Traumatic Brain Injury-Induced Fear Generalization in Mice Involves Hippocampal Memory Trace Dysfunction and Is Alleviated by (R,S)-Ketamine.

BACKGROUND: Traumatic brain injury (TBI) is a debilitating neurological disorder caused by an impact to the head by an outside force. TBI results in persistent cognitive impairments, including fear generalization and the inability to distinguish between aversive and neutral stimuli. The mechanisms underlying fear generalization have not been fully elucidated, and there are no targeted therapeutics to alleviate this symptom of TBI. METHODS: To identify the neural ensembles mediating fear generalization, we utilized ArcCreERT2 × enhanced yellow fluorescent protein (EYFP) mice, which allow for activity-dependent labeling and quantification of memory traces. Mice were administered a sham surgery or the controlled cortical impact model of TBI. Mice were then administered a contextual fear discrimination paradigm and memory traces were quantified in numerous brain regions. In a separate group of mice, we tested if (R,S)-ketamine could decrease fear generalization and alter the corresponding memory traces in TBI mice. RESULTS: TBI mice exhibited increased fear generalization when compared with sham mice. This behavioral phenotype was paralleled by altered memory traces in the dentate gyrus, CA3, and amygdala, but not by alterations in inflammation or sleep. In TBI mice, (R,S)-ketamine facilitated fear discrimination, and this behavioral improvement was reflected in dentate gyrus memory trace activity. CONCLUSIONS: These data show that TBI induces fear generalization by altering fear memory traces and that this deficit can be improved with a single injection of (R,S)-ketamine. This work enhances our understanding of the neural basis of TBI-induced fear generalization and reveals potential therapeutic avenues for alleviating this symptom.

Habenular functional connections are associated with depression state and modulated by ketamine.

BACKGROUND: Depression is a widespread mental health disorder with complex neurobiological underpinnings. The habenula, known as the 'anti-reward center', is thought to play a pivotal role in the pathophysiology of depression. This study aims to elucidate the association between the functional connections of the habenula and depression severity and to explore the modulation of these connections by ketamine. METHODS: We studied 177 participants from a 7-T resting-state functional magnetic resonance imaging subset of the Human Connectome Project dataset to determine the associations between the functional connections of the habenula and depression. Additionally, we analyzed 60 depressed patients from our ketamine database to conduct a preliminary study on alterations in the functional connections of the habenula after ketamine infusions. We also investigated whether the baseline functional connectivity of the habenula is linked to subsequent improvement in depression. RESULTS: We found that functional connections between the habenula and the substantia nigra, as well as the ventral tegmental area were negatively correlated with depression scores and elevated after ketamine infusions. Furthermore, the connection between the right habenula and the right substantia nigra was negatively associated with the improvement of depression. LIMITATIONS: The Human Connectome Project dataset primarily consists of data from healthy participants, with varying levels of depression scores. CONCLUSION: These results suggest that the habenula may facilitate depression by suppressing dopamine reward centers, and ketamine may relieve depression by disinhibiting these dopaminergic regions. This study may enhance our understanding of the neural underpinnings of depression and ketamine's antidepressant effects.

Changes in neurotrophic signaling pathways in brain areas of the chronic mild stress rat model of depression as a signature of ketamine fast antidepressant response/non-response.

Major Depressive Disorder (MDD) is a highly debilitating disorder characterized by a persistent feeling of sadness and anhedonia. Traditional antidepressants have a delayed onset of action and lack of efficacy in up to one third of patients, leading to treatment resistant depression (TRD). Recent years have witnessed a revolutionary treatment of TRD with the introduction of the fast-acting antidepressant ketamine. However, ketamine's mechanisms of action are still poorly understood. Here, we used the chronic mild stress animal model of depression on male rats to investigate the involvement of neurotrophic signaling pathways in stress vulnerability/resilience and fast antidepressant response/non-response to acute subanesthetic ketamine. We performed our analysis on both the hippocampus and the prefrontal cortex, two brain areas implicated in stress-related disorders, considering different subcellular fractions. We measured the activation by phosphorylation of protein kinase B (AKT), extracellular signal-regulated kinases (ERKs), glycogen synthase kinase-3 beta (GSK3 ß), mammalian target of rapamycin (mTOR), and eukaryotic elongation factor 2 (eEF2), key effectors in the regulation of neuroplasticity and glutamatergic transmission which were previously associated to ketamine's fast antidepressant effect. We showed here for the first time that both stress and ketamine induced brain area and subcellular fraction specific changes in these pathways. Our study represents the first attempt to identify molecular mechanisms underlying the response/non-response to ketamine in an animal model of depression. This approach could give a crucial contribution to the study of etiopathogenetic mechanisms as well as to the identification of novel targets for the development of innovative therapeutic strategies.

