[Ketamine and suicidal behavior: Contribution of animal models of aggression-impulsivity to understanding its mechanism of action]. / Kétamine et suicidalité : modèles animaux pour comprendre son mécanisme d'action.

More than two-thirds of suicides occur during a major depressive episode. Acting out prevention measures and therapeutic options to manage the suicidal crisis are limited. The impulsive-aggressive dimensions are vulnerability factors associated with suicide in patients suffering from a characterized depressive episode: this can be a dimension involved in animals. Impulsive and aggressive rodent models can help analyze, at least in part, the neurobiology of suicide and the beneficial effects of treatments. Ketamine, a glutamatergic antagonist, by rapidly improving the symptoms of depressive episodes, would help reduce suicidal thoughts in the short term. Animal models share with humans impulsive and aggressive endophenotypes modulated by the serotonergic system (5-HTB receptor, MAO-A enzyme), neuroinflammation or the hypothalamic-pituitary-adrenal axis and stress. Significant effects of ketamine on these endophenotypes remain to be demonstrated.

[Ketamine: a neuropsychotropic drug with an innovative mechanism of action]. / La kétamine : un neuropsychotrope au mécanisme d'action innovant.

Ketamine, a non-competitive antagonist of the N-methyl-D-aspartate-glutamate receptor (R-NMDA), has a rapid (from 24 h post-dose) and prolonged (up to one week) antidepressant effect in treatment resistant depression and in rodent models of anxiety/depression. Arguments regarding its cellular and molecular mechanisms underlying its antidepressant activity mainly come from animal studies. However, debates still persist on the structural remodeling of frontocortical/hippocampal neurons and the role of excitatory/inhibitory neurotransmitters involved in its behavioral effect. Neurochemical and behavioral changes are maintained 24 h after administration of ketamine, well beyond its plasma elimination half-life. The glutamatergic pyramidal cells of the medial prefrontal cortex are primarily implicated in the therapeutic effects of ketamine. Advances in knowledge of the consequences of R-NMDA blockade allowed to specify the underlying mechanisms involving the activation of AMPA glutamate receptors, which triggers a cascade of intracellular events dependent on the mechanistic target of rapamycin, brain-derived neurotrophic factor, and synaptic protein synthesis facilitating synaptic plasticity (number of dendritic spines, synaptogenesis). This review focuses on abnormalities of neurotransmitter systems involved in major depressive disorders, their potential impact on neural circuitry and beneficial effects of ketamine. Recent preclinical data pave the way for future studies to better clarify the mechanism of action of fast-acting antidepressant drugs for the development of novel, more effective therapies.

Title: La kétamine : un neuropsychotrope au mécanisme d'action innovant. Abstract: La kétamine, un antagoniste non compétitif du récepteur N-méthyl-D-aspartate (R-NMDA) du glutamate, possède un effet antidépresseur rapide (dès 24 h post-dose) et prolongé (jusqu'à une semaine) dans la dépression résistante au traitement par des antidépresseurs « classiques ¼ et dans les modèles rongeurs d'anxiété/dépression. Les arguments concernant ses mécanismes cellulaires et moléculaires sous-tendant son activité antidépressive viennent principalement d'études animales. Des débats persistent cependant sur le remodelage structurel des neurones frontocorticaux/hippocampiques et sur le rôle des neurotransmetteurs excitateurs/inhibiteurs impliqués dans cet effet comportemental observé chez l'animal. Les modifications neurochimiques et comportementales se maintiennent 24 h après l'administration de la kétamine, bien au-delà de sa demi-vie d'élimination plasmatique. L'avancée des connaissances sur les conséquences du blocage du R-NMDA permet de préciser les mécanismes sous-jacents impliquant (i) l'activation des récepteurs AMPA du glutamate, qui déclenche une cascade d'évènements intracellulaires dépendants de la cible mécanistique de la rapamycine, (ii) le facteur neurotrophique dérivé du cerveau et (iii) la synthèse de protéines synaptiques facilitant la plasticité synaptique (nombre d'épines dendritiques, synaptogenèse). Les cellules pyramidales glutamatergiques du cortex préfrontal médian sont principalement impliquées dans les effets thérapeutiques de la kétamine. La présente revue se concentre sur les anomalies des systèmes de neurotransmetteurs associées aux troubles dépressifs caractérisés, leur impact potentiel sur les circuits neuronaux et les effets bénéfiques de la kétamine. Les résultats d'études précliniques récentes devraient aider à orienter les futures études pour mieux préciser le mécanisme d'action des antidépresseurs d'action rapide et permettre ainsi le développement de nouvelles thérapies plus efficaces.

