Current Pharmaceutical Design, 2011, 17, 521-533 521

New Strategies in the Development of Antidepressants: Towards the Modulation of

Neuroplasticity Pathways

Rebeca Vidal1,2,3*, Fuencisla Pilar-Cuéllar1,2,3,*, Severiano dos Anjos1,2,3, Raquel Linge1,2,3, Begoña
Treceño1,2,3, Verónica Inés Vargas1,2,3, Antonio Rodriguez-Gaztelumendi
,1,2,3, Ricardo Mostany£,2,
Elena Castro1,2,3, Alvaro Diaz1,2,3, Elsa M. Valdizán1,2,3 and Angel Pazos1,2,3,$

1
Instituto de Biomedicina y Biotecnología (IBBTEC) (UC-CSIC-IDICAN), Santander, Cantabria, Departamento de Fisiología y
Farmacología, Universidad de Cantabria, 2Departamento de Fisiología y Farmacología, Universidad de Cantabria, Spain,
3
CIBERSAM, Ciber de Salud Mental, Instituto Carlos III, Spain

Abstract: Over the past five decades, the pharmacological treatment of depression has been based on the pathophysiological hypothesis
of a deficiency in monoamines, mainly serotonin and noradrenaline. Antidepressants prescribed today, all of them designed to enhance
central monoaminergic tone, present several important limitations, including a 2-5 weeks response lag and also a limited clinical efficacy.
As it is increasingly evident that the abnormalities associated to depression go beyond monoamines, the development of better antide-
pressants will depend on the identification and understanding of new cellular targets. In this regard, much evidence supports a role for
cellular and molecular mechanisms of neuroplasticity, including neurotrophic inputs, in mood disorders, in parallel with the biological
features associated to stress conditions. In order to illustrate the possible relevance of neuroplasticity-related pathways for the therapy of
depressive states, we here review the biological evidence supporting some therapeutic strategies in a very initial phase of development
(modulation of the Wnt/GSK-3/-catenin pathway, potentiation of endocannabinoid activity, agonism of 5-HT4 receptors), which in-
volve modulation of downstream mechanisms and neuroplasticity circuits. These strategies also show the existence of mixed mechanisms
of action, constituting a nexus between the “classic” aminergic theory and the “new” neuroplasticity hypothesis.
Keywords: Antidepressant, stress, neuroplasticity, -catenin, endocannabinoid, 5-HT4 receptors.

INTRODUCTION In the late 90’s a new hypothesis was suggested to explain

The hypothesis of a monoaminergic deficiency has determined
in the past the basis of therapeutic approaches in the field of depres-
sion, as well as of the research in this field [1, 2]. First evidence
emerged in the 50’s after observing that the administration of reser-
pine, an antihypertensive drug, induced depressive states associated
with the depletion of the catecolaminergic stores. A few years later,
the antidepressant efficacy in humans of iproniazid and imipramine,
two compounds developed for non-psychiatric disorders, was acci-
dentally discovered. These findings led to the development of new
antidepressant drugs with clinical efficacy: tricyclic antidepressants
(TCAs), monoamine oxidase inhibitors (MAOIs) and, more re-
cently, selective monoamine reuptake inhibitors [3]. Current anti-
depressants, which elevate central monoamines, are among the
most widely prescribed drugs. However, the monoaminergic hy-
pothesis has been questioned repeatedly since it does not explain
completely the mechanism of action of antidepressants or the
pathophysiology of depression. Several weeks are necessary for
their antidepressant efficacy, in spite of the fact that the increase in
monoamine concentrations in synaptic cleft occurs in a few hours
[4]. On the other hand, it has been demonstrated that some drugs
which increase monoamine levels are not effective in depression
[5]. Together, these facts suggest that although central monoamines
might contribute to the generation of depressive states, the cause of
depression is far from being only a simple deficiency of central
noradrenaline and/or serotonin activity.
$
Address correspondence to these authors at the Department of Physiology
and Pharmacology, School of Medicine, Cardenal Herrera Oria s/n, Univer-
sity of Cantabria 39011 Santander, Spain; Tel.: +34-942201985;
Fax: +34-942-201903; E-mail: pazosa@unican.es


Department of Pharmacology and Clinical Neuroscience, Umeå University,
SE-901 87 Umeå, Sweden.
£
Departments of Neurology and Neurobiology, David Geffen School of
Medicine at University of California, Los Angeles, Los Angeles, California
90095, USA.
* These authors contributed equally to this work.
major depression on the basis of the changes in stress-vulnerable
hippocampal neurons and the possible role of neurotrophic factors
[6]. A morphologic and morphometric analysis of the hippocampus
in depressed patients frequently reveals structural changes [7, 8, 9]
that go beyond volume loss and include gray matter alterations. To
a certain degree, these alterations seem to be reversible in the re-
mission phases of the disease [10]. Furthermore, it is now well
documented that chronic antidepressant treatment enhances cell
proliferation in adult rodent and nonhuman primate subgranular
zone (SGZ) of hippocampus and that the time required for the
differentiation and maturation of newborn neurons correlates well
with the appearance of clinical response to the antidepressant treat-
ment [11, 12, 13]. Adult hippocampal neurogenesis varies greatly in
response to numerous kinds of stimuli [14]. Among these, the bio-
chemical changes associated with stress and depression, such as
hypercortisolaemia or alterations in the serotonergic system, not
only influence general hippocampal morphology but also affect
adult hippocampal neurogenesis [9]. Furthermore, antidepressant
treatments also increase BDNF level through an increase in cAMP
and further CREB activation that activates a series of genes such as
BDNF and other trophic factors [15]. In human, the reduction of the
rate of proliferation in hippocampus is accompanied by a reduction
in brain derived neurotrophic factor (BDNF) levels in serum [16],
lymphocytes and platelets [17] and brain [18], as observed also in
animal models [19, 20]. Furthermore, studies in mice show that an
increase of BDNF in the dentate gyrus of the hippocampus, but not
in the CA1 region, is necessary to obtain behavioral effects after
antidepressant treatment [21]. Taken together, all these results have
allowed the development of a novel theory on the basis of major
depression, supporting a critical role for the cellular and molecular
mechanisms of neuroplasticity in the pathophysiology of this dis-
ease [22].
The study of the mechanisms underlying depression has been
limited by the lack of good animal models to work on. This prob-
lem is mainly due to the difficulty in identifying in the animals
signs which could correspond to symptoms observed in human

1381-6128/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd.

