Immobility In Forced Swim Test Research Articles

L-type calcium channel regulation of depression, anxiety and anhedonia-related behavioral phenotypes following chronic stress exposure

Exposure to chronic and unpredictable stressors can precipitate mood-related disorders in humans, particularly in individuals with pre-existing mental health challenges. L-type calcium channels (LTCCs) have been implicated in numerous neuropsychiatric disorders, as LTCC encoding genes have been identified as candidate risk factors for neuropsychiatric illnesses. In these sets of experiments, we sought to examine the ability of LTCC blockade to alter depression, anxiety, and anhedonic-related behavioral responses to chronic unpredictable stress (CUS) exposure in female and male rats. Rats first underwent either 21 days of CUS or no exposure to chronic stressors, serving as home cage controls (HCC). Then rats were examined for anhedonia-related behavior, anxiety and depression-like behavioral responses as measured by the sucrose preference test (SPT), elevated plus maze (EPM), and forced swim test (FST). CUS exposed females and males showed anhedonic and anxiogenic-like behavioral responses on the SPT and EPM, respectively, when compared to HCCs. In female and male rats, systemic administration of the LTCC blocker isradipine (0.4 mg/kg and 1.2 mg/kg, I.P.) attenuated the CUS-induced decrease in sucrose preference and reversed the CUS-induced decrease in open arm time. In the FST, systemic isradipine decreased immobility time across all groups, consistent with an antidepressant-like response. However, there were no significant differences in forced swim test immobility time between HCC and CUS exposed animals. Taken together, these data point to a role of LTCCs in the regulation of mood disorder-related behavioral phenotype responses to chronic stress exposure.

Effects of Subchronic Buspirone Treatment on Depressive Profile in Socially Isolated Rats: Implication of Early Life Experience on 5-HT1A Receptor-Related Depression.

The heterogeneity of etiology may serve as a crucial factor in the challenges of treatment, including the low response rate and the delay in establishing therapeutic effect. In the present study, we examined whether social experience since early life is one of the etiologies, with the involvement of the 5-HT1A receptors, and explored the potentially therapeutic action of the subchronic administration of buspirone, a partial 5-HT1A agonist. Rats were isolation reared (IR) since their weaning, and the depressive profile indexed by the forced-swim test (FST) was examined in adulthood. Nonspecific locomotor activity was used for the IR validation. Buspirone administration (1 mg/kg/day) was introduced for 14 days (week 9-11). The immobility score of the FST was examined before and after the buspirone administration. Tissue levels of serotonin (5-HT) and its metabolite 5-HIAA were measured in the hippocampus, the amygdala, and the prefrontal cortex. Efflux levels of 5-HT, dopamine (DA), and norepinephrine (NE) were detected in the hippocampus by brain dialysis. Finally, the full 5-HT1A agonist 8-OH-DPAT (0.5 mg/kg) was acutely administered in both behavioral testing and the dialysis experiment. Our results showed (i) increased immobility time in the FST for the IR rats as compared to the social controls, which could not be reversed by the buspirone administration; (ii) IR-induced FST immobility in rats receiving buspirone was corrected by the 8-OH-DPAT; and (iii) IR-induced reduction in hippocampal 5-HT levels can be reversed by the buspirone administration. Our data indicated the 5-HT1A receptor-linked early life social experience as one of the mechanisms of later life depressive mood.

Nicotinamide Riboside Attenuates Memory Impairment and Depressive-like Behavior in an Alzheimer’s Disease Animal Model