A tale of two receptors: simultaneous targeting of NMDARs and 5-HT 4 Rs exerts additive effects against stress.

BACKGROUND: Serotonin (5-HT) receptors and N -methyl-D-aspartate receptors (NMDARs) have both been implicated in the pathophysiology of depression and anxiety disorders. Here, we evaluated whether targeting both receptors through combined dosing of ( R , S )-ketamine, an NMDAR antagonist, and prucalopride, a serotonin type IV receptor (5-HT 4 R) agonist, would have additive effects, resulting in reductions in stress-induced fear, behavioral despair, and hyponeophagia. METHODS: A single injection of saline (Sal), ( R , S )-ketamine (K), prucalopride (P), or a combined dose of ( R , S )-ketamine and prucalopride (K+P) was administered before or after contextual fear conditioning (CFC) stress in both sexes. Drug efficacy was assayed using the forced swim test (FST), elevated plus maze (EPM), open field (OF), marble burying (MB), and novelty-suppressed feeding (NSF). Patch clamp electrophysiology was used to measure the effects of combined drug on neural activity in hippocampal CA3. c-fos and parvalbumin (PV) expression in the hippocampus (HPC) and medial prefrontal cortex (mPFC) was examined using immunohistochemistry and network analysis. RESULTS: We found that a combination of K+P, given before or after stress, exerted additive effects, compared to either drug alone, in reducing a variety of stress-induced behaviors in both sexes. Combined K+P administration significantly altered c-fos and PV expression and network activity in the HPC and mPFC. CONCLUSIONS: Our results indicate that combined K+P has additive benefits for combating stress-induced pathophysiology, both at the behavioral and neural level. Our findings provide preliminary evidence that future clinical studies using this combined treatment strategy may prove advantageous in protecting against a broader range of stress-induced psychiatric disorders.

A complex relation between levels of adult hippocampal neurogenesis and expression of the immature neuron marker doublecortin.

We investigated the mechanisms underlying the effects of the antidepressant fluoxetine on behavior and adult hippocampal neurogenesis (AHN). After confirming our earlier report that the signaling molecule ß-arrestin-2 (ß-Arr2) is required for the antidepressant-like effects of fluoxetine, we found that the effects of fluoxetine on proliferation of neural progenitors and survival of adult-born granule cells are absent in the ß-Arr2 knockout (KO) mice. To our surprise, fluoxetine induced a dramatic upregulation of the number of doublecortin (DCX)-expressing cells in the ß-Arr2 KO mice, indicating that this marker can be increased even though AHN is not. We discovered two other conditions where a complex relationship occurs between the number of DCX-expressing cells compared to levels of AHN: a chronic antidepressant model where DCX is upregulated and an inflammation model where DCX is downregulated. We concluded that assessing the number of DCX-expressing cells alone to quantify levels of AHN can be complex and that caution should be applied when label retention techniques are unavailable.

Intrahippocampal injection of a selective blocker of NMDA receptors containing the GluN2B subunit, Ro25-6981, increases glutamate neurotransmission and induces antidepressant-like effects.