522 Current Pharmaceutical Design, 2011, Vol. 17, No. 5 Vidal et al.

depression. Another difficulty comes from the lack of a known gene
or molecule acting as the main responsible of this illness, as its
etiology is still unknown [23]. In humans, besides depressed or
irritable mood, depression also includes cognitive symptoms (guilt
and suicidality), emotional symptoms (anhedonia), homeostatic or
‘neurovegetative’ symptoms (abnormalities in sleep, appetite,
weight and energy), and psychomotor agitation or retardation. Only
a subset (homeostatic symptoms, anhedonia and psychomotor
behavior) can be measured objectively in rodents. Nevertheless and
bearing in mind these limitations, some animal models of depres-
sion have been generated, including selective breeding (i.e. Flinders
sensitive line rats), brain lesions (i.e. bilateral olfactory bulbec-
tomy) and environmental stress (i.e. learned helpless, forced swim-
ming test or chronic mild stress) [24].
Stress induces a series of responses of the body to maintain the
homeostasis in adverse life events. Depression is often character-
ized by excessive activity of the hypothalamic-pituitary-adrenal
(HPA) axis that regulates stress. The dysregulation of the HPA axis,
leading to a hypersecretion of corticotrophin releasing factor (CRF)
and cortisol is observed in 30 to 50% cases of major depression
[25]. Elevated levels of cortisol in some patients with depression
can also result from a reduced negative feedback response to corti-
sol that is reflected by a nonsuppression response in the dexametha-
sone suppression test. Hypercortisolaemia has been examined as a
potential predictor of various outcomes as well as one cause of the
brain structural anomalies observed in depressed patients [26].
Some of the animal models used in the study of depression are
based on this dysregulation, as it is the case of the chronic mild
stress [27], and the corticosterone model [28], in which a depres-
sive-like phenotype and altered hippocampal neurogenesis have
been reported. Another valuable model is based on the use of glu-
cocorticoid receptor (GR) heterozygous mice (GR +/-) that exhibits
a depression-related phenotype characterized by increased learned
helplessness on the behavioral level, neuroendocrine alterations
with hypothalamo-pituitary-adrenal (HPA) axis overactivity, and
reduced hippocampal BNDF expression [29].
On the other hand, the bilateral ablation of the olfactory bulbs
precipitates complex changes of behavioral, neurochemical, and
neuroimmunological parameters, similar to those observed in pa-
tients with major depression. This animal model has been proposed
as a model for chronic psychomotor agitated depression in which
there is an impaired serotonergic neurotransmission [30, 31]. Bul-
bectomy is associated with structural changes within the hippocam-
pus that are reversed by chronic antidepressant treatments [32].
This is of particular interest given the hypothesis that stress induced
neurodegeneration of hippocampal neurons can be reversed by
chronic antidepressant treatment, thereby suggesting that bulbec-
tomy results in an increased vulnerability of the rat to the adverse
impact of environmental stress. Moreover, it has also a high predic-
tive validity to chronic, but not acute, antidepressant treatment [30,
31].
FOCUSING ON NEUROPLASTICITY: A ROLE FOR THE
WNT/GSK-3/-CATENIN PATHWAY IN THE MEDIA-
TION OF ANTIDEPRESSANT RESPONSES
The Wnt/-catenin pathway has been classically involved in the
regulation of cellular proliferation, mainly through the activation of
transcription factors at the nuclear level. In this regard, its role in
cancer is well known [33]. Activation of the canonical Wnt path-
way leads to the inhibition of GSK-3, allowing -catenin to be
stabilized in the cytosol (see Fig. 1) and translocated to the nucleus,
where it activates transcription of target genes [34].

Fig. (1). Different pathways that are activated following antidepressant treatments. Activation of Gs or Gi by different receptors (i.e.: serotonin 5-HT4 or
cannabinoid, respectively), produce changes in cAMP levels modulating the activation of cAMP response element-binding protein (CREB) cascade, via
cAMP-dependent protein kinase (PKA), PKC and/or Akt proteins, respectively. The activation of CREB leads to an increase of brain-derived neurotrophic
factor (BDNF) that binds to tyrosine kinase (trkB) receptors and activates Ras/MAPK pathway, maintaining synaptic function and neural plasticity.
BDNF/TrkB can also activate CREB through activation of PI3K and Akt, or via MAPK pathway. Regarding Wnt/-catenin pathway, the canonical pathway
acts through activation of frizzled receptors that results in the inhibition of GSK-3, increasing the amount of cytoplasmic -catenin that translocates to the
nucleus, activating TCF/Lef transcription factors. The Wnt/-catenin pathway can be also activated through inhibition of GSK-3 by Akt, promoted by G-
protein coupled receptors.
New Antidepressant Targets Current Pharmaceutical Design, 2011, Vol. 17, No. 5 523