IntroductionDepression in Alzheimer’s disease (AD) differs from major depression in terms of clinical features and treatment. Antidepressants do not provide the expected benefits in depressive symptoms accompanying cognitive decline in AD, suggesting distinct mechanisms. Emerging research suggest that compromised mitophagy, the selective removal of damaged mitochondria, may contribute to the pathogenesis of AD. However boosting nicotinamide adenine dinucleotide (NAD+) to induce mitophagy reduces amyloid β (Aβ) aggregation and enhances cognitive function in AD models (Kerr et al.,Trends Neurosci 2017;40:151-66). Nevertheless, data on NAD’s impact on depression in AD remains limited.ObjectivesThis study aimed to examine the impact of the NAD+ precursor nicotinamide riboside (NR) on cognitive and neuropsychiatric symptoms in a AD rat model.MethodsTo induce the AD, a single dose of 5 μl Aβ1-42 was injected into each lateral ventricle of rats (day 0), while the control group received an intracerebroventricular (icv) saline (0.9%NaCl).Four experimental groups were designed: control (icv saline+po saline), NR (icv saline+po NR), Aβ (icv Aβ+po saline), and Aβ+NR (icv Aβ+po NR).After the injection, to reduce Aβ clearance (Kang et al. Science. 2009;32 1005-7.) rats were subjected to 96 hours of sleep deprivation.Starting from day 6, rats were given either 700 mg/kg oral NR or saline, and handling test scores were recorded daily.The procedures were repeated daily until the rats were sacrificed on day 28.Behavioral experiments were randomly conducted at the end, and statistical analysis was performed using repeated measures ANOVA, followed by the Tukey post hoc test.ResultsPassive avoidance test results showed that the Aβ group had the shortest latency to enter the dark area. However, the Aβ+NR group exhibited a prolonged latency compared to the Aβ group (F(3,2)=5.5;p<0.05). Aβ injection induced depressive-like behavior in rats, as indicated by the forced swim test (FST) for behavioral despair and the sucrose preference test (SPT) for anhedonia. In AD rats treated with NR (Aβ+NR), Aβ-induced depressive-like behavior was reduced, with lower FST immobility scores (F(3,2)=6.2;p<0.05) and increased sucrose preference in the SPT (F(3,2)=7.5;p<0.05). There were no significant differences in anxiety-like behaviors among the groups, assessed by the time spent in the open arm in the elevated plus maze test (F(3,2)=1.9;p>0.05). During the 28-day monitoring period, the Aβ+NR group of rats exhibited a more rapid decrease in aggression levels compared to the other groups in the handling test. This decrease was significant between days 7 and 10 compared to the Aβ group (F(48,5)=1.5;p<0.05).ConclusionsNR improved memory, reduced depressive behavior, and lowered aggression in AD rats. This suggests that NAD+ precursor NR effectively treats cognitive decline and neuropsychiatric symptoms in an AD model.Disclosure of InterestNone Declared

Genetic loss of the dopamine transporter significantly impacts behavioral and molecular responses to sub-chronic stress in mice.

Dopaminergic neurotransmission has emerged as a critical determinant of stress susceptibility and resilience. Although the dopamine transporter (DAT) is known to play a key role in maintaining dopamine (DA) homeostasis, its importance for the regulation of stress susceptibility remains largely unknown. Indeed, while numerous studies have examined the neurochemical and behavioral consequences of genetic loss of DAT, very few have compared responses to stress in wild-type and DAT-knockout (KO) animals. The current study compared the responses of male and female WT and DAT-KO mice to a model of sub-chronic stress. Our results reveal that DAT-KO mice are resistant to stress-induced increases in the latency to enter the light chamber of the light-dark emergence test and demonstrate that DAT-KO mice exhibit baseline reductions in forced swim test immobility and grooming time in the splash test of grooming behavior. In addition to these behavioral changes, our results highlight the importance of sex and dopaminergic neurotransmission on stress-induced changes in the expression and phosphorylation of several signal transduction molecules in the nucleus accumbens that have previously been implicated in the regulation of stress susceptibility, including ERK, GSK3β, and ΔFosB. Overall, these results provide further evidence of the importance of dopaminergic neurotransmission in regulating stress susceptibility and suggest that genetic loss of DAT prevents stress-induced increases in anxiety-like behavior.

Neuronal and Molecular Mechanisms Underlying Chronic Pain and Depression Comorbidity in the Paraventricular Thalamus.

Patients with chronic pain often develop comorbid depressive symptoms, which makes the pain symptoms more complicated and refractory. However, the underlying mechanisms are poorly known. Here, in a repeated complete Freund's adjuvant (CFA) male mouse model, we reported a specific regulatory role of the paraventricular thalamic nucleus (PVT) glutamatergic neurons, particularly the anterior PVT (PVA) neurons, in mediating chronic pain and depression comorbidity (CDC). Our c-Fos protein staining observed increased PVA neuronal activity in CFA-CDC mice. In wild-type mice, chemogenetic activation of PVA glutamatergic neurons was sufficient to decrease the 50% paw withdrawal thresholds (50% PWTs), while depressive-like behaviors evaluated with immobile time in tail suspension test (TST) and forced swim test (FST) could only be achieved by repeated chemogenetic activation. Chemogenetic inhibition of PVA glutamatergic neurons reversed the decreased 50% PWTs in CFA mice without depressive-like symptoms and the increased TST and FST immobility in CFA-CDC mice. Surprisingly, in CFA-CDC mice, chemogenetically inhibiting PVA glutamatergic neurons failed to reverse the decrease of 50% PWTs, which could be restored by rapid-onset antidepressant S-ketamine. Further behavioral tests in chronic restraint stress mice and CFA pain mice indicated that PVA glutamatergic neuron inhibition and S-ketamine independently alleviate sensory and affective pain. Molecular profiling and pharmacological studies revealed the 5-hydroxytryptamine receptor 1D (Htr1d) in CFA pain-related PVT engram neurons as a potential target for treating CDC. These findings identified novel CDC neuronal and molecular mechanisms in the PVT and provided insight into the complicated pain neuropathology under a comorbid state with depression and related drug development.

