Thome J, Duman RS, Henn FA.
of antidepressive therapy. Transsynaptic effects on signal transduction, gene
expression and neuronal plasticity]
Nervenarzt. 2002 Jul;73(7):595-9.
neurotransmitter theories cannot sufficiently explain the mode of action of antidepressant
drugs. Molecular pharmacological studies demonstrate that antidepressive treatment
initially modulates the neurotransmitter-receptor interaction, subsequently influences
signal transduction cascades beyond the synapse and gene transcription mechanisms,
and ultimately triggers the expression of specific target genes. Such genes often
code for molecules which play an important role in the maintenance of neural and
synaptic plasticity. Chronic (but not acute) treatment with antidepressants modulates,
for example, the cAMP-second-messenger system and increases the expression of
neurotrophic factors. Furthermore, antidepressants promote hippocampal neurogenesis.
Stress, an important risk factor for psychiatric disorders, often induces opposite
effects. A better understanding of the molecular and cellular effects of stress
and therapy with psychotropic drugs will stimulate the development of innovative
treatment strategies for which an optimised antidepressant efficacy with a simultaneously
improved tolerance is expected." [Abstract]
K, Shimizu E, Iyo M.
Critical role of brain-derived neurotrophic
factor in mood disorders.
Brain Res Brain Res Rev. 2004
"The purpose of this review is to integrate what is
currently known about the role of brain-derived neurotrophic factor (BDNF) in
the pathophysiology of mood disorders including major depressive disorder (MDD)
and bipolar disorder (BD). We reviewed the pre-clinical and clinical papers demonstrating
that BDNF plays a role in the pathophysiology of mood disorders and in the mechanism
of action of therapeutic agents. Pre-clinical studies suggest that the expression
of BDNF might be a downstream target of antidepressant treatments and mood stabilizers
such as lithium and valproate, and that BDNF exerts antidepressant activity in
animal models of depression. Furthermore, BDNF protects against stress-induced
neuronal damage, and it might affect neurogenesis in the hippocampus, which is
thought to be involved in the pathogenesis of mood disorders. Clinical studies
have demonstrated that serum levels of BDNF in drug-naive patients with MDD are
significantly decreased as compared with normal controls, and that BDNF might
be an important agent for therapeutic recovery from MDD. Moreover, recent findings
from family-based association studies have suggested that the BDNF gene is a potential
risk locus for the development of BD. These findings suggest that BDNF plays a
critical role in the pathophysiology of mood disorders and in the activity of
therapeutic agents in patients with mood disorders. New agents capable of enhancing
BDNF levels may lead aid the development of novel therapeutic drugs for patients
with mood disorders." [Abstract]
F, Perret G, Bondolfi G, Schwald M, Bertschy G, Aubry JM.
serum brain-derived neurotrophic factor levels in major depressed patients.
Res. 2002 Mar 15;109(2):143-8.
"Recent findings with animal models have
suggested a possible role for brain-derived neurotrophic factor (BDNF) in depression.
We have therefore hypothesized that depression could be characterized by low levels
of serum BDNF. Major depressed patients (15F + 15M) diagnosed according to DSM-IV
criteria and healthy controls (15F + 15M) participated in the study. Serum BDNF
was assayed with the ELISA method and the severity of depression was evaluated
with Montgomery-Asberg-Depression Rating Scale (MADRS). BDNF levels were significantly
lower in patients than in controls: 22.6 +/- 3 and 26.5 +/- 7 ng/ml (t-test =
2.7; d.f. = 58; P < 0.01). They were negatively correlated to the MADRS scores
(r = -0.55; P < 0.02). Female patients were more depressed and released less
BDNF than men. Analysis of covariance (MADRS and gender as independent variable
vs. BDNF as dependent variable) indicated that depression severity mainly accounted
for the negative correlation. These results suggest that major depression is characterized
by low serum BDNF levels and support the hypothesis of neurotrophic factor involvement
in affective disorders." [Abstract]
B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT.
BDNF immunoreactivity in subjects treated with antidepressant medication.
Psychiatry. 2001 Aug 15;50(4):260-5.
"BACKGROUND: The cAMP signaling pathway,
and its downstream neurotrophic factor BDNF, are major targets of antidepressant
medications. Abnormalities in this pathway have previously been reported in postmortem
brain of subjects with mood disorders. This study was designed to test whether
the diagnosis of a mood disorder, or treatment with an antidepressant or mood
stabilizer was associated with changes in hippocampal BDNF in postmortem brain.
METHODS: Frozen postmortem anterior hippocampus sections were obtained from the
Stanley Foundation Neuropathology Consortium. Tissue from subjects with major
depression, bipolar disorder, schizophrenia and nonpsychiatric control subjects
were stained for BDNF using immunohistochemistry. RESULTS: Increased BDNF expression
was found in dentate gyrus, hilus and supragranular regions in subjects treated
with antidepressant medications at the time of death, compared with antidepressant-untreated
subjects. Furthermore, there was a trend toward increased BDNF expression in hilar
and supragranular regions in depressed subjects treated with antidepressants,
compared with the subjects not on these medications at the time of death. CONCLUSIONS:
These findings are consistent with recent studies measuring CREB levels in this
same subject sample, and support current animal and cellular models of antidepressant
E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, Nakazato M, Watanabe
H, Shinoda N, Okada S, Iyo M.
Alterations of serum levels of brain-derived
neurotrophic factor (BDNF) in depressed patients with or without antidepressants.
Psychiatry. 2003 Jul 1;54(1):70-5.
"BACKGROUND: Because researchers have
reported that antidepressants increase the expression of brain-derived neurotrophic
factor (BDNF) in the rat hippocampus, we investigated whether serum BDNF levels
may be used as a putative biological marker for major depressive disorders (MDD).
METHODS: We measured serum BDNF in the following three groups: antidepressant-naive
patients with MDD (n = 16), antidepressant-treated patients with MDD (n = 17),
and normal control subjects (n = 50). Patients were evaluated using the Hamilton
Rating Scale for Depression (HAM-D). Serum BDNF was assayed with the sandwich
ELISA method. RESULTS: We found that serum BDNF was significantly lower in the
antidepressant-naive group (mean, 17.6 ng/mL; SD, 9.6) than in the treated (mean,
30.6 ng/mL; SD, 12.3; p =.001) or in the control group (mean, 27.7 ng/mL; SD,
11.4; p =.002). There was a significant negative correlation (r = -.350, z = -2.003,
p =.045) between serum BDNF and HAM-D scores in all patients. In a preliminary
examination, reduced BDNF values of three drug-naive patients recovered to basal
levels after antidepressant treatment. CONCLUSIONS: Our study suggests that low
BDNF levels may play a pivotal role in the pathophysiology of MDD and that antidepressants
may increase BDNF in depressed patients." [Abstract]
M, Potkin SG, Bunney WE, Jones EG.
MRNA expression patterns and distribution
of white matter neurons in dorsolateral prefrontal cortex of depressed patients
differ from those in schizophrenia patients.
2003 Jan 1;53(1):39-47.
"Expression of CAMKII-alpha and TBR1 mRNAs was
significantly increased in bipolar patients but not in major depressed patients,
and there was a trend toward reduced BDNF expression in both groups." [Abstract]
Schaaf MJ, De Kloet ER, Vreugdenhil E.
effects on BDNF expression in the hippocampus. Implications for memory formation.
"The adrenal steroid corticosterone has profound
effect on the structure and function of the hippocampus. Probably as a result
of that, it modulates memory formation. In this review, the question is addressed
if the corticosterone effects on memory processes are mediated by alterations
in the expression of the neurotrophin Brain-Derived Neurotrophic Factor (BDNF)
in the hippocampus. First, studies are described investigating the effect of corticosterone
on BDNF expression in the rat hippocampus. It appears that corticosterone suppresses
the BDNF expression at the mRNA and protein level in a subfield-specific way.
Second, a model for the mechanism of action is proposed. In this model, activated
mineralocorticoid and glucocorticoid receptors repress transcriptional activity
of the BDNF promoter site-specifically via interaction with other transcription
factors. Third, the implications for learning and memory are discussed. Studies
show that during water maze training, corticosterone levels rise significantly,
but the BDNF expression is not suppressed in any hippocampal subfield. Furthermore,
high BDNF expression levels in specific subfields correlate with a good memory
performance. Therefore, we suggest that the resistance of the hippocampal BDNF
expression to suppression by corticosterone, as seen after water maze training,
may contribute to an optimal memory performance." [Abstract]
J, Zhang F, Zhang Y.
Corticosterone inhibits generation of long-term
potentiation in rat hippocampal slice: involvement of brain-derived neurotrophic
Brain Res. 2000 Dec 8;885(2):182-91.
the present study, the effect of corticosterone (CORT) on the generation of long-term
potentiation (LTP) and its underlying mechanism involving neurotrophin gene expression
in CA1 synapses of rat hippocampal slice were examined. Our experimental results
showed incubation of hippocampal slice with CORT for 3 h had no effect on either
the slope or amplitude of excitatory postsynaptic potentials (EPSP) evoked in
hippocampal CA1 pyramidal dentrites, indicating no marked change in basal synaptic
transmission. However, when tetanic stimulation (100 pulses, 100 Hz) was delivered
to the Schaffer collateral pathway, CORT application significantly attenuated
the tetanus-induced increases of both EPSP slope and amplitude, demonstrating
an inhibitory effect of CORT on LTP generation. In addition, CORT treatment significantly
reduced both slope and amplitude ratios of the second evoked EPSP to the first
one when paired-pulse facilitation (PPF) was established at different interpulse
intervals from 20 to 40 ms, suggesting that a presynaptic mechanism may be involved
in CORT-induced hippocampal synaptic plasticity. Reverse-transcription polymerase
chain reaction (RT-PCR) analysis showed that CORT-treated hippocampal CA1 cells
underwent a significant decrease in the expression of mRNA for nerve growth factor-beta
(NGF-beta) and brain-derived neurotrophic factor (BDNF), but not for neurotrophin-3
(NT-3) compared with those in control. Moreover, BDNF co-applied with CORT significantly
antagonized CORT-induced deficit in PPF. Taken together, the present results suggest
that CORT-induced inhibition of LTP may be, at least to some extent, mediated
by a presynaptic mechanism and decrease in the BDNF expression in rat hippocampal
CA1 cells induced by CORT may partially account for this presynaptic mechanism."
JM, Tascedda F, Carra S, Ferraguti C, Barden N, Brunello N.
regulation of CREB by chronic antidepressant administration in the brain of transgenic
mice with impaired glucocorticoid receptor function.
"Various effects of antidepressant drugs on gene
transcription have been described and altered gene expression has been proposed
as being a common biological basis underlying depressive illness. One target for
the common action of antidepressants is a modifying effect on the regulation of
postreceptor pathways and genes related to the cAMP cascade. Recent studies have
demonstrated that long-term antidepressant treatment resulted in sustained activation
of the cyclic adenosine 3',5'-monophosphate system and in increased expression
of the transcription factor cAMP response element binding protein (CREB). A transgenic
animal model of depression with impaired glucocorticoid receptor function was
used to investigate the effect of chronic antidepressant treatments on CREB expression
in different brain areas. Wild-type and transgenic mice received one administration
of saline, desipramine, or fluoxetine, daily for 21 days. The effects of antidepressants
on CREB mRNA were analyzed using a sensitive RNase protection assay. Antidepressant
treatment resulted in a neuroanatomically and animal specific expression pattern
of CREB. Our findings suggest that life-long central glucocorticoid receptor dysfunction
results in an altered sensitivity with respect to the effects of antidepressants
on the expression of CREB." [Abstract]
Y, Rao JS, Rizavi HS, Kotowski J, Conley RR, Roberts RC, Tamminga CA, Pandey GN.
expression and functional characteristics of cyclic adenosine monophosphate response
element binding protein in postmortem brain of suicide subjects.
