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The Journal of Neuroscience, June 1, 2000, 20(11):4030-4036
cAMP Response Element-Mediated Gene Transcription Is Upregulated
by Chronic Antidepressant Treatment
J.
Thome1,
N.
Sakai1,
K.-H.
Shin1,
C.
Steffen1,
Y.-J.
Zhang1,
S.
Impey2,
D.
Storm2, and
R. S.
Duman1
1 Division of Molecular Psychiatry, Yale University
School of Medicine, New Haven, Connecticut 06508, and
2 Department of Pharmacology, University of Washington,
Seattle, Washington 98195
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ABSTRACT |
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 agents.
Key words:
CRE enhancer;  -galactosidase; gene transcription; phosphorylation; fluoxetine; desipramine; tranylcypromine
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INTRODUCTION |
Although the acute action of
antidepressant treatment is known to be mediated by blockade of the
reuptake or breakdown of serotonin (5-HT) and norepinephrine (NE), the
molecular adaptations underlying the therapeutic action of these agents
has not been determined. One signal transduction pathway that has been
implicated in the action of antidepressant treatment is the cAMP second
messenger cascade. Recent studies have demonstrated that different
classes of antidepressants upregulate the cAMP system at several sites, including increased Gs activation of adenylyl cyclase (Ozawa and Rasenick, 1991 ) and upregulation of cAMP-dependent protein kinase (PKA)
(Nestler et al., 1989; Perez et al., 1989). In addition, inhibition of
cAMP metabolism produces antidepressant-like effects in behavioral
models of depression (Wachtel, 1983; Griebel et al., 1991;
O'Donnell, 1993) as well as therapeutic responses in depressed
patients (Horowski and Sastre-Y-Hernandez, 1985; Bobon et al.,
1988; Fleischhacker et al., 1992; Malison et al., 1997).
One potential target of the cAMP system that could mediate the action
of antidepressants is the cAMP response element binding protein (CREB)
(Montminy, 1990; Meyer and Habener, 1993). CREB is a
transcription factor that mediates the actions of cAMP on gene
expression and could thereby underlie some of the long-term effects of
antidepressant treatment. A role for CREB in the action of
antidepressants is supported by studies demonstrating that chronic
antidepressant treatment increases the expression of CREB in limbic
regions of rat brain (Nibuya et al., 1996). CREB regulates gene
transcription by binding to a cAMP response element (CRE), a
cis-acting enhancer element in the regulatory region of
various genes. The function of CREB is regulated largely by its state of phosphorylation at Ser133, which
results in activation of gene transcription (Montminy, 1990;
Meyer and Habener, 1993). Phosphorylation of CREB at
Ser133 can occur via activation of the
cAMP cascade and PKA, but also via activation of calcium-dependent
protein kinases (i.e., protein kinase C and
calcium/calmodulin-dependent protein kinase) (Duman et al., 1997,
1999). This raises the possibility that CREB could act as a common
downstream target of different classes of antidepressants that
influence 5-HT and/or NE (Duman et al., 1997, 1999).
The focus of the present study is to determine the influence of
antidepressant treatment on the function of CREB. This is a critical
issue because although CREB expression is upregulated by antidepressant
treatment, the function of this transcription factor could be unchanged
without a corresponding increase in phosphorylation. To address this
issue, the influence of antidepressant administration on CRE-mediated
gene expression and CREB phosphorylation were examined in CRE-LacZ
transgenic mice. The transgene in these mice is a CRE-LacZ reporter
gene construct, and stimulation of the CRE site leads to increased
expression of the LacZ gene product, -galactosidase. These mice have
been used to establish the role of CRE-mediated gene expression in
cellular and behavioral models of learning and memory and in circadian
rhythm (Impey et al., 1996, 1998; Obrietan et al., 1998; Pham et al.,
1999).
