Role of oxidative phosphorylation in the antidepressant effects of arketamine via the vagus nerve-dependent spleen-brain axis.

Arketamine, the (R)-enantiomer of ketamine, exhibits antidepressant-like effects in mice, though the precise molecular mechanisms remain elusive. It has been shown to reduce splenomegaly and depression-like behaviors in the chronic social defeat stress (CSDS) model of depression. This study investigated whether the spleen contributes to the antidepressant-like effects of arketamine in the CSDS model. We found that splenectomy significantly inhibited arketamine's antidepressant-like effects in CSDS-susceptible mice. RNA-sequencing analysis identified the oxidative phosphorylation (OXPHOS) pathway in the prefrontal cortex (PFC) as a key mediator of splenectomy's impact on arketamine's effects. Furthermore, oligomycin A, an inhibitor of the OXPHOS pathway, reversed the suppressive effects of splenectomy on arketamine's antidepressant-like effects. Specific genes within the OXPHOS pathways, such as COX11, UQCR11 and ATP5e, may contribute to these inhibitory effects. Notably, transforming growth factor (TGF)-ß1, along with COX11, appears to modulate the suppressive effects of splenectomy and contribute to arketamine's antidepressant-like effects. Additionally, SRI-01138, an agonist of the TGF-ß1 receptor, alleviated the inhibitory effects of splenectomy on arketamine's antidepressant-like effects. Subdiaphragmatic vagotomy also counteracted the inhibitory effects of splenectomy on arketamine's antidepressant-like effects in CSDS-susceptible mice. These findings suggest that the OXPHOS pathway and TGF-ß1 in the PFC play significant roles in the antidepressant-like effects of arketamine, mediated through the spleen-brain axis via the vagus nerve.

Key role of the gut-microbiota-brain axis via the subdiaphragmatic vagus nerve in demyelination of the cuprizone-treated mouse brain.

Multiple sclerosis (MS) is the most common demyelinating disease that attacks the central nervous system. Dietary intake of cuprizone (CPZ) produces demyelination resembling that of patients with MS. Given the role of the vagus nerve in gut-microbiota-brain axis in development of MS, we performed this study to investigate whether subdiaphragmatic vagotomy (SDV) affects demyelination in CPZ-treated mice. SDV significantly ameliorated demyelination and microglial activation in the brain compared with sham-operated CPZ-treated mice. Furthermore, 16S ribosomal RNA analysis revealed that SDV significantly improved the abnormal gut microbiota composition of CPZ-treated mice. An untargeted metabolomic analysis demonstrated that SDV significantly improved abnormal blood levels of metabolites in CPZ-treated mice compared with sham-operated CPZ-treated mice. Notably, there were correlations between demyelination or microglial activation in the brain and the relative abundance of several microbiome populations, suggesting a link between gut microbiota and the brain. There were also correlations between demyelination or microglial activation in the brain and blood levels of metabolites. Together, these data suggest that CPZ produces demyelination in the brain through the gut-microbiota-brain axis via the subdiaphragmatic vagus nerve.

Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor.

The discovery of robust antidepressant actions exerted by the N-methyl-D-aspartate receptor (NMDAR) antagonist (R,S)-ketamine has been a crucial breakthrough in mood disorder research. (R,S)-ketamine is a racemic mixture of equal amounts of (R)-ketamine (arketamine) and (S)-ketamine (esketamine). In 2019, an esketamine nasal spray from Johnson & Johnson was approved in the United States of America and Europe for treatment-resistant depression. However, an increasing number of preclinical studies show that arketamine has greater potency and longer-lasting antidepressant-like effects than esketamine in rodents, despite the lower binding affinity of arketamine for the NMDAR. In clinical trials, non-ketamine NMDAR-related compounds did not exhibit ketamine-like robust antidepressant actions in patients with depression, despite these compounds showing antidepressant-like effects in rodents. Thus, the rodent data do not necessarily translate to humans due to the complexity of human psychiatric disorders. Collectively, the available studies indicate that it is unlikely that NMDAR plays a major role in the antidepressant action of (R,S)-ketamine and its enantiomers, although the precise molecular mechanisms underlying antidepressant actions of (R,S)-ketamine and its enantiomers remain unclear. In this paper, we review recent findings on the molecular mechanisms underlying the antidepressant actions of (R,S)-ketamine and its potent enantiomer arketamine. Furthermore, we discuss the possible role of the brain-gut-microbiota axis and brain-spleen axis in stress-related psychiatric disorders and in the antidepressant-like action of arketamine. Finally, we discuss the potential of arketamine as a treatment for cognitive impairment in psychiatric disorders, Parkinson's disease, osteoporosis, inflammatory bowel diseases, and stroke.