Gen Psychiatry. 2003 Mar;60(3):273-82.
"BACKGROUND: Cyclic adenosine monophosphate
response element binding protein (CREB) is a transcription factor that, on phosphorylation
by protein kinases, is activated, and in response, regulates the transcription
of many neuronally expressed genes. In view of the recent observations that catalytic
properties and/or expression of many kinases that mediate their physiological
responses through the activation of CREB are altered in the postmortem brain of
subjects who commit suicide (hereafter referred to as suicide subjects), we examined
the status of CREB in suicidal behavior. METHODS: These studies were performed
in Brodmann area (BA) 9 and hippocampus obtained from 26 suicide subjects and
20 nonpsychiatric healthy control subjects. Messenger RNA levels of CREB and neuron-specific
enolase were determined in total RNA by means of quantitative reverse transcriptase-polymerase
chain reaction. Protein levels and the functional characteristics of CREB were
determined in nuclear fractions by means of Western blot and cyclic adenosine
monophosphate response element (CRE)-DNA binding activity, respectively. In the
same nuclear fraction, we determined the catalytic activity of cyclic adenosine
monophosphate-stimulated protein kinase A by means of enzymatic assay. RESULTS:
We observed a significant reduction in messenger RNA and protein levels of CREB,
CRE-DNA binding activity, and basal and cyclic adenosine monophosphate-stimulated
protein kinase A activity in BA 9 and hippocampus of suicide subjects, without
any change in messenger RNA levels of neuron-specific enolase in BA 9. Except
for protein kinase A activity, changes in CREB expression and CRE-DNA binding
activity were present in all suicide subjects, irrespective of diagnosis. These
changes were unrelated to postmortem intervals, age, sex, or antidepressant treatment.
CONCLUSIONS: Given the significance of CREB in mediating various physiological
functions through gene transcription, our results of decreased expression and
functional characteristics of CREB in postmortem brain of suicide subjects suggest
that CREB may play an important role in suicidal behavior." [Abstract]
LT, Bezchlibnyk YB, Chen B, Wang JF, MacQueen GM.
adenosine monophosphate response element binding protein phosphorylation in patients
with mood disorders: effects of diagnosis, suicide, and drug treatment.
Psychiatry. 2004 Mar 15;55(6):570-7.
"BACKGROUND: Signal transduction
abnormalities have been identified in patients with bipolar (BD) and major depressive
(MDD) disorders and are targets for lithium and antidepressant drugs. A key downstream
target for signal transduction pathways is the transcription factor cyclic adenosine
monophosphate (cAMP) response element binding protein (CREB). Therefore, we measured
the levels of phosphorylated CREB (pCREB) in the amygdala, a region critical to
emotional processing and important in the pathophysiology of both BD and MDD.
METHODS: Human postmortem amygdala sections were generously provided by the Stanley
Foundation Neuropathology Consortium. Samples consisted of subjects with MDD,
BD, schizophrenia (SCZ), and nonpsychiatric-nonneurologic comparison subjects
(n = 15 per group). Levels of pCREB were measured by immunohistochemistry, relative
to total cell number. RESULTS: There were no differences between diagnostic groups--control
subjects and subjects with BD, MDD, or SCZ--but increased numbers of pCREB stained
cells were found in several amygdalar nuclei in subjects who had died by suicide.
In contrast, patients treated with lithium at the time of death had significantly
lower pCREB levels in the same region. CONCLUSIONS: These results suggest that
CREB activity may be an important factor in the neurobiology of suicide and the
well-documented antisuicidal effect of lithium." [Abstract]
JM, Kell S, Hinze-Selch D, Aldenhoff JB.
Changes in CREB-phosphorylation
during recovery from major depression.
J Psychiatr Res.
"For decades psychiatrists have been looking
for biological state markers measurable by easy blood test in order to follow
up and predict early on treatment response in patients with major depression.
In the present study we investigated whether or not measuring CREB (cAMP-response-element-binding-protein)
phosphorylation in peripheral blood T lymphocytes is a state marker of treatment
response. CREB is an ubiquitous key-element of intracellular signal transduction
cascades and its transcriptional activity depends on phosphorylation at Ser-133.
Several studies in animals demonstrated that the transcriptional activity of CREB
is up-regulated by antidepressant treatment. Therefore, it has been hypothesized
that antidepressant treatment exerts its therapeutic effect by this mechanism.
In the present study, we investigated CREB-phosphorylation in T-lymphocytes of
20 patients before and in the end of week one and two of either psychopharmacological
or psychotherapeutic treatment. After two weeks, 15 patients fulfilled the criteria
of treatment response (i.e. 30% reduction in HAMD score compared to baseline),
whereas five patients did not. In the end of week two, the responders showed a
significant increase in CREB-phosphorylation (P = 0.018) compared to the non-responders.
This was true for all patients with either treatment regimen. In conclusion, these
results indicate for the first time that the increase in CREB-phosphorylation
might be a molecular state marker for the response to antidepressant treatment."
Lai IC, Hong CJ, Tsai SJ.
of cAMP response element-binding protein in major depression before and after
usually take weeks to exert significant therapeutic effects. This lag phase is
suggested to be due to neural plasticity, which may be mediated by the coupling
of receptors to their respective intracellular signal transduction pathways. Phosphorylated
cAMP response element-binding protein (CREB), a downstream target of the cAMP
signaling pathway, has been reported to be a molecular state marker for the response
to antidepressant treatment in patients with major depressive disorder (MDD).
In order to explore the role of CREB expression in MDD, we used quantitative reverse
transcriptase-polymerase chain reaction to quantify CREB messenger RNA of the
peripheral lymphocytes obtained from 21 MDD patients, before and after antidepressant
treatment, and 21 normal controls. The results revealed no significant difference
of CREB expression between untreated MDD patients and normal controls. However,
after 8 weeks of antidepressant treatment, CREB expression was significantly decreased
in MDD patients (p = 0.025). The CREB change is not associated with the types
of antidepressants and therapeutic response." [Abstract]
D, MacQueen GM, Wang JF, Reiach JS, Young LT.
G Protein-coupled cyclic
AMP signaling in postmortem brain of subjects with mood disorders: effects of
diagnosis, suicide, and treatment at the time of death.
Neurochem. 1999 Sep;73(3):1121-6.
"Components of cyclic AMP (cAMP) signaling
were examined in postmortem cerebral cortex of a well characterized group of patients
with mood disorders and nonpsychiatric control subjects. We measured G protein
levels, adenylyl cyclase (AC) activity, and CREB levels in cerebral cortex of
the subjects with respect to diagnosis, treatment, and suicide. There was no effect
of diagnosis on any measure, except for a trend toward decreased stimulated AC
activity in subjects with mood disorders relative to control subjects. We also
detected a significant effect of suicide on temporal cortex CREB levels in subjects
that died as a result of suicide relative to those that did not, which was more
evident in patients with major depressive disorder. Bipolar disorder (BD) subjects
treated with anticonvulsants at the time of death had decreased temporal cortex
CREB levels relative to those not receiving anticonvulsants. Furthermore, we found
a trend toward decreased occipital cortex G alpha(s) (short) levels in BD subjects
treated with lithium. These results support the hypothesis of altered cAMP signaling
in mood disorders and raise the possibility that factors other than diagnosis,
such as treatment and suicide, may be relevant to cell-signaling abnormalities
reported in the literature." [Abstract]
Odagaki Y, Garcia-Sevilla JA, Huguelet P, La Harpe
R, Koyama T, Guimon J.
Cyclic AMP-mediated signaling components are
upregulated in the prefrontal cortex of depressed suicide victims.
Res. 2001 Apr 20;898(2):224-31.
"The components of cyclic AMP signaling
cascade (catalytic (Calpha) subunit of cyclic AMP-dependent protein kinase (PKA)
and cyclic AMP response element binding protein (CREB)) were quantitated by Western
blotting in the prefrontal cortex of depressed suicide victims (n=23) and their
matched controls (n=14). There was a significant increase in the levels of CREB,
both in total (tCREB; 121+/-8% (mean+/-S.E.M.), P<0.02) and phosphorylated
(pCREB; 128+/-9%, P<0.01) forms, but not in PKA Calpha levels (109+/-9%, ns),
in brains of depressed suicides compared to those in control subjects. The increases
in CREB were specifically observed in antidepressant drug-free subjects (tCREB:
137+/-11%, P<0.01; pCREB: 136+/-12%, P<0.02; n=9), but not in the antidepressant-treated
subjects (tCREB: 108+/-18%, ns; pCREB: 111+/-17%, ns; n=8). There were significant
correlations between the levels of PKA and those of tCREB and pCREB in the prefrontal
cortex of depressed suicides. These results indicate that the components of cyclic
AMP signaling are upregulated in a coordinated manner in brains of depressed suicides
and that this alteration is not related to antidepressant treatment." [Abstract]
S, Yamamoto M, Ozawa H, Riederer P, Saito T.
of cyclic AMP-responsive element binding protein in the postmortem orbitofrontal
cortex of patients with major depressive disorder.
Transm. 2003 Jun;110(6):671-80.
"In this study, we examined the amounts
of cAMP-responsive element binding protein (CREB) and its phosphorylated form
in homogenate preparations from postmortem orbitofrontal cortices of antidepressant
drug-free patients with major depressive disorder and age-matched controls by
immunoblotting. Immunoreactivies of both CREB and phosphorylated CREB were significantly
decreased in depressive subjects compared to controls. The immunoreactivity of
phosphorylated CREB was diminished to a greater extent than that of CREB in depressive
patients. It has been indicated from animal studies that a transcription factor
likely mediates neural plasticity in the mammalian brain and neural tissues. Our
results suggest that alterations in the cAMP signaling system, especially in CREB,
may be involved in the pathophysiology of depression and be potential targets
for antidepressant treatment." [Abstract]
Thome, J., Sakai, N., Shin, K.-H., Steffen, C., Zhang,
Y.-J., Impey, S., Storm, D., Duman, R. S.
cAMP Response Element-Mediated
Gene Transcription Is Upregulated by Chronic Antidepressant Treatment
Neurosci. 2000 20: 4030-4036
"Regulation of gene transcription via the
cAMP-mediated second messenger pathway has been implicated in the actions of antidepressant
drugs, but studies to date have not demonstrated such an effect in vivo. To directly
study the regulation of cAMP response element (CRE)-mediated gene transcription
by antidepressants, transgenic mice with a CRE-LacZ reporter gene construct were
administered one of three different classes of antidepressants: a norepinephrine
selective reuptake inhibitor (desipramine), a serotonin selective reuptake inhibitor
(fluoxetine), or a monoamine oxidase inhibitor (tranylcypromine). Chronic, but
not acute, administration of these antidepressants significantly increased CRE-mediated
gene transcription, as well as the phosphorylation of CRE binding protein (CREB),
in several limbic brain regions thought to mediate the action of antidepressants,
including the cerebral cortex, hippocampus, amygdala, and hypothalamus. These
results demonstrate that chronic antidepressant treatment induces CRE-mediated
gene expression in a neuroanatomically differentiated pattern and further elucidate
the molecular mechanisms underlying the actions of these widely used therapeutic
Dias BG, Banerjee SB, Duman RS, Vaidya VA.
regulation of Brain Derived Neurotrophic Factor transcripts by antidepressant
treatments in the adult rat brain.
