Effets anxiolytiques/antidépresseurs et neurogéniques des ligands du récepteur 5-HT4 chez la Souris (rôle de la protéine b-arrestin 1)

Les inhibiteurs sélectifs de recapture de la sérotonine (ISRS), agonistes indirects des récepteurs de la sérotonine (5-HT), ont un début d'effet antidépresseur retardé de plusieurs semaines. Des travaux antérieurs suggèrent que le récepteur 5-HT4 de la sérotonine serait une cible directe pour traiter la dépression et un nouvel espoir pour traiter plus rapidement ces pathologies anxio-dépressives. Toutefois, l'hypothèse 5-HT4 doit encore être validée dans des modèles animaux d'anxiété/dépression. Les questions posées étaient : la stimulation des récepteurs 5-HT4 centraux est-elle nécessaire aux effets comportementaux des ISRS ? la neurogenèse hippocampique adulte contribue-t-elle à ces effets ? En utilisant le modèle de stress chronique à la corticostérone (CORT) chez la souris, nous avons évalué les effets sur ces paramètres d un traitement chronique avec un agoniste du récepteur 5-HT4 (RS67333, 1,5 mg/kg/jour pendant 4 semaines) comparé à un traitement à la fluoxétine (18 mg/kg/jour). Nous avons ensuite utilisé ce modèle murin combiné à l ablation de la neurogenèse hippocampique par rayons-X afin d examiner si la neurogenèse est nécessaire aux effets comportementaux d un traitement subchronique (7 jours) ou chronique (28 jours) avec le RS67333. Nous avons également évalué le blocage des effets de la fluoxétine par un antagoniste du récepteur 5-HT4 (GR125487, 1 mg/kg/jour). Le traitement chronique avec RS67333, comme celui de la fluoxétine, induit une activité anxiolytique/antidépressive et stimule la neurogenèse hippocampique adulte. Cependant, contrairement à la fluoxétine , les effets anxiolytiques du RS67333 sont déjà présents après 7 jours de traitement, sans nécessité l activation de la neurogenèse. Le traitement chronique avec le GR125487 empêche les deux effets anxiolytique/antidépresseur et neurogènique de la fluoxétine, indiquant que l'activation du récepteur 5-HT4 est nécessaire à ces effets de l ISRS. Nous avons ensuite cherché à savoir si le court délai d action antidépresseur du RS67333 peut être prédit par l'expression d'un biomarqueur périphérique. Des données de la littérature indiquent que la cascade de signalisation de b-arrestine 1 (impliquée dans la désensibilisation et l internalisation du récepteur 5-HT4) serait un biomarqueur potentiel pré-clinique/clinique des états dépressifs et des effets d un traitement antidépresseur. À cette fin, nous avons développé une nouvelle méthode d évaluation des taux de protéines circulantes grâce à une analyse par immunoblot des leucocytes (PBMC) isolés à partir du sang total de souris. Les taux de b-arrestine 1 sont diminués dans les leucocytes des souris pré-traitées à la CORT. Il faut 7 jours de traitement avec le RS67333, mais 28 jours avec la fluoxétine chez ces animaux pour restaurer un taux de b-arrestine 1 comparable à celui des animaux contrôles. Ces résultats suggèrent que le taux sanguin de b-arrestine 1 est un biomarqueur de la rapidité de la réponse antidépressive. Enfin, l'activation du récepteur 5-HT4 dans le cerveau peut représenter une approche thérapeutique innovante d apparition pour traiter plus rapidement des symptômes dépressifs associés à l anxiété.Selective serotonin reuptake inhibitors (SSRIs) display a delayed onset of action of several weeks. Past work demonstrated evidence that the 5-HT4 receptor may be a direct target for treating depression and a new hope for fast acting antidepressant treatment. However, the 5-HT4 hypothesis still needs to be validated in models of anxiety/depression.We decided to investigate whether 5-HT4 receptor stimulation was necessary for the effects of SSRIs in a mouse model of anxiety/depression and whether hippocampal neurogenesis contributed to these effects. Using the mouse corticosterone model of anxiety/depression, we assessed whether chronic treatment with a 5-HT4 receptor agonist (RS67333, 1.5 mg/kg/day) had effects on anxiety and depression-related behaviors as well as on hippocampal neurogenesis in comparison to chronic fluoxetine treatment (18 mg/kg/day). Then, using our model combined with ablation of hippocampal neurogenesis, we investigated whether neurogenesis was necessary for the behavioral effects of subchronic (7-days) or chronic (28-days) RS67333 treatment. We also assessed whether a 5-HT4 receptor antagonist, (GR125487, 1 mg/kg/day) could prevent the behavioral and neurogenic effects of fluoxetine. Chronic treatment with RS67333, similar to fluoxetine, induced anxiolytic/antidepressant-like activity and stimulated adult hippocampal neurogenesis. However, unlike fluoxetine, the anxiolytic effects of RS67333 were already present after 7 days and did not require hippocampal neurogenesis. Chronic treatment with GR125487 prevented both anxiolytic/antidepressant-like and neurogenic effects of fluoxetine, indicating that 5-HT4 receptor activation is necessary for these effects of SSRIs. We then explored whether the fast onset of action of the 5-HT4 receptor agonist RS67333 could be predicted by expression of a peripheral biomarker. The b-arrestin-signaling cascade which is involved in 5-HT4 receptor desensitization and internalization, has recently gained attention as a potential pre-clinical/clinical bridging biomarker for depressive states and treatment effects. To this end, we developed a new method to assess levels of circulating proteins through immunoblot analyses of mouse PBMCs isolated from whole blood of anesthetized animals. While we did not detect any change in b-arrestin 1 in mouse leukocytes after 7 days of fluoxetine in corticosterone-treated animals, a short term treatment with RS67333, restored the level of this protein to control levels. In fluoxetine-treated animals, a restoration was only observed in the corticosterone model after a longer exposure. These results suggest that blood levels of b-arrestin 1 may be a useful biomarker to predict antidepressant/anxiolytic activities. Finally, the activation of 5-HT4 receptors in the brain may represent an innovative and rapid onset therapeutic approach to treat depression with comorbid anxiety.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

