Effect of different LED light colors on welfare, performance, some behavioral patterns, and blood parameters of Muscovy ducks.

BACKGROUND: The current study was conducted to assess the impact of different LED light colors on welfare indicators in Muscovy ducks. These welfare parameters encompassed growth performance, specific behaviors, tonic immobility (TI), feather score, haematological, and serum biochemical parameters. Eighty-four healthy unsexed Muscovy ducklings aged two weeks were randomly assigned to four groups (3replicates/group; each replicate contains 7 birds) based on different LED light colors. The first group was raised under white light, the second under red light, the third under blue light, and the fourth under yellow light. To assess the impact of various LED light colors on welfare, growth performance indicators (body weight, body weight gain, feed intake, and feed conversion ratio) were measured. Behavioral patterns including feeding, drinking, standing, walking, sitting, feather pecking, and other activities were recorded. Tonic immobility test (TI) and feather condition scoring were conducted at 3, 6, and 10 weeks of age. At the end of the study blood samples were collected for hematological and serum biochemical analyses. RESULTS: The results revealed that using blue, yellow, and red colors had no adverse effect on the final body weight of the ducks (P > 0.05). Unlike to red light, blue light significantly reduced feather pecking, TI time and cortisol concentrations and improved the feather condition score (P ≤ 0.05). CONCLUSIONS: The current findings suggest that the application of blue light effectively improves welfare indices and has no detrimental impact on the growth performance of Muscovy ducks thereby positively contributing to their welfare.

Dominance and inheritance patterns of mobility and death feigning in beetle strains selected for moving activity.

Reciprocal crossing of different strains is a suitable method to investigate the dominance and inheritance of a focal trait. Herein, we performed reciprocal crossing among strains of Tribolium castaneum exhibiting a genetically high (H strain) and low (L strain) moving activity and investigated the related heritable factors in the F1 and F2 generations. We also evaluated death-feigning behavior, which negatively responded to artificial selection for moving activity in T. castaneum. The results obtained for the F1 generation suggest that low moving activity and short duration of death feigning were dominant. In the F2 generation, movement and death feigning exhibited continuous segregation. The distribution of each trait value in the F2 generation differed from that in the parental generation, and no individuals transgressing the distribution of trait values in the parental generation emerged in the F2 generation. These results suggest that the genetic correlation between movement and death-feigning behavior is controlled in a polygenic manner. Moreover, the examination of the proportions of both behaviors (high vs. low moving activity and long vs. short death-feigning duration) in the F1 generation revealed that the two behaviors may be controlled by the maternal genotype, suggesting that the gene(s) that control movement and death feigning are located on the sex chromosome in T. castaneum.

Tonic immobility (freezing) during sexual and physical assaults produces stronger memory effects than other characteristics of the assaults.

Tonic immobility (TI) is a phylogenetically conserved, passive, obligatory defense mechanism commonly engaged during sexual and physical assaults. During TI, people become immobile while remaining conscious and later reexperience intrusive memories of both their assault and of its accompanying immobility. Here we show that this well-studied biological process has powerful effects on memory and other processes. Participants had experienced either a serious sexual (n = 234) or physical (n = 137) assault. For both the assault and its accompanying immobility, the standard measure of the peritraumatic severity of TI correlated between .40 and .65 with post-assault effects on memory, including memory of the assault and memory of the immobility, the two memory-based self-concept measures of self-blame and event centrality, and post-assault anxiety and depression. The correlations with TI were much higher than other peritraumatic characteristics commonly used to predict and describe posttraumatic effects in assaults and other traumas. The results suggest that TI should be considered for a broader, more biologically based and ecologically valid understanding of the effects of trauma on memory and memory-based reactions.

Responses to artificial selection for locomotor activity: A focus on death feigning in red flour beetle.

