Molecular and Cellular PharmacologyTime-dependent effects of escitalopram on brain derived neurotrophic factor (BDNF) and neuroplasticity related targets in the central nervous system of rats
Introduction
In recent years more and more interest has focused on the molecular mechanisms involved in neuroplasticity for its possible implication in the treatment of major depression (Krishnan and Nestler, 2008). In particular, selective serotonin reuptake inhibitors (SSRIs), currently among the most used antidepressants (ADs) in clinical practice, trigger a complex biochemical cascade mediating the actions of the neurotrophin brain derived neurotrophic factor (BDNF) and leading ultimately to promote neuronal plasticity (Duman & Monteggia, 2006, Martinowich & Lu, 2008).
We used as a pharmacological tool the S-enantiomer of citalopram, escitalopram, the SSRI with the highest selectivity for the serotonin transporter (Owens et al., 1997, Owens et al., 2001) to gain further insights into antidepressant actions in the CNS and to explore molecular mechanisms that can be responsible for an earlier appearance of the therapeutic effect. In fact this drug has been shown to be effective as early as after 7 days of treatment in several behavioural models of depression (Capone et al., 2006, Montgomery et al., 2001, Sanchez et al., 2003, Reed et al., 2009).
Taking advantage of this peculiar feature we tested the hypothesis that different temporal molecular mechanisms may be involved in mediating escitalopram effects by using two treatment regimens. We treated healthy rats with escitalopram for 7 or 21 days at a dose that has been shown to be active (10 mg/kg) and examined the temporal effects on neuroplasticity related targets of this SSRI in key areas involved in the etiopatogenesis of depression and in mediating the outcome of the ADs: hippocampus, frontal and prefrontal cortex (Holmes & Wellman, 2009, Kennedy et al., 1997, Manji & Duman, 2001, Mayberg, 2003, Nestler et al., 2002). In doing so, we followed a four-step approach: first, we evaluated the effects of the two treatment regimens on gene expression of BDNF and of cAMP response element binding (CREB) protein that acts as a regulator of BDNF expression (Blendy, 2006, Martinowich & Lu, 2008).
Our attention was then focused in those areas where at least one of the two treatment regimens was able to affect gene expression. As second step, we evaluated the protein levels of BDNF (mature and Pro-BDNF) and CREB to assess whether changes in gene expression could be coupled to changes also in protein levels.
Third, protein kinases acting as downstream targets of BDNF signalling, participating at least in regulating CREB activation and that likely play a role in mediating antidepressant behavioural effects were investigated. In particular, calcium/calmodulin-dependent protein kinase II (CaMKII), extracellular signal-regulated kinases (ERKs) and p38 MAPK total and phosphorylated (activated) levels were measured to assess whether these kinases could be regulated by these two treatment regimens (Barbiero et al., 2007, Gourley et al., 2008, Huang & Reichardt, 2001, Miller & Raison, 2006). Fourth, we investigated the effects of escitalopram on another transcription factor, the calcium responsive transcription factor (CaRF), which regulates BDNF neuronal expression in a calcium selective manner (Tao et al., 2002),after 7 and 21 days of treatment with escitalopram. The present study was undertaken to test whether this complex interconnected pathway, may present a temporal and area-specific profile in response to escitalopram treatment.
Section snippets
Animals
Experiments were performed on adult male Sprague–Dawley albino rats of 8 weeks of age at the beginning of the experimental procedure (Charles River, Calco, Italy). Animals were housed 3 per cage in polycarbonate cages (28 × 17 × 12 cm) in a temperature- and humidity-controlled environment on a 12-h light–dark cycle (lights on at 6.00 a.m.) with ad libitum access to food and tap water. The procedures used in this study were in strict accordance with the European legislation on the use and care of
Results
The effects of a subchronic (7 days) or a chronic (21 days) treatment with escitalopram (10 mg/kg) on BNDF and neuroplasticity related targets were investigated in areas playing a role in the response of ADs. For a comprehensive summary of the results see Supplementary Tables 1 and 2.
Discussion
Even if an improvement of clinical symptoms appears in the earlier weeks after the beginning of an antidepressant (AD) treatment, the significant improvement in mood appears over a longer time. This delay in the therapeutic outcome of antidepressants leads to the hypothesis that long-term adaptative responses of the CNS need to be evoked to treat major depression (Castrén, 2004). Solid research efforts have been spent to evaluate the effects of chronic (3–4 weeks) AD treatments on synaptic
Conclusions
Next, we will evaluate the functional and behavioural impacts of the molecular effects evoked by escitalopram using specific tests in animal models, in an attempt to link the observed changes on neuroplasticity related targets to behavioural outcomes induced by escitalopram. Another compelling aim will be to compare the effect of escitalopram on these neuroplasticity related targets to those of other AD treatments acting on the serotonergic system, and also on other neurotransmitter systems, in
Acknowledgment
This work has been supported in part by an unrestricted grant Lundbeck. We are greatful to Mr. Ian David Haworth for English language support.
References (66)
The role of CREB in depression and antidepressant treatment
Biol. Psychiatry
(2006)The pharmacology of putative early-onset antidepressant strategies
Eur. Neuropsychopharmacol.
(2003)- et al.
Altered regulation of CREB by chronic antidepressant administration in the brain of transgenic mice with impaired glucocorticoid receptor function
Neuropsychopharmacology
(2002) - et al.