A method for biomarker measurements in peripheral blood mononuclear cells isolated from anxious and depressed mice: β-arrestin 1 protein levels in depression and treatment

A limited number of biomarkers in the central and peripheral systems which are known may be useful for diagnosing major depressive disorders and predicting the effectiveness of antidepressant (AD) treatments. Since 60% of depressed patients do not respond adequately to medication or are resistant to ADs, it is imperative to delineate more accurate biomarkers. Recent clinical studies suggest that β-arrestin 1 levels in human mononuclear leukocytes may be an efficient biomarker. If potential biomarkers such as β-arrestin 1 could be assessed from a source such as peripheral blood cells, then they could be easily monitored and used to predict therapeutic responses. However, no previous studies have measured β-arrestin 1 levels in peripheral blood mononuclear cells (PBMCs) in anxious/depressive rodents. This study aimed to develop a method to detect β-arrestin protein levels through immunoblot analyses of mouse PBMCs isolated from whole blood. In order to validate the approach, β-arrestin levels were then compared in naïve, anxious/depressed mice, and anxious/depressed mice treated with a selective serotonin reuptake inhibitor (fluoxetine, 18 mg/kg/day in the drinking water). The results demonstrated that mouse whole blood collected by submandibular bleeding permitted isolation of enough PBMCs to assess circulating proteins such as β-arrestin 1. β-Arrestin 1 levels were successfully measured in healthy human subject and naïve mouse PBMCs. Interestingly, PBMCs from anxious/depressed mice showed significantly reduced β-arrestin 1 levels. These decreased β-arrestin 1 expression levels were restored to normal levels with chronic fluoxetine treatment. The results suggest that isolation of PBMCs from mice by submandibular bleeding is a useful technique to screen putative biomarkers of the pathophysiology of mood disorders and the response to ADs. In addition, these results confirm that β-arrestin 1 is a potential biomarker for depression

S 38093, a histamine H3 antagonist/inverse agonist, promotes hippocampal neurogenesis and improves context discrimination task in aged mice