In the last years, the role of this pathway in neural development,

through the modulation of neural stem cells (NSC), proliferation
and differentiation, has been clearly demonstrated [35]. Some of the
processes regulated by Wnt/-catenin activity are: neural differen-
tiation [36], hippocampal formation [37, 38], dendritic morpho-
genesis [39], axon guidance [40, 41] and synapse formation [42].
Moreover, it also plays a role in spatial learning [43] and memory,
including long term potentiation (LTP) phenomena [44]. On the
other hand it is of relevance the reported existence of an overex-
pression of GSK-3 in Alzheimer’s disease, leading to the attempts
to develop inhibitors of this kinase as possible therapeutic tools for
this disorder [45]. These results reinforce the interest of the
Wnt/GSK-3/-catenin pathway as a candidate for developing new
pharmacological treatments for neurological and psychiatric disor-
ders.
Recent studies have also identified the Wnt/GSK-3/-catenin
signaling pathway as a key regulator of adult neurogenesis in hip-
pocampus [35, 46] or subventricular zone [47]. NSC in the adult
hippocampus express several Wnts as well as their corresponding
receptors, and therefore receive Wnt signals produced not only
from astrocytes but also from themselves [35, 48]. The autocrine
signaling of Wnt, results in the proliferation and multipotency of
NSC through the canonical pathway. Because of all that, the possi-
ble involvement of Wnt/-catenin signaling in the responses in-
duced by long-term administration of antidepressants has to be
taken into account.
Interestingly, an upregulation of this system has been reported
following electroconvulsive therapies [46]. Moreover, it is well
known that the treatment with lithium modifies GSK-3 activity
[49, 50], further supporting its role in antidepressant responses.
We have demonstrated that chronic administration of antide-
pressants (14 days), such as the serotonin-noradrenaline reuptake
inhibitor (SNRI) venlafaxine [51] (Figs. 2,3) or the serotonin reup-
take inhibitor (SSRI) fluoxetine (unpublished data) (Fig. 3) resulted
in the nuclear accumulation of -catenin in the subgranular cell
layer of the dentate gyrus of the hippocampus [47] (Figs. 2,3). -
catenin expression was increased in both membrane and nuclear
fractions of the hippocampus [51] (Fig. 3), after venlafaxine treat-
ment, and immunoelectron microscopy studies further demonstrated
an increased presence of -catenin at the nuclear level. In parallel
with that, increased cell proliferation (BrdU incorporation) in sub-
granular zone (SGZ) was achieved after chronic treatment with a
high dose of venlafaxine [51]. Electroconvulsive therapy, known to
present antidepressant efficacy also results in an increased expres- Fig. (2). Immunohystochemical images representative of the increase of -
sion of -catenin in cytosolic and nuclear fractions of the hippo- catenin+ clusters in the subgranular zone (SGZ) of the dentate gyrus of the
campus [46]. hippocampus associated to chronic antidepressant treatment: vehicle (A),
Interestingly, we have very recently found that the antidepres- venlafaxine 10 mg/kg/day (B) and venlafaxine 40 mg/kg/day (C). Note that
sant-like behavior observed following the administration of the the increase in labeling is more outstanding at a higher dose.
SSRI fluoxetine in combination with a 5-HT2A antagonist for 7 days
is paralleled by an increase of -catenin in the hippocampal mem-
brane fraction but not in the nuclear one, in contrast to the results It is noteworthy that -catenin, being a part of the N-cadherin/-
obtained with classical antidepressants. These results are not ac- catenin complex attached to the cell membrane, plays an important
companied by an increase in hippocampal proliferation [52]. Taking role in cell-cell adhesion [56]. In the membrane, -catenin is lo-
into account the dual role of -catenin in proliferation and in cell cated pre- and postsynaptically associated to synapses [57, 58] and
adhesion, these results from our group may reflect an increased recruits synaptic scaffolding molecules for the development of new
neuroplasticity instead of a pro-proliferative response [12]. synapses [59]. This -catenin-dependent non-canonical cascade
could also contribute to the regulation of mood.
As already mentioned, for a number of years, GSK-3 has been
identified as a target for the treatment of Alzheimer’s disease and On the other hand, frizzled receptors and GPCRs can interact
other cognitive disorders [53]. Interestingly, the results reviewed through several pathways [60, 61]. Some GPCRs act through Gq
strongly suggest that the axis Wnt/GSK-3/-catenin can also play and/or Gi activating PKB/Akt which inhibits GSK-3 via phos-
a role in affective disorders: it is tempting to speculate that this is phorylation. These receptors can also activate Gs proteins that
due to its involvement in central nervous system proliferation and would activate PGE2, PI3-K, PKB/Akt, leading to the inhibition of
differentiation. In this regard, GSK-3 has been very recently iden- GSK-3. Another of the pathways activated by GPCRs is through
tified as a key regulator of neural progenitor homeostasis [54]. Du Gq or G12/13, that activates PLC and PKCs, inhibiting GSK-3
et al. [55] have recently identified a kinesin signaling complex that [60]. Taken together, these data support the possible existence of
mediates the regulatory role of GSK-3 in mood behavior. interactions between the GSK-3/-catenin pathway and other
524 Current Pharmaceutical Design, 2011, Vol. 17, No. 5 Vidal et al.

Fig. (3). -catenin protein level increase associated to chronic antidepressant treatment in different subcellular fractions. (A) Venlafaxine treatment affects -
catenin protein level in total cell lysate (TCL), membrane-associated and nuclear subcellular fractions of rat hippocampus. (B) Fluoxetine treatment increases
-catenin protein level in total cell lysate (TCL) of rat hippocampus. Densitometric measurement levels were normalized to actin protein amounts and data are
expressed as Mean ± S.E.M. *p<0.05; **p<0.01; ***p<0.001, vs vehicle;
p<0.05;

p<0.01, vs venlafaxine 10 mg/kg/day.

