Action Of Ketamine Research Articles

Effects of ketamine on GABAergic and glutamatergic activity in the mPFC: biphasic recruitment of GABA function in antidepressant-like responses.

Major depressive disorder (MDD) is associated with disruptions in glutamatergic and GABAergic activity in the medial prefrontal cortex (mPFC), leading to altered synaptic formation and function. Low doses of ketamine rapidly rescue these deficits, inducing fast and sustained antidepressant effects. While it is suggested that ketamine produces a rapid glutamatergic enhancement in the mPFC, the temporal dynamics and the involvement of GABA interneurons in its sustained effects remain unclear. Using simultaneous photometry recordings of calcium activity in mPFC pyramidal and GABA neurons, as well as chemogenetic approaches in Gad1-Cre mice, we explored the hypothesis that initial effects of ketamine on glutamate signaling trigger subsequent enhancement of GABAergic responses, contributing to its sustained antidepressant responses. Calcium recordings revealed a biphasic effect of ketamine on activity of mPFC GABA neurons, characterized by an initial transient decrease (phase 1, <30 min) followed by an increase (phase 2, >60 min), in parallel with a transient increase in excitation/inhibition levels (10 min) and lasting enhancement of glutamatergic activity (30-120 min). Previous administration of ketamine enhanced GABA neuron activity during the sucrose splash test (SUST) and novelty suppressed feeding test (NSFT), 24 h and 72 h post-treatment, respectively. Chemogenetic inhibition of GABA interneurons during the surge of GABAergic activity (phase 2), or immediately before the SUST or NSFT, occluded ketamine's behavioral actions. These results indicate that time-dependent modulation of GABAergic activity is required for the sustained antidepressant-like responses induced by ketamine, suggesting that approaches to enhance GABAergic plasticity and function are promising therapeutic targets for antidepressant development.

Repeated subcutaneous esketamine on treatment-resistant depression: An open-label dose titration study

BackgroundKetamine has recently gained prominence as one of the most effective therapeutic options in unipolar treatment-resistant depression (TRD). However, most studies related to the antidepressant action of ketamine used intravenous (IV) or intranasal (IN) administration. The subcutaneous (SC) route of administration is a promising alternative, as it results in plasma levels comparable to IV, causes fewer side effects, and is easier and cheaper to administer than both IV and IN routes. MethodsIn this context, we conducted an open-label clinical trial for investigating the efficacy and safety of 8 weekly sessions of SC esketamine in TRD patients (n = 30). ResultsAt the end of the treatment, a partial response rate of 26.09 %, a response rate of 52.17 % and remission rate of 34.78 % were observed. The self-reported depressive symptoms, as measured by the Beck Depression Inventory II, significantly decreased from the baseline to the final session, and the improvements were sustained throughout the week. Follow-up evaluations up to the sixth month consistently showed scores lower than the baseline. LimitationsThe small sample size and the drop-out during the follow-up phase may limit the generalizability of the findings. Additionally, the absence of a control group necessitates cautious interpretation of causality. ConclusionsThis pioneering study, which addresses SC esketamine treatment for TRD, reported promising response and remission rates, as well as sustained effects. It highlights the need for further research to improve and expand our knowledge of this innovative, more accessible, and cost-effective therapeutic approach.

Prefrontal cortex molecular clock modulates development of depression-like phenotype and rapid antidepressant response in mice

Depression is associated with dysregulated circadian rhythms, but the role of intrinsic clocks in mood-controlling brain regions remains poorly understood. We found increased circadian negative loop and decreased positive clock regulators expression in the medial prefrontal cortex (mPFC) of a mouse model of depression, and a subsequent clock countermodulation by the rapid antidepressant ketamine. Selective Bmal1KO in CaMK2a excitatory neurons revealed that the functional mPFC clock is an essential factor for the development of a depression-like phenotype and ketamine effects. Per2 silencing in mPFC produced antidepressant-like effects, while REV-ERB agonism enhanced the depression-like phenotype and suppressed ketamine action. Pharmacological potentiation of clock positive modulator ROR elicited antidepressant-like effects, upregulating plasticity protein Homer1a, synaptic AMPA receptors expression and plasticity-related slow wave activity specifically in the mPFC. Our data demonstrate a critical role for mPFC molecular clock in regulating depression-like behavior and the therapeutic potential of clock pharmacological manipulations influencing glutamatergic-dependent plasticity.

