NMDA
glutamate receptor blockers, including ketamine[81].
Placebo-controlled, double-blinded trials found a sig-
nificant improvement in depressive symptoms 72 hours
after ketamine infusion[86]. Zarate et al. (2006) also
showed the rapid (within 110 min) positive influence
of ketamine in treatment-resistant major depressive dis-
order patients[87]. Importantly, Autry et al. reported
that blockade of NMDA glutamate receptors produce a
behavioral antidepressant response[88]. In their mouse
model, ketamine induced rapid antidepressant-like ef-
fects via increasing BDNF proteins. They demonstrated
that ketamine-dependent blockade of NMDA receptors
reduced phosphorylation of eukaryotic elongation fac-
tor 2, inhibiting suppression of BDNF translation[88].
In humans, chronic ketamine administration was found
to increase serum levels of BDNF, though NGF was
not changed by ketamine use[89]. Furthermore, it
has been reported that oroxylin A (5,7-dihydroxy-6-
methoxyfavone, a flavonoid compound) has antagonis-
tic eects on GABA
receptors. Phosphorylation of
ERK1/2 and CREB as well as production of oroxylinA-
stimulated BDNF was inhibited by NMDA receptor in-
hibitors, suggesting that activation of NMDA receptors
through blocking GABA
receptors is involved in the
mechanism of oroxylin A action[90]. We recently re-
ported that L-theanine, an amino acid uniquely found in
green tea, exerts antipsychotic-like and antidepressant-
like eects in mice[91]. Single pre-administration of
L-theanine reverses MK-801-induced deficits in the pre-
pulse inhibition test, which is established as a model for
schizophrenia. Furthermore, subchronic L-theanine ad-
ministration for 3-weeks reduced immobility time in the
FST, suggesting that L-theanine has an antidepressant-
like eect. Interestingly, western blotting revealed an
increased expression of BDNF protein in the hippocam-
pus after chronic L-theanine treatment, implying that
the L-theanine action is induced via upregulation of
hippocampal BDNF ([91] and see Figure 3).
Several reports demonstrate that activation of neu-
rotrophin receptors are stimulated in the absence of the
neurotrophin ligand. Adenosine, which exerts its neu-
ronal eect via G protein-coupled receptors, induces ac-
tivation of TrkA (receptor for NGF) in PC12 cells and of
TrkB in hippocampal neurons[92]. Pituitary adenylate
cyclase-activating polypeptide (PACAP) also stimulates
Trks activation in basal forebrain neurons[93]. Inter-
estingly, Trks activation in response to PACAP is pre-
dominantly observed in intracellular locations associ-
ated with Golgi membranes. Recently, zinc-dependent
transactivation of TrkB has been reported[94, 95]. In
their system, zinc activates TrkB via increasing activ-
ity of Src family kinase and enhances the ecacy of
the hippocampal mossy fiber-CA3 synapse through the
TrkB-dependent mechanism.
Tadahiro Numakawa et al. / Journal of Biological Medicine 2011:1(3) 1–10
Figure 3. Administration of L-theanine induced upregulation of
hippocampal BDNF. Though TrkB and p75 were not altered by L-
theanine administration, BDNF levels increased significantly. Vehicle
or L-theanine (0.4 mg/kg) was subchronically administered (i.p.) to
5-week-old C57BL/6 male mice every other day for 3 weeks. The
hippocampus was removed 24 hours after the last administration.
(Please see [91] for details).
Glucocorticoid, an important stress hormone, has
both positive and negative eects on the nervous system
and is suggested to be involved in the pathophysiology
of mental disorders including depression[4, 96]. In-
terestingly, Jeanneteau et al. showed that acute DEX
(a synthetic glucocorticoid receptor (GR) selective ag-
onist) administration induces TrkB phosphorylation in
the dentate gyrus of hippocampal tissue, though such
DEX application did not change neurotrophin protein
levels[97]. Furthermore, using cultured hippocampal
and cortical neurons, DEX-dependent survival promo-
tion was confirmed[97]. On the other hand, we showed
a negative impact of DEX on neuronal function[78].