Strategies designed to increase adult hippocampal neurogenesis (AHN) may have therapeutic potential for reversing memory impairments. H3 receptor antagonists/inverse agonists also may be useful for treating cognitive deficits. However, it remains unclear whether these ligands have effects on AHN. The present study aimed to investigate the effects of a 28-day treatment with S 38093, a novel brain-penetrant antagonist/inverse agonist of H3 receptors, on AHN (proliferation, maturation and survival) in 3-month-old and in aged 16-month-old mice. In addition, the effects of S 38093 treatment on 7-month-old APPSWE Tg2576 transgenic mice, a model of Alzheimer’s disease, were also assessed. In all tested models, chronic treatment with S 38093 stimulated all steps of AHN. In aged animals, S 38093 induced a reversal of age-dependent effects on hippocampal brain-derived neurotrophic factor (BDNF) BDNF-IX, BDNF-IV and BDNF-I transcripts and increased vascular endothelial growth factor (VEGF) expression. Finally, the effects of chronic administration of S 38093 were assessed on a neurogenesis-dependent “context discrimination (CS) test” in aged mice. While ageing altered mouse CS, chronic S 38093 treatment significantly improved CS. Taken together, these results provide evidence that chronic S 38093 treatment increases adult hippocampal neurogenesis and may provide an innovative strategy to improve age-associated cognitive deficits

Anxiolytic/antidepressant-like and neurogenic effects of 5-HT4 receptor ligand in mice : role of β-arrestin 1 protein

Les inhibiteurs sélectifs de recapture de la sérotonine (ISRS), agonistes indirects des récepteurs de la sérotonine (5-HT), ont un début d'effet antidépresseur retardé de plusieurs semaines. Des travaux antérieurs suggèrent que le récepteur 5-HT4 de la sérotonine serait une cible directe pour traiter la dépression et un nouvel espoir pour traiter plus rapidement ces pathologies anxio-dépressives. Toutefois, l'hypothèse « 5-HT4 » doit encore être validée dans des modèles animaux d'anxiété/dépression. Les questions posées étaient : la stimulation des récepteurs 5-HT4 centraux est-elle nécessaire aux effets comportementaux des ISRS ? la neurogenèse hippocampique adulte contribue-t-elle à ces effets ? En utilisant le modèle de stress chronique à la corticostérone (CORT) chez la souris, nous avons évalué les effets sur ces paramètres d’un traitement chronique avec un agoniste du récepteur 5-HT4 (RS67333, 1,5 mg/kg/jour pendant 4 semaines) comparé à un traitement à la fluoxétine (18 mg/kg/jour). Nous avons ensuite utilisé ce modèle murin combiné à l’ablation de la neurogenèse hippocampique par rayons-X afin d’examiner si la neurogenèse est nécessaire aux effets comportementaux d’un traitement subchronique (7 jours) ou chronique (28 jours) avec le RS67333. Nous avons également évalué le blocage des effets de la fluoxétine par un antagoniste du récepteur 5-HT4 (GR125487, 1 mg/kg/jour). Le traitement chronique avec RS67333, comme celui de la fluoxétine, induit une activité anxiolytique/antidépressive et stimule la neurogenèse hippocampique adulte. Cependant, contrairement à la fluoxétine , les effets anxiolytiques du RS67333 sont déjà présents après 7 jours de traitement, sans nécessité l’activation de la neurogenèse. Le traitement chronique avec le GR125487 empêche les deux effets anxiolytique/antidépresseur et neurogènique de la fluoxétine, indiquant que l'activation du récepteur 5-HT4 est nécessaire à ces effets de l’ISRS. Nous avons ensuite cherché à savoir si le court délai d’action antidépresseur du RS67333 peut être prédit par l'expression d'un biomarqueur périphérique. Des données de la littérature indiquent que la cascade de signalisation de β-arrestine 1 (impliquée dans la désensibilisation et l’internalisation du récepteur 