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Review

Production of BDNF by Stimulation with Antidepressant-related Substances

Tadahiro Numakawaa,b,, Shuichi Chibaa , Misty Richardsc , Chisato Wakabayashia , Naoki Adachia,b , Hiroshi
Kunugia,b
a Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo,
187-8502, Japan
b Core Research for Evolutional Science and Technology Program (CREST), Japan Science and Technology Agency (JST), Saitama, 332-0012,

Japan
c Albany Medical College, Albany, NY 12208, USA

Abstract
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 inuenced 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 specic neurotransmitter receptors, increase BDNF levels in specic 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.

1. INTRODUCTION not experience improvement by the current rst-line

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 signicantly improved treatment options for some
patients, a substantial proportion of individuals do
Correspondingauthor
Email address: numakawa@ncnp.go.jp (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
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 benecial 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 C (PLC) 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) 110
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 specic regulation of BDNF, which
may be helpful to determine rst-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 rst-line therapeutics.
2. PROPERTIES OF BDNF TRANSCRIPTION
AND TRANSLATION
The BDNF gene has at least eight 5 exons (exon I-
VIII) each with a specic 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 conrmed
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 signicant 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 (-aminobutyric acid)
stimulation[1822]. Intracellular Ca2+ elevation via
glutamate receptors or voltage-gated Ca2+ channels also
2
contribute to increases in BDNF mRNA[20]. Binding of
cAMP-responsive element binding protein (CREB) to a
cAMP/Ca2+ -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), Ca2+ -
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-B (nuclear factor-
B)[29, 30]. BDNF promoter I is also regulated by
neuronal activity. Furthermore, CREB, USFs, MEF2D
(myocyte enhancer factor 2D), and NF-B are involved
in promoter I regulation[3133].
Using bacterial articial 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 inuences 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].
3. THE RELATIONSHIP BETWEEN BDNF EX-
PRESSION AND MONOAMINE 5-HT
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 nding, 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 uoxetine[37, 38, 40] on BDNF
levels was conrmed. 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) 110
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 uoxetine 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, nding an increase in BDNF
mRNA in rat parietal cortex after systemic adminis-
tration of 4-iodo-2,5-dimethoxyphenylisopropylamine
(an agonist for the 5-HT2A/2C receptor). However, it
was later found that 8-hydroxy-2-(di-n-propylamino)
tetralin (8-OH-DPAT, an agonist for 5-HT1A receptor)
signicantly decreased BDNF mRNA in the dentate
gyrus of euthyroid rats following chronic treatment
with T3 (thyroid hormone;[43]). Chronic treatment
with S32006 (5-HT2C 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-HT2C 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.
4. NORADRENERGIC SYSTEM
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 decient mice, suggesting involvement
3
of CREB signaling in BDNF production[46]. Dias
et al.[47] corroborated these ndings, 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 inuence on BDNF transcription.
NA itself has neuroprotective properties, protecting
against neurotoxicity stimulated by amyloid beta in
vitro[48]. NA action is mediated through canonical
1 and 2 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 -agonists was also
found in cultured astrocytes[49]. Repeated treatment
with amibegron (SR58611A, a 3 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 2 -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 -antagonism or -agonism seem to be
involved in BDNF production, the behavioral eects
elicited by acute administration may be mediated by
a dierent pathway. Zhang et al.[52] demonstrated
that the immobility reducing eect of desipramine in
the forced swimming test (FST) was mediated via 2
adrenoreceptors, but not via 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) 110

5. DOPAMINERGIC SYSTEM

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 Gs, and their
activation results in stimulation of adenylyl cyclase-
mediated signaling, while D2-like receptors bind Gi
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 Figure 2. Expression of BDNF was increased by chronic treatment
(D2 receptor antagonist) decreases BDNF protein levels with cabergoline. Chronic treatment with cabergoline (0.5 mol/kg
B.W., s.c., s.i.d. to rats) was applied to investigate the possible change
in the cerebral cortex and hippocampus[55]. Dawson in expression of BDNF, p75 (low anity receptor for BDNF), and
et al.[56] exploited the immunohistochemical approach, TrkB. Hippocampal BDNF was upregulated by cabergoline, while
revealing that a 3-day administration of haloperidol receptors (p75 and TrkB) were not changed. -actin is a control.
results in downregulation of BDNF immunoreactivity in (Please see [65] for detail).