Major depressive disorder (MDD) is a serious public health problem, as it is the most common psychiatric disorder worldwide. Antidepressant drugs increase adult hippocampal neurogenesis, which is required to induce some behavioral effects of antidepressants. Adult-born granule cells in the dentate gyrus (DG) and the glutamate receptors subunits 2 (GluN2B) subunit of N-methyl-D-aspartate (NMDA) ionotropic receptors play an important role in these effects. However, the precise neurochemical role of the GluN2B subunit of the NMDA receptor on adult-born GCs for antidepressant-like effects has yet to be elucidated. The present study aims to explore the contribution of the GluN2B-containing NMDA receptors in the ventral dentate gyrus (vDG) to the antidepressant drug treatment using a pharmacological approach. Thus, (αR)-(4-hydroxyphenyl)-(ßS)-methyl-4-(phenylmethyl)-1-piperidinepropanol (Ro25-6981), a selective antagonist of the GluN2B subunit, was acutely administered locally into the ventral DG (vDG, 1 µg each side) following a chronic fluoxetine (18 mg/kg/day) treatment-known to increase adult hippocampal neurogenesis-in a mouse model of anxiety/depression. Responses in a neurogenesis-dependent task, the novelty suppressed feeding (NSF), and neurochemical consequences on extracellular glutamate and gamma-aminobutyric acid (GABA) levels in the vDG were measured. Here, we show a rapid-acting antidepressant-like effect of local Ro25-6981 administration in the NSF independent of fluoxetine treatment. Furthermore, we revealed a fluoxetine-independent increase in the glutamatergic transmission in the vDG. Our results suggest behavioral and neurochemical effects of GluN2B subunit independent of serotonin reuptake inhibition.

Pharmacological Mechanism of Ketamine in Suicidal Behavior Based on Animal Models of Aggressiveness and Impulsivity: A Narrative Review.

Around 700,000 people die from suicide each year in the world. Approximately 90% of suicides have a history of mental illness, and more than two-thirds occur during a major depressive episode. Specific therapeutic options to manage the suicidal crisis are limited and measures to prevent acting out also remain limited. Drugs shown to reduce the risk of suicide (antidepressants, lithium, or clozapine) necessitate a long delay of onset. To date, no treatment is indicated for the treatment of suicidality. Ketamine, a glutamate NMDA receptor antagonist, is a fast-acting antidepressant with significant effects on suicidal ideation in the short term, while its effects on suicidal acts still need to be demonstrated. In the present article, we reviewed the literature on preclinical studies in order to identify the potential anti-suicidal pharmacological targets of ketamine. Impulsive-aggressive traits are one of the vulnerability factors common to suicide in patients with unipolar and bipolar depression. Preclinical studies in rodent models with impulsivity, aggressiveness, and anhedonia may help to analyze, at least in part, suicide neurobiology, as well as the beneficial effects of ketamine/esketamine on reducing suicidal ideations and preventing suicidal acts. The present review focuses on disruptions in the serotonergic system (5-HTB receptor, MAO-A enzyme), neuroinflammation, and/or the HPA axis in rodent models with an impulsive/aggressive phenotype, because these traits are critical risk factors for suicide in humans. Ketamine can modulate these endophenotypes of suicide in human as well as in animal models. The main pharmacological properties of ketamine are then summarized. Finally, numerous questions arose regarding the mechanisms by which ketamine may prevent an impulsive-aggressive phenotype in rodents and suicidal ideations in humans. Animal models of anxiety/depression are important tools to better understand the pathophysiology of depressed patients, and in helping develop novel and fast antidepressant drugs with anti-suicidal properties and clinical utility.

Ketamine and esketamine in suicidal thoughts and behaviors: a systematic review.

Background: More than 2% of the general population experience suicidal ideas each year and a large number of them will attempt suicide. Evidence-based therapeutic options to manage suicidal crisis are currently limited. Objectives: The aim of this study was to overview the findings on the use of ketamine and esketamine for the treatment of suicidal ideas and acts. Design: Systematic review. Data Sources and methods: PubMed, article references, and Clinicaltrials.gov up to June 30, 2022. Meta-analyses published within the last 2 years were also reviewed. Results: We identified 12 randomized controlled trials with reduction of suicidal ideation as the primary objective and 14 trials as secondary objectives. Intravenous racemic ketamine was superior to control drugs (placebo or midazolam) within the first 72 h, in spite of large placebo effects. Adverse events were minor and transient. In contrast, intranasal esketamine did not differ from placebo in large-scale studies. Limitations, clinical considerations, and opportunities for future research include the following points: large placebo effects when studying suicidal ideation reduction; small concerns about blinding quality due to dissociative effects; no studies on the risk/prevention of suicidal acts and mortality; lack of studies beyond affective disorders; no studies in adolescents and older people; lack of knowledge of long-term side effects, notably liability for abuse; no robust predictive markers; limited understanding of the mechanisms of ketamine on suicidal ideas; need for improved assessment of suicidal ideation in clinical trials; need for studies in outpatient settings, emergency room, and liaison consultation; need for research on ketamine administration; limited knowledge on the positive and negative effects of concomitant treatments. Conclusion: Overall, there is compelling evidence for a favorable short-term benefit-risk balance with intravenous racemic ketamine but not intranasal esketamine. The place of ketamine will have to be defined within a multimodal care strategy for suicidal patients. Caution remains necessary for clinical use, and pharmacovigilance will be essential.