Rapid effect of escitalopram in a behavioural model of depression: the chronic escape deficit
Eur. Neuropsychopharmacol.
(2006) Neurotrophic effects of antidepressant drugs
Curr. Opin. Pharmacol.
(2004)Functional anatomical abnormalities in limbic and prefrontal cortical structures in major depression
Prog. Brain Res.
(2000)- et al.
A neurotrophic model for stress-related mood disorders
Biol. Psychiatry
(2006) - et al.
A role for MAP kinase signaling in behavioral models of depression and antidepressant treatment
Biol. Psychiatry
(2007) - et al.
Regionally specific regulation of ERK MAP kinase in a model of antidepressant-sensitive chronic depression
Biol. Psychiatry
(2008) - et al.
Involvement of basal ganglia and orbitofrontal cortex in goal-directed behavior
Prog. Brain Res.
(2000)
Stress-induced prefrontal reorganization and executive dysfunction in rodents
Neurosci. Biobehav. Rev.
The effect of escitalopram, desipramine, electroconvulsive seizures and lithium on brain-derived neurotrophic factor mRNA and protein expression in the rat brain and the correlation to 5-HT and 5-HIAA levels
Brain Res.
The functional neuroanatomy of depression: distinct roles for ventromedial and dorsolateral prefrontal cortex
Behav. Brain Res.
Brain-derived neurotrophic factor and its receptor tropomyosin-related kinase B in the mechanism of action of antidepressant therapies
Pharmacol. Ther.
Unique patterns of FOS, phospho-CREB and BrdU immunoreactivity in the female rat brain following chronic stress and citalopram treatment
Neuropharmacology
Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations
Genomics
Positron emission tomography imaging in depression: a neural systems perspective
Neuroimaging Clin. N. Am.
Regulation of cAMP phosphodiesterase mRNAs expression in rat brain by acute and chronic fluoxetine treatment. An in situ hybridization study
Neuropharmacology
Preclinical models: status of basic research in depression
Biol. Psychiatry
Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine
Biol. Psychiatry
Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice
Neuron
Fluoxetine increases the activity of the ERK-CREB signal system and alleviates the depressive-like behavior in rats exposed to chronic forced swim stress
Neurobiol. Dis.
A calcium-responsive transcription factor, CaRF, that regulates neuronal activity-dependent expression of BDNF
Neuron
Interactions among the medial prefrontal cortex, hippocampus and midline thalamus in emotional and cognitive processing in the rat
Neuroscience
Selective prefrontal cortical projections to the region of the locus coeruleus and raphe nuclei in the rhesus monkey
Brain Res.
Chronic antidepressants induce redistribution and differential activation of alphaCaM kinase II between presynaptic compartments
Neuropsychopharmacology
Uptake and recycling of pro-BDNF for transmitter-induced secretion by cortical astrocytes
J. Cell Biol.
Acetylsalicylic acid accelerates the antidepressant effect of fluoxetine in the chronic escape deficit model of depression
Int. Clin. Psychopharmacol.
Role of the brain-derived neurotrophic factor at glutamatergic synapses
Br. J. Pharmacol.
Augmentation strategies for treatment-resistant depression
Curr. Opin. Psychiatry
Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: involvement of serotonin-1A, GABA(A), and glutamate receptors
J. Neurosci.
Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport
J. Neurosci.
The role of the extracellular signal-regulated kinase signaling pathway in mood modulation
J. Neurosci.
Cited by (57)
An insight into crosstalk among multiple signalling pathways contributing to the pathophysiology of PTSD and depressive disorders
2024, Progress in Neuro-Psychopharmacology and Biological PsychiatryIntegrated analyses of transcriptomics and network pharmacology reveal leukocyte characteristics and functional changes in subthreshold depression, elucidating the curative mechanism of Danzhi Xiaoyao powder
2024, Journal of Traditional Chinese Medical SciencesSelecting antidepressants according to a drug-by-environment interaction: A comparison of fluoxetine and minocycline effects in mice living either in enriched or stressful conditions
2021, Behavioural Brain ResearchCitation Excerpt :These results confirm previous studies demonstrating that SSRI administration in a favorable environment leads to a reduction of depressive symptoms while, in a stressful environment, the treatment has limited beneficial effects [5,6,20]. The role of the environment in determining the SSRI outcome could explain the apparently discordant evidence on the effects of this class of drugs, some studies reporting an improvement of depression endophenotypes [38–45], while others describing opposite results [46–54]. The environment-dependence of the outcome of treatments affecting serotonin levels is increasingly exploited to explain the results in the literature [55–58] and several studies suggest to exploit the interaction between increased neurobehavioral plasticity and the environment to improve the clinical outcome in major depression [3,6,59,60].
Shaping therapeutic trajectories in mental health: Instructive vs. permissive causality
2021, European NeuropsychopharmacologyS 47445 counteracts the behavioral manifestations and hippocampal neuroplasticity changes in bulbectomized mice
2019, Progress in Neuro-Psychopharmacology and Biological Psychiatry
- 1
Alboni S., Benatti C. and Capone G. equally contributed to this work.
- 2
Present address: Department of Experimental Medicine, University of Insubria, Via Rossi 9, 21100 Varese, Italy.