Effects of ketamine, granisetron and dexmedetomidine on postoperative shivering and hemodynamic changes after general anesthesia: a double-blind randomized clinical trial.

Postoperative shivering is one of the most common complications of surgeries. The current research compared the effects of ketamine, granisetron, and dexmedetomidine on reducing postoperative shivering after general anesthesia. This double-blind clinical trial enrolled 148 patients (39.08 ± 5.99 years old) who had been admitted to Vali-Asr Hospital of Arak, Iran in 2019-2021. The study drugs, including dexmedetomidine, ketamine, granisetron and normal saline, were administered in corresponding groups 30 minutes before the end of surgery. The results showed that dexmedetomidine reduced mean arterial pressure and heart rate in patients. The lowest incidence of shivering was observed in the dexmedetomidine group and it increased the duration of recovery. Overall, dexmedetomidine is recommended to reduce postoperative shivering after general anesthesia, but the increase in duration of recovery should be considered.

Interaction of hallucinogenic rapid-acting antidepressants with mGlu2/3 receptor ligands as a window for more effective therapies.

The desire to find a gold-standard therapy for depression is still ongoing. Developing one universal and effective pharmacotherapy remains troublesome due to the high complexity and variety of symptoms. Over the last decades, the understanding of the mechanism of pathophysiology of depression and its key consequences for brain functioning have undergone significant changes, referring to the monoaminergic theory of the disease. After the breakthrough discovery of ketamine, research began to focus on the modulation of glutamatergic transmission as a new pharmacological target. Glutamate is a crucial player in mechanisms of a novel class of antidepressants, including hallucinogens such as ketamine. The role of glutamatergic transmission is also suggested in the antidepressant (AD) action of scopolamine and psilocybin. Despite fast, robust, and sustained AD action hallucinogens belonging to a group of rapid-acting antidepressants (RAA) exert significant undesired effects, which hamper their use in the clinic. Thus, the synergistic action of more than one substance in lower doses instead of monotherapy may alleviate the likelihood of adverse effects while improving therapeutic outcomes. In this review, we explore AD-like behavioral, synaptic, and molecular action of RAAs such as ketamine, scopolamine, and psilocybin, in combination with mGlu2/3 receptor antagonists.

Ketamine Promoted Breast Cancer Invasion and Metastasis Through Up-regulating Wnt, BMP, and EGFR Signaling.

BACKGROUND/AIM: In this study, we used an orthotropic breast cancer model combined with ketamine addiction and next-generation sequencing (NGS) to comprehensively investigate molecular alterations in ketamine-mediated metastasis. Ketamine is widely used in anesthesia and drug abuse. Our previous study revealed that ketamine promotes the growth of breast cancer cells; however, the detailed molecular mechanism remains unknown. MATERIALS AND METHODS: An orthotropic breast cancer model was established by injecting EO771 breast cancer cells into the mammary fat pad of mice intraperitoneally administered ketamine (30 mg/kg, daily) for 68 days. Tumors collected at day 38 were frozen for future analysis, and their metastasis state was checked at day 68. RESULTS: Tumors were grouped and subjected to NGS analysis, followed by differential gene expression analysis (DEseq) and pathway identification. DEseq analysis showed that ketamine up-regulated metastasis-related signaling, and the key genes were BMP5, FZD6, MMP1B, EGFR, WNT5A, BMP7, and DCN. CONCLUSION: Ketamine addiction up-regulates the expression of genes involved in the Wnt, EGFR, and BMP signaling cascades, which may be associated with breast cancer progression and metastasis.

