Mild Stress Model Of Depression Research Articles

Asiaticoside produces an antidepressant‑like effect in a chronic unpredictable mild stress model of depression in mice, involving reversion of inflammation and the PKA/pCREB/BDNF signaling pathway.

Asiaticoside is one of the triterpenoid components found in Centella asiatica that has promising neuroprotective properties. The present study aimed to evaluate the antidepressant-like properties of asiaticoside and to investigate the possible mechanisms underlying its mode of action using a mouse model of chronic unpredictable mild stress (CMS). Behavioral tests, including sucrose preference test, forced swimming test and tail suspension test, were performed to evaluate symptoms of depression. The expression levels of neurotransmitters, 5-hydroxytryptamine (5-HT) and norepinephrine (NE), in the hippocampus were measured by high-performance liquid chromatography. ELISA and western blotting were used to detect protein expression. It was demonstrated that asiaticoside treatment (20 and 40 mg/kg; intragastric) significantly reversed the decrease in sucrose consumption, and reduced the immobility time in tail suspension tests and forced swimming tests in CMS mice. Furthermore, asiaticoside treatment upregulated the expression of 5-HT and NE in the CMS mouse model. Asiaticoside administration also downregulated the levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α in the hippocampus, and reduced the phosphorylation of nuclear factor (NF)-κBp65 and the expression of nod-like receptor protein 3 (NLRP3), thus decreasing the expression of mature caspase-1. Furthermore, asiaticoside significantly increased the levels of cAMP and protein kinase A (PKA), and enhanced phosphorylation of the cAMP-related specific marker vasodilator-stimulated phosphoprotein at serine 157. Therefore, asiaticoside may activate the cAMP/PKA signaling pathway to inhibit NF-κB- and NLRP3-related inflammation. Moreover, phosphorylation of the cAMP-responsive element-binding protein at serine 133 and the expression of brain-derived neurotrophic factor were increased after asiaticoside administration. Collectively, the present results suggested that asiaticoside may play a vital role as an antidepressant and anti-inflammatory agent in the CMS mouse model by regulating the cAMP/PKA signaling pathway.

Impaired neuronal and astroglial metabolic activity in chronic unpredictable mild stress model of depression: Reversal of behavioral and metabolic deficit with lanicemine

Major depressive disorder is the leading cause of disability and suicidality worldwide. Here, we evaluated neural metabolic activity in prefrontal cortex (PFC) in C57BL6 mice undergoing a chronic unpredictable mild stress (CUMS) for three weeks to induce depression. Further, the efficacy of Lanicemine, a low trapping NMDA receptor antagonist, on behavioral and neurometabolic measures in CUMS mice was evaluated. The PFC neuronal and astroglial metabolic activity was evaluated by Proton Observed Carbon Edited (POCE) MR spectroscopy together with an infusion of [1,6–13C2]glucose and [2–13C]acetate, respectively. The rates of glutamatergic, GABAergic and astrocytic TCA cycles and neurotransmitter cycling were obtained by fitting a three-compartment metabolic model to 13C turnover of amino acids. Mice subjected to CUMS exhibited significantly reduced sucrose preference (CUMS 58.0 ± 12.5%, n = 29; Control 86.3 ± 6.4%, n = 30; p < 0.0001), and increased immobility (CUMS 146.1 ± 60.8s, n = 29; Control 29.9 ± 19.3s, n = 30; p < 0.0001) in the forced swim test. The concentrations of 13C labeled amino acids from [2–13C]acetate were decreased suggesting reduced astroglial metabolic activity in CUMS mice. The glutamatergic and GABAergic TCA cycle rates were decreased in CUMS mice when compared with controls. In addition, GABA-glutamine and glutamate-glutamine neurotransmitter cycling were reduced in mice subjected to CUMS regimen. Most interestingly, a short time intervention of lanicemine restored behavioral measures (sucrose preference and immobility), and rates of glucose oxidation in glutamatergic and GABAergic neurons in CUMS mice. In summary, our findings suggest that depression leads to a reduction in excitatory and inhibitory neurotransmission in PFC, and targeting glutamatergic pathway may have potential therapeutic role in chronic depression.