Intranasal (R, S)-ketamine delivery induces sustained antidepressant effects associated with changes in cortical balance of excitatory/inhibitory synaptic activity.

In 2019, an intranasal (IN) spray of esketamine SPRAVATO® was approved as a fast-acting antidepressant by drug Agencies US FDA and European EMA. At sub-anesthetic doses, (±)-ketamine, a non-competitive glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, increases the overall excitability of the medial prefrontal cortex (mPFC), an effect being essential for its rapid antidepressant activity. We wondered if this effect of ketamine could come from changes in the balance between neuronal excitation and inhibition (E/I balance) in the mPFC. Here, we performed a preclinical approach to study neurochemical and behavioral responses to a single IN ketamine dose in BALB/cJ mice, a strain more sensitive to stress. By using in vivo microdialysis, we measured cortical E/I balance as the ratio between glutamate to GABA extracellular levels 24 h post-ketamine. We found, for the first time, that E/I balance was shifted in favor of excitation rather than inhibition in the mPFC but more robustly with IN KET than with a single intraperitoneal (IP) dose. Increases in plasma and brain ketamine, norketamine and HNKs levels suggest different metabolic profiles of IP and IN ketamine 30 min post-dose. A significantly larger proportion of ketamine and HNKs in the brain are derived from the IN route 30 min post-dose. It may be linked to the greater magnitude in E/I ratio following IN delivery relative to IP at t24 h. This study suggests that both IP and IN are effective brain delivery methods inducing similar sustained antidepressant efficacy of KET, but the way they induced neurotransmitter changes is slightly different.

Peripheral proteomic changes after electroconvulsive seizures in a rodent model of non-response to chronic fluoxetine.

Major depressive disorder (MDD) is the psychiatric disorder with the highest prevalence in the world. Pharmacological antidepressant treatment (AD), such as selective serotonin reuptake inhibitors [SSRI, i.e., fluoxetine (Flx)] is the first line of treatment for MDD. Despite its efficacy, lack of AD response occurs in numerous patients characterizing Difficult-to-treat Depression. ElectroConvulsive Therapy (ECT) is a highly effective treatment inducing rapid improvement in depressive symptoms and high remission rates of ∼50-63% in patients with pharmaco-resistant depression. Nevertheless, the need to develop reliable treatment response predictors to guide personalized AD strategies and supplement clinical observation is becoming a pressing clinical objective. Here, we propose to establish a proteomic peripheral biomarkers signature of ECT response in an anxio/depressive animal model of non-response to AD. Using an emotionality score based on the analysis complementary behavioral tests of anxiety/depression (Elevated Plus Maze, Novelty Suppressed Feeding, Splash Test), we showed that a 4-week corticosterone treatment (35 µg/ml, Cort model) in C57BL/6JRj male mice induced an anxiety/depressive-like behavior. A 28-day chronic fluoxetine treatment (Flx, 18 mg/kg/day) reduced corticosterone-induced increase in emotional behavior. A 50% decrease in emotionality score threshold before and after Flx, was used to separate Flx-responding mice (Flx-R, n = 18), or Flx non-responder mice (Flx-NR, n = 7). Then, Flx-NR mice received seven sessions of electroconvulsive seizure (ECS, equivalent to ECT in humans) and blood was collected before and after ECS treatment. Chronic ECS normalized the elevated emotionality observed in Flx-NR mice. Then, proteins were extracted from peripheral blood mononuclear cells (PBMCs) and isolated for proteomic analysis using a high-resolution MS Orbitrap. Data are available via ProteomeXchange with identifier PXD037392. The proteomic analysis revealed a signature of 33 peripheral proteins associated with response to ECS (7 down and 26 upregulated). These proteins were previously associated with mental disorders and involved in regulating pathways which participate to the depressive disorder etiology.