PFC, hippocampus, amygdala and VTA of rats. In con-
trast, the atypical antipsychotic quetiapine (a dopamine,
medium from astrocytes[64]. Interestingly, we recently
serotonin and adrenergic receptor antagonist) increases
found hippocampal BDNF upregulation following treat-
BDNF mRNA levels in hippocampal tissue of MK-
ment with cabergoline in rats[65]. In our system, it
801-treated rats, which is a well-established model of
was revealed that repeated administration of cabergo-
schizophrenia[57]. Forty-ve-days of treatment with
line for 14 days reduced both the immobility in the
olanzapine (atypical antipsychotic) also counteracts the
FST as well as the latency of feeding behavior in the
BDNF reduction caused by haloperidol[58].
novelty-suppressed feeding test, suggesting that the D2
Regulation of BDNF via both D1- and D2-like re- receptor agonist has an antidepressant eect. Following
ceptor signalings is also shown. Apomorphine, a cabergoline treatment of rat hippocampal tissue, we
D1/D2 receptor agonist, increases BDNF mRNA levels observed marked upregulation of BDNF and increased
while protecting cultured mesencephalic DA neurons activation of ERK1, one of the downstream molecules
against various stressors[59]. SKF38393, a D1 agonist, of BDNF/TrkB signaling, with no change in BDNF
upregulates BDNF mRNA levels in striatal neuronal receptor levels (TrkB and p75) ([65] and see Figure 2).
cultures[60]. Williams and Undieh[61] also showed that DA receptor agonists have been proposed as an inter-
24-h incubation with DA or SKF38393 enhances BDNF vention for treatment-refractory depression, and some
protein expression in cortical, striatal, and hippocam- studies report its ecacy[6669]. Understanding the
pal acute slices. Importantly, a three day-treatment mechanism behind the antidepressive properties of the
with pramipexole or ropinirole (D3-preferential ago- dopaminergic system may help to unravel the puzzling
nists) protected primary mesencephalic cells from in- pathology of depression.
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 6. BDNF PRODUCTION AND GLUTAMATE
media[62]. Furthermore, pramipexole-treated medium
of astroglial cultures protected SH-SY5Y cells from cell BDNF and glutamate, an excitatory neurotransmitter,
death caused by lactacystin, a proteasome inhibitor[63]. work together in the central nervous system to aect
Cabergoline (a D2 receptor agonist) also elevated con- neuronal function. Many studies have found that BDNF
centrations of NGF, BDNF and GDNF in culture plays a critical role in glutamatergic neurotransmis-

4
 Tadahiro Numakawa et al. / Journal of Biological Medicine 2011:1(3) 110
sion and synaptic plasticity[70]. For example, regu-
lation of NMDA and -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 PLC 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 Huntingtons 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]. Specically,
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-
nicant improvement in depressive symptoms 72 hours
after ketamine infusion[86]. Zarate et al. (2006) also
showed the rapid (within 110 min) positive inuence
of ketamine in treatment-resistant major depressive dis-
order patients[87]. Importantly, Autry et al. reported
5
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 avonoid compound) has antagonis-
tic eects on GABAA 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 GABAA 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 decits 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).
7. LIGANDS-INDEPENDENT ACTIVATION OF
TRKS
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 ber-CA3 synapse through the
TrkB-dependent mechanism.
 Tadahiro Numakawa et al. / Journal of Biological Medicine 2011:1(3) 110
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 signicantly. 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 conrmed[97]. On the other hand, we showed
a negative impact of DEX on neuronal function[78].
Pretreatment with DEX for 48 hours signicantly 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
release[78].
It has been demonstrated that activation of TrkB is
induced by antidepressant drugs independently of TrkB-
specic 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 uoxetine, 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
6
activation by uoxetine[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.
8. CONCLUDING REMARKS
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 clarica-
tion on the detailed molecular mechanisms underlying
BDNF upregulation should be elucidated.
ACKNOWLEDGEMENTS
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 Scientic 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.
REFERENCES
[1] F. Lopez-Munoz & C. Alamo (2009), Monoaminergic neuro-
transmission: the history of the discovery of antidepressants
from 1950s until today. Curr Pharm Des, 15(14) 15631586
[2] M. B. Keller (2005), Issues in treatment-resistant depression. J
Clin Psychiatry, 66(Suppl 8) 512
[3] R. S. Duman & L. M. Monteggia (2006), A neurotrophic model
for stress-related mood disorders. Biol Psychiatry, 59(12)
11161127
 Tadahiro Numakawa et al. / Journal of Biological Medicine 2011:1(3) 110
[4] H. Kunugi, H. Hori, N. Adachi & T. Numakawa (2010), In-
terface between hypothalamic-pituitary-adrenal axis and brain-
derived neurotrophic factor in depression. Psychiatry Clin
Neurosci, 64(5) 447459
[5] E. Castren & T. Rantamaki (2010), The role of BDNF and
its receptors in depression and antidepressant drug action:
Reactivation of developmental plasticity. Dev Neurobiol, 70(5)
289297
[6] D. R. Kaplan & F. D. Miller (1997), Signal transduction by the
neurotrophin receptors. Curr Opin Cell Biol, 9(2) 213221
[7] E. J. Huang & L. F. Reichardt (2001), Neurotrophins: roles
in neuronal development and function. Annu Rev Neurosci, 24
677736
[8] Q.-R. Liu, L. Lu, X.-G. Zhu, J.-P. Gong, Y. Shaham & G. R.