Pretreatment with DEX for 48 hours significantly in-
hibited BDNF-induced glutamate release in cultured
cortical neurons. In our system, it is possible that
the interaction of GR with TrkB plays a role in intra-
cellular signaling stimulated by BDNF for glutamate
It has been demonstrated that activation of TrkB is
induced by antidepressant drugs independently of TrkB-
specific ligands. Rantamaki et al. showed that in
vivo application of imipramine induces TrkB phospho-
rylation in conditional BDNF knock-out mice, suggest-
ing that the ligand BDNF is not required to elicit an
antidepressive eect[98]. Interestingly, they observed
that fluoxetine, a serotonin reuptake inhibitor, achieves
similar activation of TrkB in the brains of wild-type
and serotonin transporter knock-out mice, suggesting
that the monoamine transmitter is not involved in TrkB
activation by fluoxetine[98]. As mentioned above,
antidepressants are recognized as monoamine reuptake
inhibitors and increase BDNF levels after long-term
treatment. It is possible that several mechanisms con-
tribute to antidepressant-dependent Trk activation.
In this review, we summarized current issues on the
interaction between BDNF production and 5-HT, NA,
DA, and glutamate systems. Many studies indicate that
stimulation of 5-HT, NA, DA, and glutamate systems
leads to upregulation of BDNF levels. Because the
eciency of BDNF crossing the blood brain barrier is
very low, the number of studies investigating chemicals
that produce BDNF within the brain is increasing. As
shown above, it has been demonstrated that ketamine,
a NMDA glutamate receptor antagonist useful for in-
duction of schizophrenia-like behavior[99], rapidly in-
creases BDNF translation and has antidepressant-like
eects[88]. As alterations in BDNF function may be
involved in the pathogenesis of mental disorders such
as schizophrenia and depression[100], further clarifica-
tion on the detailed molecular mechanisms underlying
BDNF upregulation should be elucidated.
This research was supported by the Core Research for
Evolutional Science and Technology Program (CREST)
Japan Science and Technology Agency (JST) (T. N.
N. A. and H. K.), the Takeda Science Foundation
(T. N.), Health and Labor Sciences Research Grants
(Comprehensive Research on Disability, Health, and
Welfare) (H. K.), the Japan Health Sciences Foundation
(Research on Health Sciences focusing on Drug Inno-
vation) (H. K.), Intramural Research Grants (20-3, 21-
9) for Neurological and Psychiatric Disorders of NCNP
(H. K.), and Grants-in-Aid for Scientific Research (B)
(No. 20390318) (H. K.) and Young Scientists (A)
(No. 21680034) (T. N.) from the Ministry of Education,
Culture, Sports, Science, and Technology of Japan.
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... BDNF activates intracellular pathways, including phospholipase C-γ (PLCγ), extracellular signal-regulated kinase (ERK), and inositol triphosphate kinase/Akt, through its high-affinity receptor, TrkB (Huang and Reichardt, 2001;Kaplan and Miller, 1997). BDNF influences various cellular processes, including neuronal survival and synaptic plasticity, and downregulation of expression/function of this growth factor is suggested to be associated with the onset of depression (Huang and Reichardt, 2001;Nawa et al., 2000;Numakawa et al., 2011). Recently, we reported that BDNF regulates synaptic function in vitro (Kumamaru et al., 2011;Numakawa et al., 2009). ...
... In the cortical neurons in our previous study, BDNF-dependent glutamate release occurred through the PLC-γ/inositol 1,4,5-trisphosphate (IP 3 )/Ca 2+ pathway (Numakawa et al., 2002). It is well known that a change in glutamatergic system contributes to antidepressant response (reviewed in Numakawa et al., 2011). Thus, this function of BDNF, which deteriorated on CRS in the current study, might regulate the pathology of anxiety and depressive disorders. ...
... In addition, Dunham et al. [11] observed that BDNF mRNA and protein levels are suppressed in the postmortem brains of depressed patients. Also, Numakawa [12] have suggested that the downregulation of expression and function of BDNF is associated with the onset of depression. However, very little is known about the interrelationship of prefrontal BDNF levels and HPA axis activity during CRS. ...