Nebulized and intraperitoneal ketamine have equivalent antidepressant-like effect in the forced swim and tail suspension tests in mice.

Major depressive disorder (MDD) is a debilitating illness that affects millions of people worldwide. Currently available antidepressants often take weeks to months to reach their full effect, which leads to an increased risk of suicidal behavior in patients with MMD. Intranasally, esketamine has emerged as an alternative to current antidepressants because of its rapid onset and long-lasting effects in patients with MDD. Animal models are useful for the initial pharmacological screening and for a better understanding of the mechanisms underlying the effects of new drugs with potential against MDD. There is a lack of data on alternative routes of drug administration, either oral or injectable, that can be used in preclinical studies. This study aimed to test whether ketamine has antidepressant-like effects in mice when administered via nebulization using a low-cost apparatus. When mice whose depressive-like behavior was induced by corticosterone were treated with nebulized ketamine at concentrations of 1.3, 2.6, and 5.2 mg/mL, immobility was reduced by 38.6 %, 62.0 %, and 61.1 %, respectively, in the forced swimming test (FST) and 43.6 %, 42.1 %, and 57.9 %, respectively, in the tail suspension test (TST). When depression-like behavior was induced by dexamethasone, nebulization with ketamine reduced immobility by 79.7 %, 49.2 %, and 44.4 % in the FST and 80.9 %, 71.4 %, and 80.4 %, respectively, in the TST. When depression-like behavior was induced by the association between dexamethasone and unpredictable chronic mild stress (UCMS) exposure, immobility was reduced by 26.1 %, 55.3 %, and 19.1 % in FST. Mice treated with nebulized ketamine did not show significant changes in the distance covered or in the time spent moving in the open field test. The efficacy of intraperitoneal and nebulized ketamine is equivalent, which shows that nebulization can be an alternative inexpensive route of drug administration for behavioral studies in rodents.

[Interest and mechanisms of action of ketamine in alcohol addiction- A review of clinical and preclinical studies]. / Intérêt et mécanismes d'action de la kétamine dans le traitement de l'addiction à l'alcool ­ Revue des études cliniques et précliniques.

Alcohol Use Disorder (AUD) is a psychiatric condition characterized by chronic and excessive drinking despite negative consequences on overall health and social or occupational functioning. There are currently limited treatment options available for AUD, and the effects size and the response rates to these treatments are often low to moderate. The World Health Organization has identified the development of medications to treat AUD as one of its 24 priorities. This past decade was marked by a renewed interest in psychedelic use in psychiatry. At the centre of this renaissance, ketamine, an atypical psychedelic already used in the treatment of major depression, is an NMDA receptor antagonist that exists as a racemic compound made of two enantiomers, S-ketamine, and R-ketamine. Each form can be metabolized into different metabolites, some of which having antidepressant properties. In this article, we review both clinical and preclinical studies on ketamine and its metabolites in the treatment of AUD. Preclinical as well as clinical studies have revealed that ketamine is effective in reducing withdrawal symptoms and alcohol craving. Convergent data showed that antidepressant properties of ketamine largely contribute to the decreased likelihood of alcohol relapse, especially in patients undergoing ketamine-assisted psychotherapies. Its effectiveness is believed to be linked with its ability to regulate the glutamatergic pathway, enhance neuroplasticity, rewire brain resting state network functional connectivity and decrease depressive-like states. However, it remains to further investigate (i) why strong differences exist between male and female responses in preclinical studies and (ii) the respective roles of each of the metabolites in the ketamine effects in both genders. Interestingly, current studies are also focusing on ketamine addiction and the comorbidity between alcohol addiction and depression occurring more frequently in females.