CYP 450 enzymes influence (R,S)-ketamine brain delivery and its antidepressant activity.

Esketamine, the S-stereoisomer of (R,S)-ketamine was recently approved by drug agencies (FDA, EMA), as an antidepressant drug with a new mechanism of action. (R,S)-ketamine is a N-methyl-d-aspartate receptor (NMDA-R) antagonist putatively acting on GABAergic inhibitory synapses to increase excitatory synaptic glutamatergic neurotransmission. Unlike monoamine-based antidepressants, (R,S)-ketamine exhibits rapid and persistent antidepressant activity at subanesthetic doses in preclinical rodent models and in treatment-resistant depressed patients. Its major brain metabolite, (2R,6R)-hydroxynorketamine (HNK) is formed following (R,S)-ketamine metabolism by various cytochrome P450 enzymes (CYP) mainly activated in the liver depending on routes of administration [e.g., intravenous (largely used for a better bioavailability), intranasal spray, intracerebral, subcutaneous, intramuscular or oral]. Experimental or clinical studies suggest that (2R,6R)-HNK could be an antidepressant drug candidate. However, questions still remain regarding its molecular and cellular targets in the brain and its role in (R,S)-ketamine's fast-acting antidepressant effects. The purpose of the present review is: 1) to review (R,S)-ketamine pharmacokinetic properties in humans and rodents and its metabolism by CYP enzymes to form norketamine and HNK metabolites; 2) to provide a summary of preclinical strategies challenging the role of these metabolites by modifying (R,S)-ketamine metabolism, e.g., by administering a pre-treatment CYP inducers or inhibitors; 3) to analyze the influence of sex and age on CYP expression and (R,S)-ketamine metabolism. Importantly, this review describes (R,S)-ketamine pharmacodynamics and pharmacokinetics to alert clinicians about possible drug-drug interactions during a concomitant administration of (R,S)-ketamine and CYP inducers/inhibitors that could enhance or blunt, respectively, (R,S)-ketamine's therapeutic antidepressant efficacy in patients.

Dopaminergic neuromodulation of prefrontal cortex activity requires the NMDA receptor coagonist d-serine.

Prefrontal control of cognitive functions critically depends upon glutamatergic transmission and N-methyl D-aspartate (NMDA) receptors, the activity of which is regulated by dopamine. Yet whether the NMDA receptor coagonist d-serine is implicated in the dopamine-glutamate dialogue in the prefrontal cortex (PFC) and other brain areas remains unexplored. Here, using electrophysiological recordings, we show that d-serine is required for the fine-tuning of glutamatergic neurotransmission, neuronal excitability, and synaptic plasticity in the PFC through the actions of dopamine at D1 and D3 receptors. Using in vivo microdialysis, we show that D1 and D3 receptors exert a respective facilitatory and inhibitory influence on extracellular levels and activity of d-serine in the PFC, with actions expressed primarily via the cAMP/protein kinase A (PKA) signaling cascade. Further, using functional magnetic resonance imaging (fMRI) and behavioral assessment, we show that d-serine is required for the potentiation of cognition by D3R blockade as revealed in a test of novel object recognition memory. Collectively, these results unveil a key role for d-serine in the dopaminergic neuromodulation of glutamatergic transmission and PFC activity, findings with clear relevance to the pathogenesis and treatment of diverse brain disorders involving alterations in dopamine-glutamate cross-talk.

The olfactory deficits of depressed patients are restored after remission with venlafaxine treatment.