... Brain-derived neurotrophic factor (BDNF) is widely expressed in the mammalian brain and is involved in a variety of brain functions (22). BDNF reportedly has effects similar to those of antidepressant drugs (23,24), and there is a close relationship between BDNF signaling and animal depressive behavior caused by a variety of stress conditions (25,26). Thus, it is easy to speculate that the down-regulation of BDNF is related to psychiatric disorders, such as depression. ...
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Contributions from estrogen receptor subtypes (ERα and ERβ) to postpartum anxiogenic and depressive responses remain unresolved in rats. Using the elevated-plus maze (EPM) and forced swim (FS) tests, we confirmed that primiparous rats exhibited anxiogenic and depressive responses 3 weeks postpartum, improved 5 weeks postpartum (EPM), and recovered at 5 (FS) or 10 weeks postpartum (EPM) compared with diestrus nulliparous females. Immunohistochemistry suggested that these behavioral changes were temporally associated with decreased ERα but not ERβ expression in the medial amygdala (MEA). Additionally, ERα expression in the medial preoptic area (MPOA) significantly increased 10 weeks postpartum. Brain-derived neurotrophic factor (BDNF) expression was significantly elevated in the MEA 3 weeks postpartum. BDNF receptor tropomyosin-related kinase (TrkB) expression was significantly elevated in the MEA at 3 and 10 weeks, but not at 5 weeks postpartum. The phosphorylation of extracellular signal-regulated kinase 2 (pERK2) in the MEA, MPOA and hippocampal CA1 region was significantly elevated 3 and 5 weeks postpartum. The effects of single daily subcutaneous injections of the ER|ga-selective agonist, propyl pyrazoletriol (PPT); ERβ-selective agonist, diarylpropionitrile (DPN); 17β-estradiol (E2); and vehicle for 6 days in primiparous rats were assessed. PPT and E2 significantly produced anxiolytic and antidepressant actions in the EPM and FS tests, but PPT to a lesser degree than E2 in the EPM test. DPN affected the EPM test, but was not significantly different from vehicle. BDNF expression was significantly increased 3 weeks postpartum by all treatments in the MPOA, but not the CA1 and MEA. E2 and PPT treatment significantly increased TrkB and pERK1/2 expression in the MEA and MPOA, and increased pERK1/2 expression in the CA1.The onset of anxiety- and depression-like behaviors in postpartum rats may be partly caused by a complex estrogen-mediated mechanism; nevertheless, changes in the ERα-related system, likely in the MEA, are predominantly involved.
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L-Theanine (N-ethyl-L: -glutamine) is an amino acid uniquely found in green tea and historically considered to be a relaxing agent. It is a glutamate derivative and has an affinity for glutamatergic receptors. However, its psychotropic effects remain unclear. To elucidate effects of L: -theanine on psychiatric disease-related behaviors in mice and its molecular basis focusing on brain-derived neurotrophic factor (BDNF) and N-methyl-D: -aspartate (NMDA) receptor. We examined the effects of L: -theanine on behaviors in mice by using the open-field test (OFT), forced swim test (FST), elevated plus-maze test (EPMT), and prepulse inhibition (PPI) of acoustic startle. By western blot analysis, we looked at the effect of L: -theanine on the expression of BDNF and related proteins in the hippocampus and cerebral cortex. To determine whether L: -theanine has agonistic action on the NMDA receptor, we performed Fluo-3 intracellular Ca(2+) imaging in cultured cortical neurons. Single administration of L: -theanine significantly attenuated MK-801-induced deficits in PPI. Subchronic administration (3-week duration) of L: -theanine significantly reduced immobility time in the FST and improved baseline PPI. Western blotting analysis showed increased expression of BDNF protein in the hippocampus after subchronic administration of L: -theanine. In cultured cortical neurons, L: -theanine significantly increased the intracellular Ca(2+) concentration, and this increase was suppressed by competitive and non-competitive NMDA receptor antagonists (AP-5 and MK-801, respectively). Our results suggest that L: -theanine has antipsychotic-like and possibly antidepressant-like effects. It exerts these effects, at least in part, through induction of BDNF in the hippocampus and the agonistic action of L: -theanine on the NMDA receptor.