Uhl (2006), Rodent BDNF genes, novel promoters, novel
splice variants, and regulation by cocaine. Brain Res, 1067(1)
112
[9] T. Aid, A. Kazantseva, M. Piirsoo, K. Palm & T. Timmusk
(2007), Mouse and rat BDNF gene structure and expression
revisited. J Neurosci Res, 85(3) 525535
[10] P. Pruunsild, A. Kazantseva, T. Aid, K. Palm & T. Timmusk
(2007), Dissecting the human BDNF locus: bidirectional
transcription, complex splicing, and multiple promoters. Ge-
nomics, 90(3) 397406
[11] J. J. An, K. Gharami, G.-Y. Liao, N. H. Woo, A. G. Lau,
F. Vanevski, E. R. Torre, K. R. Jones, Y. Feng, B. Lu & B. Xu
(2008), Distinct role of long 3 UTR BDNF mRNA in spine
morphology and synaptic plasticity in hippocampal neurons.
Cell, 134(1) 175187
[12] Q.-R. Liu, D. Walther, T. Drgon, O. Polesskaya, T. G. Lesnick,
K. J. Strain, M. de Andrade, J. H. Bower, D. M. Maraganore
& G. R. Uhl (2005), Human brain derived neurotrophic factor
(BDNF) genes, splicing patterns, and assessments of associa-
tions with substance abuse and Parkinsons Disease. Am J Med
Genet B Neuropsychiatr Genet, 134B(1) 93103
[13] Y. Lin, B. L. Bloodgood, J. L. Hauser, A. D. Lapan, A. C.
Koon, T.-K. Kim, L. S. Hu, A. N. Malik & M. E. Greenberg
(2008), Activity-dependent regulation of inhibitory synapse
development by Npas4. Nature, 455(7217) 11981204
[14] P. J. Isackson, M. M. Huntsman, K. D. Murray & C. M.
Gall (1991), BDNF mRNA expression is increased in adult rat
forebrain after limbic seizures: temporal patterns of induction
distinct from NGF. Neuron, 6(6) 937948
[15] P. Ernfors, J. Bengzon, Z. Kokaia, H. Persson & O. Lindvall
(1991), Increased levels of messenger RNAs for neurotrophic
factors in the brain during kindling epileptogenesis. Neuron,
7(1) 165176
[16] E. Castren, F. Zafra, H. Thoenen & D. Lindholm (1992),
Light regulates expression of brain-derived neurotrophic factor
mRNA in rat visual cortex. Proc Natl Acad Sci U S A, 89(20)
94449448
[17] Y. Bozzi, T. Pizzorusso, F. Cremisi, F. M. Rossi, G. Barsacchi
& L. Maei (1995), Monocular deprivation decreases the
expression of messenger RNA for brain-derived neurotrophic
factor in the rat visual cortex. Neuroscience, 69(4) 11331144
[18] F. Zafra, B. Hengerer, J. Leibrock, H. Thoenen & D. Lindholm
(1990), Activity dependent regulation of BDNF and NGF
mRNAs in the rat hippocampus is mediated by non-NMDA
glutamate receptors. EMBO J, 9(11) 35453550
[19] F. Zafra, E. Castren, H. Thoenen & D. Lindholm (1991),
Interplay between glutamate and gamma-aminobutyric acid
transmitter systems in the physiological regulation of brain-
derived neurotrophic factor and nerve growth factor synthesis
in hippocampal neurons. Proc Natl Acad Sci U S A, 88(22)
1003710041
7
[20] F. Zafra, D. Lindholm, E. Castren, J. Hartikka & H. Thoenen
(1992), Regulation of brain-derived neurotrophic factor and
nerve growth factor mRNA in primary cultures of hippocampal
neurons and astrocytes. J Neurosci, 12(12) 47934799
[21] D. Lindholm, E. Castren, M. Berzaghi, A. Blochl & H. Thoe-
nen (1994), Activity-dependent and hormonal regulation of
neurotrophin mRNA levels in the brainimplications for neu-
ronal plasticity. J Neurobiol, 25(11) 13621372
[22] B. Berninger, S. Marty, F. Zafra, M. da Penha Berzaghi,
H. Thoenen & D. Lindholm (1995), GABAergic stimulation
switches from enhancing to repressing BDNF expression in rat
hippocampal neurons during maturation in vitro. Development,
121(8) 23272335
[23] P. B. Shieh, S. C. Hu, K. Bobb, T. Timmusk & A. Ghosh
(1998), Identication of a signaling pathway involved in cal-
cium regulation of BDNF expression. Neuron, 20(4) 727740
[24] X. Tao, S. Finkbeiner, D. B. Arnold, A. J. Shaywitz & M. E.