Stress-Induced Morphological, Cellular and Molecular Changes in the Brain-Lessons Learned from the Chronic Mild Stress Model of Depression.

Major depressive disorder (MDD) is a severe illness imposing an increasing social and economic burden worldwide. Numerous rodent models have been developed to investigate the pathophysiology of MDD. One of the best characterized and most widely used models is the chronic mild stress (CMS) model which was developed more than 30 years ago by Paul Willner. More than 2000 published studies used this model, mainly to assess novel compounds with potential antidepressant efficacy. Most of these studies examined the behavioral consequences of stress and concomitant drug intervention. Much fewer studies focused on the CMS-induced neurobiological changes. However, the stress-induced cellular and molecular changes are important as they may serve as potential translational biomarkers and increase our understanding of the pathophysiology of MDD. Here, we summarize current knowledge on the structural and molecular alterations in the brain that have been described using the CMS model. We discuss the latest neuroimaging and postmortem histopathological data as well as molecular changes including recent findings on microRNA levels. Different chronic stress paradigms occasionally deliver dissimilar findings, but the available experimental data provide convincing evidence that the CMS model has a high translational value. Future studies examining the neurobiological changes in the CMS model in combination with clinically effective antidepressant drug intervention will likely deliver further valuable information on the pathophysiology of MDD.

P.423 Hair corticosterone as an outcome measure in the rat chronic mild stress model of depression

P.423 Hair corticosterone as an outcome measure in the rat chronic mild stress model of depression

Reducing PRLR expression and JAK2 activity results in an increase in BDNF expression and inhibits the apoptosis of CA3 hippocampal neurons in a chronic mild stress model of depression

Patients suffering from depression most commonly present with symptoms associated with the autonomic nervous system. Despite the satisfactory results achieved following treatment with vagus nerve stimulation and drug treatment, recurrence is a common occurrence in many patients. As described in numerous studies, prolactin receptor (PRLR) has been identified as an anxiolytic and anti-depressant factor in depression. However, the effect of PRLR on chronic mild stress (CMS)-induced depression remains to be thoroughly demonstrated. Therefore, the present study was conducted on the effect of PRLR gene on brain derived neurotrophic factor (BDNF) expression and hippocampal neuron apoptosis through the establishment of CMS-induced depression mouse models, with aims of providing a new and effective therapeutic option for depression. Microarray-based analysis was initially used to retrieve depression-related expression dataset and PRLR-related signaling pathway. Lentiviral vectors overexpressing PRLR or expressing PRLR-specific shRNA were used to up- or down-regulated the expression of PRLR in mice. Subsequently, the effects of PRLR on hippocampal neurons and pyramidal cells in CA1 and CA3 regions, and ultrastructure in hippocampal region were evaluated. Serum BDNF level and the positive rate of cleaved-Caspase-3 in hippocampal CA3 region were determined. Next, the regulatory mechanism by which PRLR gene silencing influences hippocampal neuron apoptosis via the JAK2-STAT5 signaling pathway was detected. PRLR gene was assumed to participate in the development of depression by regulating the JAK-STAT signaling pathway. Our results found that the mice with CMS-induced depression exhibited locomotion activity and anhedonia. In addition, a decrease in the number of pyramidal cells was observed in the hippocampus while that of apoptotic cells was increased. In addition, serum BDNF level was increased, and the expression of Caspase-3 and Bax in hippocampal neurons and the JAK2-STAT5 signaling pathway was decreased in response to PRLR silencing, along with increased expression of BDNF and Bcl-2. From the aforementioned findings, we concluded that PRLR gene silencing results in the inhibition of hippocampal neuron apoptosis and alleviation of CMS-induced depression by inactivating the JAK2-STAT5 signaling pathway and elevating BDNF expression, providing a new insight for the treatment of depression.