BACKGROUND: It is unclear whether olfactory deficits improve after remission in depressed patients. Therefore, we aimed to assess in drug-free patients the olfactory performance of patients with major depressive episodes (MDE) and its change after antidepressant treatment. METHODS: In the DEP-ARREST-CLIN study, 69 drug-free patients with a current MDE in the context of major depressive disorder (MDD) were assessed for their olfactory performances and depression severity, before and after 1 (M1) and 3 (M3) months of venlafaxine antidepressant treatment. They were compared to 32 age- and sex-matched healthy controls (HCs). Olfaction was assessed with a psychophysical test, the Sniffin' Sticks test (Threshold: T score; Discrimination: D score; Identification: I score; total score: T + D + I = TDI score) and Pleasantness (pleasantness score: p score; neutral score: N score; unpleasantness score: U score). RESULTS: As compared to HCs, depressed patients had lower TDI olfactory scores [mean (s.d.) 30.0(4.5) v. 33.3(4.2), p < 0.001], T scores [5.6(2.6) v. 7.4(2.6), p < 0.01], p scores [7.5(3.0) v. 9.8(2.8), p < 0.001)] and higher N scores [3.5(2.6) v. 2.1(1.8), p < 0.01]. T, p and N scores at baseline were independent from depression and anhedonia severity. After venlafaxine treatment, significant increases of T scores [M1: 7.0(2.6) and M3: 6.8(3.1), p < 0.01] and p scores [M1: 8.1(3.0) and M3: 8.4(3.3), p < 0.05] were evidenced, in remitters only (T: p < 0.01; P: p < 0.01). Olfaction improvement was mediated by depression improvement. CONCLUSIONS: The olfactory signature of MDE is restored after venlafaxine treatment. This olfaction improvement is mediated by depression improvement.

Sex-specific neurobiological actions of prophylactic (R,S)-ketamine, (2R,6R)-hydroxynorketamine, and (2S,6S)-hydroxynorketamine.

Enhancing stress resilience in at-risk populations could significantly reduce the incidence of stress-related psychiatric disorders. We have previously reported that the administration of (R,S)-ketamine prevents stress-induced depressive-like behavior in male mice, perhaps by altering α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated transmission in hippocampal CA3. However, it is still unknown whether metabolites of (R,S)-ketamine can be prophylactic in both sexes. We administered (R,S)-ketamine or its metabolites (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) and (2S,6S)-hydroxynorketamine ((2S,6S)-HNK) at various doses 1 week before one of a number of stressors in male and female 129S6/SvEv mice. Patch clamp electrophysiology was used to determine the effect of prophylactic drug administration on glutamatergic activity in CA3. To examine the interaction between ovarian hormones and stress resilience, female mice also underwent ovariectomy (OVX) surgery and a hormone replacement protocol prior to drug administration. (2S,6S)-HNK and (2R,6R)-HNK protected against distinct stress-induced behaviors in both sexes, with (2S,6S)-HNK attenuating learned fear in male mice, and (2R,6R)-HNK preventing stress-induced depressive-like behavior in both sexes. (R,S)-ketamine and (2R,6R)-HNK, but not (2S,6S)-HNK, attenuated large-amplitude AMPAR-mediated bursts in hippocampal CA3. All three compounds reduced N-methyl-D-aspartate receptor (NMDAR)-mediated currents 1 week after administration. Furthermore, ovarian-derived hormones were necessary for and sufficient to restore (R,S)-ketamine- and (2R,6R)-HNK-mediated prophylaxis in female mice. Our data provide further evidence that resilience-enhancing prophylactics may alter AMPAR-mediated glutamatergic transmission in CA3. Moreover, we show that prophylactics against stress-induced depressive-like behavior can be developed in a sex-specific manner and demonstrate that ovarian hormones are necessary for the prophylactic efficacy of (R,S)-ketamine and (2R,6R)-HNK in female mice.

Cortical and raphe GABAA, AMPA receptors and glial GLT-1 glutamate transporter contribute to the sustained antidepressant activity of ketamine.