Novel XIAP mutation with early-onset Crohn's disease complicated with acute heart failure: a case report.

BACKGROUND: The X-linked inhibitor of apoptosis (XIAP) protein is encoded by the XIAP gene and is critical for multiple cell responses and plays a role in preventing cell death. XIAP mutations are associated with several diseases, primarily including hemophagocytic lymphohistiocytosis and inflammatory bowel disease (IBD). We report the clinical features and results associated with hemizygous mutation of the XIAP gene in a young male with Crohn's disease complicated with acute heart failure.This 16-year-old patient ultimately died of heart failure. CASE PRESENTATION: A young male of 16 years of age was initially diagnosed with Crohn's disease based on evidences from endoscopic and histological findings. Although supportive care, anti-infective drugs and biologics were administered consecutively for 11 months, his clinical manifestations and laboratory indices (patient's condition) did not improved. Additionally, the patient exhibited a poor nutritional status and sustained weight loss. Subsequently, acute heart failure led to the exacerbation of the patient's condition. He was diagnosed with wet beriberi according to thiamine deficiency, but the standard medical therapy for heart failure and thiamine supplementation did not reverse the adverse outcomes. Comprehensive genetic analysis of peripheral blood-derived DNA revealed a novel hemizygous mutation of the XIAP gene (c.1259_1262 delACAG), which was inherited from his mother. CONCLUSION: A novel XIAP mutation (c.1259_1262 delACAG) was identified in this study. It may be one of the potential pathogenic factors in Crohn's disease and plays an important role in the progression of heart failure. Additionally, thiamine deficiency triggers a vicious cycle.

Maternal glyphosate exposure causes autism-like behaviors in offspring through increased expression of soluble epoxide hydrolase.

Epidemiological studies suggest that exposure to herbicides during pregnancy might increase risk for autism spectrum disorder (ASD) in offspring. However, the precise mechanisms underlying the risk of ASD by herbicides such as glyphosate remain unclear. Soluble epoxide hydrolase (sEH) in the metabolism of polyunsaturated fatty acids is shown to play a key role in the development of ASD in offspring after maternal immune activation. Here, we found ASD-like behavioral abnormalities in juvenile offspring after maternal exposure to high levels of formulated glyphosate. Furthermore, we found higher levels of sEH in the prefrontal cortex (PFC), hippocampus, and striatum of juvenile offspring, and oxylipin analysis showed decreased levels of epoxy-fatty acids such as 8 (9)-EpETrE in the blood, PFC, hippocampus, and striatum of juvenile offspring after maternal glyphosate exposure, supporting increased activity of sEH in the offspring. Moreover, we found abnormal composition of gut microbiota and short-chain fatty acids in fecal samples of juvenile offspring after maternal glyphosate exposure. Interestingly, oral administration of TPPU (an sEH inhibitor) to pregnant mothers from E5 to P21 prevented ASD-like behaviors such as social interaction deficits and increased grooming time in the juvenile offspring after maternal glyphosate exposure. These findings suggest that maternal exposure to high levels of glyphosate causes ASD-like behavioral abnormalities and abnormal composition of gut microbiota in juvenile offspring, and that increased activity of sEH might play a role in ASD-like behaviors in offspring after maternal glyphosate exposure. Therefore, sEH may represent a target for ASD in offspring after maternal stress from occupational exposure to contaminants.

(R)-ketamine ameliorates demyelination and facilitates remyelination in cuprizone-treated mice: A role of gut-microbiota-brain axis.