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MATERIALS AND METHODS |
CRE-LacZ transgenic mice. All experiments were
conducted in mice heterozygous for the CRE-LacZ reporter gene
construct. This construct consists of six tandem CREs upstream of a
minimal HSV promoter driving the expression of -galactosidase
(Meinkoth et al., 1990). The mice were generated using C57BL6/SJL F2
blastocytes for microinjection; founders were bred to C57BL6 mice
(Impey et al., 1996). The animals were bred and maintained under
standard conditions (12 hr light/dark cycle, food and water ad
libitum). PCR was used to determine the genotype of individual
mice. All animal use procedures were in strict accordance with the
National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Yale Animal Care and Use Committee.
Drug administration paradigms. For chronic paradigms,
fluoxetine (10 mg/kg, i.p.), desipramine (15 mg/kg, i.p.), or
tranylcypromine (10 mg/kg, i.p.) was administered daily for 14 d.
For acute paradigms, mice received 0.9% saline (i.p.) daily for
13 d and a single injection of tranylcypromine, desipramine, or
fluoxetine (i.p.) on day 14 (same dose as above). Control animals were
administered 0.9% saline (i.p.) for 14 d. Haloperidol (1 mg/kg,
i.p.) or cocaine (10 mg/kg, i.p.) were administered daily for 14 d.
-Galactosidase staining. Mice were killed 6 hr
after the last injection. After perfusion with 0.9% NaCl solution and
4% paraformaldehyde, the brains were post-fixed overnight and
cryoprotected in 20% glycerol. Fluorescence immunohistochemistry was
performed using standard protocols. Briefly, 40 µm sections were
incubated with rabbit anti -galactosidase antibody at 1:1000
dilution (ICN Biochemicals, Costa Mesa, CA) and Alexa 594 goat
anti-rabbit IgG at 3 µg/ml (Molecular Probes, Eugene, OR).
Sections were counterstained with 4',6-diamidino-2-phenylindole (DAPI)
(see below). Images were captured on a Zeiss Axioskop fluorescence microscope.
Phosphorylation of CREB. After blocking with BSA and goat
serum, free-floating sections were incubated overnight with
anti-phosphorylated CREB (phospho-CREB) antibody from rabbit (New
England Biolabs, Beverly, MA) at 1:250 dilution. A second overnight
incubation was performed with 2.5 µg/ml fluorescin-labeled
anti-rabbit IgG antibody (Jackson ImmunoResearch, West Grove, PA), and
a third was performed with 4 µg/ml Alexa 488-antifluorescin antibody
(Molecular Probes). This method involving three antibodies results in a
considerable enhancement of the fluorescence signal. Between each
incubation step with antibody, stringent washing steps with PBS
containing NaF and Triton X-100 were performed.
Counterstaining. Vectashield Mounting Medium with DAPI
(Vector Laboratories, Burlingame, CA) was used for counterstaining. The
DAPI fluorophore binds to cellular DNA, allowing for fluorescence visualization of the cells. DAPI produces a blue fluorescence with
excitation at 360 nm and emission at 460 nm when bound to DNA. There is
no emission overlap with fluorescin, rhodamine, Texas Red, or the
fluorophores used for -galactosidase or phospho-CREB immunolabeling.
Data analysis. Images were evaluated using a four point
score system (0 = minimal, 1 = weak, 2 = intermediate,
3 = strong immunoreactivity) by two independent investigators
blinded to the treatment condition. The Kruskal-Wallis test was
performed for statistical analysis. The level of significance was
p < 0.05. A trend or tendency was assumed by
p < 0.10. Similar results were obtained when
quantified by densitometry of digitalized images. For this approach,
the images were converted into gray-scale pictures. The appropriate
areas were outlined, and staining intensity was determined using IPLab
Spectrum-Scientific Image Processing, Version 3.1.2 (Scanalytics,
Inc.).
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RESULTS |
Chronic antidepressant administration increases CRE-mediated
gene expression
To measure CRE-mediated gene expression in the CRE-LacZ
transgenic mice, levels of the LacZ gene product, -galactosidase, were determined by fluorescence immunohistochemistry. Relatively low
levels of -galactosidase were observed in most brain regions in
saline-treated mice, particularly the dentate gyrus of hippocampus and
cerebral cortex (Figs. 1,
2). Relatively higher levels of immunoreactivity were observed in amygdala and hypothalamus (Figs. 1,
2).
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Figure 1.