Greenberg (1998), Ca2+ inux regulates BDNF transcription
by a CREB family transcription factor-dependent mechanism.
Neuron, 20(4) 709726
[25] E. J. Hong, A. E. McCord & M. E. Greenberg (2008), A bio-
logical function for the neuronal activity-dependent component
of Bdnf transcription in the development of cortical inhibition.
Neuron, 60(4) 610624
[26] X. Tao, A. E. West, W. G. Chen, G. Corfas & M. E. Greenberg
(2002), A calcium-responsive transcription factor, CaRF, that
regulates neuronal activity-dependent expression of BDNF.
Neuron, 33(3) 383395
[27] W. G. Chen, Q. Chang, Y. Lin, A. Meissner, A. E. West, E. C.
Grith, R. Jaenisch & M. E. Greenberg (2003), Derepression
of BDNF transcription involves calcium-dependent phospho-
rylation of MeCP2. Science, 302(5646) 885889
[28] W. G. Chen, A. E. West, X. Tao, G. Corfas, M. N. Szentirmay,
M. Sawadogo, C. Vinson & M. E. Greenberg (2003), Up-
stream stimulatory factors are mediators of Ca2+-responsive
transcription in neurons. J Neurosci, 23(7) 25722581
[29] X. Jiang, F. Tian, Y. Du, N. G. Copeland, N. A. Jenkins,
L. Tessarollo, X. Wu, H. Pan, X.-Z. Hu, K. Xu, H. Kenney,
S. E. Egan, H. Turley, A. L. Harris, A. M. Marini & R. H.
Lipsky (2008), BHLHB2 controls Bdnf promoter 4 activity and
neuronal excitability. J Neurosci, 28(5) 11181130
[30] M. Kairisalo, L. Korhonen, M. Sepp, P. Pruunsild, J. P. Kukko-
nen, J. Kivinen, T. Timmusk, K. Blomgren & D. Lindholm
(2009), NF-kappaB-dependent regulation of brain-derived
neurotrophic factor in hippocampal neurons by X-linked in-
hibitor of apoptosis protein. Eur J Neurosci, 30(6) 958966
[31] A. Tabuchi, H. Sakaya, T. Kisukeda, H. Fushiki & M. Tsuda
(2002), Involvement of an upstream stimulatory factor as well
as cAMP-responsive element-binding protein in the activation
of brain-derived neurotrophic factor gene promoter I. J Biol
Chem, 277(39) 3592035931
[32] F. D. Lubin, Y. Ren, X. Xu & A. E. Anderson (2007), Nuclear
factor-kappa B regulates seizure threshold and gene transcrip-
tion following convulsant stimulation. J Neurochem, 103(4)
13811395
[33] S. W. Flavell, T.-K. Kim, J. M. Gray, D. A. Harmin, M. Hem-
berg, E. J. Hong, E. Markensco-Papadimitriou, D. M. Bear
& M. E. Greenberg (2008), Genome-wide analysis of MEF2
transcriptional program reveals synaptic target genes and neu-
ronal activity-dependent polyadenylation site selection. Neu-
ron, 60(6) 10221038
[34] I. Koppel, T. Aid-Pavlidis, K. Jaanson, M. Sepp, P. Pruunsild,
K. Palm & T. Timmusk (2009), Tissue-specic and neural
activity-regulated expression of human BDNF gene in BAC
transgenic mice. BMC Neurosci, 10 68
 Tadahiro Numakawa et al. / Journal of Biological Medicine 2011:1(3) 110
[35] P. Pruunsild, M. Sepp, E. Orav, I. Koppel & T. Timmusk
(2011), Identication of cis-elements and transcription factors
regulating neuronal activity-dependent transcription of human
BDNF gene. J Neurosci, 31(9) 32953308
[36] M. Nibuya, S. Morinobu & R. S. Duman (1995), Regulation
of BDNF and trkB mRNA in rat brain by chronic electrocon-
vulsive seizure and antidepressant drug treatments. J Neurosci,
15(11) 75397547
[37] M. Nibuya, E. J. Nestler & R. S. Duman (1996), Chronic an-
tidepressant administration increases the expression of cAMP
response element binding protein (CREB) in rat hippocampus.