"Antidepressants are known to increase brain derived
neurotrophic factor (BDNF) mRNA in the adult rat brain. The BDNF gene has four
differentially regulated promoters that generate four transcript forms, each containing
a unique non-coding 5' exon (exon I-IV) and a common 3' coding exon. Using in
situ hybridization with exon-specific riboprobes, we have examined whether diverse
classes of antidepressants recruit a single or multiple BDNF promoters to regulate
BDNF mRNAs. The antidepressants tested were electroconvulsive seizure (ECS) and
the pharmacological antidepressants tranylcypromine, desipramine and fluoxetine.
The effects of both acute and chronic ECS were the most prominent on exon I and
II containing BDNF mRNAs in hippocampal and cortical subfields. Chronic ECS enhanced
the acute induction of exon I, II and IV mRNAs but did not influence the acute
upregulation of exon III mRNAs. Acute pharmacological antidepressants resulted
in region-specific decreases in distinct exon-specific BDNF transcripts. In contrast,
chronic administration with tranylcypromine and desipramine enhanced exon II and
exon III mRNAs, respectively, in discrete hippocampal and cortical subfields.
Chronic fluoxetine treatment did not have a significant effect on the exon-specific
BDNF transcripts. The results indicate that distinct antidepressants differentially
regulate BDNF mRNAs through a region-specific recruitment of the four BDNF promoters
and suggest that diverse signaling mechanisms may be recruited to regulate BDNF
CA, Whitehead RE, Chen R, Wortwein G, Madsen TM.
Effects of electroconvulsive
seizures and antidepressant drugs on brain-derived neurotrophic factor protein
in rat brain.
Biol Psychiatry. 2003 Oct 1;54(7):703-9.
The antidepressant-like effects of brain-derived neurotrophic factor (BDNF) infusions
in brain, and the upregulation of BDNF mRNA and its receptor in rats exposed to
electroconvulsive seizure (ECS) and antidepressants, suggested a role for increased
BDNF protein. METHODS: We measured BDNF protein levels with a two-site enzyme-linked
immunosorbent assay (ELISA) in six brain regions of adult male rats that received
daily ECS or daily injections of antidepressant drugs. RESULTS: The BDNF ELISA
method was validated by the 50% loss of BDNF protein in the brains of +/- BDNF
knockout mice, the 60%-100% recovery of spiked recombinant BDNF, and by the amounts
and regional variations of BDNF measured in the six brain regions. Ten consecutive
daily exposures to ECS increased BDNF protein in the parietal cortex (219%), entorhinal
cortex (153%), hippocampus (132%), frontal cortex (94%), neostriatum (67%), and
septum (29%). BDNF increased gradually in the hippocampus and frontal cortex,
with a peak response by the fourth day of ECS. Increases peaked at 15 hours after
the last ECS and lasted at least 3 days thereafter. Two weeks of daily injections
with the monoamine (MAO)-A and -B inhibitor tranylcypromine (8-10 mg/kg, IP) increased
BDNF by 15% in the frontal cortex, and 3 weeks treatment increased it by 18% in
the frontal cortex and by 29% in the neostriatum. Tranylcypromine, fluoxetine,
and desmethylimipramine did not elevate BDNF in the hippocampus. CONCLUSIONS:
Elevations in BDNF protein in brain are consistent with the greater treatment
efficacy of ECS and MAO inhibitors in drug-resistant major depressive disorder
and may be predictive for the antidepressant action of the more highly efficacious
M, Morinobu S, Duman RS.
Regulation of BDNF and trkB mRNA in rat
brain by chronic electroconvulsive seizure and antidepressant drug treatments.
J Neurosci. 1995 Nov;15(11):7539-47.
"The influence of chronic electroconvulsive
seizure (ECS) or antidepressant drug treatments on expression of brain-derived
neurotrophic factor (BDNF) and its receptor, trkB, was examined by in situ hybridization
and Northern blot. In frontal cortex, acute ECS increased BDNF mRNA approximately
twofold, an effect significantly augmented by a prior course of chronic ECS treatment
(10 d). In the hippocampus, the influence of chronic ECS varied between the major
subfields. In the dentate gyrus granule cell layer, chronic ECS decreased the
acute induction of BDNF and trkB mRNA by approximately 50%, but prolonged their
expression: levels remained elevated two- to threefold 18 hr later after the last
chronic ECS treatment, but returned to control 18 hr after acute ECS. In CA3 and
CA1 pyramidal cell layers, chronic ECS significantly elevated the acute induction
of BDNF, and tended to prolong the expression of BDNF and trkB mRNA. A similar
effect was observed in layer 2 of the piriform cortex, where chronic ECS significantly
increased the acute induction and prolonged the expression of BDNF and trkB mRNA.
Chronic (21 d), but not acute (1 d), administration of several different antidepressant
drugs, including tranylcypromine, sertraline, desipramine, or mianserin, significantly
increased BDNF mRNA and all but mianserin increased trkB mRNA in hippocampus.
In contrast, chronic administration of nonantidepressant psychotropic drugs, including
morphine, cocaine, or haloperidol, did not increase levels of BDNF mRNA. Furthermore,
chronic administration of ECS or antidepressant drugs completely blocked the down-regulation
of BDNF mRNA in the hippocampus in response to restraint stress. The enhanced
induction and prolonged expression of BDNF in response to chronic ECS and antidepressant
drug treatments could promote neuronal survival, and protect neurons from the
damaging effects of stress." [Abstract]
Hoomissen JD, Chambliss HO, Holmes PV, Dishman RK.
Effects of chronic
exercise and imipramine on mRNA for BDNF after olfactory bulbectomy in rat.
Res. 2003 Jun 6;974(1-2):228-35.
"We examined the effects of chronic activity
wheel running and antidepressant treatment on brain-derived neurotrophic factor
(BDNF) messenger RNA (mRNA) in multiple brain regions-hippocampal formation (HF),
ventral tegmental area/substantia nigra (VTA/SN), nucleus accumbens (NAc), and
piriform cortex (PFx)-after bilateral olfactory bulbectomy (OBX). Male, Long-Evans
rats (n=72) underwent either sham or OBX surgery and were randomly divided into
eight experimental groups in a 2 (sham vs. OBX) x 2 (sedentary vs. activity wheel)x2
(saline vs. imipramine) factorial design. Animals were killed after 21 days of
treatment. Drug x exercise interaction effects were observed for HF (P=0.006-0.023)
and VTA/SN (P=0.021); exercise increased BDNF mRNA in the saline treated animals
but not in the imipramine treated animals. OBX did not affect BDNF mRNA in the
HF or VTA/SN (P>0.05). BDNF mRNA levels in the PFx were not altered by exercise,
drug, or OBX (P>0.05). These results suggest that the effect of exercise on
BDNF mRNA extends beyond the HF to the mesolimbic ventral tegmental area and that
the potentiation of BDNF mRNA by exercise and antidepressant pharmacotherapy,
reported by other investigators, is time limited." [Abstract]
A, Ha T, Ramirez R, Kesslak JP.
treatment combination: impact on brain-derived neurotrophic factor and behavior
in an animal model.
Behav Brain Res. 2001 Apr 8;120(1):87-95.
mechanism of antidepressant action, at the cellular level, is not clearly understood.
It has been reported that chronic antidepressant treatment leads to an up-regulation
of brain-derived neurotrophic factor (BDNF) mRNA levels in the hippocampus, and
that physical activity (voluntary running) enhances this effect. We wished to
investigate whether BDNF expression brought about by these interventions may overcome
deficits caused by acute stress, and might impact behavior in an animal model.
In this report, we have tested the hypothesis that the combination of the antidepressant,
tranylcypromine, and physical exercise could lead to decreased neurotrophin deficits
and enhanced swimming time in animals that have been forced to swim in an inescapable
water tank. Rats were either treated with tranylcypromine, engaged in voluntary
running, or both for one week. After these treatments, the animals underwent a
two-day forced swimming procedure. BDNF mRNA levels were significantly depressed
in untreated animals subjected to forced swimming. Animals that either underwent
prior activity or received antidepressant showed BDNF mRNA levels restored to
baseline. Animals receiving the combined intervention showed an increase in hippocampal
BDNF mRNA well above baseline. Swimming time during a five-minute test was significantly
enhanced in animals receiving the combined intervention over untreated animals.
Swimming time was not significantly enhanced over that of animals receiving antidepressant
alone, however. Enhanced swimming time correlated with increased levels of BDNF
mRNA in one hippocampal sub-region (CA4-hilus). These results suggest that the
combination of exercise and antidepressant treatment may have significant neurochemical,
and possibly behavioral, effects. In addition, these results support the possibility
that the enhancement of BDNF expression may be an important element in the clinical
response to antidepressant treatment. The induction of BDNF expression by activity/pharmacological
treatment combinations could represent an important intervention for further study,
to potentially improve depression treatment and management." [Abstract]
H, Shino Y, Hashimoto K, Kumakiri C, Shimizu E, Shirasawa H, Iyo M.
changes in AP-1 transcription factor DNA binding activity in rat brain following
administration of antidepressant amitriptyline and brain-derived neurotrophic
Neuropharmacology. 2003 Aug;45(2):251-259.
present study was undertaken to examine the effects of the antidepressant, amitriptyline,
and brain-derived neurotrophic factor (BDNF) on activator protein-1 (AP-1) DNA
binding activity in the rat brain. Acute administration of amitriptyline (5 or
10 mg/kg) initially increased but then decreased AP-1 DNA binding activity in
the rat frontal cortex and hippocampus. Chronic administration of amitriptyline
(5 or 10 mg/kg, once daily for 3 weeks) initially decreased AP-1 DNA binding activity
but ultimately resulted in its persistent elevation in the rat frontal cortex.
In contrast, the chronic administration of amitriptyline did not affect the low
activity of AP-1 DNA binding in the hippocampus. However, chronic administration
of amitriptyline (10 mg/kg, once daily for 3 weeks) significantly increased BDNF
protein levels in the hippocampus (by 26.9%) and frontal cortex (by 24.6%). Direct
infusion of BDNF (1 microg) into the hippocampal dentate gyrus significantly increased
hippocampal AP-1 DNA binding activity. These results suggest that AP-1 transcription
factor may be modulated by BDNF and that it may be an important target for the
action of antidepressants." [Abstract]
H, Steven Richardson J, Li XM.
Dose-related effects of chronic antidepressants
on neuroprotective proteins BDNF, Bcl-2 and Cu/Zn-SOD in rat hippocampus.