Chronic fluoxetine administration increases
CRE-mediated gene expression and CREB phosphorylation in brain. Mice
were administered saline or fluoxetine once daily for 14 d, and
the brains were processed for -galactosidase (CRE-LacZ) or
phospho-CREB immunohistochemistry 6 hr after the last treatment.
Representative images of -galactosidase
(left/red,
A-L) or phospho-CREB
(right/green,
A-L) are shown. The brain regions that
were examined include cerebral cortex (A,
B), amygdala (C, D),
dentate gyrus granule cell layer (E,
F), CA3 pyramidal cell layer (G,
H), hypothalamus (I,
J), and thalamus (K,
L). Images from saline-treated (A,
C, E, G, I,
K) and fluoxetine-treated (B,
D, F, H, J,
L) animals are shown. The subregions that are labeled
include layers II-III and IV-VI of cerebral cortex; central
(CeA), basolateral (BLA), and basomedial
(BMA) nuclei of the amygdala; dentate gyrus
(DG) granule cell layer, and CA3 and CA1 pyramidal cell
layers of hippocampus; dorsomedial (DM) and
ventromedial (VM) nuclei of the hypothalamus;
paraventricular nucleus of the thalamus (PVTh); and
third ventricle (3v).
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Figure 2.
Chronic antidepressant administration
increases CRE-mediated gene expression in brain. Mice were administered
saline, fluoxetine, desipramine, or tranylcypromine once daily for
14 d, and 6 hr after the last treatment -galactosidase
immunohistochemistry was conducted as described in Materials and
Methods. Levels of -galactosidase were scored as described in
Materials and Methods. The results are presented as the mean ± SEM of four to six separate determinations. *p < 0.05,  p < 0.10 compared with
saline (Kruskal-Wallis).
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The influence of chronic administration of several different classes of
antidepressants, including a 5-HT selective reuptake inhibitor
(fluoxetine), a norepinephrine selective reuptake inhibitor (desipramine), and a monoamine oxidase inhibitor (tranylcypromine), on
levels of CRE-induced LacZ expression were tested. Mice were administered saline or antidepressants for 14 d, and the brains were processed for levels of -galactosidase immunoreactivity 6 hr
after the last treatment. The results demonstrate that chronic antidepressant administration significantly increases levels of CRE-mediated gene expression in several brain regions, although differences were observed in the regional pattern of expression between
the different classes of antidepressants. Chronic administration of
each of the antidepressants significantly increased levels of
-galactosidase immunoreactivity in the amygdala. The subregions of
amygdala that were influenced include the central, basolateral, and
basomedial nuclei. Chronic administration of tranylcypromine or
fluoxetine, but not desipramine, also induced CRE-mediated gene
transcription in the cerebral cortex, including superficial and deep
layers. Chronic administration of tranylcypromine additionally increased levels of -galactosidase immunoreactivity in the
hippocampus (CA3 pyramidal cell layer), and there was a tendency for an
increase in the hypothalamus (dorsomedial and ventromedial nuclei). A
tendency for an increase was also observed in the dentate gyrus granule cell layer, but this effect was small and did not achieve significance. Chronic fluoxetine administration also resulted in a tendency for
induction of -galactosidase immunoreactivity in the thalamus, and
there were as well tendencies toward elevated levels in the CA3
pyramidal cell layer and hypothalamus. No alterations were observed in
the CA1 pyramidal cell layer of the hippocampus. For most experiments,
the immunohistochemical results were quantified using a subjective
scoring scale (see Materials and Methods). However, similar results
were obtained for chronic fluoxetine when the digitalized images were
quantified by densitometry (Table 1).
In contrast to the chronic paradigms, acute antidepressant
administration induced CRE-mediated gene expression to a much lower level. For the acute studies, mice received saline injections for
13 d, and on day 14 received either saline or an antidepressant at
the same dose used for the chronic paradigm. The repeated saline injections were conducted to acclimate the mice to the stress associated with the handling and injections. The brains were then processed for levels of -galactosidase immunohistochemistry 6 hr
after saline or drug treatment. No significant effects were observed in
any of the brain regions examined after acute administration of
fluoxetine or desipramine (Table 2).