J Neurosci, 16(7) 23652372
[38] A. L. Coppell, Q. Pei & T. S. C. Zetterstrom (2003), Bi-phasic
change in BDNF gene expression following antidepressant
drug treatment. Neuropharmacology, 44(7) 903910
[39] R. Martnez-Turrillas, J. D. Ro & D. Frechilla (2005), Se-
quential changes in BDNF mRNA expression and synaptic
levels of AMPA receptor subunits in rat hippocampus after
chronic antidepressant treatment. Neuropharmacology, 49(8)
11781188
[40] D. T. Balu, B. A. Hoshaw, J. E. Malberg, S. Rosenzweig-
Lipson, L. E. Schechter & I. Lucki (2008), Dierential reg-
ulation of central BDNF protein levels by antidepressant and
non-antidepressant drug treatments. Brain Res, 1211 3743
[41] A. A. Khundakar & T. S. C. Zetterstrom (2006), Biphasic
change in BDNF gene expression following antidepressant
drug treatment explained by dierential transcript regulation.
Brain Res, 1106(1) 1220
[42] V. A. Vaidya, G. J. Marek, G. K. Aghajanian & R. S. Duman
(1997), 5-HT2A receptor-mediated regulation of brain-derived
neurotrophic factor mRNA in the hippocampus and the neocor-
tex. J Neurosci, 17(8) 27852795
[43] V. A. Vaidya, M. E. Castro, Q. Pei, M. E. Sprakes &
D. G. Grahame-Smith (2001), Inuence of thyroid hormone
on 5-HT(1A) and 5-HT(2A) receptor-mediated regulation of
hippocampal BDNF mRNA expression. Neuropharmacology,
40(1) 4856
[44] A. Dekeyne, C. M. la Cour, A. Gobert, M. Brocco, F. Lejeune,
F. Serres, T. Sharp, A. Daszuta, A. Soumier, M. Papp, J.-M.
Rivet, G. Flik, T. I. Cremers, O. Muller, G. Lavielle & M. J.
Millan (2008), S32006, a novel 5-HT2C receptor antagonist
displaying broad-based antidepressant and anxiolytic prop-
erties in rodent models. Psychopharmacology (Berl), 199(4)
549568
[45] A. Soumier, M. Banasr, S. Lortet, F. Masmejean, N. Bernard,
L. Kerkerian-Le-Go, C. Gabriel, M. J. Millan, E. Mocaer
& A. Daszuta (2009), Mechanisms contributing to the phase-
dependent regulation of neurogenesis by the novel antidepres-
sant, agomelatine, in the adult rat hippocampus. Neuropsy-
chopharmacology, 34(11) 23902403
[46] A. C. Conti, J. F. Cryan, A. Dalvi, I. Lucki & J. A. Blendy
(2002), cAMP response element-binding protein is essential
for the upregulation of brain-derived neurotrophic factor tran-
scription, but not the behavioral or endocrine responses to
antidepressant drugs. J Neurosci, 22(8) 32623268
[47] B. G. Dias, S. B. Banerjee, R. S. Duman & V. A. Vaidya
(2003), Dierential regulation of brain derived neurotrophic
factor transcripts by antidepressant treatments in the adult rat
brain. Neuropharmacology, 45(4) 553563
[48] S. E. Counts & E. J. Mufson (2010), Noradrenaline activation
of neurotrophic pathways protects against neuronal amyloid
toxicity. J Neurochem, 113(3) 649660
[49] D. M. Juric, D. Loncar & M. Carman-Krzan (2008), Noradren-
ergic stimulation of BDNF synthesis in astrocytes: mediation
via alpha1- and beta1/beta2-adrenergic receptors. Neurochem
8
Int, 52(1-2) 297306
[50] A. Tamburella, V. Micale, G. M. Leggio & F. Drago (2010),
The beta3 adrenoceptor agonist, amibegron (SR58611A) coun-
teracts stress-induced behavioral and neurochemical changes.
Eur Neuropsychopharmacol, 20(10) 704713
[51] P. Rizk, J. Salazar, R. Raisman-Vozari, M. Marien, M. Ruberg,
F. Colpaert & T. Debeir (2006), The alpha2-adrenoceptor
antagonist dexefaroxan enhances hippocampal neurogenesis
by increasing the survival and dierentiation of new granule
cells. Neuropsychopharmacology, 31(6) 11461157
[52] H.-T. Zhang, L. R. Whisler, Y. Huang, Y. Xiang & J. M.