Title: Intérêt et mécanismes d'action de la kétamine dans le traitement de l'addiction à l'alcool ­ Revue des études cliniques et précliniques. Abstract: Le Trouble de l'Usage d'Alcool (TUA) est une maladie psychiatrique caractérisée par une consommation chronique et excessive d'alcool malgré des conséquences négatives sur la santé et le fonctionnement social ou professionnel. Les options de traitements du TUA sont actuellement limitées et les tailles d'effet et taux de réponse à ces traitements sont souvent faibles à modérés. L'Organisation Mondiale de la Santé a identifié le développement des médicaments pour traiter le TUA comme l'une de ses 24 priorités. Cette dernière décennie a été marquée par un intérêt renouvelé pour l'utilisation de psychédéliques en psychiatrie. La kétamine, un psychédélique atypique déjà utilisé dans le traitement de la dépression majeure, est au centre de cette renaissance. Cet antagoniste des récepteurs NMDA existe sous deux formes énantiomères, la S-kétamine et la R-kétamine, qui peuvent être métabolisées en différents dérivés, dont certains ont montré des propriétés antidépressives. Cet article de revue vise à faire le bilan des études cliniques et précliniques sur l'utilisation de la kétamine et de ses métabolites dans le traitement du TUA. L'ensemble de ces études montre que la kétamine est efficace pour réduire les symptômes de sevrage et les envies irrépressibles d'alcool. Les propriétés antidépressives avérées de la kétamine contribuent à la diminution du risque de rechute dans le mésusage d'alcool, notamment chez les patients suivant des psychothérapies. Son efficacité est supposée être liée à sa capacité à réguler la voie glutamatergique, à améliorer la neuroplasticité, à réorganiser la connectivité fonctionnelle des réseaux d'état de repos (resting state networks) du cerveau et à réduire les états dépressifs. Bien que ces premiers résultats soient prometteurs, la mise en évidence de différences importantes entre les sexes, et la méconnaissance du rôle de chacun des métabolites dans les effets observés justifient la poursuite des recherches précliniques pour mieux comprendre comment agissent véritablement la kétamine et ses métabolites sur le TUA. En clinique, les études récentes s'intéressent désormais à la dépendance à la kétamine et à la dépression comorbide, ainsi qu'à l'influence du sexe, une comorbidité plus forte entre la dépendance à l'alcool et la dépression semblant exister chez la femme.

[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.

Ketamine and the neurobiology of depression: Toward next-generation rapid-acting antidepressant treatments.

Ketamine has emerged as a transformative and mechanistically novel pharmacotherapy for depression. Its rapid onset of action, efficacy for treatment-resistant symptoms, and protection against relapse distinguish it from prior antidepressants. Its discovery emerged from a reconceptualization of the neurobiology of depression and, in turn, insights from the elaboration of its mechanisms of action inform studies of the pathophysiology of depression and related disorders. It has been 25 y since we first presented our ketamine findings in depression. Thus, it is timely for this review to consider what we have learned from studies of ketamine and to suggest future directions for the optimization of rapid-acting antidepressant treatment.

Transcriptional signatures of early-life stress and antidepressant treatment efficacy.

Individuals with a history of early-life stress (ELS) tend to have an altered course of depression and lower treatment response rates. Research suggests that ELS alters brain development, but the molecular changes in the brain following ELS that may mediate altered antidepressant response have not been systematically studied. Sex and gender also impact the risk of depression and treatment response. Here, we leveraged existing RNA sequencing datasets from 1) blood samples from depressed female- and male-identifying patients treated with escitalopram or desvenlafaxine and assessed for treatment response or failure; 2) the nucleus accumbens (NAc) of female and male mice exposed to ELS and/or adult stress; and 3) the NAc of mice after adult stress, antidepressant treatment with imipramine or ketamine, and assessed for treatment response or failure. We find that transcriptomic signatures of adult stress after a history of ELS correspond with transcriptomic signatures of treatment nonresponse, across species and multiple classes of antidepressants. Transcriptomic correspondence with treatment outcome was stronger among females and weaker among males. We next pharmacologically tested these predictions in our mouse model of early-life and adult social defeat stress and treatment with either chronic escitalopram or acute ketamine. Among female mice, the strongest predictor of behavior was an interaction between ELS and ketamine treatment. Among males, however, early experience and treatment were poor predictors of behavior, mirroring our bioinformatic predictions. These studies provide neurobiological evidence for molecular adaptations in the brain related to sex and ELS that contribute to antidepressant treatment response.

A Network Model of the Modulation of γ Oscillations by NMDA Receptors in Cerebral Cortex.