Brain region-specific action of ketamine as a rapid antidepressant.

Ketamine has been found to have rapid and potent antidepressant activity. However, despite the ubiquitous brain expression of its molecular target, the N-methyl-d-aspartate receptor (NMDAR), it was not clear whether there is a selective, primary site for ketamine's antidepressant action. We found that ketamine injection in depressive-like mice specifically blocks NMDARs in lateral habenular (LHb) neurons, but not in hippocampal pyramidal neurons. This regional specificity depended on the use-dependent nature of ketamine as a channel blocker, local neural activity, and the extrasynaptic reservoir pool size of NMDARs. Activating hippocampal or inactivating LHb neurons swapped their ketamine sensitivity. Conditional knockout of NMDARs in the LHb occluded ketamine's antidepressant effects and blocked the systemic ketamine-induced elevation of serotonin and brain-derived neurotrophic factor in the hippocampus. This distinction of the primary versus secondary brain target(s) of ketamine should help with the design of more precise and efficient antidepressant treatments.

Effects of ketamine on GABAergic and glutamatergic activity in the mPFC: biphasic recruitment of GABA function in antidepressant-like responses.

Major depressive disorder (MDD) is associated with disruptions in glutamatergic and GABAergic activity in the medial prefrontal cortex (mPFC), leading to altered synaptic formation and function. Low doses of ketamine rapidly rescue these deficits, inducing fast and sustained antidepressant effects. While it is suggested that ketamine produces a rapid glutamatergic enhancement in the mPFC, the temporal dynamics and the involvement of GABA interneurons in its sustained effects remain unclear. Using simultaneous photometry recordings of calcium activity in mPFC pyramidal and GABA neurons, as well as chemogenetic approaches in Gad1-Cre mice, we explored the hypothesis that initial effects of ketamine on glutamate signaling trigger subsequent enhancement of GABAergic responses, contributing to its sustained antidepressant responses. Calcium recordings revealed a biphasic effect of ketamine on activity of mPFC GABA neurons, characterized by an initial transient decrease (phase 1, <30 min) followed by an increase (phase 2, >60 min), in parallel with a transient increase in excitation/inhibition levels (10 min) and lasting enhancement of glutamatergic activity (30-120 min). Previous administration of ketamine enhanced GABA neuron activity during the sucrose splash test (SUST) and novelty suppressed feeding test (NSFT), 24 h and 72 h post-treatment, respectively. Chemogenetic inhibition of GABA interneurons during the surge of GABAergic activity (phase 2), or immediately before the SUST or NSFT, occluded ketamine's behavioral actions. These results indicate that time-dependent modulation of GABAergic activity is required for the sustained antidepressant-like responses induced by ketamine, suggesting that approaches to enhance GABAergic plasticity and function are promising therapeutic targets for antidepressant development.

A randomized controlled pilot study of daily intravenous ketamine over three days for treatment-resistant depression

BackgroundStudies have confirmed the rapid antidepressant action of ketamine in depressive episodes. Nevertheless, a standardized procedure for the delivery of ketamine infusion in individuals suffering from treatment-resistant depression, particularly in terms of infusion frequency and total dosage, remains undetermined. In addition, an efficacious ketamine regimen for persistent pain management involved a continuous 10-day infusion period with no notable adverse effects. Consequently, the primary objective of this study was to evaluate the antidepressant capacity of consecutive ketamine infusions spanning over three successive days, the duration of therapeutic response, and the overall safety profile of the treatment.MethodsIn this randomized controlled trial, participants aged 18–64 with treatment-resistant depression were randomized to receive either intravenous ketamine or midazolam (used as an active placebo) for 40 min daily over three consecutive days. Statistical analysis using repeated measures ANOVA was employed to assess the changes in the total score of the Montgomery–Åsberg Depression Rating Scale (MADRS) and the clinical global impression-Severity from the initial assessment to 10 and 31 days post-infusion. Additionally, the duration of response and remission was evaluated using Kaplan–Meier survival analysis.ResultsOut of 33 randomized participants, 20 underwent the treatment as planned. By day 10th, the ketamine group had a mean reduction in MADRS score of 12.55 (95% CI = 6.70–18.09), whereas the midazolam group had a decrease of 17.22 (95% CI = 11.09–23.36). This pattern continued to day 31, with ketamine showing a mean score decrease of 13.73 (95% CI = 7.54–19.91) and midazolam a fall of 12.44 (95% CI = 5.61–19.28). Both treatments were well tolerated, with dissociative symptoms in the ketamine group being temporary and ceasing by the end of each infusion.ConclusionIntravenous ketamine given for three consecutive days did not show a notable antidepressant advantage when compared to the active placebo midazolam, highlighting the need for further research into effective treatments schedules for treatment-resistant depression.Trial registrationNCT05026203, ClinicalTrials.gov, registered on 24/08/2021.