Multiple sclerosis (MS) is the most common demyelinating disease that attacks the central nervous system. We recently reported that the new antidepressant (R)-ketamine could ameliorate the disease progression in experimental autoimmune encephalomyelitis model of MS. Cuprizone (CPZ) has been used to produce demyelination which resembles demyelination in MS patients. This study was undertaken to investigate whether (R)-ketamine could affect demyelination in CPZ-treated mice and remyelination after CPZ withdrawal. Repeated treatment with (R)-ketamine (10 mg/kg/day, twice weekly, for 6 weeks) significantly ameliorated demyelination and activated microglia in the brain compared with saline-treated mice. Furthermore, pretreatment with ANA-12 (TrkB antagonist) significantly blocked the beneficial effects of (R)-ketamine on the demyelination and activated microglia in the brain of CPZ-treated mice. The 16S rRNA analysis showed that (R)-ketamine significantly improved abnormal composition of gut-microbiota and decreased levels of lactic acid of CPZ-treated mice. In addition, there were significant correlations between demyelination (or microglial activation) in the brain and the relative abundance of several microbiome, suggesting a link between gut microbiota and brain. Interestingly, (R)-ketamine could facilitate remyelination in the brain after CPZ withdrawal. In conclusion, the study suggests that (R)-ketamine could ameliorate demyelination in the brain of CPZ-treated mice through TrkB activation, and that gut-microbiota-microglia crosstalk may play a role in the demyelination of CPZ-treated mice. Therefore, it is likely that (R)-ketamine could be a new therapeutic drug for MS.

Gut-microbiota-brain axis in the vulnerability to psychosis in adulthood after repeated cannabis exposure during adolescence.

Increasing epidemiological evidence shows that the use of cannabis during adolescence could increase the risk for psychosis in adulthood. However, the precise mechanisms underlying long-lasting cannabis-induced risk for psychosis remain unclear. Accumulating evidence suggests the role of gut microbiota in the pathogenesis of psychiatric disorders. Here, we examined whether gut microbiota plays a role in the risk for psychosis of adult after exposure of cannabinoid (CB) receptor agonist WIN55,212-2 during adolescence. Repeated administration of WIN55,212-2 (2 mg/kg/day) during adolescence (P35-P45) significantly increased the expression of Iba1 (ionized calcium-binding adapter molecule 1) in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) of adult mice after administration of lipopolysaccharide (LPS: 0.5 mg/kg). In contrast, there were no changes in blood levels of pro-inflammatory cytokines between the two groups. Although alpha-diversity and beta-diversity of gut microbiota were no differences between the two groups, there were several microbes altered between the two groups. Interestingly, there were significant correlations between the relative abundance of microbiota and Iba1 expression in the mPFC and NAc. Furthermore, there were also significant correlations between the relative abundance of microbiota and several metabolites in the blood. These findings suggest that gut microbiota may play a role in the microglial activation in the mPFC and NAc of adult mice after repeated WIN55,212-2 exposure during adolescence. Therefore, it is likely that gut-microbiota-microglia crosstalk might play a role in increased risk for psychosis in adults with cannabis use during adolescence.

Repeated intermittent administration of (R)-ketamine during juvenile and adolescent stages prevents schizophrenia-relevant phenotypes in adult offspring after maternal immune activation: a role of TrkB signaling.

Maternal immune activation (MIA) plays a role in the etiology of schizophrenia. MIA by prenatal exposure of polyinosinic:polycytidylic acid [poly(I:C)] in rodents caused behavioral and neurobiological changes relevant to schizophrenia in adult offspring. We investigated whether the novel antidepressant (R)-ketamine could prevent the development of psychosis-like phenotypes in adult offspring after MIA. We examined the effects of (R)-ketamine (10 mg/kg/day, twice weekly for 4 weeks) during juvenile and adolescent stages (P28-P56) on the development of cognitive deficits, loss of parvalbumin (PV)-immunoreactivity in the medial prefrontal cortex (mPFC), and decreased dendritic spine density in the mPFC and hippocampus from adult offspring after prenatal poly(I:C) exposure. Furthermore, we examined the role of TrkB in the prophylactic effects of (R)-ketamine. Repeated intermittent administration of (R)-ketamine during juvenile and adolescent stages significantly blocked the development of cognitive deficits, reduced PV-immunoreactivity in the prelimbic (PrL) of mPFC, and decreased dendritic spine density in the PrL of mPFC, CA3 and dentate gyrus of the hippocampus from adult offspring after prenatal poly(I:C) exposure. Furthermore, pretreatment with ANA-12 (TrkB antagonist: twice weekly for 4 weeks) significantly blocked the beneficial effects of (R)-ketamine on cognitive deficits of adult offspring after prenatal poly(I:C) exposure. These data suggest that repeated intermittent administration of (R)-ketamine during juvenile and adolescent stages could prevent the development of psychosis in adult offspring after MIA. Therefore, (R)-ketamine would be a potential prophylactic drug for young subjects with high-risk for psychosis.