neurotransmission systems involved in depression, including mono-
amines.
The pharmacological modulation of the different elements of
the -catenin pathway with antidepressant purposes will be clarified
in the near future. Direct modulation at the level of Wnts or -
catenin activity is a possible approach. It is well known that GSK-
3 is one of the targets of lithium, a mood stabilizer used in the
treatment of manic disorders [62]. Li+ inhibits this enzyme at a
therapeutically relevant concentration, inducing a number of bio-
chemical features in the central nervous system [62].
Inhibitors of GSK-3 activity have shown antidepressant activ-
ity [63, 64]. Interestingly, a number of patents regarding inhibition
of GSK-3 as a mechanism of therapy for neuropsychiatric disor-
ders are being launched including treatment of depression among
their claims. They include, among many others, imidazole substi-
tuted pyrimidines, benzoimidazole derivatives, cycloalkylamino-
quinolones and triazolopyrimidine derivatives.
ENDOCANNABINOIDS AND MOOD: IS THERE A LINK?
Cannabinoid receptors, the molecular target of 9-
tetrahydrocannabinol, are physiologically engaged by the endocan-
nabinoids, a family of arachidonic acid derivatives, which include
anandamide and 2-arachidonoylglycerol [65]. After release, anan-
damide is rapidly removed from the extracellular space and subse-
quently hydrolyzed by the enzyme fatty acid amide hydrolase
(FAAH). Cannabinoid CB1 receptors, which are negatively coupled
to adenylyl cyclase via Gi/o proteins (Fig. 1) mediate most of the
actions of both endogenous and exogenous cannabinoids in the
central nervous system [65]. The involvement of these receptors in
the regulation of mood has attracted much attention in the recent
years, supported by different types of evidence: reduced levels of
circulating endocannabinoids together with an up-regulation of CB1
receptor mRNA and protein expression have been found in animals
subjected to different models of depression as well as in prefrontal
cortex samples from victims of major depression [66, 67, 68].
Furthermore, CB1 receptor knockout animals have been reported to
present “depressive-like” behavior [69]. From the pharmacological
point of view, several studies indicate that the administration of
drugs modulating CB1 receptor activity might result in antidepres-
sant-like responses [70-75]: the report by Gobbi et al. [76] showing
the antidepressant-like activity of URB597, an inhibitor of endo-
cannabinoid metabolic degradation, from a group of O-aryl-
carbamates, casted light on the relevance of this system as a possi-
ble target for the treatment of depression (Fig. 4) [76,77]. As it will
be discussed below, the overall interpretation of these studies is
complex, as some of them show conflicting results.
Interestingly, a number of studies suggest that brain endocan-
nabinoid system contributes to the chronic effects of antidepres-
sants: long-term administration of antidepressants of different
families modulates the levels of anandamide and 2-arachidonoyl-
glycerol, and CB1 receptor expression in several brain areas [78-
80]. Taking into account that a wealth of experimental data supports
the existence of cross-talk mechanisms between brain endocannabi-
noid and 5-HT systems [73, 81, 82, 83, 84, 85], and that the activity
New Antidepressant Targets
Fig. (4). Effects of acute URB597 in the forced swimming test (FST).
Results in the presence (+) and absence (-) are shown for floating time
(Float), swimming time (Swim) and struggling time (Strug). (Taken from
Gobbi et al.2005, with permission).
of 5-HT neurotransmission is still the main target of most antide-
pressants available, it is of clear interest the analysis of the possible
involvement of 5-HT receptors in the adaptive changes of the endo-
cannabinoid system induced by long-term antidepressant treatment.
In this regard, we have studied the effects of chronic admini-
stration of antidepressants on the functionality of the CB1 receptor-
dependent signal pathway. Chronic fluoxetine (14 days) induced a
significant increase in the maximal ability of the agonist
WIN55,212-2 to inhibit adenylyl cyclase (AC) activity in the pre-
frontal cortex (PFC); this increase was absent in those rats treated
with fluoxetine plus the 5-HT1A receptor antagonist WAY100635
[85]. Interestingly, chronic fluoxetine also significantly increased
basal cAMP levels in the PFC, this effect not being observed in the
Fig. (5). Long-term fluoxetine treatment modulates basal and/or CB1 receptor-mediated inhibition of AC activity in the rat brain. A. Basal AC activity in the
rat PFC after 14 days of treatment with vehicle, fluoxetine (10 mg/kg/day), WAY100635 (0.1 mg/kg/day), or the combination of both compounds. B. Inhibi-
tion of forskolin-stimulated AC by the cannabinoid agonist WIN55,212-2 in the PFC of treated rats. Percentages of inhibition were calculated for each agonist
concentration relative to forskolin-stimulated cAMP levels. Data are mean ± S.E.M. One-way ANOVA followed by Newman-Keuls test, *p<0.05 vs vehicle;
$
p<0.05; $$p<0.01 vs fluoxetine. Taken from Mato et al. 2010.
Current Pharmaceutical Design, 2011, Vol. 17, No. 5 525
animals treated with fluoxetine+WAY100635 or with WAY100635
alone (Fig. 5). Furthermore, immunoprecipitation studies of
WIN55,212-2-stimulated [35S]GTP
S labeled G
protein subunits
revealed that the level of G
i2 and G
i3 subunits activation was
significantly increased in the PFC of fluoxetine-treated rats. As
reported above for fluoxetine effect on CB1 receptor coupling to
AC in this brain area, the 5-HT1A receptor antagonist WAY100635
did not alter the profile of G
protein activation by WIN55,212-2
when administered alone, but prevented the increased stimulation of
G
i2 protein subunits when coadministered with the SSRI [85].
A number of studies have reported modifications of endocan-
nabinoid markers in animal models of depression. In this regard, we
have used the olfactory bulbectomized (OB) rat [67] to analyze the
density and functionality of CB1 receptor-mediated signaling: a)
OB animals exhibited significant increases in both CB1 receptor
density ([3H]CP55,490 binding) and functionality (stimulation of
[35S]GTP
S binding by the cannabinoid agonist WIN55,212-2) at
the prefrontal cortex (PFC) (Fig. 6); and b) the antidepressant-like
effect of chronic fluoxetine (10 mg/kg/day, 14 days, s.c) was asso-
ciated to a full reversal of that enhanced CB1-receptor signaling
(Fig 6). Furthermore, chronic fluoxetine increased the ability of the
agonist WIN55,212-2 to inhibit adenylyl cyclase (AC) activity (Fig.
7), which could contribute to the behavioral response to the antide-
pressant in OB rats. The molecular mechanism underlying this
relationship between changes in the expression/functionality of CB1
receptor and those on AC activity is unclear. Since fluoxetine per se