5-HT4) serait un biomarqueur potentiel pré-clinique/clinique des états dépressifs et des effets d’un traitement antidépresseur. À cette fin, nous avons développé une nouvelle méthode d’évaluation des taux de protéines circulantes grâce à une analyse par immunoblot des leucocytes (PBMC) isolés à partir du sang total de souris. Les taux de β-arrestine 1 sont diminués dans les leucocytes des souris pré-traitées à la CORT. Il faut 7 jours de traitement avec le RS67333, mais 28 jours avec la fluoxétine chez ces animaux pour restaurer un taux de β-arrestine 1 comparable à celui des animaux contrôles. Ces résultats suggèrent que le taux sanguin de β-arrestine 1 est un biomarqueur de la rapidité de la réponse antidépressive. Enfin, l'activation du récepteur 5-HT4 dans le cerveau peut représenter une approche thérapeutique innovante d’apparition pour traiter plus rapidement des symptômes dépressifs associés à l’anxiété.Selective serotonin reuptake inhibitors (SSRIs) display a delayed onset of action of several weeks. Past work demonstrated evidence that the 5-HT4 receptor may be a direct target for treating depression and a new hope for fast acting antidepressant treatment. However, the 5-HT4 hypothesis still needs to be validated in models of anxiety/depression.We decided to investigate whether 5-HT4 receptor stimulation was necessary for the effects of SSRIs in a mouse model of anxiety/depression and whether hippocampal neurogenesis contributed to these effects. Using the mouse corticosterone model of anxiety/depression, we assessed whether chronic treatment with a 5-HT4 receptor agonist (RS67333, 1.5 mg/kg/day) had effects on anxiety and depression-related behaviors as well as on hippocampal neurogenesis in comparison to chronic fluoxetine treatment (18 mg/kg/day). Then, using our model combined with ablation of hippocampal neurogenesis, we investigated whether neurogenesis was necessary for the behavioral effects of subchronic (7-days) or chronic (28-days) RS67333 treatment. We also assessed whether a 5-HT4 receptor antagonist, (GR125487, 1 mg/kg/day) could prevent the behavioral and neurogenic effects of fluoxetine. Chronic treatment with RS67333, similar to fluoxetine, induced anxiolytic/antidepressant-like activity and stimulated adult hippocampal neurogenesis. However, unlike fluoxetine, the anxiolytic effects of RS67333 were already present after 7 days and did not require hippocampal neurogenesis. Chronic treatment with GR125487 prevented both anxiolytic/antidepressant-like and neurogenic effects of fluoxetine, indicating that 5-HT4 receptor activation is necessary for these effects of SSRIs. We then explored whether the fast onset of action of the 5-HT4 receptor agonist RS67333 could be predicted by expression of a peripheral biomarker. The β-arrestin-signaling cascade which is involved in 5-HT4 receptor desensitization and internalization, has recently gained attention as a potential pre-clinical/clinical bridging biomarker for depressive states and treatment effects. To this end, we developed a new method to assess levels of circulating proteins through immunoblot analyses of mouse PBMCs isolated from whole blood of anesthetized animals. While we did not detect any change in β-arrestin 1 in mouse leukocytes after 7 days of fluoxetine in corticosterone-treated animals, a short term treatment with RS67333, restored the level of this protein to control levels. In fluoxetine-treated animals, a restoration was only observed in the corticosterone model after a longer exposure. These results suggest that blood levels of β-arrestin 1 may be a useful biomarker to predict antidepressant/anxiolytic activities. Finally, the activation of 5-HT4 receptors in the brain may represent an innovative and rapid onset therapeutic approach to treat depression with comorbid anxiety

