Vortioxetine promotes early changes in dendritic morphology compared to fluoxetine in rat hippocampus
Introduction
Around 30–40% of major depressive disorder (MDD) patients fail to respond to antidepressant treatment, and 5–10% remain depressed despite repeated medical treatment (Mathers et al., 2006). Whereas the monoamine hypothesis of depression has prevailed for the last 5 decades, a more recent neuroplasticity hypothesis is gaining momentum. This suggests that neuronal plasticity in cortico-limbic brain structures plays an important role in the pathophysiology of MDD (Duman, 2004, Licznerski and Duman, 2013). In support of this hypothesis, reduced hippocampal neurogenesis, loss of dendritic spines, dendritic atrophy, and loss of synapses have been observed in the mammalian brain in response to stress and depression (Kang et al., 2012, Pittenger and Duman, 2008, Wainwright and Galea, 2013). Numerous in vivo imaging studies in humans indicate that the volume of the hippocampus may be reduced in depression (Campbell and Macqueen, 2004, Sheline et al., 2003). Moderate apoptosis and atrophy of hippocampal neurons in depressed patients (Campbell and Macqueen, 2004) and reduced spine number and dendrite complexity could contribute to the decreased hippocampal volume (Licznerski and Duman, 2013).
Antidepressant treatment may trigger molecular and cellular mechanisms linked to neuronal plasticity and counteract the structural impairments of MDD by neurogenesis, gliogenesis, dendritic arborization, and new synapse formation (Duman, 2004, Pittenger and Duman, 2008). Animal studies have demonstrated changes in number and type of synapses in the hippocampus after antidepressant treatment (Chen et al., 2008, Chen et al., 2009, Chen et al., 2010, Hajszan et al., 2009, Hajszan et al., 2010). Antidepressant drugs induce rapid hippocampal synaptogenesis in the CA1 (Hajszan et al., 2009), whereas onset of dentate gyrus (DG) neurogenesis often occurs 3–4 weeks after treatment (Malberg, 2004, Marcussen et al., 2008). Recent evidence showed that ketamine, rapidly increases spine density and function in limbic brain regions and that the behavioral effects of ketamine required synaptic protein synthesis and spine formation in rats (Li et al., 2010, Li et al., 2011, Licznerski and Duman, 2013). These findings suggest that recovery of synaptic connections is critical for a rapid antidepressant response and is not mediated entirely via neurogenesis (Kang et al., 2012, Li et al., 2010, Li et al., 2011).
Animal studies of 5-hydroxytryptamine (5-HT) receptor subtype selective ligands indicate that they have opposing effects on the activity of selective serotonin reuptake inhibitors (SSRIs) in the brain networks underlying their therapeutic effects (Lucas et al., 2007, Scorza et al., 2012). Therefore, one antidepressant strategy has been to develop drugs that combine serotonin transporter (SERT) blockade and favorable 5-HT receptor modulation (Artigas, 2013). Vortioxetine has recently gained approval for the treatment of MDD and has a multimodal mechanism of action that combines antagonism at 5-HT3, 5-HT7 and 5-HT1D receptors, agonism at 5-HT1A and partial agonism at 5-HT1B receptors, with SERT inhibition (Sanchez et al., 2015). Preclinical studies of vortioxetine revealed enhanced neuroplasticity, i.e. long-term potentiation (LTP) formation in vitro and dendritic branching in vivo compared to an SSRI (Dale et al., 2014, Guilloux et al., 2013). Gene expression studies have shown that a single dose of vortioxetine activates genes encoding dendritic spine plasticity proteins (du Jardin et al., 2013). Based on these results, we hypothesized that vortioxetine would show an enhanced effect on spinogenesis and dendritic morphology versus an SSRI. In the present study, we investigated vortioxetine׳s effects on spine number and density, dendritic length, and the number of branches in the rat hippocampus compared with the SSRI fluoxetine.
Section snippets
Animals
Adult male Sprague-Dawley rats (180–200 g) (n=96) were kept on a normal light: dark cycle and given free access to food and water. There were 12 rats in each group for each time point and dose. All rats were handled for 7 days before any procedure was initiated.
Antidepressant treatments
Vortioxetine was given in food chow (1.6 g/kg), which was provided by H. Lundbeck A/S (Copenhagen, Denmark) for 7 and 28 days. The selection of this dose was based on previously obtained data that this dosage produces >80% SERT occupancy.
Results
Dendritic spines are the major postsynaptic sites of excitatory synapses on pyramidal neurons, play a central role in plasticity, and changes in dendritic spine numbers may reflect a change in synaptic density (Moser et al., 1994). Therefore, we quantified spine number and density and dendritic morphology following vortioxetine and fluoxetine treatments.
Discussion
The aim of the present study was to compare the effects of vortioxetine and fluoxetine at similar SERT occupancies on dendritic morphology including the density and number of spines, the length of dendrites, and the number of branches in rat hippocampal CA1 pyramidal cells at two time points (i.e. 1 and 4 weeks of dosing). Overall, we found that vortioxetine significantly increased spine number and density, and increased dendritic length and branching, at the 1 week time point whereas an
Role of funding source
Funding for this study was provided by H. Lundbeck A/S including study design and the collection, analysis and interpretation of data.