"It has been proposed that antidepressants have
neuroprotective effects on hippocampal neurons. To further test this hypothesis,
brain-derived neurotrophic factor (BDNF), B cell lymphoma protein-2 (Bcl-2), and
copper-zinc superoxide dismutase (Cu/Zn-SOD) were examined immunohistochemically
in hippocampal neurons of Sprague-Dawley rats following daily treatment with 5
or 10 mg/kg of amitriptyline or venlafaxine for 21 days. At 5 mg/kg, both amitriptyline
and venlafaxine increased the intensity of BDNF immunostaining in hippocampal
pyramidal neurons, and the intensity of Bcl-2 immunostaining in hippocampal mossy
fibers, but did not alter the Cu/Zn-SOD immunoreactivity. The high dose of venlafaxine,
however, decreased the intensity of BDNF immunostaining in all subareas of the
hippocampus and increased the intensity of Cu/Zn-SOD immunostaining in the dentate
granular cell layer. The high dose of amitriptyline increased the intensity of
Cu/Zn-SOD immunostaining, but did not affect the immunoreactivity of Bcl-2 or
BDNF. These findings suggest that the chronic administration of amitriptyline
or venlafaxine at 5 mg/kg, but not 10 mg/kg, may be neuroprotective to hippocampal
neurons. These dose-related effects of antidepressant drugs on hippocampal neurons
may have relevance to disparate findings in the field." [Abstract]
V, Winterhoff H, Herkenham M.
St John's wort, hypericin, and imipramine:
a comparative analysis of mRNA levels in brain areas involved in HPA axis control
following short-term and long-term administration in normal and stressed rats.
Psychiatry. 2001 Sep;6(5):547-64.
"Clinical studies demonstrate that the
antidepressant efficacy of St John's wort (Hypericum) is comparable to that of
tricyclic antidepressants such as imipramine. Onset of efficacy of these drugs
occurs after several weeks of treatment. Therefore, we used in situhybridization
histochemistry to examine in rats the effects of short-term (2 weeks) and long-term
(8 weeks) administration of imipramine, Hypericum extract, and hypericin (an active
constituent of St John's wort) on the expression of genes that may be involved
in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Imipramine
(15 mg kg(-1)), Hypericum (500 mg kg(-1)), and hypericin (0.2 mg kg(-1)) given
daily by gavage for 8 weeks but not for 2 weeks significantly decreased levels
of corticotropin-releasing hormone (CRH) mRNA by 16-22% in the hypothalamic paraventricular
nucleus (PVN) and serotonin 5-HT(1A) receptor mRNA by 11-17% in the hippocampus.
Only imipramine decreased tyrosine hydroxylase (TH) mRNA levels in the locus coeruleus
(by 23%), and only at 8 weeks. The similar delayed effects of the three compounds
on gene transcription suggests a shared action on the centers that control HPA
axis activity. A second study was performed to assess the effects of long-term
imipramine and Hypericum administration on stress-induced changes in gene transcription
in stress-responsive circuits. Repeated immobilization stress (2 h daily for 7
days) increased mRNA levels of CRH in the PVN, proopiomelanocortin (POMC) in the
anterior pituitary, glutamic acid decarboxylase (GAD 65/67) in the bed nucleus
of the stria terminalis (BST), cyclic AMP response element binding protein (CREB)
in the hippocampus, and TH in the locus coeruleus. It decreased mRNA levels of
5-HT(1A) and brain-derived neurotrophic factor (BDNF) in the hippocampus. Long-term
pre-treatment with either imipramine or Hypericum reduced to control levels the
stress-induced increases in gene transcription of GAD in the BST, CREB in the
hippocampus, and POMC in the pituitary. The stress-induced increases in mRNA levels
of CRH in the PVN and TH in the locus coeruleus were reduced by imipramine but
not by Hypericum. The stress-induced decreases in BDNF and 5-HT(1A)mRNA levels
were not prevented by either drug. Taken together, these data show: (1) that Hypericum
and hypericin have delayed effects on HPA axis control centers similar to those
of imipramine; and (2) that select stress-induced changes in gene transcription
in particular brain areas can be prevented by long-term treatment with either
the prototypic tricyclic antidepressant imipramine or the herbiceutical St John's
wort. However, imipramine appears to be more effective in blocking stress effects
on the HPA axis than the plant extract." [Abstract]
YF, Yang M, Zhao YM, Luo ZP.
[Protective effect of bajitian oligosaccharide
on PC12 cells lesioned by corticosterone]
Yao Za Zhi. 2000 Sep;25(9):551-4.
"OBJECTIVE: To study the possible mechanism
of antidepressant effect of Bajitian oligosaccharide (MW-97). METHODS AND RESULTS:
After incubating with the PC12 cells in the presence of corticosterone(2 x 10(-4)
mol.L-1) for 48 h, it was found that MW-97 could protect PC12 cells from the lesion
done by corticosterone in a concentration-dependent manner. Furthermore, using
RT-PCR mediated cross-species partial cDNA cloning, it was found that MW-97 and
desipramine(DIM) increased NGF, BDNF mRNA in the frontal cortex after chronic
administration for 21 days, meanwhile, BDNF mRNA in hippocampus was also increased.
CONCLUSION: The cytoprotective effect of MW-97 consists in the possible mechanism
of its antidepressant action, while the increasing expression of neurotrophic
factors (NGF, BDNF mRNA) may be contributes to the cytoprotective effect."
Coppell AL, Pei Q, Zetterstrom TS.
change in BDNF gene expression following antidepressant drug treatment.
"The gene for brain derived neurotrophic factor
(BDNF) has recently received attention in relation to the therapeutic action of
antidepressant treatment. This study aimed to clarify the influence of post drug
interval on the effect of acute and repeated treatment with antidepressant drugs
on BDNF gene expression in the rat brain. It was found that repeated administration
of either the monoamine oxidase inhibitor tranylcypromine (TCP) or 5-hydroxytryptamine
(5-HT) re-uptake inhibitors (fluoxetine, paroxetine and sertraline), evoke a bi-phasic
and time-dependent effect on BDNF gene expression in the rat hippocampus (especially
dentate gyrus). A down-regulation of the BDNF gene was detected at 4 h (TCP and
fluoxetine) and an up-regulation at 24 h (TCP, paroxetine, fluoxetine, sertraline)
after the last of twice daily injections for 14 days. After a single injection
the down-regulation was detected at 4 h (TCP, fluoxetine, paroxetine and sertraline)
but BDNF mRNA levels were not altered at 24 h post drug (TCP, fluoxetine and paroxetine).
Administration of inhibitors of noradrenaline re-uptake (desipramine and maprotiline)
or the atypical antidepressant mianserin had no effect on BDNF mRNA levels at
either single (4 h post drug, desipramine) or repeated (24 h post drug, desipramine,
maprotiline, mianserin) treatment. The gene expression for NT-3, which is distributed
in a high density in the dentate gyrus, was not affected by single or repeated
injections of antidepressant drugs (TCP, fluoxetine, paroxetine, sertraline, desipramine,
maprotiline or mianserin) at 4 or 24 h post drug. In conclusion, these data show
that the effect of antidepressant drugs on BDNF gene expression may be more complex
and less widespread across treatments than previously thought. Thus, in this study
drugs interacting with the central 5-HT system altered BDNF expression but the
effect was bi-phasic over the 24 h post drug period." [Abstract]
HK, Quiroz JA, Sporn J, Payne JL, Denicoff K, A Gray N, Zarate CA Jr, Charney
Enhancing neuronal plasticity and cellular resilience to develop
novel, improved therapeutics for difficult-to-treat depression.
Psychiatry. 2003 Apr 15;53(8):707-42.
"There is growing evidence from
neuroimaging and ostmortem studies that severe mood disorders, which have traditionally
been conceptualized as neurochemical disorders, are associated with impairments
of structural plasticity and cellular resilience. It is thus noteworthy that recent
preclinical studies have shown that critical molecules in neurotrophic signaling
cascades (most notably cyclic adenosine monophosphate [cAMP] response element
binding protein, brain-derived neurotrophic factor, bcl-2, and mitogen activated
protein [MAP] kinases) are long-term targets for antidepressant agents and antidepressant
potentiating modalities. This suggests that effective treatments provide both
trophic and neurochemical support, which serves to enhance and maintainnormal
synaptic connectivity, thereby allowing the chemical signal to reinstate the optimal
functioning of critical circuits necessary for normal affective functioning. For
many refractory patients, drugs mimicking "traditional" strategies,
which directly or indirectly alter monoaminergic levels, may be of limited benefit.
Newer "plasticity enhancing" strategies that may have utility in the
treatment of refractory depression include N-methyl-D-aspartate antagonists, alpha-amino-3-hydroxy-5-methylisoxazole
propionate (AMPA) potentiators, cAMP phosphodiesterase inhibitors, and glucocorticoid
receptor antagonists. Small-molecule agents that regulate the activity f growth
factors, MAP kinases cascades, and the bcl-2 family of proteins are also promising
future avenues. The development of novel, nonaminergic-based therapeutics holds
much promise for improved treatment of severe, refractory mood disorders."
M, Nestler EJ, Duman RS.
Chronic antidepressant administration increases
the expression of cAMP response element binding protein (CREB) in rat hippocampus.
Neurosci. 1996 Apr 1;16(7):2365-72.
"The present study demonstrates that
chronic, but not acute, adminstration of several different classes of antidepressants,
including serotonin- and norepinephrine-selective reuptake inhibitors, increases
the expression of cAMP response element binding protein (CREB) mRNA in rat hippocampus.
In contrast, chronic administration of several nonantidepressant psychotropic
drugs did not influence expression of CREB mRNA, demonstrating the pharmacological
specificity of this effect. In situ hybridization analysis demonstrates that antidepressant
administration increases expression of CREB mRNA in CA1 and CA3 pyramidal and
dentate gyrus granule cell layers of the hippocampus. In addition, levels of CRE
immunoreactivity and of CRE binding activity were increased by chronic antidepressant
administration, which indicates that expression and function of CREB protein are
increased along with its mRNA. Chronic administration of the phosphodiesterase
(PDE) inhibitors rolipram or papaverine also increased expression of CREB mRNA
in hippocampus, demonstrating a role for the cAMP cascade. Moreover, coadministration
of rolipram with imipramine resulted in a more rapid induction of CREB than with
either treatment alone. Increased expression and function of CREB suggest that
specific target genes may be regulated by these treatments. We have found that
levels of brain-derived neurotrophic factor (BDNF) and trkB mRNA are also increased
by administration of antidepressants or PDE inhibitors. These findings indicate
that upregulation of CREB is a common action of chronic antidepressant treatments
that may lead to regulation of specific target genes, such as BDNF and trkB, and
to the long-term effects of these treatments on brain function." [Abstract]
X, Perez-Torres S, Artigas F, Puigdomenech P, Palacios JM, Mengod G.
of cAMP phosphodiesterase mRNAs expression in rat brain by acute and chronic fluoxetine
treatment. An in situ hybridization study.
"Changes in brain cyclic AMP (cAMP) have been
suggested to underlie the clinical action of antidepressant treatments. Also,
a regionally-selective regulation of cAMP-specific phosphodiesterases (PDEs) has
been demonstrated for some antidepressants. To further investigate the effects
of antidepressant treatments on PDEs, we examined the expression of different
cAMP-specific PDEs in the brain of rats treated (1 and 14 days) with fluoxetine
3 mg/kg day. The mRNAs coding for PDE4A, PDE4B, PDE4D, and the five known PDE4D
splice variants were analyzed by in situ hybridization on 45 brain structures
of acute and chronic fluoxetine-treated rats. We also examined the binding sites
for the putative antidepressant drug [(3)H]rolipram, a PDE4-selective inhibitor.
