Gaël Quesseveur

BDNF overexpression in mouse hippocampal astrocytes promotes local neurogenesis and elicits anxiolytic-like activities

The therapeutic activity of selective serotonin (5-HT) reuptake inhibitors (SSRIs) relies on long-term adaptation at pre- and post-synaptic levels. The sustained administration of SSRIs increases the serotonergic neurotransmission in response to a functional desensitization of the inhibitory 5-HT1A autoreceptor in the dorsal raphe. At nerve terminal such as the hippocampus, the enhancement of 5-HT availability increases brain-derived neurotrophic factor (BDNF) synthesis and signaling, a major event in the stimulation of adult neurogenesis. In physiological conditions, BDNF would be expressed at functionally relevant levels in neurons. However, the recent observation that SSRIs upregulate BDNF mRNA in primary cultures of astrocytes strongly suggest that the therapeutic activity of antidepressant drugs might result from an increase in BDNF synthesis in this cell type. In this study, by overexpressing BDNF in astrocytes, we balanced the ratio between astrocytic and neuronal BDNF raising the possibility that such manipulation could positively reverberate on anxiolytic-/antidepressant-like activities in transfected mice. Our results indicate that BDNF overexpression in hippocampal astrocytes produced anxiolytic-/antidepressant-like activity in the novelty suppressed feeding in relation with the stimulation of hippocampal neurogenesis whereas it did not potentiate the effects of the SSRI fluoxetine on these parameters. Moreover, overexpressing BDNF revealed the anxiolytic-like activity of fluoxetine in the elevated plus maze while attenuating 5-HT neurotransmission in response to a blunted downregulation of the 5-HT1A autoreceptor. These results emphasize an original role of hippocampal astrocytes in the synthesis of BDNF, which can act through neurogenesis-dependent and -independent mechanisms to regulate different facets of anxiolytic-like responses.

Functional Status of Somatodendritic Serotonin 1A Autoreceptor after Long-Term Treatment with Fluoxetine in a Mouse Model of Anxiety/Depression Based on Repeated Corticosterone Administration

Most preclinical studies investigating the effects and the mechanism of action of antidepressants have been performed in naive rodents. This is inappropriate because antidepressants act on specific symptoms of the pathological condition, such as distress and anxiety. We have developed a mouse model of anxiety/depression based on addition of corticosterone to drinking water. This model is highly reproducible and easy to set up compared with unpredictable chronic mild stress. The serotonin 1A (5-HT1A) autoreceptor is known to play a role in mood disorders and their treatments. An increase in somatodendritic 5-HT1A autoreceptor density in the dorsal raphe (DR) attenuates the therapeutic activity of selective serotonin-reuptake inhibitors (SSRIs), whereas their functional desensitization promotes activation of brain serotonergic transmission, thereby representing an adaptive change relevant to their therapeutic effect. Here we assessed the effects of sustained administration of the SSRI fluoxetine on 5-HT1A autoreceptor sensitivity in mice administered with corticosterone. Fluoxetine attenuated hypothermia induced by the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin, decreased DR 5-HT neuronal activity, and decreased 5-HT release in both vehicle- and corticosterone-pretreated mice. However, such desensitization was more pronounced in corticosterone-pretreated mice. This change had an overall effect on serotonergic tone because we found a greater firing rate of 5-HT neurons associated with an enhancement of 5-HT outflow in the DR of corticosterone-pretreated mice in response to fluoxetine compared with the corresponding group of vehicle-pretreated mice. These results provide cellular explanations for the antidepressant effects produced by SSRIs in subjects with pathological conditions but not in naive animals or healthy volunteers.

5-HT2 ligands in the treatment of anxiety and depression

Introduction: One third of depressed patients do not respond adequately to conventional antidepressants including the selective serotonin reuptake inhibitors (SSRIs). Therefore, multi-target drugs or augmentation strategies have been developed for the management of SSRIs-resistant patients. In this context, the 5-HT2 receptor subtypes represent promising targets but their precise roles have yet to be determined. Areas covered: The aim of this review is to shed some light on the preclinical evidence supporting the use of 5-HT2A and/or 5-HT2C receptor antagonists such as antipsychotics, as potential effective adjuncts in SSRIs-resistant depression. This review synthesizes the current literature about the behavioral, electrophysiological and neurochemical effects of 5-HT2 receptors ligands on the monoaminergic systems but also on adult hippocampal neurogenesis. Expert opinion: Although studies support the hypothesis that the inactivation of 5-HT2A and/or 5-HT2C receptors might be of interest to reinforce different facets of the therapeutic activity of SSRIs, this pharmacological strategy remains debatable notably because of the lack of chronic data in relevant animal models. Conversely, emerging evidence suggests that the activation of 5-HT2B receptor is required for antidepressant-like activity, opening the way to new therapeutic approaches. However, the potential risks related to the enhancement of monoaminergic neurotransmissions could represent a major concern.