Psychotic drugs such as ketamine induce symptoms close to schizophrenia and stimulate the production of γ oscillations, as also seen in patients, but the underlying mechanisms are still unclear. Here, we have used computational models of cortical networks generating γ oscillations, and have integrated the action of drugs such as ketamine to partially block NMDA receptors (NMDARs). The model can reproduce the paradoxical increase of γ oscillations by NMDA receptor antagonists, assuming that antagonists affect NMDA receptors with higher affinity on inhibitory interneurons. We next used the model to compare the responsiveness of the network to external stimuli, and found that when NMDA channels are blocked, an increase of γ power is observed altogether with an increase of network responsiveness. However, this responsiveness increase applies not only to γ states, but also to asynchronous states with no apparent γ. We conclude that NMDA antagonists induce an increased excitability state, which may or may not produce γ oscillations, but the response to external inputs is exacerbated, which may explain phenomena such as altered perception or hallucinations.

[Ketamine in antidepressant treatment: a revolution?] / Évolution ou révolution dans le traitement des dépressions avec la kétamine ?

Thirty percent of depressed patients are treatment resistant (TRD) suggesting the need of new therapeutic strategy. Recently, it has been shown that ketamine, an anesthetic agent with dissociative effects, has potent and rapid antidepressant properties. Ketamine is a ionotropic glutamatergic NMDA antagonist that inhibits gabaergic neurons. Its antidepressant effect peaks at 24 h post-treatment. Several meta-analyses of placebo randomized clinical trials emphasized its efficacy. More recently, a meta-analysis showed its efficiency in real-world population of TRD patients. Although there is no clear biological or clinical predictors of response or remission to ketamine, patients with high level of resistance were found to remit less often. Restoring both the optimism bias and the asymmetry in belief updating mediates the antidepressant ketamine's effect. Consistent with predictive bayesian model and terror management theory, this suggests that dissociation induced by ketamine may contribute to its clinical antidepressant action. Although increasing access to ketamine and esketamine is welcome, legitimate concerns have been raised with respect to long-term safety and abuse risk.

Title: Évolution ou révolution dans le traitement des dépressions avec la kétamine ? Abstract: Définie par l'échec d'au moins deux antidépresseurs de mécanismes d'action différents, la dépression résistante est fréquente et concerne 30 % des patients déprimés. Elle justifie le recours à des stratégies thérapeutiques innovantes. Depuis quelques années, on utilise un agent anesthésiant et dissociatif, la kétamine, et ses dérivés, dans le traitement de la dépression résistante. Dans cette brève revue de la littérature, nous rapportons les données attestant de l'efficacité et de l'efficience de la kétamine dans cette indication. Certains patients bénéficient plus que d'autres de la kétamine qui est recommandée pour un niveau modéré de résistance. Même si cela reste débattu, la dissociation pourrait contribuer aux effets bénéfiques de la kétamine.

The effects of repeated doses of xylazine-ketamine and medetomidineketamine anesthesia on DNA damage in the liver and kidney.

PURPOSE: This study evaluated the DNA damage caused by repeated doses of xylazine-ketamine and medetomidine-ketamine anesthesia in the liver and kidneys. METHODS: In this study, 60 rats were used. The rats were divided into group 1 (xylazine-ketamine), and group 2 (medetomidine-ketamine), and these anesthetic combinations were administered to the rats at repeated doses with 30-min intervals. The effects of these anesthetic agents on the tumor necrosis factor-alpha gene for DNA damage were investigated. RESULTS: According to the gene expression results, it was observed that a single dose of xylazine-ketamine was 2.9-fold expressed, while first and second repeat doses did not show significant changes in expression levels. However, in the case of the third repetition, it was observed to be 3.8-fold overexpressed. In the case of medetomidine-ketamine administration, it was observed that a single-dose application resulted in a 1.04-fold expression, while the first and the third repeat doses showed a significant down expression. The samples from the second repeat dose administration group were found to have insignificant levels of expression. CONCLUSIONS: This study can contribute to understanding the safe anesthetic combination in research and operations in which xylazine-ketamine and medetomidine-ketamine combinations are used.

The possible place for psychedelics in pharmacotherapy of mental disorders.

