Chronic Stress Rat Model Research Articles

The role of brevican regulation in the antidepressant effects of electroacupuncture in a chronic stress rat model

ObjectiveTo investigate the mechanism of electroacupuncture (EA) for treating depression and to explore the role of brevican in the medial prefrontal cortex (mPFC) in modulating stress susceptibility and the antidepressant effects of EA in rats. MethodsTwenty-four Sprague–Dawley (SD) rats were equally divided into three groups: green fluorescent protein (GFP) + control, GFP + chronic unpredicted mild stress (CUMS), and short-hairpin RNA targeting on brevican (shBcan) + CUMS. Another 24 SD rats were equally divided into CUMS + GFP, CUMS + GFP + EA, and CUMS + shBcan + EA groups. Behavioral tests were conducted to assess depression-like behavior. Western blot analysis was used to evaluate the expression of brevican, aggrecan, GLuA1, and PSD95 in mPFC subregions. ResultsBehavioral parameter evaluation show that rats in the shBcan + CUMS group exhibited a significantly reduced sucrose preference (P = .0002) and increased immobility time (P = .0011) compared to those in rats in the GFP + CUMS group. Western blotting showed that brevican expression was significantly downregulated in the PrL of the shBcan + CUMS group compared with that in the GFP + CUMS group (P = .0192). Furthermore, compared to the CUMS + GFP + EA group, the CUMS + shBcan + EA group exhibited a significantly decreased sucrose preference (P = .0334), increased immobility time (P = .0465), and increased latency to food (P = .0261). In the CUMS + shBcan + EA group, the EA-induced brevican and PSD95 overexpression was reversed, compared with that in the CUMS + GFP + EA group (P = .0454 and P = .0198, respectively). ConclusionEA exerts its antidepressant effects through the modulation of brevican expression in rats. Our findings highlight the important role for brevican in stress susceptibility, which could be a potential target for treating depression.

Chronic corticosterone exposure evokes itch hypersensitivity and sexual dysfunction in male rats: Relationship between the two distinct gastrin-releasing peptide systems in the spinal cord

In today’s society, people are subjected to many social stressors, and excessive chronic stress causes functional disruption of the neuroendocrine system and many diseases. Although the exacerbation of atopic dermatitis with symptoms of itching and erectile dysfunction is induced by chronic stress, the details of the mechanisms are unknown. Here, we examined the effects of chronic stress on itch sensation and male sexual function at the behavioral and molecular levels, focusing on two distinct gastrin-releasing peptide (GRP) systems that independently regulate itch transmission, i.e., the somatosensory GRP system, and male sexual function, i.e., the lumbosacral autonomic GRP system, in the spinal cord. In a rat model of chronic stress induced by chronic corticosterone (CORT) administration, we observed increased plasma CORT concentrations, decreased body weight, and increased anxiety-like behavior, similar to that observed in humans. Chronic CORT exposure induced hypersensitivity to itch and increased the Grp mRNA level in the spinal somatosensory system, but there was no change in pain or tactile sensitivity. Antagonists of the somatosensory GRP receptor, an itch-specific mediator, suppressed itch hypersensitivity induced by chronic CORT exposure. In contrast, chronic CORT exposure decreased male sexual behavior, ejaculated semen volume, vesicular gland weight, and plasma testosterone levels. However, there were no effects on the expression of Grp mRNA or protein in the lumbosacral autonomic GRP system, which regulates male sexual function. In summary, chronic stress model rats showed itch hypersensitivity and impaired sexual function in males, and the involvement of the spinal GRP systems was apparent in itch hypersensitivity.

The effects of chronic unpredicted mild stress on maternal negative emotions and gut microbiota and metabolites in pregnant rats.