ODonnell (2009), Postsynaptic alpha-2 adrenergic receptors
are critical for the antidepressant-like eects of desipramine
on behavior. Neuropsychopharmacology, 34(4) 10671077
[53] E. J. Nestler & W. A. Carlezon (2006), The mesolimbic
dopamine reward circuit in depression. Biol Psychiatry, 59(12)
11511159
[54] C. Missale, S. R. Nash, S. W. Robinson, M. Jaber & M. G.
Caron (1998), Dopamine receptors: from structure to function.
Physiol Rev, 78(1) 189225
[55] F. Angelucci, A. A. Mathe & L. Aloe (2000), Brain-derived
neurotrophic factor and tyrosine kinase receptor TrkB in rat
brain are signicantly altered after haloperidol and risperidone
administration. J Neurosci Res, 60(6) 783794
[56] N. M. Dawson, E. H. Hamid, M. F. Egan & G. E. Meredith
(2001), Changes in the pattern of brain-derived neurotrophic
factor immunoreactivity in the rat brain after acute and sub-
chronic haloperidol treatment. Synapse, 39(1) 7081
[57] F. Fumagalli, R. Molteni, F. Bedogni, M. Gennarelli, J. Perez,
G. Racagni & M. A. Riva (2004), Quetiapine regulates FGF-2
and BDNF expression in the hippocampus of animals treated
with MK-801. Neuroreport, 15(13) 21092112
[58] V. Parikh, M. M. Khan & S. P. Mahadik (2004), Olanzapine
counteracts reduction of brain-derived neurotrophic factor and
TrkB receptors in rat hippocampus produced by haloperidol.
Neurosci Lett, 356(2) 135139
[59] H. Guo, Z. Tang, Y. Yu, L. Xu, G. Jin & J. Zhou (2002),
Apomorphine induces trophic factors that support fetal rat mes-
encephalic dopaminergic neurons in cultures. Eur J Neurosci,
16(10) 18611870
[60] E. Kuppers & C. Beyer (2001), Dopamine regulates brain-
derived neurotrophic factor (BDNF) expression in cultured
embryonic mouse striatal cells. Neuroreport, 12(6) 11751179
[61] S. N. Williams & A. S. Undieh (2009), Dopamine D1-like
receptor activation induces brain-derived neurotrophic factor
protein expression. Neuroreport, 20(6) 606610
[62] F. Du, R. Li, Y. Huang, X. Li & W. Le (2005), Dopamine
D3 receptor-preferring agonists induce neurotrophic eects
on mesencephalic dopamine neurons. Eur J Neurosci, 22(10)
24222430
[63] K. Imamura, T. Takeshima, K. Nakaso, S. Ito & K. Nakashima
(2008), Pramipexole has astrocyte-mediated neuroprotective
eects against lactacystin toxicity. Neurosci Lett, 440(2) 97
102
[64] K. Ohta, A. Fujinami, S. Kuno, A. Sakakimoto, H. Mat-
sui, Y. Kawahara & M. Ohta (2004), Cabergoline stimulates
synthesis and secretion of nerve growth factor, brain-derived
neurotrophic factor and glial cell line-derived neurotrophic
factor by mouse astrocytes in primary culture. Pharmacology,
71(3) 162168
[65] S. Chiba, T. Numakawa, M. Ninomiya, H. S. Yoon &
H. Kunugi (2010), Cabergoline, a dopamine receptor ago-
nist, has an antidepressant-like property and enhances brain-
derived neurotrophic factor signaling. Psychopharmacology
(Berl), 211(3) 291301
 Tadahiro Numakawa et al. / Journal of Biological Medicine 2011:1(3) 110
[66] T. Inoue, K. Tsuchiya, J. Miura, S. Sakakibara, K. Denda,
T. Kasahara & T. Koyama (1996), Bromocriptine treatment of
tricyclic and heterocyclic antidepressant-resistant depression.
Biol Psychiatry, 40(2) 151153
[67] T. Izumi, T. Inoue, N. Kitagawa, N. Nishi, S. Shimanaka,
Y. Takahashi, I. Kusumi, Y. Odagaki, K. Denda, T. Ohmori
& T. Koyama (2000), Open pergolide treatment of tricyclic
and heterocyclic antidepressant-resistant depression. J Aect
Disord, 61(1-2) 127132
[68] L. Lattanzi, L. DellOsso, P. Cassano, S. Pini, P. Rucci, P. R.