Antidepressant-like effects of agmatine and NOS inhibitors in chronic unpredictable mild stress model of depression in rats: The involvement of NLRP inflammasomes

Innate immunity activation in the central nervous system (CNS) is known to contribute to the development of depression through NOD-like receptors containing pyrin domain 3 (NLRP3) inflammasome assembly. Furthermore, administration of agmatine (AGM), a nitric oxide synthase (NOS) inhibitor, reverses stress-induced NLRP3 inflammasome activation in rats. We examined the effects of chronically-administered nitric oxide (NO) pathway modulating drugs on NLRP1/3-mediated neuroinflammatory responses and depressive-like behaviors in chronic unpredictable mild stress (CUMS) depression model of rats. CUMS model was applied to the adult male Sprague-Dawley rats for 6 weeks and the treatments were daily administered via intraperitoneal route in the last 3 weeks of CUMS procedure. Depressive-like behaviors were assessed by sucrose preference and forced swimming tests. The levels of NLRP inflammasome components (NLRP1, NLRP3, ASC, caspase-1 and IL-1β) were investigated in the prefrontal cortex by real time PCR and western blot methods. CUMS-induced depressive-like behaviors were coupled with the overactivation of NLRP1 and NLRP3 inflammasome sensors and increased levels of IL-1β. Depressive-like behaviors were ameliorated by chronic AGM and NOS inhibitor treatments. AGM and other NOS inhibitor treatments were found to be more effective in suppressing NLRP3 and NLRP1, respectively. All inhibitor reagents downregulated inflammasome components and IL-1β. These results suggest that both neuronal NLRP1 and microglial NLRP3 inflammasomes are involved in chronic stress-induced depressive-like behaviors. The antidepressant effects of AGM, iNOS and nNOS inhibitors are associated with the downregulation of CNS inflammasome expression levels. NO-pathway modulating drugs might provide novel therapeutic strategies for depression.

Ginsenoside Rg1 attenuates chronic unpredictable mild stress-induced depressive-like effect via regulating NF-κB/NLRP3 pathway in rats.

Ginsenoside (GS Rg1), which has neuroprotection and anti-inflammation activities, is the main active ingredient of Radix Ginseng. However, its antidepressant-like effect in rats remains unclear. Our study was conducted to investigate whether GS Rg1 confers an antidepressant effect in rats exposed to a chronic unpredictable mild stress model of depression and to explore its possible mechanisms. Our results revealed that GS Rg1 treatments for 3 weeks alleviated the depression-related behaviors of chronic unpredictable mild stress-exposed rats, as indicated by increasing sucrose preference, improving locomotor activity and shortening immobile time in both the forced swimming tests and tail suspension tests. And these ameliorative effects of GS Rg1 treatment were involved with regulating chronic unpredictable mild stress-induced pro-inflammatory cytokine interleukin beta (IL-1β) related neuro-inflammation. In addition, we further found that GS Rg1 reversed chronic unpredictable mild stress-induced IL-1β elevation, possibly by inhibiting nuclear factor kappa B pathway activation and regulating nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 inflammasome expression. In short, our results suggested that GS Rg1 exerted a potential antidepressant-like effect in chronic unpredictable mild stress rat model of depression, which may provide an insight into the potential of GS Rg1 in therapeutic implications for depression.

Deficiency in Androgen Receptor Aggravates the Depressive-Like Behaviors in Chronic Mild Stress Model of Depression.

While androgen receptor (AR) and stress may influence the development of the major depressive disorder (MDD), the detailed relationship, however, remains unclear. Here we found loss of AR accelerated development of depressive-like behaviors in mice under chronic mild stress (CMS). Mechanism dissection indicated that AR might function via altering the expression of miR-204-5p to modulate the brain-derived neurotrophic factor (BDNF) expression to influence the depressive-like behaviors in the mice under the CMS. Adding the antiandrogen flutamide with the stress hormone corticosterone can additively decrease BDNF mRNA in mouse hippocampus mHippoE-14 cells, which can then be reversed via down-regulating the miR-204-5p expression. Importantly, targeting this newly identified AR-mediated miR-204-5p/BDNF/AKT/MAPK signaling with small molecules including 7,8-DHF and fluoxetine, all led to alter the depressive-like behavior in AR knockout mice under CMS exposure. Together, results from these preclinical studies conclude that decreased AR may accelerate the stress-induced MDD via altering miR-204-5p/BDNF/AKT/MAPK signaling, and targeting this newly identified signaling may help in the development of better therapeutic approaches to reduce the development of MDD.

Andrographolide Exerts Significant Antidepressant-Like Effects Involving the Hippocampal BDNF System in Mice.