Effets anxiolytiques/antidépresseurs et neurogéniques des ligands du récepteur 5-HT4 chez la Souris : rôle de la protéine β-arrestin 1

Selective serotonin reuptake inhibitors (SSRIs) display a delayed onset of action of several weeks. Past work demonstrated evidence that the 5-HT4 receptor may be a direct target for treating depression and a new hope for fast acting antidepressant treatment. However, the 5-HT4 hypothesis still needs to be validated in models of anxiety/depression.We decided to investigate whether 5-HT4 receptor stimulation was necessary for the effects of SSRIs in a mouse model of anxiety/depression and whether hippocampal neurogenesis contributed to these effects. Using the mouse corticosterone model of anxiety/depression, we assessed whether chronic treatment with a 5-HT4 receptor agonist (RS67333, 1.5 mg/kg/day) had effects on anxiety and depression-related behaviors as well as on hippocampal neurogenesis in comparison to chronic fluoxetine treatment (18 mg/kg/day). Then, using our model combined with ablation of hippocampal neurogenesis, we investigated whether neurogenesis was necessary for the behavioral effects of subchronic (7-days) or chronic (28-days) RS67333 treatment. We also assessed whether a 5-HT4 receptor antagonist, (GR125487, 1 mg/kg/day) could prevent the behavioral and neurogenic effects of fluoxetine. Chronic treatment with RS67333, similar to fluoxetine, induced anxiolytic/antidepressant-like activity and stimulated adult hippocampal neurogenesis. However, unlike fluoxetine, the anxiolytic effects of RS67333 were already present after 7 days and did not require hippocampal neurogenesis. Chronic treatment with GR125487 prevented both anxiolytic/antidepressant-like and neurogenic effects of fluoxetine, indicating that 5-HT4 receptor activation is necessary for these effects of SSRIs. We then explored whether the fast onset of action of the 5-HT4 receptor agonist RS67333 could be predicted by expression of a peripheral biomarker. The β-arrestin-signaling cascade which is involved in 5-HT4 receptor desensitization and internalization, has recently gained attention as a potential pre-clinical/clinical bridging biomarker for depressive states and treatment effects. To this end, we developed a new method to assess levels of circulating proteins through immunoblot analyses of mouse PBMCs isolated from whole blood of anesthetized animals. While we did not detect any change in β-arrestin 1 in mouse leukocytes after 7 days of fluoxetine in corticosterone-treated animals, a short term treatment with RS67333, restored the level of this protein to control levels. In fluoxetine-treated animals, a restoration was only observed in the corticosterone model after a longer exposure. These results suggest that blood levels of β-arrestin 1 may be a useful biomarker to predict antidepressant/anxiolytic activities. Finally, the activation of 5-HT4 receptors in the brain may represent an innovative and rapid onset therapeutic approach to treat depression with comorbid anxiety.Les inhibiteurs sélectifs de recapture de la sérotonine (ISRS), agonistes indirects des récepteurs de la sérotonine (5-HT), ont un début d'effet antidépresseur retardé de plusieurs semaines. Des travaux antérieurs suggèrent que le récepteur 5-HT4 de la sérotonine serait une cible directe pour traiter la dépression et un nouvel espoir pour traiter plus rapidement ces pathologies anxio-dépressives. Toutefois, l'hypothèse « 5-HT4 » doit encore être validée dans des modèles animaux d'anxiété/dépression. Les questions posées étaient : la stimulation des récepteurs 5-HT4 centraux est-elle nécessaire aux effets comportementaux des ISRS ? la neurogenèse hippocampique adulte contribue-t-elle à ces effets ? En utilisant le modèle de stress chronique à la corticostérone (CORT) chez la souris, nous avons évalué les effets sur ces paramètres d’un traitement chronique avec un agoniste du récepteur 5-HT4 (RS67333, 1,5 mg/kg/jour pendant 4 semaines) comparé à un traitement à la fluoxétine (18 mg/kg/jour). Nous avons ensuite utilisé ce modèle murin combiné à l’ablation de la neurogenèse hippocampique par rayons-X afin d’examiner si la neurogenèse est nécessaire aux effets comportementaux d’un traitement subchronique (7 jours) ou chronique (28 jours) avec le RS67333. Nous avons également évalué le blocage des effets de la fluoxétine par un antagoniste du récepteur 5-HT4 (GR125487, 1 mg/kg/jour). Le traitement chronique avec RS67333, comme celui de la fluoxétine, induit une activité anxiolytique/antidépressive et stimule la neurogenèse hippocampique adulte. Cependant, contrairement à la fluoxétine , les effets anxiolytiques du RS67333 sont déjà présents après 7 jours de traitement, sans nécessité l’activation de la neurogenèse. Le traitement chronique avec le GR125487 empêche les deux effets anxiolytique/antidépresseur et neurogènique de la fluoxétine, indiquant que l'activation du récepteur 5-HT4 est nécessaire à ces effets de l’ISRS. Nous avons ensuite cherché à savoir si le court délai d’action antidépresseur du RS67333 peut être prédit par l'expression d'un biomarqueur périphérique. Des données de la littérature indiquent que la cascade de signalisation de β-arrestine 1 (impliquée dans la désensibilisation et l’internalisation du récepteur 5-HT4) serait un biomarqueur potentiel pré-clinique/clinique des états dépressifs et des effets d’un traitement antidépresseur. À cette fin, nous avons développé une nouvelle méthode d’évaluation des taux de protéines circulantes grâce à une analyse par immunoblot des leucocytes (PBMC) isolés à partir du sang total de souris. Les taux de β-arrestine 1 sont diminués dans les leucocytes des souris pré-traitées à la CORT. Il faut 7 jours de traitement avec le RS67333, mais 28 jours avec la fluoxétine chez ces animaux pour restaurer un taux de β-arrestine 1 comparable à celui des animaux contrôles. Ces résultats suggèrent que le taux sanguin de β-arrestine 1 est un biomarqueur de la rapidité de la réponse antidépressive. Enfin, l'activation du récepteur 5-HT4 dans le cerveau peut représenter une approche thérapeutique innovante d’apparition pour traiter plus rapidement des symptômes dépressifs associés à l’anxiété