Differential effects of opioid receptor antagonism on the anti-dyskinetic and anti-parkinsonian effects of sub-anesthetic ketamine treatment in a preclinical model

Sub-anesthetic ketamine treatment has been shown to be an effective therapy for treatment-resistant depression and chronic pain. Our group has previously shown that sub-anesthetic ketamine produces acute anti-parkinsonian, and acute anti-dyskinetic effects in preclinical models of Parkinson's disease (PD). Ketamine is a multifunctional drug and exerts effects through blockade of N-methyl-d-aspartate receptors but also through interaction with the opioid system. In this report, we provide detailed pharmacokinetic rodent data on ketamine and its main metabolites following an intraperitoneal injection, and second, we explore the pharmacodynamic properties of ketamine in a rodent PD model with respect to the opioid system, using naloxone, a pan-opioid receptor antagonist, in unilateral 6-hydroxydopamine-lesioned male rats, treated with 6 mg/kg levodopa (l-DOPA) to establish a model of l-DOPA-induced dyskinesia (LID). As previously reported, we showed that ketamine (20 mg/kg) is highly efficacious in reducing LID and now report that the magnitude of this effect is resistant to naloxone (3 and 5 mg/kg). The higher naloxone dose of 5 mg/kg, however, led to an extension of the time-course of the LID, indicating that opioid receptor activation, while not a prerequisite for the anti-dyskinetic effects of ketamine, still exerts an acute modulatory effect. In contrast to the mild modulatory effect on LID, we found that naloxone added to the anti-parkinsonian activity of ketamine, further reducing the akinetic phenotype. In conclusion, our data show opioid receptor blockade differentially modulates the acute anti-parkinsonian and anti-dyskinetic actions of ketamine, providing novel mechanistic information to support repurposing ketamine for individuals with LID.

Ketamine and fluoxetine exert similar actions on prelimbic and infralimbic responsivity to lateral septal nucleus stimulation in Wistar rats

Ketamine is a dissociative anesthetic that has been proposed to be a useful alternative in cases of a poor response to other treatments in patients with depression. Remarkably, beneficial clinical actions of ketamine are detected once its psychotropic actions disappear. Therefore, clinical actions may occur independently of dose. Most current studies focus on actions of ketamine on neurotrophic factors, but few studies have investigated actions of ketamine on neural structures for which actions of antidepressants have been previously explored. Lateral septal nucleus (LSN) stimulation reduces neural activity in the prelimbic cortex (PL) and infralimbic cortex (IL) subregions of the medial prefrontal cortex (mPFC). Fluoxetine increases inhibitory responsivity of the LSN-IL connection. In the present study, actions of an anesthetic dose of ketamine were compared with a high dose of fluoxetine on behavior and neural responsivity 24 h after drug administration. Fluoxetine reduced immobility in the forced swim test without changing locomotor activity in the open field test. Ketamine strongly decreased locomotor activity and did not produce changes in immobility. In another set of Wistar rats that received similar drug treatment regimens, the results indicated that LSN stimulation in saline-treated animals produced a long-lasting inhibitory afterdischarge in these mPFC subregions. Actions of ketamine on the LSN-mPFC connection reproduced actions of fluoxetine, consisting of accentuated inhibition of the LSN action on the mPFC. These findings suggest that independent of different actions on neurotransmission, the common final pathway of antidepressants lies in their actions on forebrain structures that are related to emotional regulation.