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Serotonin (5-HT)(2C) receptors are implicated in the control of mood, and their blockade is of potential interest for the management of anxiodepressive states. Herein, we characterized the in vitro and in vivo pharmacological profile of the novel benzourea derivative, S32006. Standard cellular, electrophysiological, neurochemical, and behavioral procedures were used. S32006 displayed high affinity for human (h)5-HT(2C) and h5-HT(2B) receptors (pK (i)s, 8.4 and 8.0, respectively). By contrast, it had negligible (100-fold lower) affinity for h5-HT(2A) receptors and all other sites examined. In measures of Gq-protein coupling/phospholipase C activation, S32006 displayed potent antagonist properties at h5-HT(2C) receptors (pK (B) values, 8.8/8.2) and h5-HT(2B) receptors (7.8/7.7). In vivo, S32006 dose-dependently (2.5-40.0 mg/kg, i.p. and p.o.) abolished the induction of penile erections and a discriminative stimulus by the 5-HT(2C) receptor agonist, Ro60,0175, in rats. It elevated dialysis levels of noradrenaline and dopamine in the frontal cortex of freely moving rats, and accelerated the firing rate of ventrotegmental dopaminergic and locus ceruleus adrenergic neurons. At similar doses, S32006 decreased immobility in a forced-swim test in rats, reduced the motor depression elicited by 5-HT(2C) and alpha(2)-adrenoceptor agonists, and inhibited both aggressive and marble-burying behavior in mice. Supporting antidepressant properties, chronic (2-5 weeks) administration of S32006 suppressed "anhedonia" in a chronic mild stress procedure and increased both expression of BDNF and cell proliferation in rat dentate gyrus. Finally, S32006 (0.63-40 mg/kg, i.p. and p.o) displayed anxiolytic properties in Vogel conflict and social interaction tests in rats. S32006 is a potent 5-HT(2C) receptor antagonist, and possesses antidepressant and anxiolytic properties in diverse rodent models.
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Clinical studies consistently demonstrate that a single sub-psychomimetic dose of ketamine, an ionotropic glutamatergic NMDAR (N-methyl-D-aspartate receptor) antagonist, produces fast-acting antidepressant responses in patients suffering from major depressive disorder, although the underlying mechanism is unclear. Depressed patients report the alleviation of major depressive disorder symptoms within two hours of a single, low-dose intravenous infusion of ketamine, with effects lasting up to two weeks, unlike traditional antidepressants (serotonin re-uptake inhibitors), which take weeks to reach efficacy. This delay is a major drawback to current therapies for major depressive disorder and faster-acting antidepressants are needed, particularly for suicide-risk patients. The ability of ketamine to produce rapidly acting, long-lasting antidepressant responses in depressed patients provides a unique opportunity to investigate underlying cellular mechanisms. Here we show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived neurotrophic factor. We find that the ketamine-mediated blockade of NMDAR at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase (also called CaMKIII), resulting in reduced eEF2 phosphorylation and de-suppression of translation of brain-derived neurotrophic factor. Furthermore, we find that inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects. Our findings indicate that the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast-acting antidepressants.
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Brain-derived neurotrophic factor (BDNF) is an important mediator of activity-dependent functions of the nervous system and its expression is dysregulated in several neuropsychiatric disorders. Regulation of rodent BDNF neuronal activity-dependent transcription has been relatively well characterized. Here, we have studied regulation of human BDNF (hBDNF) transcription by membrane depolarization of cultured mouse or rat primary cortical neurons expressing hBDNF gene or transfected with hBDNF promoter constructs, respectively. We identified an asymmetric E-box-like element, PasRE [basic helix-loop-helix (bHLH)-PAS transcription factor response element], in hBDNF promoter I and demonstrate that binding of this element by bHLH-PAS transcription factors ARNT2 (aryl hydrocarbon receptor nuclear translocator 2) and NPAS4 (neuronal PAS domain protein 4) is crucial for neuronal activity-dependent transcription from promoter I. We show that binding of CREB (cAMP response element-binding protein) to the cAMP/Ca(2+)-response element (CRE) in hBDNF promoter IV is critical for activity-dependent transcription from this promoter and that upstream stimulatory factor (USF) transcription factors also contribute to the activation by binding to the upstream stimulatory factor binding element (UBE) in hBDNF promoter IV. However, we report that full induction of hBDNF exon IV mRNA transcription is dependent on ARNT2 and NPAS4 binding to a PasRE in promoter IV. Finally, we demonstrate that CRE and PasRE elements in hBDNF promoter IX are required for the induction of this promoter by neuronal activity. Together, the results of this study have identified the cis-elements and transcription factors regulating neuronal activity-dependent transcription of human BDNF gene.