Rapid Anxiolytic Effects of RS67333, a Serotonin Type 4 Receptor Agonist, and Diazepam, a Benzodiazepine, Are Mediated by Projections From the Prefrontal Cortex to the Dorsal Raphe Nucleus

International audienceBackground: Activation of serotonin (5-HT) type 4 receptors (5-HT4Rs) has been shown to have anxiolytic effects in a variety of animal models. Characterizing the circuits responsible for these effects should offer insights into new approaches to treat anxiety.Methods: We evaluated whether acute 5-HT4R activation in glutamatergic axon terminals arising from the medial prefrontal cortex (mPFC) to the dorsal raphe nucleus (DRN) induced fast anxiolytic effects. Anxiolytic effects of an acute systemic administration (1.5 mg/kg, intraperitoneally) or intra-mPFC infusion with the 5-HT4R agonist, RS67333 (0.5 μg/side), were examined in mice. To provide evidence that anxiolytic effects of RS67333 recruited an mPFC-DRN neural circuit, in vivo recordings of firing rate of DRN 5-HT neurons, cerebral 5-HT depletion, and optogenetic activation and silencing were performed.Results: Acute systemic administration and intra-mPFC infusion of RS67333 produced fast anxiolytic effects and increased DRN 5-HT cell firing. Serotonin depletion prevented anxiolytic effects induced by mPFC infusion of RS67333. Surprisingly the anxiolytic effects of mPFC infusion diazepam (1.5 μg/side) were also blocked by 5-HT depletion. Optogenetically activating mPFC terminals targeting the DRN reduced anxiety, whereas silencing this circuit blocked RS67333 and diazepam mPFC infusion-induced anxiolytic effects. Finally, anxiolytic effects induced by an acute systemic RS67333 or diazepam administration were partially blocked after optogenetically inhibiting cortical glutamatergic terminals in the DRN.Conclusions: Our findings suggest that activating 5-HT4R acutely in the mPFC or targeting mPFC pyramidal cell terminals in the DRN might constitute a strategy to produce a fast anxiolytic response

S 47445 Produces Antidepressant- and Anxiolytic-Like Effects through Neurogenesis Dependent and Independent Mechanisms

Glutamatergic dysfunctions are observed in the pathophysiology of depression. The glutamatergic synapse as well as the AMPA receptor’s (AMPAR) activation may represent new potential targets for therapeutic intervention in the context of major depressive disorders. S 47445 is a novel AMPARs positive allosteric modulator (AMPA-PAM) possessing procognitive, neurotrophic properties and enhancing synaptic plasticity. Here, we investigated the antidepressant/anxiolytic-like effects of S 47445 in a mouse model of anxiety/depression based on chronic corticosterone administration (CORT) and in the Chronic Mild Stress (CMS) model in rats. Four doses of S 47445 (0.3 to 10 mg/kg, oral route, 4 and 5 weeks, respectively) were assessed in both models. In mouse, behavioral effects were tested in various anxiety-and depression-related behaviors : the elevated plus maze (EPM), open field (OF), splash test (ST), forced swim test (FST), tail suspension test (TST), fur coat state and novelty suppressed feeding (NSF) as well as on hippocampal neurogenesis and dendritic arborization in comparison to chronic fluoxetine treatment (18 mg/kg, p.o.). In rats, behavioral effects of S 47445 were monitored using sucrose consumption and compared to those of imipramine or venlafaxine (10 mg/kg, i.p.) during the whole treatment period and after withdrawal of treatments. In a mouse model of genetic ablation of hippocampal neurogenesis (GFAP-Tk model), neurogenesis dependent/independent effects of chronic S 47445 treatment were tested, as well as BDNF hippocampal expression. S 47445 reversed CORT-induced depressive-like state by increasing grooming duration and reversing coat state’s deterioration. S 47445 also decreased the immobility duration in TST and FST. The highest doses (3 and 10 mg/kg) seem the most effective for antidepressant-like activity in CORT mice. Furthermore, S 47445 significantly reversed the anxiety phenotype observed in OF (at 1 mg/kg) and EPM (from 1 mg/kg). In the CMS rat model, S 47445 (from 1 mg/kg) demonstrated a rapid onset of effect on anhedonia compared to venlafaxine and imipramine. In the CORT model, S 47445 demonstrated significant neurogenic effects on proliferation, survival and maturation of hippocampal newborn neurons at doses inducing an antidepressant-like effect. It also corrected CORT-induced deficits of growth and arborization of dendrites. Finally, the antidepressant/anxiolytic-like activities of S 47445 required adult hippocampal neurogenesis in the novelty suppressed feeding test contrary to OF, EPM and ST. The observed increase in hippocampal BDNF levels could be one of the mechanisms of S 47445 responsible for the adult hippocampal neurogenesis increase. Altogether, S 47445 displays robust antidepressant-anxiolytic-like properties after chronic administration through neurogenesis dependent/independent mechanisms and neuroplastic activities. The AMPA-PAM S 47445 could have promising therapeutic potential for the treatment of major depressive disorders or generalized anxiety disorders