Since its emergence in the 1960s, the serotonergic theory of depression bore fruit in the discovery of a plethora of antidepressant drugs affecting the lives of millions of patients. While crucial in the history of drug development, recent studies undermine the effectiveness of currently used antidepressant drugs in comparison to placebo, emphasizing the long time it takes to initiate the therapeutic response and numerous adverse effects. Thus, the scope of contemporary pharmacological research shifts from drugs affecting the serotonin system to rapid-acting antidepressant drugs. The prototypical representative of the aforementioned class is ketamine, an NMDA receptor antagonist capable of alleviating the symptoms of depression shortly after the drug administration. This discovery led to a paradigm shift, focusing on amino-acidic neurotransmitters and growth factors. Alas, the drug is not perfect, as its therapeutic effect diminishes circa 2 weeks after administration. Furthermore, it is not devoid of some severe side effects. However, there seems to be another, more efficient, and safer way to target the glutamatergic system. Hallucinogenic agonists of the 5-HT2A receptor, commonly known as psychedelics, are nowadays being reconsidered in clinical practice, shedding their infamous 1970s stigma. More and more clinical studies prove their clinical efficacy and rapid onset after a single administration while bearing fewer side effects. This review focuses on the current state-of-the-art literature and most recent clinical studies concerning the use of psychedelic drugs in the treatment of mental disorders. Specifically, the antidepressant potential of LSD, psilocybin, DMT, and 5-MeO-DMT will be discussed, together with a brief summary of other possible applications.

Aromatase inhibition and ketamine in rats: sex-differences in antidepressant-like efficacy.

BACKGROUND: Ketamine has been recently approved to treat resistant depression; however preclinical studies showed sex differences in its efficacy. Sex steroids, such as estrogens and testosterone, both in the periphery and locally in the brain, are regarded as important modulators of these sex differences. Therefore, the present study evaluated how inhibiting the biosynthesis of estrogens with letrozole (an aromatase inhibitor) could affect the observed sex differences in ketamine's antidepressant-like-response. METHODS: We performed several consecutive studies in adult Sprague-Dawley rats to evaluate potential sex differences in the antidepressant-like effects of ketamine (5 mg/kg, 7 days, i.p.), letrozole (1 mg/kg, 8 days, i.p.) and their combination (letrozole pre-treatment 3 h before ketamine). Acute and repeated antidepressant-like responses were ascertained in a series of behavioral tests (forced-swim, novelty-suppressed feeding, two-bottle choice for sucrose preference). RESULTS: The main results proved clear sex differences in the antidepressant-like response induced by ketamine, which was observed following a repeated paradigm in adult male rats, but rendered inefficacious in female rats. Moreover, decreasing estrogens production with letrozole induced on itself an antidepressant-like response in female rats, while also increased ketamine's response in male rats (i.e., quicker response observed after only a single dose). Interestingly, both the antidepressant-like effects induced by ketamine in male rats or letrozole in female rats persisted over time up to 65 days post-treatment, suggesting long-term sex-directed benefits for these drugs. CONCLUSIONS: The present results demonstrated a sex-specific role for aromatase inhibition with letrozole in the antidepressant-like response induced by ketamine in male rats. Moreover, letrozole itself presented as a potential antidepressant for females with persistent effects over time. Clearly, the production of estrogens is key in modulating, in a sex-specific manner, affective-like responses and thus deserve further studies.

Ketamine is a novel fast-acting antidepressant recently approved for treatment-resistant depression. Since preclinical studies showed sex differences in its efficacy, probably driven by sex hormones (estrogens and testosterone), we evaluated the antidepressant-like effects of ketamine in male and female rats when the biosynthesis of estrogens was inhibited. To do so, we utilized letrozole, an inhibitor of the aromatase enzyme responsible for the conversion of testosterone into estrogens. The results showed, in line with the prior literature, sex-differences in the antidepressant-like response of ketamine; with efficacy in male rats and a lack of response for females. Aromatase inhibition with letrozole induced a faster response for ketamine in male rats, while did not change the lack of response for females. However, aromatase inhibition on itself was capable of inducing an antidepressant-like response in female rats. Interestingly, both ketamine's and letrozole's antidepressant-like effects in male and female rats respectively showed long-term beneficial effects, up to 65 days post-treatment.