Resveratrol as an add on therapy to sertraline in animal models of depression

BackgroundSertraline, a selective serotonin reuptake inhibitor, is a leading antidepressant. Resveratrol is a natural polyphenol with diverse biological activities, including antidepressant-like effects. In this study we evaluated the individual and combined antidepressant effects of resveratrol and sertraline alongwith effect of resveratrol on sertraline serum levels. MethodsTail Suspension Test (TST) and Forced Swim Test (FST) were used to study the antidepressant effect in adult male albino mice which were divided into 5 groups. Group 1 was treated with sertraline, group 2 with resveratrol, group 3 and 4 with sertraline (different doses) and resveratrol, and group 5 was given vehicle control only. Serum sertraline levels were estimated by high performance liquid chromatography (HPLC). Mean increase in time to immobility in TST and mean reduction in immobility in FST of the animal(s) were compared. ResultsCombination of sertraline and resveratrol demonstrated the maximum antidepressant effect followed by sertraline and resveratrol only groups. Serum sertraline levels were higher in the combination group as compared to sertraline only group. ConclusionResveratrol demonstrated antidepressant effects in this study and also had an additive effect on the effect of sertraline. It’s addition also increased serum sertraline levels.

Prophylactic effects of arketamine, but not hallucinogenic psychedelic DOI nor non-hallucinogenic psychedelic analog lisuride, in lipopolysaccharide-treated mice and mice exposed to chronic restrain stress

Anesthetic ketamine and classical psychedelics that act as 5-hydroxytryptamine-2A receptor (5-HT2AR) agonists demonstrated rapid and sustained antidepressant actions in patients with treatment-resistant depression. The new antidepressant arketamine is reported to cause long-lasting prophylactic effects in lipopolysaccharide (LPS)-treated mice and mice exposed to chronic restrain stress (CRS). However, no study has compared the prophylactic effects of DOI (2,5-dimethoxy-4-iodoamphetamine: a hallucinogenic psychedelic drug with potent 5-HT2AR agonism), lisuride (non-hallucinogenic psychedelic analog with 5-HT2AR and 5-HT1AR agonism), and arketamine on depression-like behaviors in mice. Saline (10 ml/kg), DOI (2.0 or 4.0 mg/kg), lisuride (1.0 or 2.0 mg/kg), or arketamine (10 mg/kg) was administered intraperitoneally (i.p.) to male mice 6 days before administration of LPS (1.0 mg/kg). Pretreatment with aketamine, but not DOI and lisuride, significantly ameliorated body weight loss, splenomegaly, the increased immobility time of forced swimming test (FST), and the decreased expression of PSD-95 in the prefrontal cortex (PFC) of LPS-treated mice. In another test, male mice received the same treatment one day before CRS (7 days). Pretreatment with aketamine, but not DOI and lisuride, significantly ameliorated the increased FST immobility time, the reduced sucrose preference in the sucrose preference test, and the decreased expression of PSD-95 in the PFC of CRS-exposed mice. These findings suggest that, unlike to arketamine, both DOI and lisuride did not exhibit long-lasting prophylactic effects in mouse models of depression.

Systemic Administration of Porphyromonas Gingivalis Lipopolysaccharide Induces Glial Activation and Depressive-Like Behavior in Rats.