BackgroundMajor depressive disorder is a worldwide neuropsychiatric disorder associated with various symptoms, but current antidepressants used in clinical practice have various side effects and high failure rates. Andrographolide is the main bioactive ingredient of Andrographis paniculata and exhibits numerous pharmacological actions. This study aimed to evaluate the antidepressant-like effects of andrographolide in male C57BL/6J mice.MethodsThe antidepressant-like effects of andrographolide in mice were explored in a forced swim test, tail suspension test, and chronic unpredictable mild stress model of depression. Western blotting and immunofluorescence were further performed to assess the effects of chronic unpredictable mild stress and andrographolide on the brain-derived neurotrophic factor signalling cascade and hippocampal neurogenesis. Moreover, a pharmacological inhibitor (K252a) and a lentiviral-short hairpin RNA (LV-TrkB-shRNA) were used to clarify the antidepressant-like mechanism of andrographolide.ResultsAndrographolide exhibited antidepressant-like potential in the forced swim test and tail suspension test without influencing the locomotor activity of mice. Repeated andrographolide treatment not only produced significant antidepressant-like effects in the chronic unpredictable mild stress model but also prevented the decreasing effects of chronic unpredictable mild stress on hippocampal brain-derived neurotrophic factor signalling and neurogenesis in mice. Importantly, blockade of the hippocampal brain-derived neurotrophic factor system by K252a and TrkB-shRNA fully abolished the antidepressant-like effects of andrographolide in mice.ConclusionsAndrographolide exerts antidepressant-like effects in mice via promoting the hippocampal brain-derived neurotrophic factor signalling cascade.

Antidepressant-like Effects Induced by Chronic Blockade of the Purinergic 2X7 Receptor through Inhibition of Non-like Receptor Protein 1 Inflammasome in Chronic Unpredictable Mild Stress Model of Depression in Rats.

ObjectivePurinergic 2X7 receptor (P2X7R) activation is known to be involved in pathogenesis of depression. Our aims were to investigate P2X7R-activated inflammasome pathways in parallel with induction of depression and to test the antidepressant-like effects of the selective P2X7R antagonist Brilliant Blue G (BBG) in a rat model of chronic unpredictable mild stress (CUMS).MethodsMale Wistar albino rats were divided into control, CUMS, CUMS+BBG25 (25 mg/kg/day) and CUMS+BBG50 (50 mg/kg/day) groups (n=10 for each group). Various stressors were applied to rats for 6 weeks to establish the CUMS model and daily BBG treatment was started at the end of 3rd week. Sucrose preference test and forced swim test (FST) were performed to assess antidepressant-like effects. Brain samples were obtained for real-time polymerase chain reaction and immunohistochemistry analysis.ResultsIn FST, duration of immobility was reduced in the CUMS+BBG50 group. Also, BBG treatment significantly enhanced sucrose preference. While NLRP3 gene expression levels were unchanged in rats exposed to the CUMS protocol, expression levels of other inflammasome pathway factors NLRP1, caspase-1, ASC, NF-κB, IL-1β, IL-6 and P2X7R were increased. BBG treatment reduced expression levels of these factors. Likewise, Iba-1 and GFAP immunoreactivities were enhanced by the CUMS protocol and this action was reversed by BBG treatment.ConclusionChronic administration of BBG in CUMS model results in antidepressant-like activity in a dose dependent manner. Molecular and histological results show that these effects might be at least partially related to the suppression of inflammasome-related neuroinflammatory responses and suggest involvement of NLRP1 in depression.

Chronic mild stress induces anhedonic behavior and changes in glutamate release, BDNF trafficking and dendrite morphology only in stress vulnerable rats. The rapid restorative action of ketamine