Kindling, induced by repeated subconvulsive electrical or chemical stimulations leads to progressive and permanent amplification of seizure activity, culminating in generalized seizures. We report that kindling induced by electrical stimulation in the ventral hippocampus leads to a marked and transient increase of mRNA for NGF and BDNF in the dentate gyrus, the parietal cortex, and the piriform cortex. BDNF mRNA increased also in the pyramidal layer of hippocampus and in the amygdaloid complex. No change was seen in the level of HDNF/NT-3 mRNA. The increased expression of NGF and BDNF mRNAs was not influenced by pretreatment with the NMDA receptor antagonist MK801, but was partially blocked by the quisqualate, AMPA receptor antagonist NBQX. The presumed subsequent increase of the trophic factors themselves may be important for kindling-associated plasticity in specific neuronal systems in the hippocampus, which could promote hyperexcitability and contribute to the development of epileptic syndromes.
Increased glucocorticoids (GCs) have been implicated in the pathophysiology of depressive disorder. We previously found that dexamethasone (DEX, a synthetic GC) repressed brain-derived neurotrophic factor (BDNF)-induced synaptic proteins via suppressing extracellular signal-regulated protein kinase (ERK) signaling. Here, we investigated the possible involvement of Src homology-2 domain-containing phosphatase2 (Shp2), an ERK signaling mediator. We found that DEX suppressed Shp2 interaction with TrkB, a receptor for BDNF, in cultured cortical neurons. NSC87877, a Shp2 inhibitor, mimicked DEX, and Shp2 overexpression reversed the effect of DEX, suggesting that GCs suppress ERK signaling through inhibiting the interaction of Shp2 with TrkB.
Ketamine is a non-competitive N-methyl-D: -aspartate (NMDA) receptor antagonist which interferes with the action of excitatory amino acids (EAAs) including glutamate and aspartate. The use of ketamine at subanaesthetic doses has increased because of its psychotomimetic properties. However, long-term ketamine abuse may interfere with memory processes and inhibit the induction of long-term potentiation (LTP) in the hippocampus, an effect probably mediated by its NMDA antagonist action. Neurotrophins such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) serve as survival factors for selected populations of central nervous system neurons, including cholinergic and dopaminergic neurons. In addition, neurotrophins, particularly BDNF, may regulate LTP in the hippocampus and influence synaptic plasticity. The purpose of this study was to test the hypothesis that ketamine use in humans is associated with altered serum levels of neurotrophins. We measured by enzyme-linked immunosorbent assay the NGF and BDNF serum levels in two groups of subjects: frequent ketamine users and healthy subjects. Our data show that BDNF serum levels were increased in chronic ketamine users as compared to healthy subjects, while NGF levels were not affected by ketamine use. These findings suggest that chronic ketamine intake is associated with increases in BDNF serum levels in humans. Other studies are needed to explore the pharmacological and molecular mechanism by which ketamine, and/or other NMDA antagonists, may induce modification in the production and utilization of BDNF and alter normal brain function.