Ketamine can produce oscillatory dynamics by engaging mechanisms dependent on the kinetics of NMDA receptors

Ketamine is an N-methyl-D-aspartate (NMDA)-receptor antagonist that produces sedation, analgesia, and dissociation at low doses and profound unconsciousness with antinociception at high doses. At high and low doses, ketamine can generate gamma oscillations (>25 Hz) in the electroencephalogram (EEG). The gamma oscillations are interrupted by slow-delta oscillations (0.1 to 4 Hz) at high doses. Ketamine's primary molecular targets and its oscillatory dynamics have been characterized. However, how the actions of ketamine at the subcellular level give rise to the oscillatory dynamics observed at the network level remains unknown. By developing a biophysical model of cortical circuits, we demonstrate how NMDA-receptor antagonism by ketamine can produce the oscillatory dynamics observed in human EEG recordings and nonhuman primate local field potential recordings. We have identified how impaired NMDA-receptor kinetics can cause disinhibition in neuronal circuits and how a disinhibited interaction between NMDA-receptor-mediated excitation and GABA-receptor-mediated inhibition can produce gamma oscillations at high and low doses, and slow-delta oscillations at high doses. Our work uncovers general mechanisms for generating oscillatory brain dynamics that differs from ones previously reported and provides important insights into ketamine's mechanisms of action as an anesthetic and as a therapy for treatment-resistant depression.

Ahnak in the prefrontal cortex mediates behavioral correlates of stress resilience and rapid antidepressant action in mice.

The prefrontal cortex (PFC) is a key neural node mediating behavioral responses to stress and the actions of ketamine, a fast-acting antidepressant. The molecular mechanisms underlying these processes, however, are not fully understood. Our recent study revealed a pivotal role of hippocampal Ahnak as a regulator of cellular and behavioral adaptations to chronic stress. However, despite its significant expression in the PFC, the contribution of cortical Ahnak to behavioral responses to stress and antidepressants remains unknown. Here, using a mouse model for chronic social stress, we find that Ahnak expression in the PFC is significantly increased in stress-resilient mice and positively correlated with social interaction after stress exposure. Conditional deletion of Ahnak in the PFC or forebrain glutamatergic neurons facilitates stress susceptibility, suggesting that Ahnak is required for behavioral resilience. Further supporting this notion, Ahnak expression in the PFC is increased after the administration of ketamine or its metabolite (2R, 6R)-hydroxynorketamine (HNK). Moreover, Ahnak deletion in forebrain glutamatergic neurons blocks the restorative behavioral effects of ketamine or HNK in stress-susceptible mice. This forebrain excitatory neuron-specific Ahnak deletion reduces the frequency of mini excitatory postsynaptic currents in layer II/III pyramidal neurons, suggesting that Ahnak may induce its behavioral effects via modulation of glutamatergic transmission in the PFC. Altogether, these data suggest that Ahnak in glutamatergic PFC neurons may be critical for behavioral resilience and antidepressant actions of ketamine or HNK in chronic social stress-exposed mice.

Partial mGlu5 receptor NAM, M-5MPEP, induces rapid and sustained antidepressant-like effects in the BDNF-dependent mechanism and enhances (R)-ketamine action in mice.

Partial negative allosteric modulators (NAM) of the metabotropic glutamate 5 (mGlu5) receptor are an excellent alternative to full antagonists and NAMs because they retain therapeutic effects and have a much broader therapeutic window. Here, we investigated whether partial mGlu5 NAM, 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP), induced a fast and sustained antidepressant-like effect, characteristic of rapid-acting antidepressant drugs (RAADs) like ketamine, in mice. A tail suspension test (TST) was used to investigate acute antidepressant-like effects. Sustained effects were studied 24h after the four intraperitoneal (ip) administrations using the splash test, designed to measure apathy-like state, the sucrose preference test (SPT), reflecting anhedonia, and the TST. Western blot and ELISA techniques were used to measure brain-derived neurotrophic factor (BDNF) and selected protein levels. A tail suspension test (TST) was used to investigate acute antidepressant-like effects. Sustained effects were studied 24h after the four intraperitoneal (ip) administrations using the splash test, designed to measure apathy-like state, the sucrose preference test (SPT), reflecting anhedonia, and the TST. Western blot and ELISA techniques were used to measure brain-derived neurotrophic factor (BDNF) and selected protein levels. Partial mGlu5 receptor NAM, M-5MPEP, induced rapid and sustained antidepressant-like effects in the BDNF-dependent mechanism and enhanced (R)-ketamine action in mice, indicating both substances' convergent mechanisms of action and the possibility of their practical use in treating depression as RAAD.