At sub-anaesthetic doses, ketamine, a non competitive N-methyl-d-aspartate (NMDA) receptor antagonist, has demonstrated remarkable and rapid antidepressant (AD) efficacy in patients with treatment-resistant depression (TRD). However, its mechanism of action of ketamine is not fully understood. Since comorbid depression and anxiety disorders often occur, GABAergic/inhibitory and glutamatergic/excitatory drug treatments may be co-administered in these patients. Information regarding this combination is critical to establish efficacy or treatment restrictions to maximize translation from animal models to TRD patients, effectiveness and safety. To assess the specific role of excitatory/inhibitory neurotransmission in the medial prefrontal cortex-raphe nuclei (mPFC-DRN) circuit in the sustained antidepressant-like activity (AD) of ketamine (at t24h post dose), AMPA-R antagonist (intra-DRN) and GABAA-R agonist (intra-mPFC) were co-administered with ketamine (intra-mPFC). Twenty-four hours later, responses in the forced swim test (FST) and neurochemical consequences on extracellular mPFC glutamate, GABA and 5-HT levels were measured in BALB/cJ mice. Intra-DRN NBQX prevented the sustained AD-like activity of ketamine evidenced by decreases in FST swimming duration and blunted cortical 5-HText and Gluext. Intra-mPFC muscimol blocked ketamine AD-like activity and its effects on cortical 5-HText. Moreover, a selective glutamate transporter GLT-1 inhibitor, dihydrokainic acid (DHK) locally perfused into the mPFC produced an AD-like activity at t24h associated with robust increases in mPFC 5-HText, Gluext and GABAext. Thus, the sustained AD-like activity of ketamine is triggered by AMPA-R activation in the DRN and 5-HT - glutamate release in the mPFC, but limited by GABAA-R activation - GABA release in the mPFC. The local blockade of GLT-1 in the mPFC also mimics the rapid responses of ketamine, thus highlighting the role of neuronal-glial adaptation in these effects. These results also suggests the need to test for the concomitant prescription of ketamine and BZD to see whether its sustained antidepressant activity is maintained in TRD patients.

Prophylactic efficacy of 5-HT4R agonists against stress.

Enhancing stress resilience could protect against stress-induced psychiatric disorders in at-risk populations. We and others have previously reported that (R,S)-ketamine acts as a prophylactic against stress when administered 1 week before stress. While we have shown that the selective 5-hydroxytryptamine (5-HT) (serotonin) reuptake inhibitor (SSRI) fluoxetine (Flx) is ineffective as a prophylactic, we hypothesized that other serotonergic compounds such as serotonin 4 receptor (5-HT4R) agonists could act as prophylactics. We tested if three 5-HT4R agonists with varying affinity could protect against stress in two mouse strains by utilizing chronic corticosterone (CORT) administration or contextual fear conditioning (CFC). Mice were administered saline, (R,S)-ketamine, Flx, RS-67,333, prucalopride, or PF-04995274 at varying doses, and then 1 week later were subjected to chronic CORT or CFC. In C57BL/6N mice, chronic Flx administration attenuated CORT-induced weight changes and increased open-arm entries in the elevated plus maze (EPM). Chronic RS-67,333 administration attenuated CORT-mediated weight changes and protected against depressive- and anxiety-like behavior. In 129S6/SvEv mice, RS-67,333 attenuated learned fear in male, but not female mice. RS-67,333 was ineffective against stress-induced depressive-like behavior in the forced swim test (FST), but prevented anxiety-like behavior in both sexes. Prucalopride and PF-04995274 attenuated learned fear and decreased stress-induced depressive-like behavior. Electrophysiological recordings following (R,S)-ketamine or prucalopride administration revealed that both drugs alter AMPA receptor-mediated synaptic transmission in CA3. These data show that in addition to (R,S)-ketamine, 5-HT4R agonists are also effective prophylactics against stress, suggesting that the 5-HT4R may be a novel target for prophylactic drug development.

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.

BACKGROUND: 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.

Role of adult-born granule cells in the hippocampal functions: Focus on the GluN2B-containing NMDA receptors.