Whole-organism performance, including locomotor activity, is an important fitness trait in many animals. Locomotor activity is often classified into sprint speed and locomotor endurance and differences in sprint speed and locomotor endurance affect on other traits such as life-history traits. Previous studies found that locomotor endurance, sprint speed and brain dopamine (DA) levels are correlated with artificial selection for death feigning (an anti-predator behaviour that we refer to as 'death-feigning syndrome') in some insect species. Thus, if the syndrome has a genetic basis, death feigning, sprint speed and brain DA levels may be affected by artificial selection for locomotor endurance. We artificially selected for locomotor endurance over 10 generations in the red flour beetle Tribolium castaneum, and established higher (H) and lower activity (L) strains, then compared their death-feigning behaviour, sprint speed and brain DA levels. H-strain beetles exhibited significantly shorter duration of death-feigning, and significantly higher sprint speeds, suggesting variation in death-feigning syndrome. Surprisingly, although brain DA expression affects various animal behaviours, we found no significant differences in the brain DA expressions of H- and L-strain beetles. Thus, our results imply genetic correlations between locomotor endurance, sprint speed and death feigning, but not with brain DA expression, suggesting that differences in the biogenic amine results of our and previous studies may reflect differences in behavioural expression mechanisms.

Stuck in a Moment: Tonic Immobility Predicts Poor Quality of Life in Treated PTSD Patients.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a prevalent and disabling multisystem disorder, with significant physical and psychiatric morbidity and poor quality of life (QOL). Although peritraumatic reactions - tonic immobility and dissociation - are established predictors of PTSD severity and development, there is a dearth of investigation assessing the impact of peritraumatic reactions on QOL of PTSD patients. Quality of life has become increasingly important in health care and research as a reliable outcome measure. It comprises psychological, physical, social and environmental domains, providing important information about the impact of diseases on patient's life. This study aims to investigate the impact of peritraumatic tonic immobility and peritraumatic dissociation on QOL of PTSD civilian outpatients. SUBJECTS AND METHODS: It is a cross-sectional study of 50 victims of urban violence with current PTSD, recruited in a specialized outpatient clinic. Instruments used were: Structured Clinical Interview IV, Peritraumatic Dissociative Experiences Questionnaire, Tonic Immobility Scale and WHOQOL-BREF (psychological, physical, social and environmental domains). Linear regression models were fitted to evaluate the impact of peritraumatic reactions - tonic immobility and dissociation - on WHOQOL-BREF scores. We controlled for sex as potential confounding. RESULTS: The severity of peritraumatic tonic immobility negatively impacted on psychological and environment domains of quality of life. For each additional point on the Tonic Immobility Scale, there was a decreased of 0.8 points on the scores of these domains of WHOQOL-BREF. Neither the peritraumatic reactions showed effects on physical nor social domains. Possible limitations of this study include cross-sectional design, relatively small sample size of tertiary center outpatients and recall bias. CONCLUSIONS: Peritraumatic tonic immobility is related to poor quality of life, adding new insights about the relationship between this immobility reaction and PTSD.

Differential effects of the novel neurosteroid hypnotic (3ß,5ß,17ß)-3-hydroxyandrostane-17-carbonitrile on electroencephalogram activity in male and female rats.

BACKGROUND: We recently showed that a neurosteroid analogue, (3ß,5ß,17ß)-3-hydroxyandrostane-17-carbonitrile (3ß-OH), induced hypnosis in rats. The aim of the present study was to evaluate the hypnotic and anaesthetic potential of 3ß-OH further using electroencephalography. METHODS: We used behavioural assessment and cortical electroencephalogram (EEG) spectral power analysis to examine hypnotic and anaesthetic effects of 3ß-OH (30 and 60 mg kg-1) administered intraperitoneally or intravenously to young adult male and female rats. RESULTS: We found dose-dependent sex differences in 3ß-OH-induced hypnosis and EEG changes. Both male and female rats responded similarly to i.p. 3ß-OH 30 mg kg-1. However, at the higher dose (60 mg kg-1, i.p.), female rats had two-fold longer duration of spontaneous immobility than male rats (203.4 [61.6] min vs 101.3 [32.1] min), and their EEG was suppressed in the low-frequency range (2-6 Hz), in contrast to male rats. Although a sex-dependent hypnotic effect was not confirmed after 30 mg kg-1 i.v., female rats appeared more sensitive to 3ß-OH with relatively small changes within delta (1-4 Hz) and alpha (8-13 Hz) bands. Finally, 3ß-OH had a rapid onset of action and potent hypnotic/anaesthetic effect after 60 mg kg-1 i.v. in rats of both sexes; however, all female rats and only half of the male rats reached burst suppression, an EEG pattern usually associated with profound inhibition of thalamocortical networks. CONCLUSIONS: Based on its behavioural effects and EEG signature, 3ß-OH is a potent hypnotic in rats, with female rats being more sensitive than male rats.