Oroxylin A (5,7-dihydroxy-6-methoxyfavone) is a flavonoid compound originated from the root of Scutellaria baicalensis Georgi. Our previous reports suggested that oroxylin A improves memory function in rat, at least in part, by its antagonistic effects on GABA(A) receptor. In addition, oroxylin A protects neurons from ischemic damage by mechanisms currently not clear. In this study we determined whether oroxylin A modulates the level of brain derived neurotrophic factor (BDNF) in primary rat cortical neuronal culture, which is well known for its role on neuronal survival, neurogenesis, differentiation of neurons and synapses and learning and memory. Treatment of oroxylin A for 3-48h increased BDNF expression which was analyzed by ELISA assay and Western blot analysis. Oroxylin A induced slow but sustained increases in intracellular calcium level and activated ERK1/2 mitogen activated protein kinase (MAPK). In addition, oroxylin A phosphorylated cyclic AMP response element binding protein (CREB) at Ser 133 in concentration and time dependent manner. Pretreatment with the MAPK inhibitor PD98059 (10μM) attenuated phosphorylation of ERK1/2 and CREB as well as BDNF production, which suggests that oroxylin A regulates BDNF production by activating MAPK-CREB pathway. GABA(A) antagonist bicuculline mimicked the effects of oroxylin A on BDNF production as well as MAPK-CREB pathway. Increase in intracellular Ca(2+) concentration, phosphorylation of ERK1/2 and CREB, and BDNF expression by oroxylin A was blocked by NMDA receptor inhibitor MK-801 (10μM) as well as tetrodotoxin (TTX, 0.5 and 1μM). The results from the present study suggest that the calcium and p-CREB dependent induction of BDNF expression, possibly via activation of synaptic NMDA receptor through the blockade of GABA(A) activity in cortical neuronal circuitry, might be responsible for the neuroprotective or memory enhancing effects of oroxylin A.
Although the pathophysiology of depressive disorder remains elusive, two hypothetical frameworks seem to be promising: the involvement of hypothalamic pituitary-adrenal (HPA) axis abnormalities and brain-derived neurotrophic factor (BDNF) in the pathogenesis and in the mechanism of action of antidepressant treatments. In this review, we focused on research based on these two frameworks in relation to depression and related conditions and tried to formulate an integrated theory of the disorder. Hormonal challenge tests, such as the dexamethasone/corticotropin-releasing hormone test, have revealed elevated HPA activity (hypercortisolism) in at least a portion of patients with depression, although growing evidence has suggested that abnormally low HPA axis (hypocortisolism) has also been implicated in a variety of stress-related conditions. Several lines of evidence from postmortem studies, animal studies, blood levels, and genetic studies have suggested that BDNF is involved in the pathogenesis of depression and in the mechanism of action of biological treatments for depression. Considerable evidence has suggested that stress reduces the expression of BDNF and that antidepressant treatments increase it. Moreover, the glucocorticoid receptor interacts with the specific receptor of BDNF, TrkB, and excessive glucocorticoid interferes with BDNF signaling. Altered BDNF function is involved in the structural changes and possibly impaired neurogenesis in the brain of depressed patients. Based on these findings, an integrated schema of the pathological and recovery processes of depression is illustrated.
These experiments were made to study the mechanisms underlying the antidepressant-like effects of the beta(3) adrenoceptor agonist amibegron (SR58611A). To this purpose, the expression levels of the hippocampal cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), B-cell lymphoma-2 (Bcl-2) and Bax proteins were assessed, by using western blot analysis, in rats tested in the forced swim test (FST). Under basal conditions (no previous exposure to stressors), different groups of male Wistar rats received acutely or repeatedly (once/day for 7days) intraperitoneal (i.p.) injections of amibegron (1, 5 and 10mg/kg), the tricyclic antidepressant (TCA) clomipramine (50mg/kg), the selective serotonin reuptake inhibitor (SSRI) citalopram (15mg/kg) or their vehicles. The influence of stress-related conditions was studied in rats subjected to acute (4h) or repeated (4h/day for 7days) restraint stress, applied prior to the FST procedure. Compared to the control groups, both stressor procedures increased the immobility time in the FST and reduced hippocampal BDNF and Bcl-2/Bax ratio proteins expression, which were counteracted by amibegron (5 and 10mg/kg) treatment. Opposite effects were found in the CREB expression, since it was lower after acute and higher after repeated stress procedure, respectively. Again, these effects were reversed by amibegron treatment. Different results were obtained in animals treated with clomipramine or citalopram. Hence, it is likely that the observed behavioral effects of amibegron could be due, at least in part, to its action on hippocampal expression of neurotrophic and/or anti-apoptotic factors, supporting the hypothesis that beta(3) adrenoceptors may be a therapeutic target for the treatment of stress-related disorders.