Chronic long-term stress is associated with a range of disorders, including depression and a variety of other chronic illnesses. It is well known that maternal exposure to psychosocial stress during pregnancy significantly increases the likelihood of adverse pregnancy outcomes. The gut microbiota has been a popular topic, it is a key mediator of the gut-brain axis and plays an important role in human health; changes in the gut microbiota have been related to chronic stress-induced health impairment, however, the relationship between maternal negative emotions and abnormal gut microbiota and its metabolites during maternal exposure to chronic stress during pregnancy remains unclear. Pregnant rats were subjected to chronic unpredicted mild stress (CUMS) to establish the rat model of chronic stress during pregnancy. The behavioral changes were recorded using sucrose preference test (SPT) and open-field test (OFT), plasma corticosterone levels were determined by radioimmunoassay, and a comprehensive method combining 16S rRNA gene sequencing and gas chromatography-mass spectrometry (GC-MS) metabolomics was used to study the effects of stress during pregnancy on the function of intestinal microbiota and its metabolites. Chronic stress during pregnancy not only increased maternal plasma corticosterone (P < 0.05), but also caused maternal depression-like behaviors (P < 0.05). Chronic stress during pregnancy changed the species composition at the family level of maternal gut microbiota, the species abundance of Ruminococcaceae in the stress group (23.45%) was lower than the control group (32.67%) and the species abundance of Prevotellaceae in the stress group (10.45%) was higher than the control group (0.03%) (P < 0.05). Vertical locomotion and 1% sucrose preference percentage in pregnant rats were negatively correlated with Prevotellaceae (r=-0.90, P<0.05). Principal component analysis with partial least squares discriminant analysis showed that the integration points of metabolic components in the stress and control groups were completely separated, indicating that there were significant differences in the metabolic patterns of the two groups, and there were seven endogenous metabolites that differed (P < 0.05). The negative emotional behaviors that occur in pregnant rats as a result of prenatal chronic stress may be associated with alterations in the gut microbiota and its metabolites. These findings provide a basis for future targeted metabolomics and gut flora studies on the effects of chronic stress during pregnancy on gut flora.

A repeated measures cognitive affective bias test in rats: comparison with forced swim test.

There is an urgent need to identify behaviours in animals that can provide insight into the aetiology and potential treatment of depression in humans. This study aimed to validate a repeated measures cognitive affective bias (CAB) test in a rat model of chronic stress and compare CAB with forced swim test (FST) measures. Male and female Sprague Dawley rats were trained to associate large and small rewards with scent, spatial, and tactile cues, and their response to an ambiguous tactile stimulus tested. Rats underwent weekly CAB testing for 4weeks with no intervention, or for 2weeks of chronic restraint stress (CRS), followed by 2weeks of fluoxetine, vehicle, or no treatment. CRS rats also underwent the FST at selected timepoints. In control rats, CAB was positive and remained stable over the 4-week period. In CRS-fluoxetine and CRS-vehicle groups, CAB was initially positive, became negative during chronic restraint stress, and returned to positive by 2weeks after treatment. However, in the CRS-no treatment group, CAB was variable at the outset and unstable over time. Behaviour in the FST was not affected by treatment, and there was no correlation between CAB and FST outcomes. Instability in the CRS-no treatment group precluded interpretation of the impact of fluoxetine on CAB post-CRS. Our results suggest that behaviour in the FST does not reflect or alter affective state and support the use of CAB tests as part of the behavioural testing repertoire for preclinical animal models of affective disorders.

Diosmectite treatment reduces stress-induced visceral hypersensitivity but does not affect the gut microbiota in rats.