Periodontitis is one of the most common chronic inflammatory disorders in adults. Although clinical studies have suggested a causal relationship between periodontitis and major depression (MD), the biological mechanisms by which periodontitis instigates MD are unknown. We investigated whether a systemic administration of lipopolysaccharide (LPS) from Porphyromonas gingivalis (Pg), a major Gram-negative pathogen of periodontitis, causes depressive-like behavior and glial activation in the hippocampus and the prefrontal cortex (PFC), which are MD-related brain regions. Eight-week-old male Sprague Dawley rats were randomly divided into a behavioral test group and an immunohistochemistry group. The rats in each group were further assigned to the sham injection (saline) and Porphyromonas gingivalis-lipopolysaccharide (Pg-LPS) injection protocols. The rats received an intraperitoneal injection of saline or Pg-LPS with gradually increasing doses (day 1: 0.5, day 2: 0.5, day 3: 0.75, day 4: 0.75, day 5: 1.0, day 6: 1.0, and day 7: 1.0 mg/kg of body weight) for seven consecutive days. After the systemic administration, the behavior test group underwent the forced swimming test (FST) and Y-maze test. For the immunohistochemistry group, we quantified the immunoreactivity for microglial Iba-1 (ionized calcium-binding adapter molecule 1) and astrocytic glial fibrillary acidic protein (GFAP) in the hippocampus (dentate gyrus [DG], cornu ammonis [CA1 and CA3]) and PFC (prelimbic [PrL] and the infralimbic [IL]) areas. The FST immobility time in the Pg-LPS group was significantly longer than that in the sham group. In the Y-maze test, a significant decline in spontaneous alternation behavior was observed in the Pg-LPS group compared to the sham group. The peripheral administration of Pg-LPS significantly increased the immunoreactivity for Iba-1 in the CA3 and PrL. Pg-LPS injection significantly increased the immunoreactivity for GFAP in the DG, CA1, and CA3. The major result of this study is that a repeated systemic administration of Pg-LPS caused depressive-like behavior and both microglial and astrocytic activation in rats. This finding may comprise biological evidence of a causal relationship between periodontitis and MD.

Correlation between immune-related genes and depression-like features in an animal model and in humans

A growing body of evidence suggests that immune-related genes play pivotal roles in the pathophysiology of depression. In the present study, we investigated a plausible connection between gene expression, DNA methylation, and brain structural changes in the pathophysiology of depression using a combined approach of murine and human studies. We ranked the immobility behaviors of 30 outbred Crl:CD1 (ICR) mice in the forced swim test (FST) and harvested their prefrontal cortices for RNA sequencing. Of the 24,532 analyzed genes, 141 showed significant correlations with FST immobility time, as determined through linear regression analysis with p ≤ 0.01. The identified genes were mostly involved in immune responses, especially interferon signaling pathways. Moreover, induction of virus-like neuroinflammation in the brains of two separate mouse cohorts (n = 30 each) using intracerebroventricular polyinosinic:polycytidylic acid injection resulted in increased immobility during FST and similar expression of top immobility-correlated genes. In human blood samples, candidate gene (top 5%) expression profiling using DNA methylation analysis found the interferon-related USP18 (cg25484698, p = 7.04 × 10−11, Δβ = 1.57 × 10–2; cg02518889, p = 2.92 × 10−3, Δβ = − 8.20 × 10–3) and IFI44 (cg07107453, p = 3.76 × 10–3, Δβ = − 4.94 × 10–3) genes to be differentially methylated between patients with major depressive disorder (n = 350) and healthy controls (n = 161). Furthermore, cortical thickness analyses using T1-weighted images revealed that the DNA methylation scores for USP18 were negatively correlated with the thicknesses of several cortical regions, including the prefrontal cortex. Our results reveal the important role of the interferon pathway in depression and suggest USP18 as a potential candidate target. The results of the correlation analysis between transcriptomic data and animal behavior carried out in this study provide insights that could enhance our understanding of depression in humans.

Short-active gestational photoperiod reduces effortful choice behavior in mice, partial normalization by d-amphetamine.

Seasonal birth patterns consistently implicate winter gestation as a risk factor for several psychiatric conditions. We recently demonstrated that short-active (SA; 19:5 light:dark)-i.e., "winter-like"-photoperiod exposure across gestation and early life (E0-P28) induces psychiatrically relevant behavioral abnormalities in adult mice, including reduced immobility in the forced swim test (FST) and effortful amotivation. It is unknown, however, whether these effects were driven primarily by prenatal or postnatal mechanisms, and whether perinatal SA photoperiod would similarly reduce effort expenditure in a task relevant to everyday decision-making. We first tested male and female mice exposed to either gestational (E0-P0) or postnatal (E0-P28) SA photoperiod in the FST to determine whether the previously observed alteration was driven primarily by prenatal versus postnatal photoperiod. We then assessed whether SA gestational photoperiod reduces effortful choice behavior in the cross-species effort-based decision-making task (EBDMT) and whether any such deficit could be remediated by d-amphetamine (0.1 and 0.3 mg/kg, i.p.). Mice exposed to prenatal, but not postnatal, SA photoperiod exhibited reduced FST immobility relative to controls and also demonstrated condition-dependently reduced preference for high-effort/high-reward versus low-effort/low-reward contingencies in the EBDMT. This effortful choice deficit was normalized by 0.1 mg/kg amphetamine. These data: (1) suggest a greater contribution of gestational versus postnatal light conditions to the behavioral effects of perinatal SA photoperiod; and (2) implicate altered dopamine signaling in the behavioral phenotype of the SA-born mouse and possibly in the etiology of winter gestation-associated cases of psychiatric disease.