induces hypersensitization on CB1 receptor-mediated inhibition of
AC also in naïve rats [67, 85], it might be speculated that the modi-
fications observed in OB rats along the CB1 receptor-associated
signaling cascade at PFC could reflect a compensatory mechanism
to maintain endocannabinoid homeostasis.
Although it has been consistently reported that potentiation of
endocannabinoid activity by low doses of CB1 receptor agonists or
inhibitors of endocannabinoid metabolism results in an antidepres-
sant-like effect in rodents [71, 76, 77] it should be mentioned that
526 Current Pharmaceutical Design, 2011, Vol. 17, No. 5
Fig. (6). Effect of chronic fluoxetine (10 mg/kg/day, 14 days) or vehicle on
(A) the density of CB1 receptor (Bmax) and (B) CB1 receptor-mediated
stimulation of [35S]GTPS binding in prefrontal cortical membranes from
sham-operated and OB rats. Data are mean ± S.E.M. of individual values.
**p<0.01 vs sham-vehicle group and ++p<0.01 vs OB-vehicle group. Modi-
fied from Rodriguez-Gaztelumendi et al. 2009.
CB1 receptor antagonists have also been reported to behave as
antidepressants in behavioral models [70, 72]. An important con-
sideration is that, although studies specifically addressing the anti-
depressants effects of CB1 cannabinoid agonists and antagonists in
humans are lacking, the high incidence of depression and anxiety in
placebo-controlled clinical trials with the CB1 receptor antagonist
rimonabant for the treatment of obesity, has motivated its with-
drawal or lack of approval [86].
Most of the studies that have addressed the effects of chronic
antidepressants exposure on the activity of brain endocannabinoid
system suggest an enhancement of CB1 receptor expression in brain
areas with a well established role in depression [78-80]. Increased
CB1 receptor density in the rat hippocampus has been reported
following long-term administration of the noradrenaline uptake
inhibitor desipramine [80], and in the PFC after chronic treatment
with the monoamine oxidase inhibitor tranylcypromine or with
fluoxetine [80]. Taken together, data available strongly suggest that
the forebrain endocannabinoid system may be important for the
efficacy of these treatments, reinforcing the interest of simultane-
ously analyzing the effects of antidepressant administration on the
different levels of the CB1 receptor signal transduction cascade.
Vidal et al.
Fig. (7). Long-term fluoxetine treatment modulates CB1 receptor-mediated
inhibition of AC activity in the rat brain of sham and bulbectomized (OB)
rats. Inhibition of forskolin-stimulated AC by the cannabinoid agonist
WIN55,212-2 in the PFC. Percentages of inhibition were calculated for each
agonist concentration relative to forskolin-stimulated cAMP levels. Data are
mean ± S.E.M.
In this regard, it is noteworthy that some of the modifications of
endocannabinoid neurotransmission found in animal models of
depression are normalized by the administration of antidepressants.
As here reviewed, the chronic administration of fluoxetine to bul-
bectomized rats not only exhibits antidepressant-like activity (aboli-
tion of motor hyperactivity), but this response is associated to the
reversion of the upregulation of CB1 receptor G coupling function-
ality present in these animals [67]. The different results described
stress the importance of transductional mechanisms: in agreement
with the recent theories about depression, the role of endocannabi-
noid neuromodulation mostly involves downstream molecular,
rather than only receptor protein levels.
A relevant issue is the possible relationship between the role of
the endocannabinoid system in the pathophysiology of depressive
states and the mediation of antidepressant responses, and the classic
monoaminergic hypothesis of depression. Our results regarding the
blockade of 5-HT1A receptors with WAY100635 point out to a
special involvement of this 5-HT1 receptor subtype. Interestingly,
modifications in the expression of 5-HT1A and 5-HT2 receptors,
similar to those observed in depression, have been described in
cortical areas of bulbectomized animals; furthermore, adequate CB1
receptor functionality seems to be important for 5-HT1A receptor-
mediated biochemical and behavioral responses, as decreased effi-
cacy of the 8-OH-DPAT to activate Gi/o proteins and impaired
anxiolytic and/or hypothermic effects of 5-HT1A agonists have been
detected in CB1 knockout animals [83, 87]. The present report
uncovers the possibility that modulation of CB1 receptors partici-
pates in those effects of chronic fluoxetine that are triggered by 5-
HT1A receptors. In this regard, our results showing a 5-HT1A recep-
tor-dependent increase in basal AC activity following long-term
fluoxetine are in good agreement with previous studies where a role
for the activation of Gi/o coupled receptors has been suggested [88,
89]. It is noteworthy that WAY100635 also prevented fluoxetine-
induced increase in CB1 receptor coupling to G
i2 protein, suggest-
ing that up-regulated CB1 receptor signaling contributes to some
extent to 5-HT1A receptor-mediated modulation of the cAMP cas-
cade after fluoxetine administration. Together with the previous
data [73], showing that cannabinoids increase firing activity of
New Antidepressant Targets
5-HT neurons in the dorsal raphe (mainly regulated by 5-HT1A
receptors), these results illustrate the existence of a link between a
“classic” (5-HT) and a “new” target for the development of new
compounds for the treatment of depression.
It is noteworthy that endocannabinoid system plays an impor-
tant role in neuroplasticity, being involved in the regulation of
neurogenesis. Recent findings have shown the presence of a func-
tional endocannabinoid system in neural progenitor cells that par-
ticipate in the regulation of cell proliferation and differentiation [90,
91]. The chronic administration of CB1 agonist HU-210 promotes
embryonic and adult hippocampal neurogenesis and induces anx-
iolytic- and antidepressant-like effects [92]. Conversely, the sub-
chronic, but not acute, administration of rimonabant causes loss of
antidepressant activity and decreases neuronal proliferation in the
mouse hippocampus [93]. The fact that cannabinoids, mainly acting
through CB1 receptors, are capable to increase cell proliferation and
neurogenesis, consistent with the effects of conventional antide-
pressants, further supports both the involvement of the endocan-
nabinoid system in mood control and the therapeutic antidepressant
potential of cannabionid agonists.
From the analysis of the different studies regarding the in-
volvement of the endocannabinoid system in depressive disorders,
it can be concluded that: 1) a deficiency in endocannabinoid signal-
ing induces symptoms of depression in humans, as well as a “de-
pressive-like” behaviour in rodents; 2) chronic antidepressant