Beyond anesthesia. Uses and actions of ketamine

Ketamine, first synthesized over six decades ago, continues to interest clinicians and fundamental researchers due to its multifaceted applications and complex mechanisms of action on the brain. This review synthesizes clinical and select preclinical studies to provide a broad overview of ketamine’s clinical uses, with a particular focus on its expanding role in psychiatry. Despite its longstanding presence in the medical field, precisely how ketamine’s effects on brain activity produce clinical benefit remains poorly understood. The review begins with a brief historical account of ketamine’s discovery and its evolution as an anesthetic and analgesic, setting the stage for its more recent advances and applications in treating psychiatric disorders. This review highlights a growing body of evidence supporting ketamine’s use for certain psychiatric diseases, such as major depressive disorder, underscoring the drug’s potential for reshaping therapeutic strategies. However, it also points to a significant gap in our understanding, for example, whether particular neurobiological mechanisms underscore ketamine’s beneficial effects. This review emphasizes the need for a cautious yet optimistic approach to integrating ketamine into clinical practice, balanced by the need to investigate its core neurobiological effects further.

Are "mystical experiences" essential for antidepressant actions of ketamine and the classic psychedelics?

The growing interest in the rapid and sustained antidepressant effects of the dissociative anesthetic ketamine and classic psychedelics, such as psilocybin, is remarkable. However, both ketamine and psychedelics are known to induce acute mystical experiences; ketamine can cause dissociative symptoms such as out-of-body experience, while psychedelics typically bring about hallucinogenic experiences, like a profound sense of unity with the universe or nature. The role of these mystical experiences in enhancing the antidepressant outcomes for patients with depression is currently an area of ongoing investigation and debate. Clinical studies have shown that the dissociative symptoms following the administration of ketamine or (S)-ketamine (esketamine) are not directly linked to their antidepressant properties. In contrast, the antidepressant potential of (R)-ketamine (arketamine), thought to lack dissociative side effects, has yet to be conclusively proven in large-scale clinical trials. Moreover, although the activation of the serotonin 5-HT2A receptor is crucial for the hallucinogenic effects of psychedelics in humans, its precise role in their antidepressant action is still under discussion. This article explores the importance of mystical experiences in enhancing the antidepressant efficacy of both ketamine and classic psychedelics.

RGS4 Actions in Mouse Prefrontal Cortex Modulate Behavioral and Transcriptomic Responses to Chronic Stress and Ketamine.

The signal transduction protein, regulator of G protein signaling 4 (RGS4), plays a prominent role in physiologic and pharmacological responses by controlling multiple intracellular pathways. Our earlier work identified the dynamic but distinct roles of RGS4 in the efficacy of monoamine-targeting versus fast-acting antidepressants. Using a modified chronic variable stress (CVS) paradigm in mice, we demonstrate that stress-induced behavioral abnormalities are associated with the downregulation of RGS4 in the medial prefrontal cortex (mPFC). Knockout of RGS4 (RGS4KO) increases susceptibility to CVS, as mutant mice develop behavioral abnormalities as early as 2 weeks after CVS resting-state functional magnetic resonance imaging I (rs-fMRI) experiments indicate that stress susceptibility in RGS4KO mice is associated with changes in connectivity between the mediodorsal thalamus (MD-THL) and the mPFC. Notably, RGS4KO also paradoxically enhances the antidepressant efficacy of ketamine in the CVS paradigm. RNA-sequencing analysis of naive and CVS samples obtained from mPFC reveals that RGS4KO triggers unique gene expression signatures and affects several intracellular pathways associated with human major depressive disorder. Our analysis suggests that ketamine treatment in the RGS4KO group triggers changes in pathways implicated in synaptic activity and responses to stress, including pathways associated with axonal guidance and myelination. Overall, we show that reducing RGS4 activity triggers unique gene expression adaptations that contribute to chronic stress disorders and that RGS4 is a negative modulator of ketamine actions. SIGNIFICANCE STATEMENT: Chronic stress promotes robust maladaptation in the brain, but the exact intracellular pathways contributing to stress vulnerability and mood disorders have not been thoroughly investigated. In this study, the authors used murine models of chronic stress and multiple methodologies to demonstrate the critical role of the signal transduction modulator regulator of G protein signaling 4 in the medial prefrontal cortex in vulnerability to chronic stress and the efficacy of the fast-acting antidepressant ketamine.