Adult-born granule cells constitute a small subpopulation of the dentate gyrus (DG) in the hippocampus. However, they greatly influence several hippocampus-dependent behaviors, suggesting that adult-born granule cells have specific roles that influence behavior. In order to understand how exactly these adult-born granule cells contribute to behavior, it is critical to understand the underlying electrophysiology and neurochemistry of these cells. Here, this review simultaneously focuses on the specific electrophysiological properties of adult-born granule cells, relying on the GluN2B subunit of NMDA glutamate receptors, and how it influences neurochemistry throughout the brain. Especially in a critical age from 4 to 6 weeks post-division during which they modulate hippocampal functions, adult-born granule cells exhibit a higher intrinsic excitability and an enhanced long-term potentiation. Their stimulation decreases the overall excitation/inhibition balance of the DG via recruitment of local interneurons, and in the CA3 region of the hippocampus. However, the link between neurochemical effects of adult-born granule cells and behavior remain to be further examined.

Muscular and mitochondrial effects of long-term fluoxetine treatment in mice, combined with physical endurance exercise on treadmill.

AIM: Fluoxetine, one of the first newer SSRI antidepressant, is an extremely popular treatment for depression that could improve mental health problems. Many recent studies have suggested that SSRI have potential beneficial effects on skeletal muscle tissue. MAIN METHOD: We evaluated the potential beneficial effects of oral fluoxetine (18 mg/kg/day for 6 weeks) on muscle performance, after 6 weeks of physical exercise on treadmill. Male mice were randomly assigned to four groups (n = 12 per group) for treatment. Each group received treatment with following specifications: 1) no exercise with vehicle treatment (SED-S); 2) no exercise with fluoxetine treatment (SED-F); 3) exercise with vehicle treatment (EX-S); and 4) exercise with fluoxetine treatment (EX-F). Exercise performances were assessed based on the exhaustive running time and forelimb grip strength, anxious behavior by elevated plus-maze and open-field tests. Mitochondrial enzymes activity and ROS production were measured in the gastrocnemius and soleus muscles. KEY FINDING: Fluoxetine treatment had a significant effect on maximal aerobic capacity in mice without exercise, but more significant effects on gripping strength and anxiety when combined with exercise training, e.g. increased strength and decreased anxiety. SIGNIFICANCE: Fluoxetine treatment and exercise stimulation also had synergistic effects on strength and increased mitochondrial activity, cellular oxidative and antioxidant capacity in two different muscles.

Fast-acting antidepressant activity of ketamine: highlights on brain serotonin, glutamate, and GABA neurotransmission in preclinical studies.

Ketamine, a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptor, displays a fast antidepressant activity in treatment-resistant depression and in rodent models of anxiety/depression. A large body of evidence concerning the cellular and molecular mechanisms underlying its fast antidepressant-like activity comes from animal studies. Although structural remodeling of frontocortical/hippocampal neurons has been proposed as critical, the role of excitatory/inhibitory neurotransmitters in this behavioral effect is unclear. Neurochemical and behavioral changes are maintained 24h after ketamine administration, well beyond its plasma elimination half-life. Thus, ketamine is believed to initiate a cascade of cellular mechanisms supporting its fast antidepressant-like activity. To date, the underlying mechanism involves glutamate release, then downstream activation of AMPA receptors, which trigger mammalian target of rapamycin (mTOR)-dependent structural plasticity via brain-derived neurotrophic factor (BDNF) and protein neo-synthesis in the medial prefrontal cortex (mPFC), a brain region strongly involved in ketamine therapeutic effects. However, these mPFC effects are not restricted to glutamatergic pyramidal cells, but extend to other neurotransmitters (GABA, serotonin), glial cells, and brain circuits (mPFC/dorsal raphe nucleus-DRN). It could be also mediated by one or several ketamine metabolites (e.g., (2R,6R)-HNK). The present review focuses on evidence for mPFC neurotransmission abnormalities in major depressive disorder (MDD) and their potential impact on neural circuits (mPFC/DRN). We will integrate these considerations with results from recent preclinical studies showing that ketamine, at antidepressant-relevant doses, induces neuronal adaptations that involve the glutamate-excitatory/GABA-inhibitory balance. Our analyses will help direct future studies to further elucidate the mechanism of action of fast-acting antidepressant drugs, and to inform development of novel, more efficacious therapeutics.

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.