treatment modulate CB1 receptor-dependent signaling; 3) facilita-
tion of endocannabinoid neurotransmission results in the production
of biochemical and behavioural responses similar to those reported
for “classic” antidepressants. Therefore, the potentiation of endo-
cannabinoid activity could be of interest in depression. Two main
pharmacological approaches are possible: the direct activation of
CB receptors, mainly of the CB1 class, and the augmentation of the
endogenous endocannabinoid tone through the inhibition of the
degradation of endocannabinoids. The first approach can be
achieved by administering CB agonists: in this regard,
9 -
tetrahydro-cannabinol has been shown to induce antidepressant
effects, especially at low doses and under acute administration [67].
However, the possible induction of psychotomimetic effects by CB1
receptor agonists strongly limits the future of these compounds. The
fact that acute cannabidiol, a non psychotomimetic compound, is
able to induce antidepressant-like responses in rodents opens an
interesting perspective.
The potentiation of anandamide activity though the inhibition of
FAAH constitutes a new target for the treatment of depression: the
pharmacological profile of URB597 and other pioneering com-
pounds includes antidepressant-like responses in animal models of
stress and depression [77], but without other typical cannabinoid
responses, such as rewarding effects. In fact, a number of com-
pounds are being recently patented under the hypothesis of antide-
pressant efficacy as a result of inhibition of FAAH, including,
among others, carbamates, imidazole derivatives, substituted het-
erocyclic urea compounds, heteroaril substituted urea compounds
and isoxazolines.
5-HT4 RECEPTORS: A TARGET FOR FASTER ANTIDE-
PRESSANT RESPONSES?
5-HT, through the activation of different receptor subtypes,
plays a pivotal role in the mediation of the effects of most currently
used antidepressants. 5-HT1A and 5-HT2A receptor subtypes have
been classically identified as those mediating the majority of ac-
tions of 5-HT in the regulation of mood [1, 2]. In line with that, the
existence of changes in the properties of these receptors in de-
pressed patients has been proposed [94, 95]. Furthermore, the ef-
fects of chronic treatment with antidepressants on 5-HT1A receptors,
at both pre- and postsynaptic levels have received considerable
interest: in the case of raphe presynaptic receptors, a desensitization
Current Pharmaceutical Design, 2011, Vol. 17, No. 5 527
at both biochemical and functional levels has been consistently
found [96, 97, 98, 99, 100].
In the recent years, increasing attention is being paid to 5-HT4
receptors. These receptors are widely distributed in brain areas
including basal ganglia, hippocampus, amygdala or cortex [101,
102, 103]. These receptors belong to the superfamily of G-protein
coupled receptors which are positively coupled to adenylate cyclase
(AC) [104] leading to the intracellular accumulation of cAMP. This
increase of cAMP observed after the application of 5-HT4 agonists
contributes to the neuronal excitability of pyramidal cells of hippo-
campus by inhibiting potassium channels [105, 106, 107]. It is well
known that 5-HT4 receptors control important functions in periph-
eral nervous system [108, 109]; however, some of their brain func-
tions are also of possible clinical relevance since this receptor has
been implicated in memory, anxiety, anorexia and recently in de-
pression [110, 111, 112, 113].
The presence of the 5-HT4 receptors in cortical and limbic areas
suggests a potential role in learning and memory, as well as in
affective behaviour. In fact, an increase of 5-HT4 receptors in corti-
cal and striatal areas was described in post mortem brain from
depressed patients [114]. Over the last few years, evidence indicates
that 5-HT4 agonists might exert antidepressant-like effects with a
greater onset than the classical antidepressant drugs. It has been
recently shown that acute and subchronic (3 days) administration of
5-HT4 receptor agonists (prucaloride, 2.5 mg/kg and RS67333, 1.5
mg/kg) induces an increase of dorsal raphe nucleus 5-HT neuronal
mean firing [115]. This is expected to result in an increase of 5-HT
release in postsynaptic areas. More interestingly, there are many
evidences that 5-HT4 receptor agonists are effective in improving
the behavioural performance in some experimental models widely
used to assess antidepressant-like effects in a similar way of SSRIs,
with a faster onset of action. Lucas et al. reported in 2007 that acute
or subacute administration of the partial agonist RS67333, reduced
immobility time in FST [113]. Furthermore, in two animal models
considered to be predictive of chronic antidepressant response, a
partial reversion of the hyperactivity induced by olfactory bulbec-
tomy and chronic mild stress was reported after 3 days treatment
with RS67333. Interestingly, studies carried out in the hippocampus
showed that 3 days treatment with RS67333 induce a slight increase
in neuronal proliferation in the dentate gyrus [113] (Fig. 8) suggest-
ing the involvement of neuroplasticity mechanisms in this pharma-
cological response. This study has been pioneer in the identification
of a new target for the development of new antidepressant drugs. In
this context, the antidepressant-like response for another partial 5-
HT4 receptor agonist (SL65.0155) has been also reported in a ro-
dent paradigm of depression (FST), associated to increased levels
of several neurotrophic factors including BDNF, pCREB and the
antiapoptotic protein Bcl-2 [116]. In addition, it has been reported
that 3 days of treatment with RS67333 not only increases extracel-
lular 5-HT concentrations, but potentiates the increase in 5-HT
elicited by the classical SSRIs [117, 118].
Recent data from our laboratory have confirmed the antidepres-
sant-like effects of RS67333, showing that seven days of treatment
are required to obtain a full antidepressant response in the novelty
suppressed feeding and sucrose consumption after chronic corticos-
terone. They also suggest that, after seven days of treatment, in-
creased hippocampal cell proliferation is accompanied by the ac-
cumulation of -catenin in amplifying neural progenitors promoting
their differentiation to immature neuroblasts and the increase in
BDNF expression [119]. It has also been reported an increase in
BDNF expression following acute administration of another partial
5-HT4 agonist (SL65.0155) [116].
On the other hand, the modulation of 5-HT4 receptors by anti-
depressants strongly supports the role of these receptors in the
control of mood. In this regard, our group has recently shown for
the first time that long term treatment with antidepressants modu-
late 5-HT4 receptors at different levels of the 5-HT4 transductional
528 Current Pharmaceutical Design, 2011, Vol. 17, No. 5 Vidal et al.