Acute administration of tranylcypromine significantly increased
-galactosidase immunoreactivity in hypothalamus, and there was a
similar trend in the thalamus and dentate gyrus. However, there was no
significant effect of acute tranylcypromine administration in any of
the other brain regions examined.
To determine whether the induction of CRE-mediated gene expression is
specific to antidepressants, two other classes of psychotropic drugs
were examined. This included an antipsychotic (haloperidol) and a
psychostimulant (cocaine). However, chronic administration of these
nonantidepressant drugs did not significantly influence levels of
-galactosidase immunoreactivity in any of the brain regions examined
(Table 3).
Chronic antidepressant administration increases the phosphorylation
of CREB
To study the possible mechanisms underlying the induction of
CRE-mediated gene expression, the influence of antidepressants on the
phosphorylation of CREB was examined. Levels of phospho-CREB were
determined by fluorescence immunohistochemistry using an antibody
specific for the phosphorylated form of CREB. Alternate sections from
the same brains used for analysis of -galactosidase immunohistochemistry were used for most experiments. Phospho-CREB immunoreactivity was observed in most brain regions of saline-treated mice, including the dentate gyrus granule cell layer and the cerebral cortex. Relatively high levels of immunoreactivity were found in
amygdala and hypothalamus.
Chronic administration of fluoxetine significantly increased levels of
phospho-CREB immunoreactivity in several brain regions, including
amygdala, cerebral cortex, dentate gyrus granule cell layer, thalamus,
and hypothalamus (Figs. 1, 3). The
subregions that were influenced within each of these areas were similar
to those observed for -galactosidase immunohistochemistry. Chronic administration of desipramine also increased phospho-CREB
immunoreactivity in the dentate gyrus granule cell layer, although to a
lower level than observed with fluoxetine. No significant effects were
observed in response to chronic desipramine administration in any of
the other brain regions examined. The influence of tranylcypromine administration on levels of phospho-CREB immunoreactivity was not
determined.
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Figure 3.
Chronic antidepressant administration increases
CREB phosphorylation in brain. Mice were administered saline,
fluoxetine, or desipramine once daily for 14 d, and 6 hr after the
last treatment phospho-CREB immunohistochemistry was conducted as
described in Materials and Methods. Levels of phospho-CREB staining
were scored, and results are presented as the mean ± SEM of four
to six separate determinations. *p < 0.05 compared
with saline (Kruskal-Wallis).
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The influence of acute antidepressant administration on levels of
phospho-CREB was also examined. Alternate sections from the mouse
brains used for -galactosidase immunohistochemistry were used for
these experiments. Acute administration of fluoxetine or desipramine
did not significantly influence levels of phospho-CREB immunostaining
in any of the brain regions examined (Table
4). However, there was a tendency for
acute administration of these antidepressants to increase levels of
phospho-CREB in the dentate gyrus granule cell layer of
hippocampus.
Several other classes of psychotropic drugs were also examined to
determine whether the induction of phospho-CREB was specific to
antidepressants. Chronic administration of haloperidol or cocaine did
not significantly influence levels of phospho-CREB immunoreactivity in
any of the brain regions examined (data not shown).
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DISCUSSION |
The results of this study demonstrate that chronic antidepressant
administration increases CRE-mediated gene expression and CREB
phosphorylation in a region- and drug-specific manner. The most
consistent effects observed between the different antidepressants tested were in the amygdala and cerebral cortex. In addition, significant effects were observed in several other limbic brain regions, including the hippocampus, hypothalamus, and thalamus. Induction of CRE-mediated gene expression and CREB phosphorylation were
observed in response to chronic, but not acute, antidepressant administration, consistent with the time course for the therapeutic action of these agents. Induction of CRE-mediated gene expression in
these brain regions appears to be relatively specific to
antidepressants in that administration of nonantidepressant
psychotropic drugs does not result in similar effects. These
results demonstrate that induction of CRE-mediated gene expression in
specific limbic brain structures is an intracellular target of
different classes of antidepressants.
The time lag for induction of CRE-mediated gene expression could result
from the time required for upregulation of one or more of the upstream
components of the cAMP cascade. Previous studies have demonstrated that
upregulation of PKA enzyme activity and induction of CREB expression is
dependent on chronic antidepressant treatment (Duman et al., 1999).