Anti-fatigue effect of tormentic acid through alleviating oxidative stress and energy metabolism-modulating property in C2C12 cells and animal models.

Oxidative stress is caused by reactive oxygen species and free radicals that accelerate inflammatory responses and exacerbate fatigue. Tormentic acid (TA) has antioxidant and anti-inflammatory properties. Thus, the aim of present study is to determine the fatigue-regulatory effects of TA in H2O2-stimulated myoblast cell line, C2C12 cells and treadmill stress test (TST) and forced swimming test (FST) animal models. In the in vitro study, C2C12 cells were pretreated with TA before stimulation with H2O2. Then, malondialdehyde (MDA), lactate dehydrogenase (LDH), creatine kinase (CK) activity, tumor necrosis factor (TNF)-α, interleukin (IL)-6, superoxide dismutase (SOD), catalase (CAT), glycogen, and cell viability were analyzed. In the in vivo study, the ICR male mice were administered TA or distilled water orally daily for 28 days. FST and TST were then performed on the last day. In addition, biochemical analysis of the serum, muscle, and liver was performed. TA dose-dependently alleviated the levels of MDA, LDH, CK activity, TNF-α, and IL-6 in H2O2-stimulated C2C12 cells without affecting the cytotoxicity. TA increased the SOD and CAT activities and the glycogen levels in H2O2-stimulated C2C12 cells. In TST and FST animal models, TA decreased the FST immobility time significantly while increasing the TST exhaustion time without weight fluctuations. The in vivo studies showed that the levels of SOD, CAT, citrate synthase, glycogen, and free fatty acid were increased by TA administration, whereas TA significantly reduced the levels of glucose, MDA, LDH, lactate, CK, inflammatory cytokines, alanine transaminase, aspartate transaminase, blood urea nitrogen, and cortisol compared to the control group. TA improves fatigue by modulating oxidative stress and energy metabolism in C2C12 cells and animal models. Therefore, we suggest that TA can be a powerful substance in healthy functional foods and therapeutics to improve fatigue.

Intravenous Reelin Treatment Rescues Atrophy of Spleen White Pulp and Correlates to Rescue of Forced Swim Test Immobility and Neurochemical Alterations Induced by Chronic Stress

Reelin, an extracellular matrix protein with putative antidepressant-like properties, becomes dysregulated by chronic stress. Improvement in cognitive dysfunction and depression-like behavior induced by chronic stress has been reported with both intrahippocampal and intravenous Reelin treatment but the mechanisms responsible are not clear. To determine if treatment with Reelin modifies chronic stress-induced dysfunction in immune organs and whether this relates to behavioral and/or neurochemical outcomes, spleens were collected from both male (n = 62) and female (n = 53) rats treated with daily corticosterone injections for three weeks that received Reelin or vehicle. Reelin was intravenously administered once on the final day of chronic stress, or repeatedly, with weekly treatments throughout chronic stress. Behavior was assessed during the forced swim test and the object-in-place test. Chronic corticosterone caused significant atrophy of the spleen white pulp, but treatment with a single shot of Reelin restored white pulp in both males and females. Repeated Reelin injections also resolved atrophy in females. Correlations were observed between recovery of white pulp atrophy and recovery of behavioral deficits and expression of both Reelin and glutamate receptor 1 in the hippocampus, supporting a role of the peripheral immune system in the recovery of chronic stress-induced behaviors following treatment with Reelin. Our data adds to research indicating Reelin could be a valuable therapeutic target for chronic stress-related disorders including major depression.