Houck, A. Gemignani, G. Battistini, A. Bassi, M. Abelli
& G. B. Cassano (2002), Pramipexole in treatment-resistant
depression: a 16-week naturalistic study. Bipolar Disord, 4(5)
307314
[69] H. Takahashi, K. Yoshida, H. Higuchi, T. Shimizu, T. Inoue
& T. Koyama (2003), Addition of a dopamine agonist, caber-
goline, to a serotonin-noradrenalin reuptake inhibitor, mil-
nacipran as a therapeutic option in the treatment of refractory
depression: two case reports. Clin Neuropharmacol, 26(5)
230232
[70] A. Yoshii & M. Constantine-Paton (2010), Postsynaptic
BDNF-TrkB signaling in synapse maturation, plasticity, and
disease. Dev Neurobiol, 70(5) 304322
[71] M. V. Caldeira, C. V. Melo, D. B. Pereira, R. F. Carvalho, A. L.
Carvalho & C. B. Duarte (2007), BDNF regulates the expres-
sion and trac of NMDA receptors in cultured hippocampal
neurons. Mol Cell Neurosci, 35(2) 208219
[72] M. V. Caldeira, C. V. Melo, D. B. Pereira, R. Carvalho, S. S.
Correia, D. S. Backos, A. L. Carvalho, J. A. Esteban & C. B.
Duarte (2007), Brain-derived neurotrophic factor regulates the
expression and synaptic delivery of alpha-amino-3-hydroxy-
5-methyl-4-isoxazole propionic acid receptor subunits in hip-
pocampal neurons. J Biol Chem, 282(17) 1261912628
[73] E. Kumamaru, T. Numakawa, N. Adachi & H. Kunugi (2011),
Glucocorticoid suppresses BDNF-stimulated MAPK/ERK
pathway via inhibiting interaction of Shp2 with TrkB. FEBS
Lett, 585(20) 32243228
[74] V. Lessmann, K. Gottmann & R. Heumann (1994), BDNF
and NT-4/5 enhance glutamatergic synaptic transmission in
cultured hippocampal neurones. Neuroreport, 6(1) 2125
[75] B. Lu (2003), BDNF and activity-dependent synaptic modula-
tion. Learn Mem, 10(2) 8698
[76] T. Numakawa, S. Yamagishi, N. Adachi, T. Matsumoto,
D. Yokomaku, M. Yamada & H. Hatanaka (2002), Brain-
derived neurotrophic factor-induced potentiation of Ca(2+) os-
cillations in developing cortical neurons. J Biol Chem, 277(8)
65206529
[77] T. Numakawa, D. Yokomaku, K. Kiyosue, N. Adachi, T. Mat-
sumoto, Y. Numakawa, T. Taguchi, H. Hatanaka & M. Yamada
(2002), Basic broblast growth factor evokes a rapid glutamate
release through activation of the MAPK pathway in cultured
cortical neurons. J Biol Chem, 277(32) 2886128869
[78] T. Numakawa, E. Kumamaru, N. Adachi, Y. Yagasaki,
A. Izumi & H. Kunugi (2009), Glucocorticoid receptor in-
teraction with TrkB promotes BDNF-triggered PLC-gamma
signaling for glutamate release via a glutamate transporter.
Proc Natl Acad Sci U S A, 106(2) 647652
[79] D. A. Simmons, C. S. Rex, L. Palmer, V. Pandyarajan, V. Fed-
ulov, C. M. Gall & G. Lynch (2009), Up-regulating BDNF
with an ampakine rescues synaptic plasticity and memory in
Huntingtons disease knockin mice. Proc Natl Acad Sci U S A,
106(12) 49064911
[80] K.-D. Destot-Wong, K. Liang, S. K. Gupta, G. Favrais,
L. Schwendimann, J. Pansiot, O. Baud, M. Spedding,
V. Lelievre, S. Mani & P. Gressens (2009), The AMPA recep-
9
tor positive allosteric modulator, S18986, is neuroprotective
against neonatal excitotoxic and inammatory brain damage
through BDNF synthesis. Neuropharmacology, 57(3) 277286
[81] R. Machado-Vieira, G. Salvadore, N. Diazgranados & C. A.
Zarate (2009), Ketamine and the next generation of antide-
pressants with a rapid onset of action. Pharmacol Ther, 123(2)
143150
[82] R. Trullas & P. Skolnick (1990), Functional antagonists at the
NMDA receptor complex exhibit antidepressant actions. Eur J
Pharmacol, 185(1) 110
[83] J. Maj, Z. Rogoz, G. Skuza & H. Sowinska (1992), The eect
of CGP 37849 and CGP 39551, competitive NMDA receptor
antagonists, in the forced swimming test. Pol J Pharmacol
Pharm, 44(4) 337346
[84] M. Papp & E. Moryl (1993), New evidence for the antide-
pressant activity of MK-801, a non-competitive antagonist of
NMDA receptors. Pol J Pharmacol, 45(5-6) 549553
[85] E. Przegalinski, E. Tatarczynska, A. Deren-Wesoek &
E. Chojnacka-Wojcik (1997), Antidepressant-like eects of a
partial agonist at strychnine-insensitive glycine receptors and a
competitive NMDA receptor antagonist. Neuropharmacology,
36(1) 3137
[86] R. M. Berman, A. Cappiello, A. Anand, D. A. Oren, G. R.