Should Catatonia Be Conceptualized as a Pathological Response to Trauma?

ABSTRACT: Although catatonia is related to several medical conditions, catatonia as a response to trauma and posttraumatic stress disorder (PTSD) is less clear. The aim of this review is to explore the small emerging body of preliminary evidence that suggests a possible correlation between psychological trauma and catatonia. Initial data suggests a correlation between episodes of intense fear associated with trauma and PTSD and some forms of catatonic responses. Although this relationship is still speculative to be causative, it can have important implications if confirmed. This is especially salient when it is examined alongside existing studies of the response to fear in animals and the phenomenon of tonic immobility, which bears a striking resemblance to catatonia in humans. If prospective studies further support the initial findings, it could change our conceptual understanding of the etiology of a subtype of catatonia substantially while pointing to likely targets of further research to understand the biological mechanisms that underlie the illness.

Thermal dependence and individual variation in tonic immobility varies between sympatric amphibians.

Tonic immobility (TI) is an important antipredator response employed by prey in the last stages of a predation sequence. Evolution by natural selection assumes consistent individual variation (repeatability) in this trait. In ectotherms, which experience variable body temperatures, TI should be repeatable over a thermal gradient to be targeted by natural selection; however, information on thermal repeatability of this trait is missing. We examined thermal repeatability of TI in juveniles of two sympatric amphibians, smooth (Lissotriton vulgaris) and alpine (Ichthyosaura alpestris) newts. Both species showed disparate TI responses to body temperature variation (13-28 °C). While the proportion of TI response was repeatable in both taxa, it increased with body temperature in alpine newts but was temperature independent in smooth newts. Duration of TI decreased with body temperature in both taxa but was only repeatable in smooth newts. Our results suggest that a warming climate may affect population dynamics of sympatric ectotherms through asymmetry in thermal reaction norms for antipredator responses.

Genetic Architecture of Innate Fear Behavior in Chickens.

The genetic architecture of innate fear behavior in chickens is poorly understood. Here, we performed quantitative trait loci (QTL) analysis of innate responses to tonic immobility (TI) and open field (OF) fears in 242 newly hatched chicks of an F2 population between the native Japanese Nagoya breed and the White Leghorn breed using 881 single nucleotide polymorphism markers obtained by restriction site-associated DNA sequencing. At genome-wide 5% significance levels, four QTL for TI traits were revealed on chromosomes 1-3 and 24. Two of these loci had sex-specific effects on the traits. For OF traits, three QTL were revealed on chromosomes 2, 4 and 7. The TI and OF QTL identified showed no overlaps in genomic regions and different modes of inheritance. The three TI QTL and one OF QTL exerted antagonistic effects on the traits. The results demonstrated that context-dependent QTL underlie the variations in innate TI and OF behaviors.

Evaluation of the antidepressive property of ß-hydroxybutyrate in mice.