There is also a corresponding delay in the upregulation of CRE binding
in response to antidepressant administration (Nibuya et al., 1996;
Frechilla et al., 1998). In addition, it is possible that
adaptations of 5-HT and NE autoreceptors and monoamine
neurotransmission contribute to a stable upregulation of the cAMP
cascade and consequently of CRE-mediated gene expression (Blier and de
Montigny, 1994).
Both the NE and 5-HT selective reuptake inhibitors increase
CRE-mediated gene expression and CREB phosphorylation in amygdala. In
contrast, fluoxetine, but not desipramine, significantly increases -galactosidase and CREB phosphorylation in cerebral cortex. Chronic fluoxetine administration also increases phospho-CREB in several other
limbic structures, including the dentate gyrus, hypothalamus, and
thalamus. The reasons for these regional differences between fluoxetine
and desipramine are not clear because these structures receive diffuse
projections from both the NE and 5-HT systems. However, there is
evidence for a more rapid adaptation of autoreceptor inhibition of the
5-HT than the NE neurotransmitter system (Blier and de Montigny,
1994). Alternatively, it is possible that higher brain levels of
fluoxetine are achieved because of its relatively long half-life. It is
notable that there is a tendency for desipramine to increase
phospho-CREB in brain regions in which fluoxetine produces a
significant effect (i.e., dentate gyrus and thalamus). It is possible
that a higher dose of desipramine would produce a significant response,
although we were not able to test this possibility because of the side
effects of this antidepressant. It will be interesting to examine more
selective NE reuptake inhibitors with fewer side effects, such as
reboxetine, to further study the influence of the NE system on
CRE-mediated gene expression.
The corresponding induction of phospho-CREB and -galactosidase
in amygdala and cerebral cortex indicates that CREB phosphorylation could mediate the induction of CRE-mediated gene expression in these
brain regions. However, it was somewhat surprising to find that there
was not a significant induction of CRE-mediated gene expression in some
brain regions where there was an induction of phospho-CREB (i.e.,
dentate gyrus, hypothalamus, and thalamus in response to fluoxetine).
It is conceivable that transcription factors other than CREB are also
required for induction of CRE-mediated gene expression and that these
transcription factors are not regulated by antidepressants in all brain
regions. This is consistent with previous reports that phosphorylation
of CREB at Ser133 is not always sufficient
to induce CRE-mediated gene expression (Enslen et al.,
1994; Thompson et al., 1995; Impey et al., 1998). Alternatively, the
induction of -galactosidase may not be as responsive as
phospho-CREB. This possibility is supported by the observation that
there was a trend for an induction of -galactosidase in some of the
brain regions where an induction of phospho-CREB was observed (i.e.,
thalamus and hypothalamus).
Antidepressant induction of CREB phosphorylation and CRE-mediated gene
expression is observed in brain structures that are thought to play a
role in the regulation of emotion and responses to stress. Moreover,
clinical studies have reported that there are alterations in blood
flow, volume, and neurochemistry of many of these same brain regions in
depressed patients. For example, previous studies have demonstrated
that amygdala mediates some of the behavioral actions of
antidepressants and that neurochemical adaptations to antidepressants
are observed in this brain region (Ordway et al., 1991; Beck and
Fibiger, 1995; Duncan et al., 1996; Dawes et al., 1998; Morelli et al.,
1999). In addition, clinical brain imaging studies report alterations
in blood flow and glucose metabolism in amygdala of depressed patients
(Drevets et al., 1992). The amygdala plays a significant role in
fear conditioning and conditioned avoidance behavior and is thought to
encode the emotional component of aversive stimulus conditioning
(Fanselow et al., 1999; Holland and Gallagher, 1999). The
possibility that CREB influences the function of amygdala is supported
by a recent report that overexpression of CREB in this brain regions
alters long-term memory of fearful conditions (Josselyn et al.,
2000). On the basis of these observations, it is also possible
that neurochemical alterations in amygdala could contribute to the
displaced emotion, as well as anxiety, that is often observed in
depressed patients. The possibility that CREB influences amygdala
function can be directly tested by studying the influence of the
cAMP-CREB cascade on behavioral models of depression, as well as
behaviors that are controlled by amygdala (i.e., fear conditioning and
conditioned avoidance behavior).