Heninger, D. S. Charney & J. H. Krystal (2000), Antidepres-
sant eects of ketamine in depressed patients. Biol Psychiatry,
47(4) 351354
[87] C. A. Zarate, J. B. Singh, P. J. Carlson, N. E. Brutsche,
R. Ameli, D. A. Luckenbaugh, D. S. Charney & H. K.
Manji (2006), A randomized trial of an N-methyl-D-aspartate
antagonist in treatment-resistant major depression. Arch Gen
Psychiatry, 63(8) 856864
[88] A. E. Autry, M. Adachi, E. Nosyreva, E. S. Na, M. F. Los,
P. fei Cheng, E. T. Kavalali & L. M. Monteggia (2011),
NMDA receptor blockade at rest triggers rapid behavioural
antidepressant responses. Nature, 475(7354) 9195
[89] V. Ricci, G. Martinotti, F. Gelfo, F. Tonioni, C. Caltagirone,
P. Bria & F. Angelucci (2011), Chronic ketamine use increases
serum levels of brain-derived neurotrophic factor. Psychophar-
macology (Berl), 215(1) 143148
[90] S. J. Jeon, S. Y. Rhee, J. E. Seo, H. R. Bak, S. H. Lee,
J. H. Ryu, J. H. Cheong, C. Y. Shin, G.-H. Kim, Y. S. Lee
& K. H. Ko (2011), Oroxylin A increases BDNF production
by activation of MAPK-CREB pathway in rat primary cortical
neuronal culture. Neurosci Res, 69(3) 214222
[91] C. Wakabayashi, T. Numakawa, M. Ninomiya, S. Chiba &
H. Kunugi (2011), Behavioral and molecular evidence for psy-
chotropic eects in L: -theanine. Psychopharmacology (Berl),
[Epub ahead of print]
[92] F. S. Lee & M. V. Chao (2001), Activation of Trk neurotrophin
receptors in the absence of neurotrophins. Proc Natl Acad Sci
U S A, 98(6) 35553560
[93] R. Rajagopal, Z.-Y. Chen, F. S. Lee & M. V. Chao (2004),
Transactivation of Trk neurotrophin receptors by G-protein-
coupled receptor ligands occurs on intracellular membranes.
J Neurosci, 24(30) 66506658
[94] Y. Z. Huang, E. Pan, Z.-Q. Xiong & J. O. McNamara (2008),
Zinc-mediated transactivation of TrkB potentiates the hip-
pocampal mossy ber-CA3 pyramid synapse. Neuron, 57(4)
546558
[95] Y. Z. Huang & J. O. McNamara (2010), Mutual regulation of
Src family kinases and the neurotrophin receptor TrkB. J Biol
Chem, 285(11) 82078217
[96] B. S. McEwen (2005), Glucocorticoids, depression, and mood
disorders: structural remodeling in the brain. Metabolism, 54(5
Suppl 1) 2023
 Tadahiro Numakawa et al. / Journal of Biological Medicine 2011:1(3) 110

[97] F. Jeanneteau, M. J. Garabedian & M. V. Chao (2008), Activa-

tion of Trk neurotrophin receptors by glucocorticoids provides
a neuroprotective eect. Proc Natl Acad Sci U S A, 105(12)
48624867
[98] T. Rantamaki, L. Vesa, H. Antila, A. D. Lieto, P. Tammela,
A. Schmitt, K.-P. Lesch, M. Rios & E. Castren (2011), An-
tidepressant drugs transactivate TrkB neurotrophin receptors in
the adult rodent brain independently of BDNF and monoamine
transporter blockade. PLoS One, 6(6) e20567
[99] S. A. Brody, M. A. Geyer & C. H. Large (2003), Lamotrig-
ine prevents ketamine but not amphetamine-induced decits
in prepulse inhibition in mice. Psychopharmacology (Berl),
169(3-4) 240246
[100] F. Angelucci, S. Brene & A. A. Mathe (2005), BDNF in
schizophrenia, depression and corresponding animal models.
Mol Psychiatry, 10(4) 345352

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