Microglial depletion and abnormalities in gut microbiota composition and short-chain fatty acids in mice after repeated administration of colony stimulating factor 1 receptor inhibitor PLX5622.

PLX5622, a brain-penetrant highly specific inhibitor of the colony-stimulating factor 1 receptor (CSF1R), is used to eliminate microglia in the brain. Considering the role of microglia and gut microbiota in the brain homeostasis, this study was undertaken to investigate whether repeated intragastric administration of PLX5622 (65 mg/kg/day for consecutive 7 days) could affect the composition of gut microbiota and the concentration of short-chain fatty acids (SCFAs) in fresh feces of adult mice. Repeated administration of PLX5622 caused significant reductions of the expression of genes and proteins for microglial markers in the prefrontal cortex (PFC) and hippocampus compared to control mice although the elimination of brain's microglia was partial. There was a significant alteration in the ß-diversity of intestine microbiota in the PLX5622-treated group. Linear discriminant analysis effect size identified eight significant enriched bacteria as microbial markers for PLX5622-treated group. Repeated administration of PLX5622 affected the relative abundance of several bacteria at the genus and species levels. Furthermore, repeated administration of PLX5622 caused a significant change in lactic acid compared to control group. Interestingly, we found significant correlations between microglial markers in the brain and the relative abundance of several bacteria, suggesting microbiome-microglia crosstalk through the brain-gut axis. These data demonstrate that repeated administration of PLX5622 leads to an abnormal composition of the gut microbiota and lactic acid in adult mice. Therefore, abnormalities in the composition of gut microbiota after repeated treatment of PLX5622 should be considered for behavioral and biological functions in animals treated with CSF1R inhibitors.

A role of the subdiaphragmatic vagus nerve in depression-like phenotypes in mice after fecal microbiota transplantation from Chrna7 knock-out mice with depression-like phenotypes.

The α7 subtype of the nicotinic acetylcholine receptor (α7 nAChR: coded by Chrna7) regulates the cholinergic ascending anti-inflammatory pathway involved in depression. We previously reported that Chrna7 knock-out (KO) mice show depression-like phenotypes through systemic inflammation. In this study, we investigated whether fecal microbiota transplantation (FMT) from Chrna7 KO mice causes depression-like phenotypes in mice treated with an antibiotic cocktail (ABX). Chrna7 KO mice with depression-like phenotypes show an abnormal gut microbiota composition, although the alpha diversity and beta diversity were not altered. FMT from Chrna7 KO mice caused depression-like phenotypes, systemic inflammation, and downregulation of synaptic proteins in the prefrontal cortex (PFC) in the ABX-treated mice compared to FMT from the control mice. The Principal component analysis based on the OTU level showed that the FMT group from the KO mice were different from the FMT group from the control mice. We found differences in abundance for several bacteria in the FMT group from the KO mice at the taxonomic level when compared with the other group. Interestingly, subdiaphragmatic vagotomy significantly blocked the development of depression-like phenotypes in the ABX-treated mice after FMT from Chrna7 KO mice. These data suggest that FMT from Chrna7 KO mice produce depression-like phenotypes in ABX-treated mice via the subdiaphragmatic vagus nerve. The brain-gut-microbiota axis association with the subdiaphragmatic vagus nerve plays an important role in the development of depression.

Rapid-acting and long-lasting antidepressant-like action of (R)-ketamine in Nrf2 knock-out mice: a role of TrkB signaling.

The transcription nuclear factor-erythroid factor 2-related factor 2 (Nrf2) plays a key role in inflammation that is involved in depression. We previously reported that Nrf2 knock-out (KO) mice exhibit depression-like phenotypes through systemic inflammation. (R)-ketamine, an enantiomer of ketamine, has rapid-acting and long-lasting antidepressant-like effects in rodents. We investigated whether (R)-ketamine can produce antidepressant-like effects in Nrf2 KO mice. Effects of (R)-ketamine on the depression-like phenotypes in Nrf2 KO mice were examined. Furthermore, the role of TrkB in the antidepressant-like actions of (R)-ketamine was also examined. In the tail-suspension test (TST) and forced swimming test (FST), (R)-ketamine (10 mg/kg) significantly attenuated the increased immobility times of TST and FST in the Nrf2 KO mice. In the sucrose preference test (SPT), (R)-ketamine significantly ameliorated the reduced preference of SPT in Nrf2 KO mice. Decreased expression of synaptic proteins (i.e., GluA1 and PSD-95) in the medial prefrontal cortex (mPFC) of Nrf2 KO mice was significantly ameliorated after a single injection of (R)-ketamine. Furthermore, the pre-treatment with the TrkB antagonist ANA-12 (0.5 mg/kg) significantly blocked the rapid and long-lasting antidepressant-like effects of (R)-ketamine in Nrf2 KO mice. Furthermore, ANA-12 significantly antagonized the beneficial effects of (R)-ketamine on decreased expression of synaptic proteins in the mPFC of Nrf2 KO mice. These findings suggest that (R)-ketamine can produce rapid and long-lasting antidepressant-like actions in Nrf2 KO mice via TrkB signaling.