Sigma-1 receptor activation mediates the sustained antidepressant effect of ketamine in mice via increasing BDNF levels.

Sigma-1 receptor (S1R) is a unique multi-tasking chaperone protein in the endoplasmic reticulum. Since S1R agonists exhibit potent antidepressant-like activity, S1R has become a novel target for antidepression therapy. With a rapid and sustained antidepressant effect, ketamine may also interact with S1R. In this study, we investigated whether the antidepressant action of ketamine was related to S1R activation. Depression state was evaluated in the tail suspension test (TST) and a chronic corticosterone (CORT) procedure was used to induce despair-like behavior in mice. The neuronal activities and structural changes of pyramidal neurons in medial prefrontal cortex (mPFC) were assessed using fiber-optic recording and immunofluorescence staining, respectively. We showed that pharmacological manipulation of S1R modulated ketamine-induced behavioral effect. Furthermore, pretreatment with an S1R antagonist BD1047 (3 mg·kg-1·d-1, i.p., for 3 consecutive days) significantly weakened the structural and functional restoration of pyramidal neuron in mPFC caused by ketamine (10 mg·kg-1, i.p., once). Ketamine indirectly triggered the activation of S1R and subsequently increased the level of BDNF. Pretreatment with an S1R agonist SA4503 (1 mg·kg-1·d-1, i.p., for 3 consecutive days) enhanced the sustained antidepressant effect of ketamine, which was eliminated by knockdown of BDNF in mPFC. These results reveal a critical role of S1R in the sustained antidepressant effect of ketamine, and suggest that a combination of ketamine and S1R agonists may be more beneficial for depression patients.

Enhanced TARP-γ8-PSD-95 coupling in excitatory neurons contributes to the rapid antidepressant-like action of ketamine in male mice

Ketamine produces rapid antidepressant effects at sub-anesthetic dosage through early and sustained activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), however, the exact molecular mechanism still remains unclear. Transmembrane AMPAR regulatory protein-γ8 (TARP-γ8) is identified as one of AMPAR auxiliary subunits, which controls assemblies, surface trafficking and gating of AMPARs. Here, we show that ketamine rescues both depressive-like behaviors and the decreased AMPARs-mediated neurotransmission by recruitment of TARP-γ8 at the postsynaptic sites in the ventral hippocampus of stressed male mice. Furthermore, the rapid antidepressant effects of ketamine are abolished by selective blockade of TARP-γ8-containing AMPAR or uncoupling of TARP-γ8 from PSD-95. Overexpression of TARP-γ8 reverses chronic stress-induced depressive-like behaviors and attenuation of AMPARs-mediated neurotransmission. Conversely, knockdown of TARP-γ8 in excitatory neurons prevents the rapid antidepressant effects of ketamine.

Ketamine Produces Antidepressant Effects by Inhibiting Histone Deacetylases and Upregulating Hippocampal Brain-Derived Neurotrophic Factor Levels in a Diisopropyl Fluorophosphate-Based Rat Model of Gulf War Illness.

Approximately one-third of Gulf War veterans suffer from Gulf War Illness (GWI), which encompasses mood disorders and depressive symptoms. Deployment-related exposure to organophosphate compounds has been associated with GWI development. Epigenetic modifications have been reported in GWI veterans. We previously showed that epigenetic histone dysregulations were associated with decreased brain-derived neurotrophic factor (BDNF) expression in a GWI rat model. GWI has no effective therapies. Ketamine (KET) has recently been approved by the Food and Drug Administration for therapy-resistant depression. Interestingly, BDNF upregulation underlies KET's antidepressant effect in GWI-related depression. Here, we investigated whether KET's effect on histone mechanisms signals BDNF upregulations in GWI. Male Sprague-Dawley rats were injected once daily with diisopropyl fluorophosphate (DFP; 0.5 mg/kg, s.c., 5 days). At 6 months following DFP exposure, KET (10 mg/kg, i.p.) was injected, and brains were dissected 24 hours later. Western blotting was used for protein expression, and epigenetic studies used chromatin immunoprecipitation methods. Dil staining was conducted for assessing dendritic spines. Our results indicated that an antidepressant dose of KET inhibited the upregulation of histone deacetylase (HDAC) enzymes in DFP rats. Furthermore, KET restored acetylated histone occupancy at the Bdnf promoter IV and induced BDNF protein expression in DFP rats. Finally, KET treatment also increased the spine density and altered the spine diversity with increased T-type and decreased S-type spines in DFP rats. Given these findings, we propose that KET's actions involve the inhibition of HDAC expression, upregulation of BDNF, and dendritic modifications that together ameliorates the pathologic synaptic plasticity and exerts an antidepressant effect in DFP rats. SIGNIFICANCE STATEMENT: This study offers evidence supporting the involvement of epigenetic histone pathways in the antidepressant effects of ketamine (KET) in a rat model of Gulf War Illness (GWI)-like depression. This effect is achieved through the modulation of histone acetylation at the Bdnf promoter, resulting in elevated brain-derived neurotrophic factor expression and subsequent dendritic remodeling in the hippocampus. These findings underscore the rationale for considering KET as a potential candidate for clinical trials aimed at managing GWI-related depression.

Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb

Ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist1, has revolutionized the treatment of depression because of its potent, rapid and sustained antidepressant effects2–4. Although the elimination half-life of ketamine is only 13 min in mice5, its antidepressant activities can last for at least 24 h6–9. This large discrepancy poses an interesting basic biological question and has strong clinical implications. Here we demonstrate that after a single systemic injection, ketamine continues to suppress burst firing and block NMDARs in the lateral habenula (LHb) for up to 24 h. This long inhibition of NMDARs is not due to endocytosis but depends on the use-dependent trapping of ketamine in NMDARs. The rate of untrapping is regulated by neural activity. Harnessing the dynamic equilibrium of ketamine–NMDAR interactions by activating the LHb and opening local NMDARs at different plasma ketamine concentrations, we were able to either shorten or prolong the antidepressant effects of ketamine in vivo. These results provide new insights into the causal mechanisms of the sustained antidepressant effects of ketamine. The ability to modulate the duration of ketamine action based on the biophysical properties of ketamine–NMDAR interactions opens up new opportunities for the therapeutic use of ketamine.

Temporal dynamics of BDNF signaling recruitment in the rat prefrontal cortex and hippocampus following a single infusion of a translational dose of ketamine

Despite several decades of investigations, the mechanisms underlying the rapid action of ketamine as antidepressant are still far from being completely understood. Several studies indicated Brain-Derived Neurotrophic Factor (BDNF) as critical for the fast antidepressant action of ketamine, due to its contribution in early and rapid synaptic adaptations. However, previous reports have been essentially based on ketamine dosing modes that differ from the clinical route of administration (slow intravenous infusion). In this report, we investigated the effects of a ketamine dosing mode in male Sprague-Dawley rats showed to be translational to the clinically effective mode in patients. We focused on the first 24 h after infusion to finely dissect potential differences in the contribution of BDNF signaling pathway in prefrontal cortex and hippocampus, two brain regions involved in the antidepressant effects of ketamine.Our data show that the slow ketamine infusion activates the BDNF-mTOR-S6 pathway in prefrontal cortex as early as 2 h and remains on until at least 6 h after the infusion. At the 12 h timepoint, this pathway is turned off in prefrontal cortex while it becomes activated in hippocampus. Interestingly, this pathway appears to be activated in both brain regions at 24 h through a BDNF-independent mechanism adding complexity to the early action of ketamine.We have captured previously unknown dynamics of the early effects of ketamine showing rapid activation/deactivation of BDNF and its downstream signaling in prefrontal cortex and hippocampus, following a precise temporal profile.

Ketamine: Mechanisms and Relevance to Treatment of Depression.

Major depressive disorder (MDD) is a leading cause of suicide in the world. Monoamine-based antidepressant drugs are a primary line of treatment for this mental disorder, although the delayed response and incomplete efficacy in some patients highlight the need for improved therapeutic approaches. Over the past two decades, ketamine has shown rapid onset with sustained (up to several days) antidepressant effects in patients whose MDD has not responded to conventional antidepressant drugs. Recent preclinical studies have started to elucidate the underlying mechanisms of ketamine's antidepressant properties. Herein, we describe and compare recent clinical and preclinical findings to provide a broad perspective of the relevant mechanisms for the antidepressant action of ketamine.