Behavioral effect of Cassia singueana Del. (Fabaceae) extract against isolation rearing-induced cognitive impairment in albino rats

Early life stress negatively alters brain development and couldlead to the development of psychiatricdisorder. Exposing animals to early-life adverse events, including maternal separation or social isolation, greatly affects brain development and adult behaviour and may contribute to the occurrence of psychiatric manifestations, such as positive, negative and cognitive symptoms of schizophrenia. These symptoms can be depicted in different animal models. Aim: This study is aimed at evaluating the effect of Cassia singueana on isolation rearing-induced cognitive impairment in rats. Materials and Methods: Pharmacological intervention (Risperidone 1mg/kg/day, graded doses of Cassia singueana extract or Distilled water 10ml/kg) was introduced 4 weeks(adolescence) and one group 8 weeks(young adulthood) after IR (i.e., rats were 7- or 11-week-old). The intervention lasted for 8 weeks, after which the rats in all the various groups were subjected toopen field test, forced swim test, novel object recognition test, y-maze and post isolation grooming test. Rats’ hippocampus immediately after sacrifice was removed to measure the level of MDA, SOD and GSH. Results: Cassia singueana extract significantly decrease the hyper locomotion in open field, it also significantly decrease the duration of immobility in forced swim test. CSE also increase the exploration time of novel object and improved the recognition index. The extract also significantly increases the number of actual alternation and spontaneous alternation in y-maze. However the extract did not improve the duration of grooming in isolation reared rats. CSE also significantly improved the level of antioxidant enzymes. Conclusion: The study results revalidate the utility of the isolation rearing paradigm in exploring mental disorders with neurodevelopmental origin, especially schizophrenia and Cassia singueana extract contained phytochemicals with tendency to ameliorate all the three symptoms of schizophrenia possibly through their antioxidant properties.

Effects of liraglutide on depressive behavior in a mouse depression model and cognition in the probe trial of Morris water maze test

BackgroundWe investigated the effects of liraglutide, a glucagon-like peptide-1 (GLP-1) agonist, on a depression-like phenotype in mice exposed to chronic unpredictable stress (CUS). Learning and memory were also assessed using the Morris water maze (MWM) test. MethodsLiraglutide (0.3 mg/kg/day for 21 days) was administered to mice with or without exposure to CUS. After 21 days of CUS, the forced swim test (FST) was performed to assess its antidepressant effect. To evaluate cognitive function, liraglutide was administered to mice under stress-free conditions for 21 days, and then the MWM test was performed on 6 consecutive days. ResultsChronic liraglutide treatment reduced FST immobility in mice with and without CUS. In the probe trial of the Morris water maze test, the search error rate was reduced and the time spent and path length in the target quadrant and the number of platform crossings were increased. LimitationAdditional animal model experiments and molecular level studies are needed to support the results obtained in this study. ConclusionsLiraglutide appears to exert antidepressant effects and could improve cognitive function. Based on these results, GLP-1 agonists could have potential as novel antidepressants.

Ameliorative effect of Cassia singueana extract against acute ketamine induced cognitive impairment in murine models of schizophrenia

Introduction: In the quest for search of novel pharmacotherapy from medicinal plants for psychiatric disorders, it has progressed appreciably for the past few decades and their therapeutic potential has been evaluated in a variety of murine models. Cassia singueana Del. is a commonly used medicinal plant in Nigeria for management of insanity and as lactation enhancer. Aim: The main aim of this study was to evaluate the cognitive potential of Cassia singueana extract against ketamine-induced cognitive impairment in mice. Methods: The phytochemicals and elemental minerals present in the extract were determined using standard protocol and antioxidant potential of the extract was evaluated using TBA-TCAA protocols, while its oral median lethal dose (LD50) in mice was estimated by OECD protocol. The effect of Cassia singueana extract (100, 200 and 400 mg/kg) on neurobehavioral deficit was evaluated in mice using behavioural paradigms: Y- maze, novel object recognition, forced swim test, open field test and catalepsy test. Results: The phytochemical constituents of Cassia singueana were alkaloids, cardiac glycosides, tannins, flavonoids, saponins, steroids and triterpenes. The extract also significantly decreased the level of MDA and increased the level of SOD and GSH. Oral LD50 was estimated to be >5000 mg/kg. Cassia singueana extract significantly (P< 0.05) increased the exploration time of novel object and percentage recognition index during the retention phase of the NORT. In Y-maze test, the extract significantly (p<0.05) increased the number of actual alternation and the percentage spontaneous alternation. It also significantly (p<0.05) decreased the duration of immobility in forced swim test. The extract also significantly (p<0.05) increased the number of central and peripheral square cross in open field. The extract also did not prolong the duration of catalepsy induced by haloperidol in glass bar test. Conclusion: Cassia singueana extract contained phytochemicals that could ameliorate cognitive impairment and negative symptoms of schizophrenics.