Splenic NKG2D confers resilience versus susceptibility in mice after chronic social defeat stress: beneficial effects of (R)-ketamine.

The spleen is a large immune organ that plays a key role in the immune system. The precise molecular mechanisms underlying the relationship between the spleen and stress-related psychiatric disorders are unknown. Here we investigated the role of spleen in stress-related psychiatric disorders. FACS analysis was applied to determine the contribution of the spleen to susceptibility and resilience in mice that were subjected to chronic social defeat stress (CSDS). We found a notable increase in splenic volume and weight in CSDS-susceptible mice compared to control (no CSDS) mice and CSDS-resilient mice. The number of granulocytes, but not of T cells and B cells, in the spleen of susceptible mice was higher than in the spleen of both control and resilient mice. Interestingly, NKG2D (natural killer group 2, member D) expression in the spleen of CSDS-susceptible mice was higher than that in control mice and CSDS-resilient mice. In addition, NKG2D expression in the spleen of patients with depression was higher than that in controls. Both increased splenic weight and increased splenic NKG2D expression in CSDS-susceptible mice were ameliorated after a subsequent administration of (R)-ketamine. The present findings indicate a novel role of splenic NKG2D in stress susceptibility versus resilience in mice subjected to CSDS. Furthermore, abnormalities in splenic functions in CSDS-susceptible mice were ameliorated after subsequent injection of (R)-ketamine. Thus, the brain-spleen axis might, at least in part, contribute to the pathogenesis of stress-related psychiatric disorders such as depression.

Ingestion of Lactobacillus intestinalis and Lactobacillus reuteri causes depression- and anhedonia-like phenotypes in antibiotic-treated mice via the vagus nerve.

BACKGROUND: The brain-gut-microbiota axis plays a role in the pathogenesis of stress-related disorders such as depression. In this study, we examined the effects of fecal microbiota transplantation (FMT) in mice with antibiotic-treated microbiota depletion. METHODS: The fecal microbiota was obtained from mice subjected to chronic social defeat stress (CSDS) and control (no CSDS) mice. FMT from these two groups was performed to antibiotic-treated mice. 16S rRNA analysis was performed to examine the composition of gut microbiota. Furthermore, the effects of subdiaphragmatic vagotomy in depression-like phenotypes after ingestion of microbes were examined. RESULTS: The ingestion of fecal microbiota from CSDS-susceptible mice resulted in an anhedonia-like phenotype, higher plasma levels of interleukin-6 (IL-6), and decreased expression of synaptic proteins in the prefrontal cortex (PFC) in antibiotic-treated mice but not in water-treated mice. 16S rRNA analysis suggested that two microbes (Lactobacillus intestinalis and Lactobacillus reuteri) may be responsible for the anhedonia-like phenotype in antibiotic-treated mice after FMT. Ingestion of these two microbes for 14 days led to depression- and anhedonia-like phenotypes, higher plasma IL-6 levels, and decreased expression of synaptic proteins in the PFC of antibiotic-treated mice. Interestingly, subdiaphragmatic vagotomy significantly blocked the development of behavioral abnormalities, elevation of plasma IL-6 levels, and downregulation of synaptic proteins in the PFC after ingestion of these two microbes. CONCLUSIONS: These findings suggest that microbiota depletion using an antibiotic cocktail is essential for the development of FMT-induced behavioral changes and that the vagus nerve plays a key role in behavioral abnormalities in antibiotic-treated mice after the ingestion of L. intestinalis and L. reuteri. Therefore, it is likely that the brain-gut-microbiota axis participates in the pathogenesis of depression via the vagus nerve.