To evaluate the effect of diosmectite on visceral hypersensitivity and intestinal transit in a rat chronic stress model and on the faecal microbiota. Wistar rats (175-225 g; n=10) were randomized into four groups: diosmectite/control, diosmectite/stress, vehicle/control, and vehicle/stress. Diosmectite (500 mg/kg, PO) was administered for five days for assessment of visceral hypersensitivity and intestinal transit and for three weeks for assessment of faecal microbiota. The stress procedure was a daily chronic passive water avoidance session. Intestinal transit was evaluated by faecal output in the hour following the last stress session. Visceral sensitivity in response to colorectal distension (CRD) was assessed at baseline and 30 min after the last stress session. In another group of rats, faecal material was collected before and after treatment with diosmectite or vehicle; genomic DNA was extracted and sequenced to characterize the faecal microbiota. Under nonstressed conditions, diosmectite treatment did not modify intestinal transit compared to the vehicle group (p=0.33). After the stress procedure, a trend towards reduction in stress-induced stool production was observed with diosmectite compared to vehicle (6.3±1.1 vs. 4.9±1.2 respectively; p=0.38). In the control condition, the number of CRD-evoked abdominal contractions was 20±4 after diosmectite and 24±2 after vehicle (p=0.75). In the stressed condition, the number of contractions increased to 34.4±2.4 after vehicle (p<0.05 compared to control). Stress-related hypersensitivity was attenuated after diosmectite treatment (26.9±2.2; p<0.05 compared to vehicle). No relevant changes were observed in the faecal microbiotic profile after treatment with diosmectite or vehicle. Diosmectite treatment attenuates stress-induced visceral hypersensitivity; this effect may contribute to the therapeutic effect of diosmectite in IBS in humans.

Docosahexaenoic Acid and Tualang Honey Improve Brain Oxidative Status in Chronic Stress Rat Model

The main objective of this study was to investigate the protective effects of docosahexaenoic acid (DHA) and Tualang honey (TH) and their combination on several parameters of oxidative stress of the brain following exposure to chronic stress. Five groups of male Sprague Dawley rats ( 10 animal per group) were allocated in which Group 1 received normal saline and used as control; Group 2 was exposed to stress and received normal saline; Group 3 was exposed to stress and reviewed DHA (450 mg/kg body weight BD); Group 4 was exposed to stress and received TH (1 g/kg body weight BD), and Group 5 was exposed to stress and received combination of DHA and TH. Animals were exposed to chronic stress from 9 am to 2 pm daily for 4 weeks. The following oxidative parameters were measured: total antioxidant status (TAS) , glutathione, thiobarbituric acid reactive substances (TBARS) and protein carbonyl. The results showed that DHA, TH and their combination significantly reduced (p&lt;0.05) stress-induced elevation of corticosterone and TBARS levels and concurrently caused a significantly increased (p&lt;0.05) in TAS level. With regard to glutathione and protein carbonyl, only TH and combination of DHA+TH significantly reduced (p&lt;0.05) the oxidised glutathione and protein carbonyl. In all parameters, there was no significant difference between Group 5 in comparison to Group 3 and Group 4 indicating combination of DHA and TH was not superior to consuming DHA and TH alone. In conclusion, TH and to lesser extent DHA may protect the brain against oxidative stress induced by exposure to chronic stress but consuming these substances together does not give synergistic effect.&#x0D; Keywords: Oxidative stress, Honey, Docosahexaenoic acid, Chronic stress, Brain

Shugan Hewei Decoction Alleviates Cecum Mucosal Injury and Improves Depressive- and Anxiety-Like Behaviors in Chronic Stress Model Rats by Regulating Cecal Microbiota and Inhibiting NLRP3 Inflammasome.

Chronic stress is a significant cause of depression, anxiety, and intestinal mucosal injury. Gut microbiota disturbances are also associated with these disorders. Shugan Hewei Decoction (SHD), which is a traditional Chinese medicine formula developed by our team, has shown superior therapeutic effects in the treatment of depression, anxiety, and functional gastrointestinal diseases caused by chronic stress. In this study, we investigated the modulatory effect of SHD on the cecal microbiota and cecum mucosal NOD-like receptor protein 3 (NLRP3) inflammasome in a chronic unpredictable stress (CUS)/social isolation rat model. After the SHD intervention, the CUS model rats showed improvements in their depressive- and anxiety-like behaviors, as well as sustained body weight growth and improved fecal characteristics. SHD improved the cecal microbiota diversity and changed the abundance of six microbial genera. A Spearman’s correlation analysis showed a strong correlation between the NLRP3 inflammasome and CUS-perturbed cecal biomarker microbiota. SHD regulated the excessive expression of NLRP3, ASC, caspase-1, interleukin-1β (IL-1β), and IL-18 in the serum and cecum mucosa induced by CUS, as well as the activation of the Toll-like receptor 4/nuclear factor-κB signaling cascades. Our results reveal the pharmacological mechanisms of SHD and provide a validated therapeutic method for the treatment of depression, anxiety, and cecum mucosal injury.