Fig. (8). Effect of RS67333 (1.5 mg/kg/day, 3 days) on the number of BrdU-positive cells in the subgranular zone (SGZ) of the hippocampus. Photomicro-
graphs representative of the RS67333 (A) and control (B) groups. Please note the clusters of positive cells found in the presence of RS67333 (small rectan-
gles). Inset shows the summary (mean ± SEM) of the effect of RS67333 on the volumetric density of BrdU-positive cells (per mm3), as measured by a stere-
ological count. Rats received intraperitoneal injections of BrdU at the dose of 50 mg/kg twice daily (8 h interval), starting from the day of minipump insertion
until day 2 postsurgery. (Modified from Lucas et al. 2007, with permission).

pathway [120, 121]. Our results show that while chronic admini- receptor elements involved in the production of cAMP, such as AC
stration (21 days) of fluoxetine [120] or venlafaxine [121] does not activity [123]. In this sense, we have demonstrated that chronic
modify the expression of 5-HT4 mRNA, these drugs decrease their administration of either a SSRI (fluoxetine) or a SNRI (venlafaxine)
density (Table 1) suggesting that changes observed are due to post- induce a decrease, in a dose-dependent way, in the accumulation of
transcriptional alterations. The downregulation of 5-HT4 receptors cAMP after activation of 5-HT4 receptors with zacopride (Fig. 9)
has also been demonstrated with paroxetine after chronic treatment [120, 121]. It is noteworthy that our results indicate that the admini-
[122]. stration of RS67333 for 7 days also lead to a functional desensitiza-
Table 1. Antidepressants Effect on 5-HT4 Receptors tion of striatal 5-HT4 receptors [119].
Further evidences of the modulation of 5-HT4 receptors by
antidepressants have come from electrophysiological studies: it has
Region Vehicle Fluoxetine Venlafaxine been shown that 5-HT4 receptors modulate excitatory responses of
pyramidal cells of hippocampus [105]. 5-HT4 receptors are coupled
mPFCx 7.3 ± 0.7 6.7 ± 0.7 6.0 ± 0.8 to K+ channels through a signaling pathway that involve Gs pro-
teins, adenylate cyclase and PKA [see 107], so the activation of this
Caudate-putamen 19.8 ± 1.5 15.8 ± 0.8* 14.6 ± 1.1*
receptor leads to the blockade of K+ channels resulting in an in-
GP 15.6 ± 1.5 10.9 ± 0.9* 11.6 ± 1.1 crease of neuronal excitability. We have reported that chronic
treatment with antidepressants (fluoxetine, venlafaxine) leads to a
SN 12.8 ± 1.5 6.2 ± 0.4** 6.5 ± 0.6** desensibilization of the response induced by activation of 5-HT 4
receptors (Figs. 10 and 11) measured as a decrease of amplitude of
CA1, hippocampus 13.9 ± 1.4 9.3 ± 0.9* 8.5 ± 0.9* population spike induced by zacopride [120, 121], an effect also
Effect of chronic antidepressants (fluoxetine 10 mg/kg/day and venlafaxine 40 observed with other antidepressants, such as imipramine [124].
mg/kg/day, 21 days, p.o.) on specific [3H]GR113808 binding (5-HT4 receptors) in rat
brain. Data are the mean ± S.E.M and specific binding is expressed as Bmax (fmol/mg Taken together, these results support the hypothesis that 5-HT4
tissue). *p<0.05; **p<0.01. One-way ANOVA followed by Dunnett test. mPFCx: receptors are mediating an important part of the involvement of 5-
medial prefrontal cortex; GP: globus pallidus; SN: substantia nigra. HT neurotransmission in the regulation of affective disorders. In
this regard, an increase in the density of these receptors in ventral
Among the numerous actions of antidepressants, it has been hippocampus has been reported in bulbectomized rats [125], a
already mentioned that these drugs might induce changes in post-
New Antidepressant Targets
Fig. (9). Effect of increasing concentrations of the 5-HT4 agonists zacopride
on cAMP levels (expressed as mean ± S.E.M of the percentage of increase
over the basal) in striatum membranes from vehicle (
), fluoxetine (10
mg/kg/day, 21 days, p.o.) () and venlafaxine (40 mg/kg/day, 21 days, p.o.)
() treated rats. One-way ANOVA followed by Dunnett test, *p<0.05.
Fig. (10). Zacopride-induced stimulation (2 concentrations) of population
spike in pyramidal cells of hippocampus in rats treated chronically with
vehicle (
), fluoxetine (10 mg/kg/day, 21 days, p.o.) () and venlafaxine (40
mg/kg/day, 21 days, p.o.) () treated rats. One-way ANOVA followed by
Dunnett test, *p<0.05; **p<0.01.
Fig. (11). Effect of zacopride (10
M) on the population spike recorded in
CA1 pyramidal cell after stimulation of the stratum radiatum after chronic
treatment with fluoxetine (10 mg/kg/day, 21 days, p.o) or venlafaxine (40
mg/kg/day, 21 days, p.o).
similar finding to that described in some post mortem brain areas
from depressed patients [114]. Although the antidepressant re-
sponses induced by “partial” agonists of 5-HT4 receptors and the
desensitization of these receptors following chronic administration
of SSRI could seem contradictory, it could be speculated that a
Current Pharmaceutical Design, 2011, Vol. 17, No. 5 529
“partial” activation of 5-HT4 receptors may be responsible for the
antidepressant-like induced effects and the related molecular
changes. In fact, this “partial” activation of 5-HT4 receptor could be
achieved either by using a partial agonist or by inducing receptor
desensitization (through chronic administration of antidepressants),
without totally blocking 5-HT4-receptor signaling, as it would be
the case with an antagonist. Thus, this “lower” endogenous tonus of
5-HT4 receptors may account for the antidepressant effect of
RS67333 in the OB model of depression. Moreover, it could be also
beneficial to reduce the enhanced 5-HT4 receptor signaling reported
in post mortem frontal cortex from depressed patients [114].
If the exciting results showing that partial agonists of these
receptors induce antidepressant-like responses in short periods of
time (3 or 7 days) are finally confirmed in humans, this will repre-
sent a chance for overcoming one of the main limitations of current
therapy: the 2-3 weeks latency in the onset of action. It has been
very recently reported that SSRI potentiate the rapid antidepressant-
like effects of partial 5-HT4 receptor agonists [118].
Furthermore, the results obtained with partial agonists of 5-HT4
receptors clearly demonstrate that both “classic” aminergic and
“new” neuroproliferative hypothesis are complementary, as illus-
trated by the increase of hippocampal cell proliferation, increase in
BDNF expression and, interestingly, augmentation of -catenin
expression. These results are not surprising at all taking into ac-
count the well documented role of 5-HT in the development of
nervous system, mediated among others by the activation of the 5-
HT1A receptor [126] and the pivotal role that this amine plays in
both depression and the regulation of adult hippocampal neuro-
genesis [127, 128].