In some brain areas single fluoxetine administration increased the density of
the mRNA of all PDE4 isozymes, except PDE4D and PDE4D5. Chronic fluoxetine treatment
increased PDE4A mRNA levels and decreased those for PDE4B, PDE4D and PDE4D1 mRNAs
in some brain regions. The study was complemented with the analysis of the expression
of the transcripts of BDNF. Chronic fluoxetine treatment down-regulated the expression
of BDNF. These results show that the expression of PDE4 isozymes is modulated
by a clinically relevant fluoxetine dose. The significance of these changes in
PDE4 expression to the antidepressant effect of fluoxetine is discussed."
D'Sa C, Tolbert LM, Conti M, Duman RS.
of cAMP-specific phosphodiesterases type 4B and 4D (PDE4) splice variants by cAMP
signaling in primary cortical neurons.
J Neurochem. 2002
"This study examined the regulation of all known phosphodiesterase
(PDE) type PDE4A, PDE4B and PDE4D splice variants in cortical neurons by cAMP
signaling. Treatment with dibutyryl-cAMP (db-cAMP) caused the induction of two
of the known splice variants, PDE4B2 and PDE4D1/PDE4D2. Although the splice variants
PDE4A1, PDE4A5/PDE4A10, PDE4B3, PDE4B1, PDE4D3 and PDE4D4 were present in cortical
neurons, their mRNA was not regulated at the transcriptional level by db-cAMP.
To assess the increase in PDE4B2 and PDE4D1/D2 mRNA expression, the promoters
containing these genes were characterized. Transcription from both promoters was
stimulated by db-cAMP. Because chronic antidepressant treatment increases PDE4B,
and not PDE4D, mRNA expression, we focused on the regulation of the PDE4B2 promoter
by cAMP and CREB. Dominant negative mutants of CREB suppressed PDE4B2 promoter
activity and a constitutively active form of CREB robustly stimulated it. These
data demonstrate that in cortical neurons, a short PDE4B2 intronic promoter is
regulated by CREB, confers cAMP responsitivity and directs PDE4B2 mRNA and protein
K, Morinobu S, Duman RS.
Administration of a cAMP phosphodiesterase
4 inhibitor enhances antidepressant-induction of BDNF mRNA in rat hippocampus.
"The influence of two selective phosphodiesterase
4 (PDE4) inhibitors, rolipram and Ro 20-1724, on the induction of BDNF mRNA by
antidepressant treatment was examined. Coadministration of rolipram or Ro 20-1724
with an antidepressant (either desipramine or Org 4428) for 21 d resulted in a
significant induction of BDNF mRNA in hippocampus relative to administration of
vehicle. Coadministration of a PDE4 inhibitor with an antidepressant for 7 or
14 d also increased levels of BDNF mRNA. In contrast, acute coadministration did
not influence levels of BDNF mRNA. In situ hybridization analysis demonstrated
that the induction of BDNF mRNA in response to the repeated coadministration paradigm
occurs in the dentate gyrus granule and CA1 and CA3 pyramidal cell layers of hippocampus.
These findings demonstrate that coadministration shortens the time required for
the upregulation of BDNF mRNA, supporting the possibility that this treatment
may provide an effective therapy for major depression." [Abstract]
MB, Toschi N, Kresse AE, Post A, Keck ME.
Long-term repetitive transcranial
magnetic stimulation increases the expression of brain-derived neurotrophic factor
and cholecystokinin mRNA, but not neuropeptide tyrosine mRNA in specific areas
of rat brain.
Neuropsychopharmacology. 2000 Aug;23(2):205-15.
transcranial magnetic stimulation (rTMS) is increasingly used as a therapeutic
tool in various neurological and psychiatric disorders, and we recently found
that it has a neuroprotective effect both in vitro and in vivo. However, the neurochemical
mechanisms underlying the therapeutic effects are still unknown. We investigated
the effects of long-term rTMS on the expression of brain-derived neurotrophic
factor (BDNF), cholecystokinin (CCK), and neuropeptide tyrosine (NPY) mRNA in
rat brain. In situ hybridization revealed a significant increase in BDNF mRNA
in the hippocampal areas CA3 and CA3c, the granule cell layer, as well as in the
parietal and the piriform cortex after rTMS. BDNF-like immunoreactivity was markedly
increased in the same areas. A significant increase in CCK mRNA was observed in
all brain regions examined. NPY mRNA expression, in contrast, was not altered.
The present results suggest that BDNF may contribute to the neuroprotective effects
of rTMS. Furthermore, the rTMS-induced changes in BDNF and CCK expression are
similar to those reported after antidepressant drug treatment and electroconvulsive
seizures, suggesting that a common molecular mechanism may underlie different
antidepressant treatment strategies." [Abstract]
REID, IAN C., STEWART, CAROLINE A.
antidepressants work: New perspectives on the pathophysiology of depressive disorder
J Psychiatry 2001 178: 299-303
"BACKGROUND: New research in animals is
beginning to change radically our understanding of the biology of stress and the
effects of antidepressant agents. AIMS: To relate recent findings from the basic
neurosciences to the pathophysiology of depressive disorder. METHOD: Drawing together
findings from molecular and physiological studies in rats, social studies in primates
and neuropsychological studies in humans, we review the neurotrophic and neuroplastic
effects of antidepressants and stress. RESULTS: Stress and antidepressants have
reciprocal actions on neuronal growth and vulnerability (mediated by the expression
of neurotrophins) and synaptic plasticity (mediated by excitatory amino acid neurotransmission)
in the hippocampus and other brain structures. Stressors have the capacity to
progressively disrupt both the activities of individual cells and the operating
characteristics of networks of neurons throughout the life cycle, while antidepressant
treatments act to reverse such injurious effects. CONCLUSIONS: We propose a central
role for the regulation of synaptic connectivity in the pathophysiology of depressive
Robert M. Sapolsky
and the shrinking hippocampus
PNAS 98: 12320-12322. 2001.
M. MacQueen, Stephanie Campbell, Bruce S. McEwen, Kathryn Macdonald, Shigeko Amano,
Russell T. Joffe, Claude Nahmias, and L. Trevor Young
illness, hippocampal function, and hippocampal volume in major depression
100: 1387-1392; published online before print as 10.1073/pnas.0337481100
have examined hippocampal function and volume in depressed subjects, but none
have systematically compared never-treated first-episode patients with those who
have had multiple episodes. We sought to compare hippocampal function, as assessed
by performance on hippocampal-dependent recollection memory tests, and hippocampal
volumes, as measured in a 1.5-T magnetic resonance imager, in depressed subjects
experiencing a postpubertal onset of depression. Twenty never-treated depressed
subjects in a first episode of depression were compared with matched healthy control
subjects. Seventeen depressed subjects with multiple past episodes of depression
were also compared with matched healthy controls and to the first-episode patients.
Both first- and multiple-episode depressed groups had hippocampal dysfunction
apparent on several tests of recollection memory; only depressed subjects with
multiple depressive episodes had hippocampal volume reductions. Curve-fitting
analysis revealed a significant logarithmic association between illness duration
and hippocampal volume. Reductions in hippocampal volume may not antedate illness
onset, but volume may decrease at the greatest rate in the early years after illness
Sheline, Yvette I., Sanghavi, Milan,
Mintun, Mark A., Gado, Mokhtar H.
Depression Duration But Not Age
Predicts Hippocampal Volume Loss in Medically Healthy Women with Recurrent Major
J. Neurosci. 1999 19: 5034-5043
study takes advantage of continuing advances in the precision of magnetic resonance
imaging (MRI) to quantify hippocampal volumes in a series of human subjects with
a history of depression compared with controls. We sought to test the hypothesis
that both age and duration of past depression would be inversely and independently
correlated with hippocampal volume. A sample of 24 women ranging in age from 23
to 86 years with a history of recurrent major depression, but no medical comorbidity,
and 24 case-matched controls underwent MRI scanning. Subjects with a history of
depression (post-depressed) had smaller hippocampal volumes bilaterally than controls.
Post-depressives also had smaller amygdala core nuclei volumes, and these volumes
correlated with hippocampal volumes. In addition, post-depressives scored lower
in verbal memory, a neuropsychological measure of hippocampal function, suggesting
that the volume loss was related to an aspect of cognitive functioning. In contrast,
there was no difference in overall brain size or general intellectual performance.
Contrary to our initial hypothesis, there was no significant correlation between
hippocampal volume and age in either post-depressive or control subjects, whereas
there was a significant correlation with total lifetime duration of depression.
This suggests that repeated stress during recurrent depressive episodes may result
in cumulative hippocampal injury as reflected in volume loss." [Full
Sheline, Yvette I., Gado, Mokhtar H., Kraemer,
Untreated Depression and Hippocampal Volume Loss
J Psychiatry 2003 160: 1516-1518
"OBJECTIVE: The purpose of this study
was to investigate the effect of antidepressant treatment on hippocampal volumes
in patients with major depression. METHOD: For 38 female outpatients, the total
time each had been in a depressive episode was divided into days during which
the patient was receiving antidepressant medication and days during which no antidepressant
treatment was received. Hippocampal gray matter volumes were determined by high
resolution magnetic resonance imaging and unbiased stereological measurement.
RESULTS: Longer durations during which depressive episodes went untreated with
antidepressant medication were associated with reductions in hippocampal volume.
There was no significant relationship between hippocampal volume loss and time
depressed while taking antidepressant medication or with lifetime exposure to
antidepressants. CONCLUSIONS: Antidepressants may have a neuroprotective effect
during depression." [Abstract]
C, Duman RS.
Antidepressants and neuroplasticity.
Disord. 2002 Jun;4(3):183-94.
"OBJECTIVE: We review the literature on
the cellular changes that underlie the structural impairments observed in brains
of animals exposed to stress and in subjects with depressive disorders. We discuss
the molecular, cellular and structural adaptations that underlie the therapeutic
responses of different classes of antidepressants and contribute to the adaptive
plasticity induced in the brain by these drugs. METHODS: We review results from
various clinical and basic research studies. RESULTS: Studies demonstrate that
chronic antidepressant treatment increases the rate of neurogenesis in the adult
hippocampus. Studies also show that antidepressants up-regulate the cyclic adenosine
monophosphate (cAMP) and the neurotrophin signaling pathways involved in plasticity
and survival. In vitro and in vivo data provide direct evidence that the transcription
factor, cAMP response element-binding protein (CREB) and the neurotrophin, brain
derived-neurotrophic factor (BDNF) are key mediators of the therapeutic response
to antidepressants. CONCLUSIONS: These results suggest that depression maybe associated
with a disruption of mechanisms that govern cell survival and neural plasticity
in the brain. Antidepressants could mediate their effects by increasing neurogenesis
and modulating the signaling pathways involved in plasticity and survival."
Stress, metaplasticity, and
Curr Mol Med. 2002 Nov;2(7):629-38.
large body of evidence has established a link between stressful life events and
development or exacerbation of depression. At the cellular level, evidence has
emerged indicating neuronal atrophy and cell loss in response to stress and in
depression. At the molecular level, it has been suggested that these cellular
deficiencies, mostly detected in the hippocampus, result from a decrease in the
expression of brain-derived neurotrophic factor (BDNF) associated with elevation
of glucocorticoids. Thus, an increase in expression of BDNF, facilitating both
neuronal survival and neurogenesis, is thought to represent a converging mechanism
of action of various types of antidepressant treatments (e.g., antidepressant
drugs and transcranial magnetic stimulation). However, as also revealed by converging
lines of evidence, high levels of glucocorticoids down-regulate hippocampal synaptic
connectivity ('negative' metaplasticity), whereas an increase in expression of
BDNF up-regulates connectivity in the hippocampus ('positive' metaplasticity).