Interleukin-6 expression and its modulation by diacerein in a rat model of chronic stress induced cardiac dysfunction

People with chronic stress have higher levels of pro-inflammatory cytokines, which enhance their susceptibility to cardiovascular diseases. Diacerein has ability to modulate pro-inflammatory cytokines such as IL-1β and IL-6; however, its efficacy in chronic stress associated cardiovascular diseases is not yet assessed. In this study, we standardized a rat model of chronic unpredictable stress (CUS) demonstrating cardiovascular dysfunctions and further assessed the effect of IL-6 modulator, diacerein, on cardiovascular functions in CUS exposed rats. The CUS procedure consisted of exposing male albino Wistar rats to random stressors, everyday for 8 weeks. The binding affinity of diacerein with IL-6 was ascertained using Docking tools viz AutoDock and SwissDock. Moreover, diacerein was administered (50 mg/kg/day x 20 days P.O) post CUS exposure to rats and the serum IL-6 levels and heart functions of CUS rats were determined by ELISA and ECG-HRV analysis, respectively. 8 weeks of CUS exposure resulted in two-fold increase in serum corticosterone and IL-6 levels in rats. The ECG and HRV analysis of CUS rats showed altered sinus rhythm, elevated heart rate, systolic blood pressure and sympathetic tone. Molecular docking studies revealed diacerein high binding affinity towards IL-6 receptor. The post-treatment of diacerein in CUS rats prevented these cardiovascular dysfunctions. Our findings thus suggests that IL-6 may have a prominent role in chronic stress induced cardiovascular dysfunctions and diacerein, could be used as a preventive measure for such conditions.

DHA-rich fish oil and Tualang honey reduce chronic stress-induced oxidative damage in the brain of rat model

BackgroundExposure to chronic stress induces oxidative damage which alters the dynamic balance between antioxidant and pro-oxidant activities in the brain. Tualang honey (TH) is a Malaysian wild multifloral honey which has been shown to contain high amount antioxidants. DHA-rich fish oil is a form of omega-3 fatty acids found in fish which also possesses some antioxidant activity. This study aimed to evaluate anti-stress activity of DHA-rich fish oil, TH and their combination on several parameters of oxidative stress in chronic stress rat model. MethodsFifty male Sprague Dawley rats were divided into (i) control, (ii) stress-exposed, (iii) stress-exposed and treated with TH (1 g/kg body weight twice daily), (iv) stress-exposed and treated with DHA-rich fish oil (450 mg/kg body weight twice daily), and (v) stress-exposed and treated with a combination of TH and DHA-rich fish oil. The chronic stress regimen consisted of a combination of restraint stress and a swim stress test for 28 days. ResultsDHA-rich fish oil and TH significantly (p < 0.05) supressed stress-induced elevation of serum corticosterone and lipid peroxidation, and caused a significant increase in total antioxidant capacity. For glutathione status, only TH significantly reduced stress-induced elevation of oxidised glutathione (GSSG) and normalised GSH/GSSG ratio. Conclusion: Both DHA-rich fish oil and TH have protective effects against brain oxidative stress but consuming these substances together does not seem to provide an additional benefit compared to consuming them separately.

Acupuncture inhibits NLRP3 inflammasome activation in the prefrontal cortex of a chronic stress rat model of depression.

The Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-driven inflammatory response plays a key role in the pathophysiology of depression. Mounting evidence suggests that acupuncture is an effective treatment for depression. In this study, we investigated the effects of acupuncture treatment at the acupoints Baihui (GV20) and Yintang (GV29) on NLRP3 inflammasome in the prefrontal cortex (PFC) of an animal model of depression. Rats that underwent chronic unpredictable mild stress (CUMS) for 6 weeks showed depressive-like behaviors, which were confirmed by sucrose preference and locomotor activity in the open field test. The protein levels of NLRP3, apoptotic speck-containing protein with a card (ASC), and cysteinyl aspartate specific proteinase-1 (Caspase-1) in the PFC were detected by Western blot analysis. The mRNA and protein expressions of interleukin-1β (IL-1β) and interleukin-18 (IL-18) in the PFC were measured by the real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Our results showed that the depressive-like behaviors in stressed rats were reversed by acupuncture treatment. Compared with control rats, the protein expression of NLRP3, ASC, and Caspase-1 and the mRNA and protein expressions of IL-1β and IL-18 in the PFC were markedly increased in CUMS rats. Acupuncture treatment significantly decreased the levels of NLRP3 inflammasome components and inflammatory cytokines in the PFC. Acupuncture treatment also reduced the number of TUNEL-positive cells in the PFC. These results suggested that acupuncture has antidepressant-like effects, and its mechanism appears to be involved in the inhibition of NLRP3 inflammasome activation and apoptosis in the PFC.

Downregulation of miR-383 reduces depression-like behavior through targeting Wnt family member 2 (Wnt2) in rats

This study aimed to evaluate the role of miR-383 in the regulation of Wnt-2 signaling in the rat model of chronic stress. The male SD rats with depressive-like behaviors were stimulated with chronic unpredictable mild stress (CUMS) including ice-water swimming for 5 min, food deprivation for 24 h, water deprivation for 24 h, stimulating tail for 1 min, turning night into day, shaking for 15 min (once/s), and wrap restraint (5 min/time) every day for 21 days. The expression levels of miRNAs were detected by qRT-PCR, and the expression levels of Wnt2, depression-impacted proteins (GFAP, BDNF, CREB), brain neurotransmitters (5-HT, NE, DA) and apoptosis-related proteins (Bax and Bcl-2) were evaluated by qRT-PCR and western blot. Bioinformatic analysis and luciferase reporter assay were performed to determine the relationship between miR-383 and Wnt2. Ethological analysis was evaluated by sugar preference test, refuge island test and open field tests. Rescue experiments including knockdown of miR-383, overexpression and silencing of Wnt2 were performed to determine the role of miR-383. High expression levels of miR-383 were observed in the hippocampus of rats submitted to CUMS model. Downregulation of miR-383 significantly inhibited the apoptosis and inflammatory response of hippocampal neurons, and increased the expression levels of GFAP, BDNF and CREB which were impacted in depression, as well as neurotransmitters, then attenuated neural injury in rats induced by CUMS. Furthermore, Wnt family member 2 (Wnt2) was identified as a target of miR-383, and silencing of Wnt2 obviously attenuated the protective effect of miR-383 inhibitor on the apoptosis and inflammatory response in hippocampal neurons, as well as neural injury in CUMS-induced rats. Downregulation of miR-383 ameliorated the behavioral and neurochemical changes induced by chronic stress in rats by directly targeting Wnt2, indicating that the miR-383/Wnt2 axis might be a potential therapeutic target for MDD.

Waterfall Forest Environment Regulates Chronic Stress via the NOX4/ROS/NF-κB Signaling Pathway.