Lack of dopamine D1 receptors in the antidepressant actions of (R)-ketamine in a chronic social defeat stress model.

It is reported that dopamine D1 receptors in the medial prefrontal cortex play a role in the antidepressant actions of (R,S)-ketamine. However, its role in the antidepressant actions of (R)-ketamine, which is more potent than (S)-ketamine, is unknown. In the locomotion test, tail suspension test, forced swimming test and 1% sucrose preference test, pretreatment with dopamine D1 receptor antagonist SCH-23390 did not block the antidepressant effects of (R)-ketamine in the susceptible mice after chronic social defeat stress. These findings suggest that dopamine D1 receptors may not play a major role in the antidepressant actions of (R)-ketamine.

(R)-Ketamine Rapidly Ameliorates the Decreased Spine Density in the Medial Prefrontal Cortex and Hippocampus of Susceptible Mice After Chronic Social Defeat Stress.

BACKGROUND: A recent study demonstrated that spine formation rates by ketamine in the prefrontal cortex (PFC) were not altered at 3-6 h following a single injection, but were markedly altered at 12-24 h. Here, we investigated the acute (3 h post-treatment) effects of (R)-ketamine in the decreased spine density in the medial PFC (mPFC) and hippocampus in susceptible mice after chronic social defeat stress (CSDS). METHODS: (R)-ketamine (10 mg/kg) or saline was administered intraperitoneally to CSDS-susceptible mice. Dendritic spine density in the mPFC and hippocampus was measured 3 h after a single injection. RESULTS: (R)-ketamine significantly ameliorated the decreased spine density in the prelimbic area of mPFC, Cornu Ammonis3, and dentate gyrus of the hippocampus of CSDS-susceptible mice. CONCLUSIONS: This study suggests that (R)-ketamine rapidly ameliorates the decreased spine density in the mPFC and hippocampus of CSDS-susceptible mice, resulting in its rapid-acting antidepressant effects.

Lack of Antidepressant Effects of Low-Voltage-Sensitive T-Type Calcium Channel Blocker Ethosuximide in a Chronic Social Defeat Stress Model: Comparison with (R)-Ketamine.

Background: A recent study demonstrated that low-voltage-sensitive T-type calcium channel blocker ethosuximide shows rapid antidepressant actions. This study was conducted to compare the antidepressant actions of ethosuximide and (R)-ketamine in a chronic social defeat stress model. Methods: Ethosuximide (100, 200, or 400 mg/kg), (R)-ketamine (10 mg/kg), or saline was administered i.p. to chronic social defeat stress-susceptible mice. Subsequently, locomotion test, tail suspension test, forced swimming test, and 1% sucrose preference test were performed. Results: (R)-ketamine showed rapid and long-lasting antidepressant actions in chronic social defeat stress-susceptible mice. In contrast, ethosuximide did not attenuate the increased immobility time of tail suspension test and forced swimming test in chronic social defeat stress-susceptible mice. In the sucrose preference test, ethosuximide did not improve decreased sucrose preference in chronic social defeat stress-susceptible mice. Conclusions: Unlike (R)-ketamine, ethosuximide did not show rapid and sustained antidepressant effects in a chronic social defeat stress model. Therefore, it is unlikely that low-voltage-sensitive T-type calcium channel inhibitors may have ketamine-like robust antidepressant actions.

No Sex-Specific Differences in the Acute Antidepressant Actions of (R)-Ketamine in an Inflammation Model.

Background: Although previous reports suggest sex-specific differences in the antidepressant actions of (R,S)-ketamine, these differences in the antidepressant actions of (R)-ketamine, which is more potent than (S)-ketamine, are unknown. Methods: Saline or (R)-ketamine was administered 23 hours post lipopolysaccharide administration to adult male or female mice. Subsequently, antidepressant effects were assessed using a forced swimming test. Furthermore, the concentration of (R)-ketamine and its 2 major metabolites, (R)-norketamine and (2R,6R)-hydroxynorketamine, was measured in the plasma and brain after the administration of (R)-ketamine in the mice. Results: (R)-ketamine (10 mg/kg) significantly attenuated the increased immobility time of forced swimming test in the lipopolysaccharide-treated mice. There were no sex-specific differences in the concentrations of (R)-ketamine and its 2 metabolites in the plasma and brain. Conclusions: These findings showed no sex-specific differences in terms of the acute antidepressant effects and pharmacokinetic profile of (R)-ketamine.