Therefore, antidepressant treatments might not only restore cell density but also
regulate higher-order synaptic plasticity in the hippocampus by abolishing 'negative'
metaplasticity, and thus restore hippocampal cognitive processes that are altered
by stress and in depressed patients. This antidepressant regulatory effect on
hippocampal synaptic plasticity function, which may, in turn, suppress 'negative'
metaplasticity in other limbic structures, is discussed." [Abstract]
Ronald S., Malberg, Jessica, Nakagawa, Shin
Regulation of Adult Neurogenesis
by Psychotropic Drugs and Stress
J Pharmacol Exp Ther 2001
"Proliferation and maturation of neurons has been demonstrated
to occur at a significant rate in discrete regions of adult brain, including the
hippocampus and subventricular zone. Moreover, adult neurogenesis is an extremely
dynamic process that is regulated in both a positive and negative manner by neuronal
activity and environmental factors. It has been suggested to play a role in several
important neuronal functions, including learning, memory, and response to novelty.
In addition, exposure to psychotropic drugs or stress regulates the rate of neurogenesis
in adult brain, suggesting a possible role for neurogenesis in the pathophysiology
and treatment of neurobiological illnesses such as depression, post-traumatic
stress disorder, and drug abuse. As the mechanisms that control adult neurogenesis
continue to be identified, the exciting prospect of developing pharmacological
agents that specifically regulate the proliferation and maturation of neurons
in the adult brain could be fulfilled." [Full
Malberg, Jessica E., Eisch, Amelia J., Nestler,
Eric J., Duman, Ronald S.
Chronic Antidepressant Treatment Increases
Neurogenesis in Adult Rat Hippocampus
J. Neurosci. 2000
"Recent studies suggest that stress-induced atrophy and
loss of hippocampal neurons may contribute to the pathophysiology of depression.
The aim of this study was to investigate the effect of antidepressants on hippocampal
neurogenesis in the adult rat, using the thymidine analog bromodeoxyuridine (BrdU)
as a marker for dividing cells. Our studies demonstrate that chronic antidepressant
treatment significantly increases the number of BrdU-labeled cells in the dentate
gyrus and hilus of the hippocampus. Administration of several different classes
of antidepressant, but not non-antidepressant, agents was found to increase BrdU-labeled
cell number, indicating that this is a common and selective action of antidepressants.
In addition, upregulation of the number of BrdU-labeled cells is observed after
chronic, but not acute, treatment, consistent with the time course for the therapeutic
action of antidepressants. Additional studies demonstrated that antidepressant
treatment increases the proliferation of hippocampal cells and that these new
cells mature and become neurons, as determined by triple labeling for BrdU and
neuronal- or glial-specific markers. These findings raise the possibility that
increased cell proliferation and increased neuronal number may be a mechanism
by which antidepressant treatment overcomes the stress-induced atrophy and loss
of hippocampal neurons and may contribute to the therapeutic actions of antidepressant
Santarelli, Luca, Saxe, Michael, Gross,
Cornelius, Surget, Alexandre, Battaglia, Fortunato, Dulawa, Stephanie, Weisstaub,
Noelia, Lee, James, Duman, Ronald, Arancio, Ottavio, Belzung, Catherine, Hen,
Requirement of Hippocampal Neurogenesis for the Behavioral Effects
Science 2003 301: 805-809
chronic antidepressant treatments increase adult hippocampal neurogenesis, but
the functional importance of this phenomenon remains unclear. Here, using genetic
and radiological methods, we show that disrupting antidepressant-induced neurogenesis
blocks behavioral responses to antidepressants. Serotonin 1A receptor null mice
were insensitive to the neurogenic and behavioral effects of fluoxetine, a serotonin
selective reuptake inhibitor. X-irradiation of a restricted region of mouse brain
containing the hippocampus prevented the neurogenic and behavioral effects of
two classes of antidepressants. These findings suggest that the behavioral effects
of chronic antidepressants may be mediated by the stimulation of neurogenesis
in the hippocampus." [Abstract]
AC, Cryan JF, Dalvi A, Lucki I, Blendy JA.
cAMP response element-binding
protein is essential for the upregulation of brain-derived neurotrophic factor
transcription, but not the behavioral or endocrine responses to antidepressant
J Neurosci. 2002 Apr 15;22(8):3262-8.
drugs activate the cAMP signal transduction pathway through a variety of monoamine
neurotransmitter receptors. Recently, molecular studies have identified a role
for cAMP response element-binding protein (CREB) in the mechanism of action of
chronically administered antidepressant drugs. However, the function of CREB in
the behavioral and endocrine responses to these drugs has not been thoroughly
investigated. We have used CREB-deficient mice to study the effects of two antidepressants,
desipramine (DMI) and fluoxetine (FLX), in behavioral, endocrine, and molecular
analyses. Behaviorally, CREB-deficient mice and wild-type mice respond similarly
to DMI and FLX administration in the forced swim test and tail suspension test.
Furthermore, the ability of DMI to suppress an acute corticosterone response after
swim stress is maintained in CREB-deficient mice. However, upregulation of a molecular
target of CREB, BDNF, is abolished in the CREB-deficient mice after chronic administration
of DMI. These data are the first to demonstrate that CREB activation is upstream
of BDNF mechanistically in response to antidepressant drug treatment. Therefore,
although behavioral and endocrine responses to antidepressants may occur by CREB-independent
mechanisms, CREB is critical to target gene regulation after chronic drug administration,
which may contribute to long-term adaptations of the system to antidepressant
drug treatment." [Full
Chen AC, Shirayama Y, Shin KH, Neve RL,
Expression of the cAMP response element binding protein
(CREB) in hippocampus produces an antidepressant effect.
Psychiatry. 2001 May 1;49(9):753-62.
"BACKGROUND: Recent studies have
demonstrated that chronic antidepressant treatment increases the expression of
the cyclic amp (cAMP) response element binding protein (CREB) in rat hippocampus.
The study presented here was conducted to determine if CREB is a relevant target
that produces an antidepressant-like effect. METHODS: We employed the herpes simplex
virus (HSV)-mediated gene transfer technique to overexpress CREB and determined
its effect on the learned helplessness and forced swim tests, two established
models used for pharmacological screening of antidepressant drugs. RESULTS: In
the learned helplessness model, rats that received bilateral microinjection of
HSV-CREB into the dentate gyrus showed significantly fewer escape failures in
the subsequent conditioned avoidance test than those injected with control vector
(HSV-LacZ). In contrast, microinjection of HSV-CREB in either the CA1 pyramidal
cell layer of hippocampus or the prefrontal cortex did not produce an antidepressant
response. In the forced swim test, CREB expression in the dentate gyrus resulted
in a significantly shorter immobility time than those injected with HSV-LacZ.
CONCLUSIONS: These results demonstrate that over-expression of CREB in hippocampus
results in an antidepressant effect and suggest that CREB may serve as a potential
molecular target for novel therapeutic agents." [Abstract]
Shin, Kim, Ji-Eun, Lee, Rena, Malberg, Jessica E., Chen, Jingshan, Steffen, Cathy,
Zhang, Ya-Jun, Nestler, Eric J., Duman, Ronald S.
Regulation of Neurogenesis
in Adult Mouse Hippocampus by cAMP and the cAMP Response Element-Binding Protein
Neurosci. 2002 22: 3673-3682
"The cAMP cascade, including the cAMP response
element-binding protein (CREB), is known to play an important role in neuronal
survival and plasticity. Here the influence of this cascade on neurogenesis in
adult hippocampus was determined. Activation of the cAMP cascade by administration
of rolipram, an inhibitor of cAMP breakdown, increased the proliferation of newborn
cells in adult mouse hippocampus. In addition, rolipram induction of cell proliferation
resulted in mature granule cells that express neuronal-specific markers. Increased
cell proliferation is accompanied by activation of CREB phosphorylation in dentate
gyrus granule cells, suggesting a role for this transcription factor. This possibility
is supported by studies demonstrating that cell proliferation is decreased in
conditional transgenic mice that express a dominant negative mutant of CREB in
hippocampus. The results suggest that the cAMP-CREB cascade could contribute to
the actions of neurotransmitters and neurotrophic factors on adult neurogenesis."
Tao X, Finkbeiner S, Arnold DB, Shaywitz
AJ, Greenberg ME.
Ca2+ influx regulates BDNF transcription by a CREB
family transcription factor-dependent mechanism.
"CREB is a transcription factor implicated in the
control of adaptive neuronal responses. Although one function of CREB in neurons
is believed to be the regulation of genes whose products control synaptic function,
the targets of CREB that mediate synaptic function have not yet been identified.
This report describes experiments demonstrating that CREB or a closely related
protein mediates Ca2+-dependent regulation of BDNF, a neurotrophin that modulates
synaptic activity. In cortical neurons, Ca2+ influx triggers phosphorylation of
CREB, which by binding to a critical Ca2+ response element (CRE) within the BDNF
gene activates BDNF transcription. Mutation of the BDNF CRE or an adjacent novel
regulatory element as well as a blockade of CREB function resulted in a dramatic
loss of BDNF transcription. These findings suggest that a CREB family member acts
cooperatively with an additional transcription factor(s) to regulate BDNF transcription.
We conclude that the BDNF gene is a CREB family target whose protein product functions
at synapses to control adaptive neuronal responses." [Abstract]
PB, Hu SC, Bobb K, Timmusk T, Ghosh A.
Identification of a signaling
pathway involved in calcium regulation of BDNF expression.
"A signaling pathway by which calcium influx regulates
the expression of the major activity-dependent transcript of BDNF in cortical
neurons has been elucidated. Deletion and mutational analysis of the promoter
upstream of exon III reveals that transactivation of the BDNF gene involves two
elements 5' to the mRNA start site. The first element, located between 72 and
47 bp upstream of the mRNA start site, is a novel calcium response element and
is required for calcium-dependent BDNF expression in both embryonic and postnatal
cortical neurons. The second element, located between 40 and 30 bp upstream of
the mRNA start site, matches the consensus sequence of a cAMP response element
(CRE) and is required for transactivation of the promoter in postnatal but not
embryonic neurons. The CRE-dependent component of the response appears to be mediated
by CREB since it is part of the complex that binds to this CRE, and since dominant
negative mutants of CREB attenuate transactivation of the promoter. A constitutively
active mutant of CaM kinase IV, but not of CaM kinase II, leads to activation
of the promoter in the absence of extracellular stimuli, and partially occludes
calcium-dependent transactivation. The effects of CaM kinase IV on the promoter
require an intact CRE. These mechanisms, which implicate CaM kinase IV and CREB
in the control of BDNF expression, are likely to be centrally involved in activity-dependent
plasticity during development." [Abstract]
Saarelainen T, Hendolin P, Lucas G, Koponen E, Sairanen
M, MacDonald E, Agerman K, Haapasalo A, Nawa H, Aloyz R, Ernfors P, Castren E.
of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required
for antidepressant-induced behavioral effects.
2003 Jan 1;23(1):349-57.
"Recent studies have indicated that exogenously
administered neurotrophins produce antidepressant-like behavioral effects. We
have here investigated the role of endogenous brain-derived neurotrophic factor
(BDNF) and its receptor trkB in the mechanism of action of antidepressant drugs.