Depression is a debilitating mental disease, characterized by persistent low mood and anhedonia. Stress represents a major environmental risk factor for depression; the complex interaction of stress with genetic factors results in different individual vulnerability or resilience to the disorder. Dysfunctions of the glutamate system have a primary role in depression. Clinical neuroimaging studies have consistently reported alterations in volume and connectivity of cortico-limbic areas, where glutamate neurons and synapses predominate. This is confirmed by preclinical studies in rodents, showing that repeated stress induces morphological and functional maladaptive changes in the same brain regions altered in humans. Confirming the key role of glutamatergic transmission in depression, compelling evidence has shown that the non-competitive NMDA receptor antagonist, ketamine, induces, at sub-anesthetic dose, rapid and sustained antidepressant response in both humans and rodents.We show here that the Chronic Mild Stress model of depression induces, only in stress-vulnerable rats, depressed-like anhedonic behavior, together with impairment of glutamate/GABA presynaptic release, BDNF mRNA trafficking in dendrites and dendritic morphology in hippocampus. Moreover, we show that a single administration of ketamine restores, in 24 h, normal behavior and most of the cellular/molecular maladaptive changes in vulnerable rats. Interestingly, ketamine treatment did not restore BDNF mRNA levels reduced by chronic stress but rescued dendritic trafficking of BDNF mRNA.The present results are consistent with a mechanism of ketamine involving rapid restoration of synaptic homeostasis, through re-equilibration of glutamate/GABA release and dendritic BDNF for synaptic translation and reversal of synaptic and circuitry impairment.

23.1 Gut Microbial Community and Behavioral Changes in a Chronic Mild Stress Model of Depression in Rats

Recent evidence demonstrates that the gut microbiome affects brain function and emotional behavior, suggesting that the microbiome-gut-brain axis may play a pathophysiological role in mental illnesses such as depression. At this time, there are limited studies investigating whether gut microbiome and brain interactions have directional causality. To this end, the current study evaluated time-dependent changes in gut microbial communities in male Sprague-Dawley rats during exposure to 7 weeks of chronic, variable mild stress and evaluated the effects of microbial exposures on mood.

Mesolimbic dopamine system and its modulation by vitamin D in a chronic mild stress model of depression in the rat

Depression, a common mood disorder, involves anhedonia and defects in reward circuits and mesolimbic dopamine transmission in the striatum and nucleus accumbens (NAc). Active vitamin-D, (1,25-(OH)2 vitamin-D3), exerts protective and regulatory effects on the brain dopamine system. In this study, key depression-like symptoms were induced in rats by chronic mild-stress (CMS) and the comparative effect of treatment with 1,25-(OH)2 vitamin-D3 (5, 10 μg/kg, or vehicle; i.p., twice weekly) or fluoxetine (5 mg/kg or vehicle, i.p., daily) on anhedonic behavior, locomotor activity and anxiety-like behavior was examined using sucrose preference test (SPT), open field test (OFT) and novel object exploration test (NOT), respectively. We also measured serum corticosterone levels and dopamine transporter-immunoreactivity (DAT-ir) levels in NAc shell and core. CMS exposure for 3 weeks was followed by a SPT and thereafter CMS was continued for 5 weeks, along with vitamin-D or fluoxetine treatment and further testing, which was concluded with another SPT. Vitamin-D treatment enhanced sucrose preference (P < 0.01; an hedonic effect) and increased object exploration (P < 0.01) in CMS rats. CMS significantly reduced the level of DAT-ir in NAc (P < 0.0001). Vitamin-D treatment restored/increased DAT-ir levels (P < 0.0001) in CMS rat NAc (core/ shell), compared to levels in fluoxetine treated and non-treated CMS rats. Vitamin-D did not alter locomotor activity or produce an anxiolytic effect in the OFT. These data suggest that similar to the antidepressant, fluoxetine, regular vitamin-D treatment can improve ‘anhedonia-like symptoms’ in rats subjected to CMS, probably by regulating the effect of dopamine-related actions in the NAc.

Effect of Vitamin D on Hippocampus Brain-Derived Neurotrophic Factor Level in Chronic Mild Stress Model of Depression in Rats