CONCLUDING REMARKS
Over the past five decades, the pharmacological treatment of
depression has been based on the monoaminergic hypothesis of the
pathophysiology of this disease [129, 130]. Although this hypothe-
sis has been instrumental in the pharmaceutical development of
compounds, the full demonstration of a deficit in monoaminergic
neurotransmission as the key factor in the generation of the disease
is lacking.
Treatment of depressive disorders with the antidepressants
clinically available has undoubtedly resulted in a significant im-
provement in the quality of life and clinical symptoms of depressive
patients. However, as mentioned in the Introduction, a number of
relevant issues remain unsolved with regard to antidepressant
pharmacology: first, although the increase in monoaminergic tone
induced by these drugs is immediate, two to five weeks are required
before a significant clinical improvement is achieved. Second, these
drugs show lack of efficacy in a number of patients; finally, avail-
able antidepressants present a number of adverse reactions that
frequently limit their use [2]. Because of all that, the development
of drugs showing an antidepressant profile, which overcome the
above-mentioned limitations, is strongly required. The success in
the search of better antidepressants will surely depend on the identi-
fication of new cellular targets which would help in the understand-
ing of the biological basis of depressive disorders.
The identification of the downstream molecular changes in-
duced by antidepressants has allowed the generation of new theo-
ries about both the pathophysiology of the depression and the final
targets of these compounds, focusing on transduction mechanisms
beyond receptors [22]. These findings have also suggested a role for
the cellular and molecular mechanisms of neuroplasticity in the
mediation of antidepressant responses. The transcription factor
CREB is a very good example of that: it has been repeatedly shown
that chronic administration of antidepressants might result in the
modulation of the levels of expression of this factor, which plays an
important role in synaptic plasticity: in agreement with that, a re-
duction on CREB levels has been found in the brain of depressed
patients [131]. In a similar way, a role for the neurotrophin BDNF
530 Current Pharmaceutical Design, 2011, Vol. 17, No. 5
in depression appears to be strongly supported: several studies have
shown a reduction of BDNF levels in serum of depressed patients,
as well as its normalization by chronic antidepressant treatment. In
fact, the pharmacological potential of neurotrophic factors as anti-
depressants is under consideration [132]. Furthermore, in the recent
years the relationship between the cellular and molecular modifica-
tions induced by chronic stress and those underlying the develop-
ment of depressive states has been strongly demonstrated.
A huge variety of different agents is currently under develop-
ment for the treatment of depressive disorders [133]: in agreement
with the aminergic hypothesis, many of them are modulators of the
different subtypes of 5-HT (5-HT1, 5-HT2), noadrenaline and do-
pamine receptors, also affecting their specific transporters. In addi-
tion to that, new targets have been addressed: NK1 and CRF an-
tagonists, as well as glutamate-acting drugs are being the subject of
increasing interest in the recent years. Other families include
antiglucocorticoids, estrogenic compounds or melatonin-acting
drugs, as it is the case of agomelatine. The analysis of the preclini-
cal and clinical development of those drugs is beyond the scope of
this review: our focus has been the role of downstream signaling
mechanisms, with special emphasis on neuroplasticity pathways.
As an example, we have here reviewed the evidences support-
ing the involvement of some neuroplasticity-related (GSK-3/-
catenin) and neuromodulator (endocannabinoid) pathways in the
mediation of antidepressant effects and their relationship with
compounds addressed at more “classical” targets (5-HT4 agonists).
New strategies will be developed to address the activation of neu-
roplastic and neuroproliferative circuits. As an example of that,
recent studies suggest that a single dose of a NMDA antagonist,
ketamine, can produce a rapid antidepressant response in patients
resistant to classic antidepressants [134] and this response could be
mediated by the mTOR pathway [135]. The activation of mTOR
signaling results in rapid increase of synapse-associated proteins
and spine number in the prefrontal cortex [135]. These results
strongly support mTOR as a new and promising target in the devel-
opment of antidepressant drugs.
ABBREVIATIONS
GSK-3 = Glycogen synthase kinase 3
TCAs = Tricyclic antidepressants
MAOIs = Monoamine oxidase inhibitors
SGZ = Subgranular zone of the dentate gyrus
of the hippocampus
BDNF = Brain derived neurotrophic factor
cAMP = Cyclic Adenosine Monophosphate
CREB = cAMP response element-binding
HPA = Hypothalamus-pituitary-adrenal axis
CRF = Corticotrophin releasing factor
NSC = Neural stem cells
LTP = Long term potentiation
SNRI = Serotonin-noradrenaline reuptake
inhibitor
SSRI = Serotonin selective reuptake inhibitor
5-HT = Serotonin
GPCRs = G protein-coupled receptors
PKA, PKB, PKC = Protein kinases A, B or C
PGE2 = Prostaglandin E2
PI3-K = Phosphatidylinositol 3-kinases
PLC = Phosphoinositide phospholipase C
FAAH = Fatty acid amide hydrolase
CB1 = Cannabinoid receptor 1
Vidal et al.
PFC = Prefrontal cortex
[35S]GTP
S = Guanosine 5'(
-thio)triphosphate,
[35S]
OB = Olfactory bulbectomized
AC = Adenylyl cyclase
FST = Forced swimming test
NK1 = Neurokinin 1
NMDA = N-Methyl-D-aspartic acid receptor
mTOR = Mammalian target of rapamycin
CONFLICT OF INTEREST
The authors declare that EC, AD, EMV and AP have received
support for research from Faes Farma, S.A. All other authors report
no biomedical financial interests or potential conflicts of interest.
The present study is not related to any of these professional or
collaboration relationships.
ACKNOWLEDGMENTS
We are grateful to Alicia Martín, Rebeca Madureira, Beatriz Ro-
mero, Helena Blanco, Isabel Ruiz, María Josefa Castillo and
Lourdes Lanza for their excellent technical assistance. The scien-
tific work of former coworkers Olga Guitérrez, Susana Mato, Elena
del Olmo, María Luisa Rojo and Jesús Pascual-Brazo, is kindly
acknowledged. This research was supported by Ministry of Science,
SAF04-00941, SAF07-61862, Fundación Alicia Koplowitz, Fun-
dación de Investigación Médica Mutua Madrileña, Instituto de
Salud Carlos III and University of Cantabria-FAES research con-
tract. RV has been the recipient of a fellowship from University of
Cantabria-FAES, and a CIBERSAM contract.
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