We found that trkB.T1-overexpressing transgenic mice, which show reduced trkB
activation in brain, as well as heterozygous BDNF null (BDNF(+/)-) mice, were
resistant to the effects of antidepressants in the forced swim test, indicating
that normal trkB signaling is required for the behavioral effects typically produced
by antidepressants. In contrast, neurotrophin-3(+/)- mice showed a normal behavioral
response to antidepressants. Furthermore, acute as well as chronic antidepressant
treatment induced autophosphorylation and activation of trkB in cerebral cortex,
particularly in the prefrontal and anterior cingulate cortex and hippocampus.
Tyrosines in the trkB autophosphorylation site were phosphorylated in response
to antidepressants, but phosphorylation of the shc binding site was not observed.
Nevertheless, phosphorylation of cAMP response element-binding protein was increased
by antidepressants in the prefrontal cortex concomitantly with trkB phosphorylation
and this response was reduced in trkB.T1-overexpressing mice. Our data suggest
that antidepressants acutely increase trkB signaling in a BDNF-dependent manner
in cerebral cortex and that this signaling is required for the behavioral effects
typical of antidepressant drugs. Neurotrophin signaling increased by antidepressants
may induce formation and stabilization of synaptic connectivity, which gradually
leads to the clinical antidepressive effects and mood recovery." [Abstract]
TA, Schramm M, Feldmann N, Knable MB, Falkai P.
exposure is associated with mRNA levels of tyrosine receptor kinase B in major
Prog Neuropsychopharmacol Biol Psychiatry.
"1. Recent studies have provided support for the
notion that the high affinity neurotrophin receptor tyrosine receptor kinase B
(trk B) may be involved in the treatment of depression. 2. Using a quantitative
RT-PCR approach trk B mRNA levels were determined in brain material from cerebellum,
temporal cortex, and frontal cortex of control specimen and patients with major
depressive disorder, schizophrenia and bipolar disorder (15 subjects each). 3.
Interestingly, elevated trk B mRNA levels were found in cerebellum (3.6-fold)
in patients with major depressive disorder, reaching statistical significance
(p=0.03). 4. The major depressive disorder-on drugs group differed from controls
(p=0.006) in the cerebellum. 5. Since only patients with major depressive disorder
received antidepressants, elevated trk B mRNA levels are possibly related to drug
Shirayama Y, Chen AC, Nakagawa S, Russell DS,
Brain-derived neurotrophic factor produces antidepressant
effects in behavioral models of depression.
2002 Apr 15;22(8):3251-61.
"Previous studies demonstrated that antidepressant
treatment increases the expression of brain-derived neurotrophic factor (BDNF)
in rat hippocampus. The present study was conducted to test the hypothesis that
BDNF in the hippocampus produces an antidepressant effect in behavioral models
of depression, the learned helplessness (LH) and forced swim test (FST) paradigms.
A single bilateral infusion of BDNF into the dentate gyrus of hippocampus produced
an antidepressant effect in both the LH and FST that was comparable in magnitude
with repeated systemic administration of a chemical antidepressant. These effects
were observed as early as 3 d after a single infusion of BDNF and lasted for at
least 10 d. Similar effects were observed with neurotrophin-3 (NT-3) but not nerve
growth factor. Infusions of BDNF and NT-3 did not influence locomotor activity
or passive avoidance. The results provide further support for the hypothesis that
BDNF contributes to the therapeutic action of antidepressant treatment."
JA, Lewis DR, Wiegand SJ, Lindsay RM.
of brain-derived neurotrophic factor (BDNF).
Behav. 1997 Jan;56(1):131-7. [Abstract]
Mague SD, Pliakas AM, Todtenkopf MS, Tomasiewicz
HC, Zhang Y, Stevens WC Jr, Jones RM, Portoghese PS, Carlezon WA Jr.
effects of kappa-opioid receptor antagonists in the forced swim test in rats.
Pharmacol Exp Ther. 2003 Apr;305(1):323-30.
"We showed previously that
cAMP response element-binding protein (CREB) within the nucleus accumbens (NAc)
of rats regulates immobility in the forced swim test (FST), an assay used to study
depression. Because CREB regulates expression of dynorphin (which acts at kappa-opioid
receptors) in NAc neurons, these findings raised the possibility that kappa-receptors
mediate immobility behaviors in the FST. Here, we report that i.c.v. administration
of the kappa-antagonist nor-binaltorphimine dose dependently decreased immobility
in the FST, suggesting that it has antidepressant-like effects. Implicating a
specific effect at kappa-receptors, similar antidepressant-like effects were seen
after treatment with either of two novel, structurally dissimilar kappa-antagonists:
5'-guanidinonaltrindole, which was effective after i.c.v. but not systemic treatment,
and 5'-acetamidinoethylnaltrindole (ANTI), which was potent and effective after
systemic treatment. The behavioral effects of the kappa-antagonists resembled
those of tricyclic antidepressants (desipramine) and selective serotonin reuptake
inhibitors (fluoxetine and citalopram). Conversely, systemic administration of
the kappa-agonist [5alpha,7alpha,8beta]-N-methyl-N-[7-[1-pyrrolidinyl]-1-oxaspiro[4.5]dec8-yl]-benzenacetamide
(U-69593) dose dependently increased immobility in the FST, consistent with prodepressant-like
effects. The effects of the kappa-ligands in the FST were not correlated with
nonspecific effects on locomotor activity. Furthermore, the most potent and effective
kappa-antagonist (ANTI) did not affect the rewarding impact of lateral hypothalamic
brain stimulation at a dose with strong antidepressant-like effects. These findings
are consistent with the hypothesis that CREB-mediated induction of dynorphin in
the NAc "triggers" immobility behavior in the FST. Furthermore, they
raise the possibility that kappa-antagonists may have efficacy as antidepressants,
but lack stimulant or reward-related effects." [Abstract]
SS, Thome J, Wallace TL, Shirayama Y, Schlesinger L, Sakai N, Chen J, Neve R,
Nestler EJ, Duman RS.
Inhibition of cAMP response element-binding
protein or dynorphin in the nucleus accumbens produces an antidepressant-like
J Neurosci. 2002 Dec 15;22(24):10883-90.
cAMP response element-binding protein (CREB) is a critical integrator of neural
plasticity that is responsive in a brain region-specific manner to a variety of
environmental and pharmacological stimuli, including widely prescribed antidepressant
medications. We developed inducible transgenic lines of mice that express either
CREB or a dominant-negative mutant of CREB (mCREB) in forebrain regions and used
these mice to determine the functional significance of this transcription factor
in the learned helplessness paradigm, a behavioral model of depression. We also
use a complementary viral-mediated gene transfer approach to directly test the
effect of mCREB in the nucleus accumbens, a brain region important for motivation
and reward. The results demonstrate that blockade of CREB by overexpression of
mCREB in transgenic mice or by viral expression of mCREB in the nucleus accumbens
produces an antidepressant-like effect, whereas overexpression of CREB in transgenic
mice results in the opposite phenotype. In addition, mCREB expression was colocalized
with and decreased the expression of prodynorphin in nucleus accumbens medium
spiny neurons, and antagonism of dynorphin in the nucleus accumbens was sufficient
to produce an antidepressant-like effect similar to that observed after blockade
of CREB. Together, the results demonstrate that nucleus accumbens CREB-dynorphin
influence behavior in the learned helplessness model and suggest that this signaling
cascade may contribute to symptoms of depression." [Abstract]
Barrot, Jocelien D. A. Olivier, Linda I. Perrotti, Ralph J. DiLeone, Olivier Berton,
Amelia J. Eisch, Soren Impey, Daniel R. Storm, Rachael L. Neve, Jerry C. Yin,
Venetia Zachariou, and Eric J. Nestler
CREB activity in the nucleus
accumbens shell controls gating of behavioral responses to emotional stimuli
99: 11435-11440; published online before print as 10.1073/pnas.172091899
transcription factor cAMP response element (CRE)-binding protein (CREB) has been
shown to regulate neural plasticity. Drugs of abuse activate CREB in the nucleus
accumbens, an important part of the brain's reward pathways, and local manipulations
of CREB activity have been shown to affect cocaine reward, suggesting an active
role of CREB in adaptive processes that follow exposure to drugs of abuse. Using
CRE-LacZ reporter mice, we show that not only rewarding stimuli such as morphine,
but also aversive stimuli such as stress, activate CRE-mediated transcription
in the nucleus accumbens shell. Using viral-mediated gene transfer to locally
alter the activity of CREB, we show that this manipulation affects morphine reward,
as well as the preference for sucrose, a more natural reward. We then show that
local changes in CREB activity induce a more general syndrome, by altering reactions
to anxiogenic, aversive, and nociceptive stimuli as well. Increased CREB activity
in the nucleus accumbens shell decreases an animal's responses to each of these
stimuli, whereas decreased CREB activity induces an opposite phenotype. These
results show that environmental stimuli regulate CRE-mediated transcription within
the nucleus accumbens shell, and that changes in CREB activity within this brain
area subsequently alter gating between emotional stimuli and their behavioral
responses. This control appears to be independent of the intrinsic appetitive
or aversive value of the stimulus. The potential relevance of these data to addiction
and mood disorders is discussed." [Full
Koch JM, Kell S, Aldenhoff JB.
effects of fluoxetine and imipramine on the phosphorylation of the transcription
factor CREB and cell-viability.
J Psychiatr Res. 2003 Jan-Feb;37(1):53-9.
has been shown that antidepressants increase the expression of CREB (cAMP-response-element-binding-protein)
and BDNF (brain derived neurotrophic factor) in vivo. Apparently inconsistent
to these survival-promoting properties for many years antidepressants are known
to induce apoptosis in various cell types in vitro. In the present study we evaluated
if the antidepressants imipramine and fluoxetine are capable to influence the
translational expression and phosphorylation of CREB (pCREB) in cells known to
be apoptosis-inducible by antidepressants. We therefore used jurkat cells and
quantified apoptosis via propidiumiodid-staining and FACS-analysis. CREB-expression
and -phosphorylation was quantified via western blot. Both antidepressants induced
apoptosis within 24 h. Fluoxetin starts to induce significant apoptosis at a concentration
of 20 microM, whereas imipramine at 100 microM. At these concentrations both antidepressants
also increased the phosphorylation of CREB within 6 h. But even in concentrations
to low to induce apoptosis both antidepressants still increased CREB-phosphorylation.
Treating cells with lowest concentrations only imipramine revealed an increase
of CREB-phosphorylation after long-time treatment over 3 weeks. In all experiments
overall CREB-expression remained unchanged. In conclusion our experiments indicate
that antidepressants are capable to increase CREB-phosphorylation without induction
of apoptosis depending on concentration and duration of treatment. We further
assume that antidepressants induce CREB-phosphorylation via signal transduction
pathways that are different from those inducing apoptosis." [Abstract]
DH, Shelton RC, Sulser F.
Noradrenergic antidepressants: does chronic
treatment increase or decrease nuclear CREB-P?
"Chronic administration of noradrenergic antidepressants
causes a desensitization of the beta adrenoceptor coupled adenylate cyclase system.