Contributors
Funding for this study was provided by H. Lundbeck A/S. Author Fenghua Chen performed the study, analyses and wrote the first draft of the manuscript. Author Kristian Gaarn du Jardin undertook part of animal experiment. Author Jessica A. Waller revised the manuscript. Author Gregers Wegener, Jens R. Nyengaard and Connie Sanchez designed the study and managed the analyses.
Conflict of interest
Dr. Fenghua Chen report having received salary support from H. Lundbeck A/S. Kristian Gaarn du Jardin has received travel grants from H. Lundbeck A/S. Dr. Jessica A Waller and Connie Sanchez are currently full-time employees of H. Lundbeck A/S. Dr. Jens R. Nyengaard reports having received research funding from the Villum Foundation via Centre for Stochastic Geometry and Advanced Bioimaging. Dr. Gregers Wegener reported having received research funding from the Danish Medical Research Council
Acknowledgments
Maj-Britt Lundorf and Helene M. Andersen are gratefully acknowledged for skillful technical assistance. This study was supported by H. Lundbeck A/S.
References (76)
Serotonin receptors involved in antidepressant effects
Pharmacol. Ther.
(2013)- et al.
Spine architecture and synaptic plasticity
Trends Neurosci.
(2005) - et al.
Repeated electroconvulsive seizures increase the total number of synapses in adult male rat hippocampus
Eur. Neuropsychopharmacol.
(2009) - et al.
Cholecystokinin-immunopositive basket and Schaffer collateral-associated interneurones target different domains of pyramidal cells in the CA1 area of the rat hippocampus
Neuroscience
(2002) - et al.
Bi-phasic change in BDNF gene expression following antidepressant drug treatment
Neuropharmacology
(2003) - et al.
Evidence for GABAergic inhibitory deficits in major depressive disorder
Neurosci. Biobehav. Rev.
(2011) - et al.
Single dose vortioxetine or ketamine but not fluoxetine increases expression of neuroplasticity related genes in the rat prefrontal cortex
Eur. Neuropsychopharm.
(2013) - et al.
Antidepressant and anxiolytic potential of the multimodal antidepressant vortioxetine (Lu AA21004) assessed by behavioural and neurogenesis outcomes in mice
Neuropharmacology
(2013) - et al.
Remodeling of hippocampal spine synapses in the rat learned helplessness model of depression
Biol. Psychiatry
(2009) - et al.
Effects of estradiol on learned helplessness and associated remodeling of hippocampal spine synapses in female rats
Biol. Psychiatry
(2010)
Structure-stability-function relationships of dendritic spines
Trends Neurosci.
Developmental and regional differences in the consolidation of long-term potentiation
Neuroscience
Long-term potentiation induced by patterned stimulation of the commissural pathway to hippocampal CA1 region in freely moving rats
Neuroscience
Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure
Biol. Psychiatry
Remodeling of axo-spinous synapses in the pathophysiology and treatment of depression
Neuroscience
Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action
Neuron
Effects of antidepressants and benzodiazepine treatments on the dendritic structure of CA3 pyramidal neurons after chronic stress
Eur. J. Pharmacol.
Neurotrophin regulation of cortical dendritic growth requires activity
Neuron
Hippocampal interneurons express a novel form of synaptic plasticity
Neuron
Wnt2 expression and signaling is increased by different classes of antidepressant treatments
Biol. Psychiatry
Defects in dendrite and spine maturation and synaptogenesis associated with an anxious-depressive-like phenotype of GABAA receptor-deficient mice
Neuropharmacology
Vortioxetine, a novel antidepressant with multimodal activity: review of preclinical and clinical data
Pharmacol. Ther.
Calcium influx through presynaptic 5-HT3 receptors facilitates GABA release in the hippocampus: in vitro slice and synaptosome studies
Neuroscience
5-HT1a receptors mediate the neurotrophic effect of serotonin on developing dentate granule cells
Brain Res. Dev. Brain Res.
Activity-dependent dendritic spine neck changes are correlated with synaptic strength
Proc. Natl. Acad. Sci. USA
Ultrastructure of dendritic spines: correlation between synaptic and spine morphologies
Front. Neurosci.
Submillisecond precision of the input-output transformation function mediated by fast sodium dendritic spikes in basal dendrites of CA1 pyramidal neurons
J. Neurosci.
Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex
Nat. Rev. Neurosci.
Genetic approaches to investigate the role of CREB in neuronal plasticity and memory
Mol. Neurobiol.
The role of the hippocampus in the pathophysiology of major depression
J. Psychiatry Neurosci.
Prolonged ampakine exposure prunes dendritic spines and increases presynaptic release probability for enhanced long-term potentiation in the hippocampus
Eur. J. Neurosci.
Changes in rat hippocampal CA1 synapses following imipramine treatment
Hippocampus
Imipramine treatment increases the number of hippocampal synapses and neurons in a genetic animal model of depression
Hippocampus
Vortioxetine disinhibits pyramidal cell function and enhances synaptic plasticity in the rat hippocampus
J. Psychopharmacol.
New insights into the classification and nomenclature of cortical GABAergic interneurons
Nat. Rev. Neurosci.
Subcellular domain-restricted GABAergic innervation in primary visual cortex in the absence of sensory and thalamic inputs
Nat. Neurosci.
Impact of the BDNF Val66Met polymorphism on cognition: implications for behavioral genetics
Neuroscientist
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