5-HT 2A receptor inactivation potentiates the acute antidepressant-like activity of escitalopram: involvement of the noradrenergic system

Evidence suggests that the serotonin 2A receptor (5-HT2AR) modulates the therapeutic activity of selective serotonin reuptake inhibitors (SSRIs). Indeed, among the genetic factors known to influence the individual response to antidepressants, the HTR2A gene has been associated with SSRIs response in depressed patients. However, in these pharmacogenetic studies, the consequences of HTR2A gene polymorphisms on 5-HT2AR expression or function are lacking and the precise role of this receptor is still matter of debate. This study examined the effect of 5-HT2AR agonism or antagonism with DOI and MDL100907, respectively, on the serotonergic system and the antidepressant-like activity of the SSRI escitalopram in mouse. The 5-HT2AR agonist DOI decreased the firing rate of 5-HT neurons in the dorsal raphe (DR) nucleus of 5-HT2AR+/+ anesthetized mice. This inhibitory response persisted in 5-HT2CR−/− but was completely blunted in 5-HT2AR−/− mutants. Moreover, the suppressant effect of DOI on DR 5-HT neuronal activity in 5-HT2AR+/+ mice was attenuated by the loss of noradrenergic neurons induced by the neurotoxin DSP4. Conversely, in 5-HT2AR+/+ mice, the pharmacological inactivation of the 5-HT2AR by the selective antagonist MDL100907 reversed escitalopram-induced decrease in DR 5-HT neuronal activity. Remarkably, in microdialysis experiments, a single injection of escitalopram increased cortical extracellular 5-HT, but not NE, levels in awake 5-HT2AR+/+ mice. Although the addition of MDL100907 did not potentiate 5-HT neurotransmission, it allowed escitalopram to increase cortical NE outflow and consequently to elicit an antidepressant-like effect in the forced swimming test. These results suggest that the blockade of the 5-HT2AR may strengthen the antidepressant-like effect of escitalopram by facilitating the enhancement of the brain NE transmission. They provide support for the use of atypical antipsychotics with SSRIs as a relevant antidepressant augmentation strategy.

High-fat diet-induced metabolic disorders impairs 5-HT function and anxiety-like behavior in mice

The link between type 2 diabetes mellitus (T2DM) and depression is bidirectional. However, the possibility that metabolic disorders may elicit anxiogenic‐like/depressive‐like symptoms or alter the efficacy of antidepressant drugs remains poorly documented. This study explored the influence of T2DM on emotionality and proposed a therapeutic strategy that might be used in depressed diabetic patients.

High fat diet-induced metabolic disorders impairs serotonergic function and anxiety-like behaviours in mice.

The link between type 2 diabetes mellitus (T2DM) and depression is bidirectional. However, the possibility that metabolic disorders may elicit anxiogenic‐like/depressive‐like symptoms or alter the efficacy of antidepressant drugs remains poorly documented. This study explored the influence of T2DM on emotionality and proposed a therapeutic strategy that might be used in depressed diabetic patients.

Blockade of the high‐affinity noradrenaline transporter (NET) by the selective 5‐HT reuptake inhibitor escitalopram: an in vivo microdialysis study in mice

BACKGROUND AND PURPOSE Escitalopram, the S(+)‐enantiomer of citalopram is the most selective 5‐HT reuptake inhibitor approved. Although all 5‐HT selective reuptake inhibitors (SSRIs) increase extracellular levels of 5‐HT ([5‐HT]ext). some also enhance, to a lesser extent, extracellular levels of noradrenaline ([NA]ext). However, the mechanisms by which SSRIs activate noradrenergic transmission in the brain remain to be determined.

The Monoaminergic Tripartite Synapse: A Putative Target for Currently Available Antidepressant Drugs

Antidepressant drugs such as the serotonin (5-HT)/norepinephrine (NE) and dopamine (DA) reuptake inhibitors activate monoaminergic neurotransmission in various brain regions, such as the amygdala, the frontal cortex or the hippocampus. Although this property is well established, the post-synaptic mechanisms by which these pharmacological agents exert therapeutic activity in major depressive disorders (MDD) is not fully understood. Recent clinical and preclinical studies have indicated that the density and reactivity of glia and more particularly of astrocytes are reduced in MDD patients. These data along with the fact that astrocytes express monoaminergic transporters and receptors make these cells putative targets for antidepressant treatments. Accordingly, in vitro evidence has demonstrated that the application of various classes of antidepressant drugs on rodent primary astrocyte cultures elicits a wide spectrum of responses, from the rise in cytosolic calcium concentrations, as a marker of cellular activity, to the release of glucose metabolites, gliotransmitters and neurotrophic factors. Remarkably, antidepressant drugs also attenuate the release of inflammatory molecules from reactive astrocytes or microglia, suggesting that part of the beneficial effects in depressed patients or animal models of depression might result from the ability of antidepressants to regulate the synthesis and release of psychoactive substances acting on both pre- and post-synaptic neurons. Among the many long-term targets of antidepressant drugs, brainderived neurotrophic factor (BDNF) has been well studied because of the positive influence on adult hippocampal neurogenesis, synaptogenesis and the local serotonergic tone. This review will illustrate how the concept of the tripartite synapse, which is classically associated with different forms of plasticity involving glutamate, could be expanded to the monoaminergic systems to regulate antidepressant drug responses. The recent in vivo data supporting that hippocampal astrocytes act in concert with neurons to release BDNF under pharmacological conditions and thereby regulate different facets of anxiolytic-/antidepressant-like activities through neurogenesis-dependent and independent mechanisms will be emphasized.

Antinociceptive activity of the new triple reuptake inhibitor NS18283 in a mouse model of chemotherapy-induced neuropathic pain

Chronic neuropathic pain can lead to anxiety and depression. Drugs that block reuptake of serotonin, norepinephrine and/or dopamine are widely used to treat depression, and have emerged as useful drugs in the treatment of neuropathic pain. This study compared the acute antinociceptive effects of NS18283, a novel triple monoamine reuptake inhibitor (MRI) with indatraline, venlafaxine and escitalopram in a mouse model of neuropathic pain.