In the present studies, we attempted to answer the question of whether or not
this deamplification is reflected beyond the second messenger system. Nuclear
CREB-P was determined in frontal cortex of rats following acute and chronic administration
of desipramine (DMI) or reboxetine and in human fibroblasts following incubation
for 48 hours with DMI, reboxetine or venlafaxine. Nuclear CREB-P in the frontal
cortex was significantly decreased following chronic administration of DMI or
reboxetine. Moreover, incubation of human fibroblasts with DMI or reboxetine,
but not with venlafaxine, caused a highly significant reduction in nuclear CREB-P
suggesting that the noradrenergic antidepressants exert direct effects beyond
beta adrenoceptors. The results are consistent with the view that chronic treatment
with antidepressants causes a net deamplification of the norepinephrine mediated
signal transduction cascade which might "normalize" the increased noradrenergic
activity evident in major depression." [Abstract]
C, Chen MJ, Garza AA, Cotman CW, Russo-Neustadt A.
of specific noradrenergic and serotonergic lesions on the expression of hippocampal
brain-derived neurotrophic factor transcripts following voluntary physical activity.
"Previous studies have shown that hippocampal brain-derived
neurotrophic factor (BDNF) mRNA levels are significantly increased in rats allowed
free access to exercise wheels and/or administered antidepressant medications.
Enhancement of BDNF may be crucial for the clinical effect of antidepressant interventions.
Since increased function of the noradrenergic and/or serotonergic systems is thought
to be an important initial mechanism of antidepressant medications, we sought
to test the hypothesis that noradrenergic or serotonergic function is essential
for the increased BDNF transcription occurring with exercise. In addition, individual
transcript variants of BDNF were examined, as evidence exists they are differentially
regulated by discrete interventions, and are expressed in distinct sub-regions
of the hippocampus. The neurotransmitter system-specific neurotoxins p-chloroamphetamine
(serotonergic) and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (noradrenergic)
were administered to rats prior to commencing voluntary wheel-running activity.
In situ hybridization experiments revealed an absence of exercise-induced full-length
BDNF mRNA elevations in the hippocampi of noradrenergic-lesioned rats. In addition,
the striking elevation of the exon I transcript in the dentate gyrus was removed
with this noradrenergic lesion. In contrast, other transcript variants (exons
II and III) were elevated in several hippocampal regions as a result of this lesion.
In serotonin-lesioned rats, the significant increases in full-length BDNF, exon
I and exon II mRNA levels were sustained without alteration (with the exception
of exon IV in the cornus ammonis subregion 4, CA4). Overall, these results indicate
that an intact noradrenergic system may be crucial for the observed ability of
exercise to enhance full-length and exon I hippocampal BDNF mRNA expression. In
addition, these results suggest that the promoter linked to exon I may provide
a major regulatory point for BDNF mRNA expression in the dentate gyrus. Elevations
of other exons, such as II and III, may require the activation of separate neurotransmitter
systems and intracellular pathways." [Abstract]
Mattson MP, Maudsley S, Martin B.
BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders.
Trends Neurosci. 2004 Oct;27(10):589-94.
Brain-derived neurotrophic factor (BDNF) and serotonin (5-hydroxytryptamine, 5-HT) are known to regulate synaptic plasticity, neurogenesis and neuronal survival in the adult brain. These two signals co-regulate one another such that 5-HT stimulates the expression of BDNF, and BDNF enhances the growth and survival of 5-HT neurons. Impaired 5-HT and BDNF signaling is central to depression and anxiety disorders, but could also play important roles in the pathogenesis of several age-related disorders, including insulin resistance syndrome, Alzheimer's disease and Huntington's disease. Enhancement of BDNF signaling may be a key mechanism whereby cognitive stimulation, exercise, dietary restriction and antidepressant drugs preserve brain function during aging. Behavioral and pharmacological manipulations that enhance 5-HT and BDNF signaling could help promote healthy brain aging. [Abstract]
AS, Rodriguez FG, Garcia C, Chen MJ, Russo-Neustadt AA.
and serotonergic blockade inhibits BDNF mRNA activation following exercise and
Pharmacol Biochem Behav. 2003 Apr;75(1):81-8.
and physical exercise have been shown to increase the transcription of hippocampal
brain-derived neurotrophic factor (BDNF). Much evidence regarding the initial
actions of antidepressant medications as well as exercise leads to the hypothesis
that noradrenergic (NE) and/or serotonergic (5-HT) activation is a key element
in the BDNF transcriptional elevation common to both interventions. Currently,
we used short-term beta-adrenergic, 5-HT(1A), or 5-HT(2A/C) receptor blockade
to characterize the influence of NE and 5-HT systems on BDNF transcription during
physical exercise and antidepressant treatment. In situ hybridization revealed
that beta-adrenergic blockade significantly blunted the BDNF mRNA elevations due
to exercise, and also inhibited the modest elevations in the CA3 and dentate gyrus
following short-term treatment with tranylcypromine. In contrast, 5-HT(2A/C) blockade
only minimally altered exercise-induced BDNF mRNA levels, but inhibited up-regulation
of BDNF transcription via tranylcypromine. Finally, 5-HT(1A) blockade did not
inhibit exercise-induced BDNF mRNA elevations, but significantly enhanced levels
above those achieved with exercise alone in the CA4. These results suggest that
NE activation via beta-adrenergic receptors may be essential for both exercise
and antidepressant-induced BDNF regulation. 5-HT(1A) and 5-HT(2A/C) activation,
on the other hand, appear to be most important for antidepressant-induced BDNF
regulation, but may also participate significantly in exercise-induced regulation
in the CA4." [Abstract]
F, Aloe L, Vasquez PJ, Mathe AA.
Mapping the differences in the brain
concentration of brain-derived neurotrophic factor (BDNF) and nerve growth factor
(NGF) in an animal model of depression.
"Antidepressant drugs as well as electroconvulsive
stimuli can significantly influence brain concentrations of neurotrophic factors.
However, it is not known whether the baseline brain concentrations of neurotrophic
factors are altered in human subjects suffering from affective disorders or whether
there are sex differences in concentrations of neurotrophins in human brain. In
order to elucidate some of these questions, we measured by ELISA brain-derived
neurotrophic factor (BDNF) and nerve growth factor (NGF) in an animal model of
depression, the Flinders Sensitive Line (FSL) rats and their controls, the Flinders
Resistant Line (FRL). Altered BDNF and NGF concentrations were found in frontal
cortex, occipital cortex, and hypothalamus of depressed FSL compared to FRL control
rats. Furthermore, different levels of these neurotrophins were also found in
the male and female brain. Cumulatively these observations suggest that BDNF and
NGF may play a role in depression and, hypothetically, different brain regional
concentrations of BDNF and NGF in male and female animals may be relevant to gender
differences in vulnerability to depression." [Abstract]
M, Hayashi T, Su TP.
Nerve growth factor-induced neurite sprouting
in PC12 cells involves sigma-1 receptors: implications for antidepressants.
Pharmacol Exp Ther. 2002 Dec;303(3):1227-37.
"One theory concerning the
action of antidepressants relates to the drugs' ability to induce an adaptive
plasticity in neurons such as neurite sprouting. Certain antidepressants are known
to bind to sigma-1 receptors (Sig-1R) with high affinity. Sig-1R are dynamic endoplasmic
reticulum proteins that are highly concentrated at the tip of growth cones in
cultured cells. We therefore tested the hypotheses that Sig-1R might participate
in the neurite sprouting and that antidepressants with Sig-1R affinity may promote
the neuronal sprouting via Sig-1R. The prototypic Sig-1R agonist (+)-pentazocine
[(+)PTZ], as well as the Sig-1R-active antidepressants imipramine and fluvoxamine,
although ineffective by themselves, were found to enhance the nerve growth factor
(NGF)-induced neurite sprouting in PC12 cells in a dose-dependent manner. A Sig-1R
antagonist N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride
(NE100) blocked the enhancements caused by these Sig-1R agonists. In separate
experiments, we found that NGF dose and time dependently increased Sig-1R in PC12
cells. Chronic treatment of cells with (+)PTZ, imipramine, or fluvoxamine also
increased Sig-1R. These latter results suggested that NGF induces the neurite
sprouting by increasing Sig-1R. Indeed, the overexpression of Sig-1R per se in
PC12 cells enhanced the NGF-induced neurite sprouting. Furthermore, antisense
deoxyoligonucleotides directed against Sig-1R attenuated the NGF-induced neurite
sprouting. Thus, when taken together, our results indicate that Sig-1R play an
important role in the NGF-induced neurite sprouting and that certain antidepressants
may facilitate neuronal sprouting in the brain via Sig-1R." [Abstract]
DH, Shelton RC, Sulser F.
Cross-talk between PKA and PKC in human
fibroblasts: what are the pharmacotherapeutic implications?
Affect Disord. 2001 Aug;65(3):275-9.
"BACKGROUND: The present study was
designed to confirm or refute in human fibroblasts the hypothesized cross-talk
elicited via neurotransmitter transduction cascades at the level of protein kinase
mediated phosphorylation of the nuclear transcription factor CREB. METHODS: Human
fibroblasts from normal control subjects were subcultured and incubated at confluency
after five growth passages with isoproterenol (stimulation of PKA mediated phosphorylation)
and/or phorbol 12-myristate 13-acetate (PMA) (stimulation of PKC mediated phosphorylation)
followed by the determination of nuclear CREB-P by immunoblotting, enhanced chemiluminescence
and quantitation of the autoradiograms by laser densitometry. RESULTS: Using the
nuclear transcription factor CREB as a target, both the activation of the cyclic
AMP-PKA pathway by isoproterenol and the activation of the PKC pathway by PMA
caused phosphorylation of nuclear CREB. This phosphorylation is additive in nature
and appears to occur at the same molecular site, serine133 of CREB. CONCLUSIONS:
The present results in human fibroblasts demonstrate that the hypothesized cross-talk
at the level of protein kinase mediated phosphorylation of transcription factors
is no longer hypothetical. Since it is the phosphorylation of nuclear CREB that
determines its dimerization and transcriptional activation of programs of CRE
containing genes, the results suggest that this convergence of the neurotransmitter
signals may be the critical mechanism in gene expression following the administration
of antidepressant drugs that affect noradrenergic, serotonergic or both transduction
cascades. The results may also provide a rationale for the apparent superior clinical
efficacy of dual uptake inhibitors." [Abstract]
Nakagawa S, Kim JE, Lee R, Chen J, Fujioka T, Malberg
J, Tsuji S, Duman RS.
Localization of phosphorylated cAMP response
element-binding protein in immature neurons of adult hippocampus.
Neurosci. 2002 Nov 15;22(22):9868-76.
"Neurogenesis continues to occur
in the adult hippocampus, although many of the newborn cells degenerate 1-2 weeks
after birth. The number and survival of newborn cells are regulated by a variety
of environmental stimuli, but very little is known about the intracellular signal
transduction pathways that control adult neurogenesis. In the present study, we
examine the expression of the phosphorylated cAMP response element-binding protein
(pCREB) in immature neurons in adult hippocampus and the role of the cAMP cascade
in the survival of new neurons. The results demonstrate that virtually all immature
neurons, identified by triple immunohistochemistry for bromodeoxyuridine (BrdU)
and polysialic acid-neural cell adhesion molecule (PSA-NCAM), are also positive
for pCREB. In addition, upregulation of cAMP (via pharmacological inhibition of
cAMP breakdown or by antidepressant treatment) increases the survival of BrdU-positive
cells. A possible role for pCREB in the regulation of PSA-NCAM, a marker of immature
neurons involved in neuronal remodeling and neurite outgrowth, is supported by
cell culture studies demonstrating that the cAMP-CREB pathway regulates the expression
of a rate-limiting enzyme responsible for the synthesis of PSA-NCAM. These findings
indicate that the cAMP-CREB pathway regulates the survival, and possibly the differentiation
and function, of newborn neurons." [Abstract]