Background: Depression is one the most prevalent diseases. It is believed that the level of Brain Derived Neurotropic Factor (BDNF (protein is reduced in the hippocampus of depressed patients and animal models of depression. Antidepressants, such as serotonin reuptake inhibitors, increase BDNF levels in the brain. The present study investigated the effect of vitamin D, a possible drug for depression treatment, on BDNF levels in the hippocampus in a rat model of depression. Methods and Materials: Male Wistar rats (n = 42,180 to 200g) were undergone a series of Chronic Mild Stressful (CMS) procedures on a daily bases for 3 weeks and after approval of their depression by Sucrose Preference Test (SPT), they were divided to 5 groups (n = 6); two received vitamin D treatment with either 5 or 10 microgram/kg; one, vehicle of vitamin D; one, antidepressant fluoxetine 5mg/kg, and the other group did not receive any treatment for 5 weeks. In parallel, there were 3 control non-CMS groups; one treated with vitamin D, the other with fluoxetine, and the last one without any treatment. At the end of the 8-week experiment, SPT was repeated, the hippocampus was extracted, and BDNF protein was assayed using the Enzyme Linked Immunosorbent Assay (ELISA). Results: The SPT at the end of 3 weeks of CMS revealed a significant difference (P < 0.0001) in sucrose preference to water between the CMS treated (mean ± SEM, 35.18 ± 4.86) and non-CMS treated group (82.72 ± 5.73), showing the induction of depression by the CMS procedure. Treatment with vitamin D and fluoxetine improved SPT in CMS-treated rats to the level of control rats (CMS, 33.43 ± 6.26 versus vit D treated 68.78 ± 5.07, P < 0.001; CMS versus fluoxetine treated 87.19 ± 3.62, P < 0.001). The BDNF levels did not show any change in depressed versus non-depressed rats (P = 0.12). Neither vitamin D nor fluoxetine could change BDNF levels in depressed rats, though fluoxetine significantly increased protein in non-depressed rats (P < 0.0001). Conclusion: The current study showed that vitamin D did not affect BDNF protein level in the hippocampus of the depressed animals, suggesting that vitamin D could alleviate the symptoms of depression via BDNF-independent mechanisms.

Matrine Exerts Antidepressant-Like Effects on Mice: Role of the Hippocampal PI3K/Akt/mTOR Signaling.

BackgroundCurrent antidepressants in clinical use always take weeks or even months to exert full therapeutic effects, and sometimes have serious side effects. Thus, it is very necessary to develop novel antidepressants with better efficacy and fewer adverse effects. The present study focused on investigating the antidepressant potential of matrine and its possible mechanisms of action.MethodsThe forced swim test, tail suspension test, and chronic unpredictable mild stress model of depression were used to reveal the antidepressant-like effects of matrine on mice. Western blotting, immunohistochemistry, and lentivirus were further used together to explore the antidepressant mechanism of matrine.ResultsIt was found that matrine exhibited significant antidepressant actions in the forced swim test and tail suspension test without affecting the locomotor activity of mice. Chronic matrine administration fully reversed the chronic unpredictable mild stress-induced depressive-like symptoms in forced swim test, tail suspension test, and sucrose preference test. After that, western blotting analysis revealed that chronic matrine treatment restored the decreasing effects of chronic unpredictable mild stress on the PI3K/Akt/mammalian target of rapamycin signaling in hippocampus, but not prefrontal cortex. Furthermore, pharmacological and genetic blockade of the PI3K/Akt/mammalian target of rapamycin signaling in hippocampus abolished the antidepressant actions of matrine on mice.ConclusionsTaken together, matrine produces antidepressant-like effects on mice via promoting the hippocampal PI3K/Akt/ mammalian target of rapamycin signaling.

Differential microstructural alterations in rat cerebral cortex in a model of chronic mild stress depression.

Chronic mild stress leads to depression in many cases and is linked to several debilitating diseases including mental disorders. Recently, neuronal tracing techniques, stereology, and immunohistochemistry have revealed persistent and significant microstructural alterations in the hippocampus, hypothalamus, prefrontal cortex, and amygdala, which form an interconnected system known as the stress circuit. Most studies have focused only on this circuit, however, some studies indicate that manipulation of sensory and motor systems may impact genesis and therapy of mood disorders and therefore these areas should not be neglected in the study of brain microstructure alterations in response to stress and depression. For this reason, we explore the microstructural alterations in different cortical regions in a chronic mild stress model of depression. The study employs ex-vivo diffusion MRI (d-MRI) to assess cortical microstructure in stressed (anhedonic and resilient) and control animals. MRI is followed by immunohistochemistry to substantiate the d-MRI findings. We find significantly lower extracellular diffusivity in auditory cortex (AC) of stress groups and a significantly higher fractional anisotropy in the resilient group. Neurite density was not found to be significantly higher in any cortical ROIs in the stress group compared to control, although axonal density is higher in the stress groups. We also report significant thinning of motor cortex (MC) in both stress groups. This is in agreement with recent clinical and preclinical studies on depression and similar disorders where significant microstructural and metabolic alterations were found in AC and MC. Our findings provide further evidence that the AC and MC are sensitive towards stress exposure and may extend our understanding of the microstructural effects of stress beyond the stress circuit of the brain. Progress in this field may provide new avenues of research to help in diagnosis and treatment intervention for depression and related disorders.