Chronic antidepressant treatment also results in neurochemical and
cellular adaptations in cerebral cortex and hippocampus. A role for
CREB is supported by the results of our previous reports and the
present study, which demonstrate that chronic antidepressant treatment
increases the expression and function of CREB in these brain regions
(Nibuya et al., 1995, 1996; Duman et al., 1997, 1999). In addition, we
have found that antidepressant administration increases the expression
of BDNF in hippocampus. The possibility that induction of BDNF is
mediated by CREB is supported by recent reports that the promoter of
the BDNF gene contains a CRE (Shieh et al., 1998; Tao et al., 1998).
Upregulation of CREB and BDNF could act to oppose the damaging effects
of stress on hippocampal neurons (Sapolsky, 1996; McEwen, 1999).
Clinical studies also report a reduction in the volume and/or number of
neurons in hippocampus and cerebral cortex of depressed patients
(Sheline et al., 1996; Drevets et al., 1997; Ongur et al., 1998;
Rajkowska et al., 1999). A role for CREB in the pathophysiology of
depression is supported by a postmortem study demonstrating that CREB
levels are decreased in the cerebral cortex of depressed patients and
increased in patients receiving antidepressant medication at the time
of death (Dowlatshahi et al., 1998).
Alterations in the function of hippocampus and cerebral cortex could
also contribute to the cognitive deficits that are often observed in
depressed patients. The cAMP cascade is reported to be integrally
involved in the cellular adaptations underlying learning and memory in
these brain regions (Abel et al., 1997; Taylor et al., 1999). On the
basis of these findings and the results of the present study, it is
possible that amelioration of the cognitive deficits in depressed
patients could result, at least in part, from upregulation of
CRE-mediated gene expression in response to antidepressant treatment.
The actions of antidepressants on the hypothalamus and thalamus are not
as well characterized. The dorsomedial and ventromedial regions of the
hypothalamus are reported to play a role in vegetative behaviors (e.g.,
eating and sexual drive) that are also abnormal in
depression. It is possible that induction of CRE-mediated gene expression in these hypothalamic nuclei normalizes these abnormalities. There was no effect in the paraventricular nucleus of the hypothalamus, which controls the hypothalamic-pituitary adrenal (HPA) axis in response to stress. Interestingly, the paraventricular
nucleus of the thalamus is another stress-responsive brain structure
that is reported to exert negative control on the HPA axis (Bhatnagar and Dallman, 1998). Upregulation of CRE-mediated gene expression in
this structure could contribute to normalization of HPA function in
response to chronic antidepressant treatment.
The results of this study demonstrate that induction of CRE-mediated
gene expression is a common action of antidepressant treatment. The
challenge now is to directly test the role of CREB on the cellular,
behavioral, and endocrine responses that are regulated by specific
limbic brain structures. Studies are currently underway to address
these questions using viral vectors and transgenic mice to determine
the functional responses to overexpression of CREB in specific brain
regions. Another challenge is to identify the target genes, in addition
to BDNF, that are influenced by CREB and antidepressant treatment. One
approach is to use DNA microarray technology to identify gene targets
of the cAMP-CREB cascade and antidepressants. The results of the
present study, in combination with these future approaches, should
provide a more complete characterization of the role of CREB in the
action of antidepressants, as well as the gene targets that mediate the therapeutic response to these agents.
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FOOTNOTES |
Received Oct. 27, 1999; revised Jan. 28, 2000; accepted Feb. 2, 2000.
This work was supported by United States Public Health Service Grants
MH45481, MH53199, and 2 PO1 MH25642, a Veterans Administration (VA)
National Center Grant for Post-Traumatic Stress Disorder, VA
Medical Center, and German Research Council Grant DFG Th698/1-1.
Correspondence should be addressed to R. S. Duman, 34 Park Street,
New Haven, CT 06508. E-mail:
ronald.duman{at}yale.edu.
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