Background: Forest therapy has been proven to have beneficial effects on people with depression and anxiety. However, it remains unknown whether the waterfall forest environment (WF) affects the physical and psychological health of patients with chronic fatigue and how the WF regulates chronic stress.Methods: Twenty-four patients with chronic fatigue were randomly divided into two groups: the WF group and the urban (U) group. Scores on the Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), and Fatigue Scale-14 (FS-14) were evaluated before and after environmental intervention. Detection of physiological indexes and inflammatory factor levels and immunological analysis were also performed. In addition, the chronic stress rat model was constructed, and the effects of the WF on hopelessness and liver damage of rats were investigated.Results: Patients with chronic fatigue in the WF group showed a significant decrease in FS-14, HAMA, and HAMD scores compared with the U group. The expression levels of glutathione peroxidase and superoxide dismutase were remarkably higher in the WF group than in the U group. However, the expression levels of malondialdehyde and inflammatory factors (IL-1β, TNF-α, IL-6, and IL-10) were remarkably decreased after the intervention of the WF. In addition, animal experiments confirmed that the WF improved hopelessness, liver damage, and excitability of neurons of chronic stress rats. Mechanistically, the WF reduced the liver damage caused by chronic stress in rats by inhibiting the NOX4/ROS/NF-κB signaling pathway.Conclusions: Collectively, the WF had a positive effect on immune enhancement and physical and psychological health in patients with chronic fatigue and might inhibit chronic stress by regulating the NOX4/ROS/NF-κB signaling pathway.

Antidepressant-like effects of Lactobacillus plantarum DP189 in a corticosterone-induced rat model of chronic stress

Probiotic antidepressant effects demonstrated previously in clinical studies and animal models act via unknown mechanisms. Here we used a corticosterone injection-induced Sprague-Dawley rat chronic stress exposure model to investigate antidepressant-like effects of potential probiotic Lactobacillus plantarum DP189 (DP189) isolated from Chinese traditional fermented sauerkraut. After administration of DP189 (1.0 × 109CFU/d) suspension by gavage for 21 days, behavioral, histopathological and biochemical changes were assessed, including hippocampal neuronal apoptosis assessments via TUNEL staining and Western blot analysis. Behaviorally, DP189 treatment improved memory and spatial learning and reduced anhedonia, as measured using Morris water maze and sucrose preference tests, respectively. Histopathologically, DP189 treatment ameliorated hippocampal pathological changes and dramatically reduced TUNEL-positive cell numbers. Biochemically, DP189 decreased serum IL-1β and TNF-α levels, decreased hippocampal mitogen-activated protein kinase kinase 7 and c-Jun N-terminal kinase 2 levels, down-regulated pro-apoptosis protein Bax immunocontent and up-regulated anti-apoptosis protein Bcl-2 immunocontent. Collectively, these results suggest that DP189 treatment may prevent and/or alleviate depression-like behaviors and hippocampal neural injury induced by CORT.

Electro-acupuncture regulates glucose metabolism in chronic stress model rats

Studies have shown that acupuncture is very effective in treating chronic stress depression. However, little is known about the therapeutic mechanism of electro-acupuncture. Metabolomics, on the other hand, is a technology that determines the metabolic changes of organisms caused by various interventions as a whole and is related to the overall effect of electro-acupuncture (EA). 1HNMR, serum sample analysis, and histopathology and molecular biology analysis were used to evaluate the effects of EA. The results show that electro-acupuncture points can regulate the heat pain threshold of chronic stress model rats and change the morphology of adrenal cortex cells Structure, and regulate the contents of corticotropin-releasing hormone, Corticosterone (CORT), glucose, alanine and valine in the samples. These findings help to clarify the therapeutic mechanism of electro-acupuncture on heterologous chronic stress model rats. The effect of electro-acupuncture on improving chronic stress is likely to be achieved by regulating glucose metabolism, which can provide a reference for clinical acupuncture treatment of chronic stress depression.