Swimming exercise ameliorates depressive-like behavior by anti-inflammation activity, rebalancing gut Escherichia coli and Lactobacilli

Major depressive disorder (MDD) is a common mental disease with high morbidity, recurrence and mortality and is a serious global health problem.Aerobic exercise produces beneficial effects on depression and associated comorbidities.Swimming exercise with high motor complexity may be particularly beneficial for patients with depression.We hypothesized that swimming exercise improves various types of depression-like behaviors and these effects are related to improved immune and inflammatory response by regulating microbiota-gut-brain axis.We established the Lipopolysaccharides (LPS)/Chronic unpredictable stress (CUS) mice model of depression. The forced swimming test (FST) and tail suspension test (TST) were used as predictive animal models of antidepressant-like activity.Swimming exercise significantly decreased the duration of immobility in FST and TST.We found that swimming exercise could significantly decrease the levels of pro-inflammatory cytokines in the central nervous system (CNS). Shifts in the composition of the gut microbiota were significant in depression model induced by LPS/CUS, notably as decreases in lactobacilli and increases in escherichia coli (E. coli), which were reversed byswimming exercise. Current study indicated that swimming exercise has huge potential for antidepressant therapy, and gut microbiotaplays an important role inregulating inflammation. We are pleased that current can study reveal a potentially promising method with less adverse reaction for combating depression and open up an important new area for future research.

Repeated inhibition of sigma-1 receptor suppresses GABAA receptor expression and long-term depression in the nucleus accumbens leading to depressive-like behaviors.

Sigma-1 receptor (σ1R) downregulation in male mice is known to cause a depressive-like phenotype. The nucleus accumbens (NAc), a region associated with affective regulation, has high levels of σ1R. Here, we investigated the effect of repeated inhibition of σ1R in the NAc on depressive-like behaviors and synaptic plasticity by microinjecting σ1R antagonist NE-100 into NAc nuclei in mice (NE-100 mice); this was followed by behavioral tests and field potentials recordings. We first examined the effect of NE-100 administration on σ1R expression and found that cell surface levels of σ1R were significantly reduced in the NAc of NE-100 mice. Compared to control mice, NE-100 mice exhibited significantly prolonged immobility in forced swim test (FST) and tail suspension test (TST), impaired long-term depression (LTD) as well as multi-spike waveform field excitatory postsynaptic potential (fEPSP) with an extended duration and an increased paired-pulse ratio (PPR). Reduced levels of GABAA receptor (GABAAR)-α1, -α2, -β2, and -β3 subunits, membrane D2R, and PKC phosphorylation in the NAc were observed in NE-100 mice. Activation of GABAAR by muscimol corrected the extended fEPSP duration and increased PPR, restored LTD maintenance as well as alleviated depressive-like behaviors in NE-100 mice. The decline of PKC phosphorylation in the NAc of NE-100 mice was corrected by injecting NAc with quinpirole, a D2R agonist. Injections of quinpirole or PMA (a PKC activator) into NAc of NE-100 mice rescued the expression levels of GABAAR, and alleviated the increase in PPR and impairment in LTD; these effects were sensitive to GF109203X, a PKC inhibitor. Furthermore, injecting NAc with quinpirole or PMA relieved depressive-like behaviors in NE-100 mice. Collectively, these results indicate that repeated inhibition of σ1R in the NAc reduces D2R-mediated PKC phosphorylation and suppresses GABAAR expression, thus impairing LTD maintenance and leading to depressive-like behaviors.

Chronic orexin-1 receptor blockage attenuates depressive behaviors and provokes PSD-95 expression in a rat model of depression