ß-hydroxybutyrate, a ketone body metabolite, has been shown to suppress depression-like behavior in rodents. In this study, we examined its antidepressive property in acute and chronic administration modes in mice by using forced swim test and tail suspension test. Results showed that the decrease effect of ß-hydroxybutyrate (300 mg/kg) on immobility time in the tail suspension test and forced swim test in stress-naive mice began to be significant at day 11. In a dose-dependent experiment, ß-hydroxybutyrate treatment (11 days) showed significant antidepressant activities at the dose of 200 and 300 mg/kg. Unlike fluoxetine, ß-hydroxybutyrate treatment (300 mg/kg) showed no antidepressant activities in the acute (1 hour before the test) and three times administration mode within 24 hours (1, 5, and 24 hours before the test). But in a co-administration mode, ß-hydroxybutyrate (100 mg/kg) -fluoxetine (2.5 mg/kg) co-administration exhibited an obvious antidepressant activity in the tail suspension test and forced swim test. Further analysis showed that the antidepressant effects of ß-hydroxybutyrate and fluoxetine were not associated with the change in mouse locomotor activity. Furthermore, both chronic ß-hydroxybutyrate treatment and ß-hydroxybutyrate-fluoxetine co-treatment suppressed chronic unpredictable stress-induced increase in immobility time in the tail suspension test and forced swim test as well as chronic unpredictable stress-induced decrease in mouse body weight. Taken together, these results indicate that ß-hydroxybutyrate (1) needs a relatively long time to show comparable behavioral activity to that of fluoxetine in assays that are sensitive to the behavioral effects of established antidepressant compounds and (2) can augment the antidepressant action of a sub-therapeutic dose of fluoxetine.

Anti-stress effects of rosemary (Rosmarinus officinalis L.) leaf extract on intestinal goblet cells and immobility of forced-swimming test in BALB/c mice.

We investigated the anti-stress effect of rosemary (Rosmarinus officinalis L.) leaf extract (RLE) on restraint-stressed mice and found that RLE alleviated decreases in the number of intestinal goblet cells and amount of hepatic triglycerides. It also decreased the immobility time in the forced-swimming test and activation of microglia in the brain, suggesting that RLE has beneficial effects on stress-induced dysfunctions.

Are perceptual disorder signs in diplegic cerebral palsied children stable over time? A retrospective cohort analysis.

BACKGROUND: A group of diplegic cerebral palsied (CP) children presents six precise signs that can be easily observed during clinical examinations, physiotherapy sessions and everyday activities. These signs are: startle reaction, upper limbs in startle position, averted-eye gaze, grimaces, eye blinking and posture freezing. METHODS: In a population of 32 diplegic CP children (aged 1-8 years) perceptual signs were retrospectively identified through videos to verify their stability in the same child over time. RESULTS: Startle reaction, upper limb in startle position and posture freezing were the most frequently observed signs and the easiest to recognize with the highest agreement in both observations (P<0.001). Eye signs (eye blinking and averted-eye gaze) were more difficult to detect in our recordings. CONCLUSIONS: Signs of perceptual disorders were present in our sample of diplegic CP children from the second year of age and could still be observed after 1- to 3-year intervals, demonstrating they remain unaltered over time. Furthermore, if absent in the first observation, they did not appear later on. CP children with these perceptual signs could represent a new clinical entity, which we are currently describing and defining.

Genetic parameters for tonic immobility, body weight, and morphological traits of the red-winged tinamou (Rhynchotus rufescens).

This study was carried out to estimate genetic parameters for morphology, body weight, and tonic immobility traits in the red-winged tinamou (Rhynchotus rufescens). Information on 690 birds was used and genetic parameters were estimated using Bayesian methods under a multi-trait animal model. The following traits were considered in this study: tarsal length (TL), bill length (BL), wing length (WL), head width (HW), bill width (BW), mature weight (MW), weight at 90 days (W90), and tonic immobility (TI). The heritability showed estimates between 0.15 for wing length and 0.56 for bill length. Positive and negative genetic correlations were estimated, ranging from - 0.33 to 0.81. All the morphological, production, and behavioral traits studied will have moderate to high response to selection. The body weight at 90 days is a better alternative for use in breeding programs and its selection would not lead to an increase in the time of tonic immobility. Both the selection for weight gain and for reduction of tonic immobility time would lead to an increase in the size of the legs of the red-winged tinamou, which could be advantageous for thermal control of these birds in tropical systems.

Neurochemical and behavioral effects of midazolam: A dose related study.