Ciliary neurotrophic factor signaling in the rat orbitofrontal cortex ameliorates stress-induced deficits in reversal learning

Deficits in cognitive flexibility, i.e. the ability to modify behavior in response to changes in the environment, are present in several psychiatric disorders and are often refractory to treatment. However, improving treatment response has been hindered by a lack of understanding of the neurobiology of cognitive flexibility. Using a rat model of chronic stress (chronic intermittent cold stress, CIC) that produces selective deficits in reversal learning, a form of cognitive flexibility dependent on orbitofrontal cortex (OFC) function, we have previously shown that JAK2 signaling is required for optimal reversal learning. In this study we explore the molecular basis of those effects. We show that, within the OFC, CIC stress reduces the levels of phosphorylated JAK2 and of ciliary neurotrophic factor (CNTF), a promoter of neuronal survival and an activator of JAK2 signaling, and that neutralizing endogenous CNTF with an intra-OFC microinjection of a specific antibody is sufficient to produce reversal-learning deficits similar to stress. Intra-OFC delivery of recombinant CNTF to CIC-stressed rats, at a dose that induces JAK2 and Akt but not STAT3 or ERK, ameliorates reversal-learning deficits, and Akt blockade prevents the positive effects of CNTF. Further analysis revealed that CNTF may exert its beneficial effects by inhibiting GSK3β, a substrate of Akt and a regulator of protein degradation. We also revealed a novel mechanism of CNTF action through modulation of p38/Mnk1/eIF4E signaling. This cascade controls translation of select mRNAs, including those encoding several plasticity-related proteins. Thus, we suggest that CNTF-driven JAK2 signaling corrects stress-induced reversal learning deficits by modulating the steady-state levels of plasticity-related proteins in the OFC.

Effects of Enriched Environment (EE) on Depressive-Like Behavior and Hippocampal Structure in Rat Model of Chronic Stress

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Neuropsychopharmacology of JNJ-55308942: evaluation of a clinical candidate targeting P2X7 ion channels in animal models of neuroinflammation and anhedonia.

Emerging data continues to point towards a relationship between neuroinflammation and neuropsychiatric disorders. ATP-induced activation of P2X7 results in IL-1β release causing neuroinflammation and microglial activation. This study describes the in-vitro and in-vivo neuropharmacology of a novel brain-penetrant P2X7 antagonist, JNJ-55308942, currently in clinical development. JNJ-55308942 is a high-affinity, selective, brain-penetrant (brain/plasma of 1) P2X7 functional antagonist. In human blood and in mouse blood and microglia, JNJ-55308942 attenuated IL-1β release in a potent and concentration-dependent manner. After oral dosing, the compound exhibited both dose and concentration-dependent occupancy of rat brain P2X7 with an ED50 of 0.07 mg/kg. The P2X7 antagonist (3 mg/kg, oral) blocked Bz-ATP-induced brain IL-1β release in conscious rats, demonstrating functional effects of target engagement in the brain. JNJ-55308942 (30 mg/kg, oral) attenuated LPS-induced microglial activation in mice, assessed at day 2 after a single systemic LPS injection (0.8 mg/kg, i.p.), suggesting a role for P2X7 in microglial activation. In a model of BCG-induced depression, JNJ-55308942 dosed orally (30 mg/kg), reversed the BCG-induced deficits of sucrose preference and social interaction, indicating for the first time a role of P2X7 in the BCG model of depression, probably due to the neuroinflammatory component induced by BCG inoculation. Finally, in a rat model of chronic stress induced sucrose intake deficit, JNJ-55308942 reversed the deficit with concurrent high P2X7 brain occupancy as measured by autoradiography. This body of data demonstrates that JNJ-55308942 is a potent P2X7 antagonist, engages the target in brain, modulates IL-1β release and microglial activation leading to efficacy in two models of anhedonia in rodents.