Vortioxetine Improves Context Discrimination in Mice Through a Neurogenesis Independent Mechanism

Major Depressive Disorders (MDD) patients may exhibit cognitive deficits and it is currently unclear to which degree treatment with antidepressants may affect cognitive function. Preclinical and clinical observations showed that vortioxetine (VORT, an antidepressant with multimodal activity), presents beneficial effects on aspects of cognitive function. In addition, VORT treatment increases adult hippocampal neurogenesis (AHN) in rodents, a candidate mechanism for antidepressant activity. Pattern separation (PS) is the ability to discriminate between two similar contexts/events generating two distinct and non-overlapping representations. Impaired PS may lead to overgeneralization and anxiety disorders. If PS impairments were described in depressed patients, the consequences of antidepressant treatment on context discrimination (CD) are still in its infancy. We hypothesized that VORT-increased AHN may improve CD. Thus, in an attempt to elucidate the molecular mechanism underpinning VORT treatment effects on CD, a rodent model of PS, the role of AHN and stress-induced c-Fos activation was evaluated in the adult mouse hippocampus. Chronic treatment with VORT (1.8 g/kg of food weight; corresponding to a daily dose of 10 mg/kg, 3 weeks) improved CD in mice. Interestingly, chronic treatment with VORT reversed ablation of AHN-induced delay in CD and freezing behavior. VORT treatment decreased stress-induced c-Fos activation in the dorsal but not ventral dentate gyrus. VORT treatment did not affect c-Fos activity in the hippocampus of mice with ablated neurogenesis. This study highlights a role of VORT in CD, which may be independent from AHN and hippocampal c-Fos activation. Further studies elucidating the mechanisms underlying VORT\u27s effects in CD could contribute to future strategies for alleviating the disease burden for individuals suffering from depression and/or anxiety disorders

Vortioxetine Improves Context Discrimination in Mice Through a Neurogenesis Independent Mechanism

Major Depressive Disorders (MDD) patients may exhibit cognitive deficits and it is currently unclear to which degree treatment with antidepressants may affect cognitive function. Preclinical and clinical observations showed that vortioxetine (VORT, an antidepressant with multimodal activity), presents beneficial effects on aspects of cognitive function. In addition, VORT treatment increases adult hippocampal neurogenesis (AHN) in rodents, a candidate mechanism for antidepressant activity. Pattern separation (PS) is the ability to discriminate between two similar contexts/events generating two distinct and non-overlapping representations. Impaired PS may lead to overgeneralization and anxiety disorders. If PS impairments were described in depressed patients, the consequences of antidepressant treatment on context discrimination (CD) are still in its infancy. We hypothesized that VORT-increased AHN may improve CD. Thus, in an attempt to elucidate the molecular mechanism underpinning VORT treatment effects on CD, a rodent model of PS, the role of AHN and stress-induced c-Fos activation was evaluated in the adult mouse hippocampus. Chronic treatment with VORT (1.8 g/kg of food weight; corresponding to a daily dose of 10 mg/kg, 3 weeks) improved CD in mice. Interestingly, chronic treatment with VORT reversed ablation of AHN-induced delay in CD and freezing behavior. VORT treatment decreased stress-induced c-Fos activation in the dorsal but not ventral dentate gyrus. VORT treatment did not affect c-Fos activity in the hippocampus of mice with ablated neurogenesis. This study highlights a role of VORT in CD, which may be independent from AHN and hippocampal c-Fos activation. Further studies elucidating the mechanisms underlying VORT’s effects in CD could contribute to future strategies for alleviating the disease burden for individuals suffering from depression and/or anxiety disorders