In the present study we have monitored dose dependent effects of midazolam; a benzodiazepine (CNS depressant). It is the primary drug of choice for procedural sedation, preoperative sedation, and in emergency departments. Repeated administration of this drug is reported to have abuse potential and may cause this by increasing dopaminergic neurotransmission. Since an important role of 5-hydroxy tryptamine (5-HT) is there in the pathophysiology of anxiety and addiction, administration of midazolam may involve altered 5-HT metabolism as well. Present study was designed to monitor dose-dependent effects of midazolam and select the optimum dose for further experiments. Effects of midazolam were monitored on food intake, growth rate, activities in familiar and novel environments, light dark box activity, hot plate test, forced swim test and levels of dopamine, 5-HT and their metabolites. Midazolam was administered orally (0mg/kg, 2.5mg/kg, 5.0mg/kg and 10mg/kg) and behaviors were monitored post single midazolam administrations. Rats were decapitated and whole brain samples were collected and stored at -70°C until neurochemical analysis by HPLC-EC. Findings from the present study could be implicated to increased therapeutic utility of midazolam and related benzodiazepines.

Functional Connectivity within the Primate Extended Amygdala Is Heritable and Associated with Early-Life Anxious Temperament.

Children with an extremely inhibited, anxious temperament (AT) are at increased risk for anxiety disorders and depression. Using a rhesus monkey model of early-life AT, we previously demonstrated that metabolism in the central extended amygdala (EAc), including the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST), is associated with trait-like variation in AT. Here, we use fMRI to examine relationships between Ce-BST functional connectivity and AT in a large multigenerational family pedigree of rhesus monkeys (n = 170 females and 208 males). Results demonstrate that Ce-BST functional connectivity is heritable, accounts for a significant but modest portion of the variance in AT, and is coheritable with AT. Interestingly, Ce-BST functional connectivity and AT-related BST metabolism were not correlated and accounted for non-overlapping variance in AT. Exploratory analyses suggest that Ce-BST functional connectivity is associated with metabolism in the hypothalamus and periaqueductal gray. Together, these results suggest the importance of coordinated function within the EAc for determining individual differences in AT and metabolism in brain regions associated with its behavioral and neuroendocrine components.SIGNIFICANCE STATEMENT Anxiety disorders directly impact the lives of nearly one in five people, accounting for substantial worldwide suffering and disability. Here, we use a nonhuman primate model of anxious temperament (AT) to understand the neurobiology underlying the early-life risk to develop anxiety disorders. Leveraging the same kinds of neuroimaging measures routinely used in human studies, we demonstrate that coordinated activation between the central nucleus of the amygdala and the bed nucleus of the stria terminalis is correlated with, and coinherited with, early-life AT. Understanding how these central extended amygdala regions work together to produce extreme anxiety provides a neural target for early-life interventions with the promise of preventing lifelong disability in at-risk children.

Arousal from Tonic Immobility by Vibration Stimulus.

Tonic immobility (TI) is an effective anti-predator strategy. However, long immobility status on the ground increases the risk of being eaten by predators, and thus insects must rouse themselves when appropriate stimulation is provided. Here, the strength of vibration causing arousal from the state of TI was examined in strains artificially selected for longer duration of TI (L-strains: long sleeper) in a beetle. We provided different strengths of vibration stimuli to the long sleepers in Tribolium castaneum. Although immobilized beetles were never awakened by the stimuli from 0.01 to 0.12 mm in amplitude, almost of the beetles were aroused from immobilized status by the stimulus at 0.21 mm. There was a difference in sensitivity of individuals when the stimuli of 0.14 mm and 0.18 mm were provided. F2 individuals were also bred by crossing experiments of the strains selected for shorter and longer duration of TI. The arousal sensitivity to vibration was well separated in the F2 individuals. A positive relationship was observed between the duration of TI and the vibration amplitude, suggesting that immobilized beetles are difficult to arouse from a deep sleep, while light sleepers are easily aroused by even small vibrations. The results indicate a genetic basis for sensitivity to arousal from TI.