Effects of fluoxetine on changes of pain sensitivity in chronic stress model rats

Exposure to stress could facilitate or inhibit pain responses (stress-induced hyperalgesia or hypoalgesia, respectively). Fluoxetine is a selective serotonin (5-HT) reuptake inhibitor antidepressant. There have been contradictory reports on whether fluoxetine produces antinociceptive effects. The purpose of this study was to elucidate changes in pain sensitivity after chronic stress exposure, and the effects of fluoxetine on these changes. We measured thermal, mechanical, and formalin-induced acute and inflammatory pain by using the tail-flick, von Frey, and formalin tests respectively. The results showed that rats exposed to chronic stress exhibited thermal and formalin-induced acute and inflammatory hypoalgesia and transient mechanical hyperalgesia. Furthermore, fluoxetine promoted hypoalgesia in thermal and inflammatory pain and induced mechanical hyperalgesia. Our results indicate that the 5-HT system could be involved in hypoalgesia of thermal and inflammatory pain and induce transient mechanical hyperalgesia after stress exposure.

Effects of berberine on a rat model of chronic stress and depression via gastrointestinal tract pathology and gastrointestinal flora profile assays

Chronic stress and depression are challenging conditions to treat, owing to their complexity and lack of clinically available and effective therapeutic agents. The aim of the present study was to investigate the mechanism by which berberine acts, by examining alterations to gastrointestinal tract histopathology and flora profile in a rat model, following the induction of stress. Research associating gastrointestinal flora and depression has increased, thus, the present study hypothesized that stress induces depression and changes in the gastrointestinal system. The chronic mild stress rat model was previously established based on a set of 10 chronic unpredictable stress methods. In the present study, the measurements of body weight, behavior, gastrointestinal tract histopathology and gastrointestinal flora profile were collected in order to elucidate understanding of chronic stress and depression in this region. In the present study, induced stress and the resulting depression was demonstrated to significantly decrease the body weight and sucrose preference of rats, aswellas significantly increasing traverse time, vertical movement time, grooming time and motionless time in an open‑field test. Following modeling and subsequent treatment with low or high doses of berberine, the measurements were significantly different when compared with unstressed rats. Berberine appears to reverse the physical damage brought about by stress within the gastric mucosa and intestinal microvilli of the stomach, ileum, cecum and colon. Using enterobacterial repetitive intergenic consensus sequence‑based polymerase chain reaction analysis, several distinctive bands disappeared following modeling; however, novel distinctive bands appeared in response to the graded berberine treatment. In conclusion, the present study identified that high concentrations of berberine markedly protects rats from various symptoms of chronic stress and depression, with the potential of facilitating treatment within clinical practice.

Anxiolytic and neuroprotective effects of the Traditional Chinese Medicinal formulation Dan-zhi-xiao-yao-san in a rat model of chronic stress.

Dan-zhi-xiao-yao-san is a Traditional Chinese Medicinal formulation widely used for the treatment of neuropsychological disorders. The present study examined the anxiolytic and neuroprotective effects of Dan-zhi-xiao-yao-san in a rat model of chronic stress. The results of an elevated plus maze test showed that Dan‑zhi‑xiao‑yao‑san significantly attenuated the levels of anxiety-induced stress as evidenced by increases in the time spent in the open arm region, as well as the percentage of entries into this area. In addition, Dan-zhi-xiao-yao-san alleviated stress‑induced neuronal death, as indicated by histological examination. Furthermore, mechanistic studies suggested that the anxiolytic and neuroprotective effects of Dan-zhi-xiao-yao-san may be mediated via attenuation of chronic stress‑induced upregulation of α‑synuclein and corticosterone, and downregulation of protein phosphatase2A (PP2A) in the hippocampal region of the brain at the mRNA and protein level. In addition, Dan‑zhi‑xiao‑yao‑san decreased the serum levels of stress‑induced corticosterone in the model animals. In conclusion, the present study demonstrated that Dan‑zhi‑xiao‑yao‑san exerted anxiolytic and neuroprotective effects in a rat model of chronic stress via attenuation of stress‑induced upregulation of α‑synuclein and corticosterone, and downregulation of PP2A in the hippocampus.