Depression is a devastating mood disorder affecting more than 300 million people worldwide. Almost 30 % of patients still suffer from treatment resistant depression. Although many reports support the involvement of orexin in the pathophysiology of depression, the precise role of orexin is still unclear. In this study, we evaluated the role of the orexin 1 receptor (Orx1R) on depressive behaviors and the alterations in postsynaptic density-95 (PSD-95) protein in the chronic mild stress (CMS) model of depression. Fifty-four male Wistar rats were randomly allocated to 6 groups; Control, CMS, acute SB-334867 (SB), CMS+SB, chronic SB (CSB) and CMS+CSB. Rats were exposed to one or two unpredictable stressors each day for three weeks for the induction of CMS. Intracerebroventricular (icv) injection of SB-334867, a selective Orx1R antagonist, was performed either 30 min before behavioral tests (acute) or once daily for 14 days (chronic). Behavioral despair was assessed by immobility time in the forced swim test (FST), sucrose consumption in sucrose preference test (SPT), and the number of crosses in the open field test (OFT) on days 1, 11, and 22 of the experiment. Finally, rats were decapitated, and brain tissue of the hippocampus (HPC) and prefrontal cortex (PFC) were collected, and the relative expression of PSD-95 was evaluated by western blotting. The CMS model rats showed a significant increase in FST immobility time (P = 0.001) and a decrease in locomotion (P = 0.04) and sucrose preference (P = 0.039). Chronic application of SB decreased immobility time to the control values (P = 0.001) and diminished locomotion (P = 0.047) and sucrose preference (P = 0.042) in comparison to the CMS group. Acute SB reversed just the immobility time (P ≤ 0.006). Chronic SB treatment increased the relative PSD-95 expression in PFC (P = 0.001). Hence, chronic antagonism of Orx1R alleviates depressive behaviors induced by CMS and improves PSD-95 expression in PFC.

Adult stress exposure blunts dopamine system hyperresponsivity in a neurodevelopmental rodent model of schizophrenia

Stress is a major risk factor for the development of both schizophrenia and depression, and comorbidity between the two is common in schizoaffective disorders. However, the effects of stress exposure (i.e. chronic mild stress-CMS) on depression-related phenotypes in a neurodevelopmental model relevant to schizophrenia (i.e. methylazoxymethanol acetate—MAM) have yet to be explored and could provide insight into shared mechanisms of disease. To this end, we combined the prenatal MAM model with adult CMS exposure and explored the resultant pathophysiology using the social approach test (SAT), immobility in the forced swim test (FST) and amphetamine-induced hyperlocomotion (AIH) as depression- and schizophrenia-related endophenotypes and performed extracellular recordings of ventral tegmental area (VTA) DA neurons. MAM rats exhibited a reduction in social approach and increased VTA DA neuron activity compared to SAL rats or CMS groups. Separate cohorts of MAM animals were subjected to FST and AIH testing (counterbalanced order) or FST only. CMS groups exhibited increased FST immobility. Post-FST, both MAM groups (MAM-CON, MAM-CMS) exhibited blunted locomotor response to amphetamine compared with their SAL counterparts exposed to the same tests. Post-FST, MAM rats exhibited comparable VTA population activity to SAL rats, and CMS groups exhibited attenuated VTA population activity. Apomorphine administration results were consistent with the model suggesting that reductions in VTA DA neuron activity in MAM rats following FST exposure resulted from over-excitation, or depolarization block. These data suggest stress-induced DA downregulation in MAM rats, as FST exposure was sufficient to block the DA hyperresponsivity phenotype.

Hydroxynorketamine Pharmacokinetics and Antidepressant Behavioral Effects of (2,6)- and (5R)-Methyl-(2R,6R)-hydroxynorketamines.

(R,S)-Ketamine is rapidly metabolized to form a range of metabolites in vivo, including 12 unique hydroxynorketamines (HNKs) that are distinguished by a cyclohexyl ring hydroxylation at the 4, 5, or 6 position. While both (2R,6R)- and (2S,6S)-HNK readily penetrate the brain and exert rapid antidepressant-like actions in preclinical tests following peripheral administration, the pharmacokinetic profiles and pharmacodynamic actions of 10 other HNKs have not been examined. We assessed the pharmacokinetic profiles of all 12 HNKs in the plasma and brains of male and female mice and compared the relative potencies of four (2,6)-HNKs to induce antidepressant-relevant behavioral effects in the forced swim test in male mice. While all HNKs were readily brain-penetrable following intraperitoneal injection, there were robust differences in peak plasma and brain concentrations and exposures. Forced swim test immobility rank order of potency, from most to least potent, was (2R,6S)-, (2S,6R)-, (2R,6R)-, and (2S,6S)-HNK. We hypothesized that distinct structure-activity relationships and the resulting potency of each metabolite are linked to unique substitution patterns and resultant conformation of the six-membered cyclohexanone ring system. To explore this, we synthesized (5R)-methyl-(2R,6R)-HNK, which incorporates a methyl substitution on the cyclohexanone ring. (5R)-Methyl-(2R,6R)-HNK exhibited similar antidepressant-like potency to (2R,6S)-HNK. These results suggest that conformation of the cyclohexanone ring system in the (2,6)-HNKs is an important factor underlying potency and that additional engineering of this structural feature may improve the development of a new generation of HNKs. Such HNKs may represent novel drug candidates for the treatment of depression.