ERß agonist alters RNA splicing factor expression and has a longer window of antidepressant effectiveness than estradiol after long-term ovariectomy

Background: Estrogen therapy (ET), an effective treatment for perimenopausal depression, often fails to ameliorate symptoms when initiated late after the onset of menopause. Our previous work has suggested that alternative splicing of RNA might mediate these differential effects of ET. Methods: Female Sprague­Dawley rats were treated with estradiol (E2) or vehicle 6 days (early ET) or 180 days (late ET) after ovariectomy (OVX). We investigated the differential expression of RNA splicing factors and tryptophan hydroxylase 2 (TPH2) protein using a customized RT2 Profiler PCR Array, reverse-transcription polymerase chain reaction, immunoprecipitation and behaviour changes in clinically relevant early and late ET. Results: Early ET, but not late ET, prolonged swimming time in the forced swim test and reduced anxiety-like behaviours in the elevated plus maze. It reversed OVX-increased (SFRS7 and SFRS16) or OVX-decreased (ZRSR2 and CTNNB1) mRNA levels of splicing factors and ERß splicing changes in the brains of OVX rats. Early ET, but not late ET, also increased the expression of TPH2 and decreased monoamine oxidase A levels in the dorsal raphe in the brains of OVX rats. In late ET, only diarylpropionitrile (an ERß-specific agonist) achieved similar results ­ not E2 (an ERα and ERß agonist) or propylpyrazoletriol (an ERα-specific agonist). Limitations: Our experimental paradigm mimicked early and late ET in the clinical setting, but the contribution of age and OVX might be difficult to distinguish. Conclusion: These findings suggest that ERß alternative splicing and altered responses in the regulatory system for serotonin may mediate the antidepressant efficacy of ET associated with the timing of therapy initiation. It is likely that ERß-specific ligands would be effective estrogen-based antidepressants late after the onset of menopause.

The role of tonic immobility and control in the development of intrusive memories after experimental trauma.

Tonic immobility (TI; state of motor inhibition during threat) has been implicated in the onset of intrusive trauma memories, while controllability was associated with reduced anxiety. The present study investigated the interaction between TI and control in the development of intrusive memories of an analogue trauma. Sixty-four participants watched negative pictures while being allowed to close their eyes (InControl) or not (NoControl). They completed measures for spontaneous TI afterwards and recorded intrusive memories of the pictures in a diary in the subsequent week. Bayesian analyses were used to test informative hypotheses. Spontaneous TI during picture viewing was positively associated with increased intrusion frequency. Intrusion frequency did not differ for InControl versus NoControl. Moderation (control x TI) and non-moderation (main effect of TI only) were both adequate models, with no preference. Our results confirm the importance of TI in PTSD development. Implications of the findings regarding control merit more research.

Prelimbic neuronal nitric oxide synthase inhibition exerts antidepressant-like effects independently of BDNF signalling cascades.

OBJECTIVES: NMDA antagonists and nitric oxide synthase (NOS) inhibitors induce antidepressant-like effects and may represent treatment options for depression. The behavioural effects of NMDA antagonists seem to depend on Tyrosine kinase B receptor (TrkB) activation by BDNF and on mechanistic target of rapamycin (mTOR), in the medial prefrontal cortex (mPFC). However, it is unknown whether similar mechanisms are involved in the behavioural effects of NOS inhibitors. Therefore, this work aimed at determining the role of TrkB and mTOR signalling in the prelimbic area of the ventral mPFC (vmPFC-PL) in the antidepressant-like effect of NOS inhibitors. METHODS: Pharmacological treatment with LY235959 or ketamine (NMDA antagonists), NPA or 7-NI (NOS inhibitors), BDNF, K252a (Trk antagonist) and rapamycin (mTOR inhibitor) injected systemically or into vmPFC-PL followed by behavioural assessment. RESULTS: We found that bilateral injection of BDNF into the vmPFC-PL induced an antidepressant-like effect, which was blocked by pretreatment with K252a and rapamycin. Microinjection of LY 235959 into the vmPFC-PL induced antidepressant-like effect that was suppressed by local rapamycin but not by K252a pretreatment. Microinjection of NPA induced an antidepressant-like effect insensitive to both K252a and rapamycin. Similarly, the antidepressant-like effects of a systemic injection of ketamine or 7-NI were not affected by blockade of mTOR or Trk receptors in the vmPFC-PL. CONCLUSION: Our data support the hypothesis that NMDA blockade induces an antidepressant-like effect that requires mTOR but not Trk signalling into the vmPFC-PL. The antidepressant-like effect induced by local NOS inhibition is independent on both Trk and mTOR signalling in the vmPFC-PL.

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.