The Effect of Chronic Treatment with Lurasidone on Rat Liver Cytochrome P450 Expression and Activity in the Chronic Mild Stress Model of Depression.

Recent studies indicated an important role of the monoaminergic nervous systems (dopaminergic, noradrenergic, and serotonergic systems) and stress in the regulation of cytochrome P450 (CYP) expression and activity in the liver. The aim of our present research was to determine the effect of the novel atypical neuroleptic drug with antidepressant properties lurasidone, on the expression (mRNA and protein level) and activity of liver CYP isoforms involved in the metabolism of drugs and endogenous steroids, in the chronic mild stress (CMS) model of depression. Male Wistar rats were subjected to CMS for 7 weeks. Lurasidone (3 mg/kg per os per day) was administered to nonstressed or stressed animals for 5 weeks (weeks 3-7 of CMS). It has been found that 1) CMS moderately affects CYP (CYP2B, CYP2C11, and CYP3A), and its effects are different from those observed after other kinds of psychologic stress, such as repeated restraint stress or early-life maternal deprivation; 2) chronic lurasidone influences the expression and/or activity of CYP2B, CYP2C11, and CYP3A isoforms; and 3) CMS modifies the action of lurasidone on CYP expression and function, leading to different effects of the neuroleptic in nonstressed and stressed rats. Based on the obtained results, it can be suggested that the metabolism of endogenous substrates (e.g., steroids) and drugs, catalyzed by the isoforms CYP2B, CYP2C11, or CYP3A, may proceed at a different rate in the two groups of animals (nonstressed and stressed) in the rat CMS model.

Re-evaluation of the interrelationships among the behavioral tests in rats exposed to chronic unpredictable mild stress.

The chronic unpredictable mild stress model of depression has been widely used as an experimental tool to investigate human psychopathology. Our objective was to provide an update on the validity and reliability of the chronic unpredictable mild stress model, by analyzing the interrelationships among the indexes using stepwise discriminant analysis and Pearson correlation coefficient to examine the possible combinations. We evaluated the depressive rats in both the presence and the absence of chronic unpredictable mild stress, using weight change, percentage of sucrose preference, coat state, splash test, open-field test, elevated plus-maze test, forced swimming test, and Morris water maze test. The results showed that 6-week-long chronic unpredictable mild stress produces significant depression and anxiety-like behavior. The combination of body weight change, percentage of sucrose preference, coat state score, open-field score, grooming latency of splash test, immobility time in force swimming test, and platform crossing in the Morris water maze test can effectively discriminate between normal and chronic unpredictable mild stress rats. Strong interrelationships were noted among these indexes in both open-field test and elevated plus-maze test. In conclusion, there might be certain criteria for the combination of behavioral endpoints, which is advantageous to more effectively and reliably assess the chronic unpredictable mild stress induced depression model.

Antidepressant-like effects of ginsenoside Rg2 in a chronic mild stress model of depression.

Major depression is a common neuropsychiatric disease with high lifetime prevalence and high incidence of suicide. This study aimed to evaluate the antidepressant effects of ginsenoside Rg2 in mice, and the possible mechanism was also determined. A single injection of both Rg2 (10 and 20mg/kg) and fluoxetine (positive control, 20mg/kg) induced notable antidepressant-like effects in the forced swim test and tail suspension test without affecting the locomotor activity of mice, and the tests were done 30min after the injection. Also, repeated daily treatment of Rg2 and fluoxetine for the last 2 weeks fully reversed the chronic mild stress (6 weeks)-induced depressive-like symptoms in mice. Moreover, western blot analysis showed that Rg2 administration significantly increased the BDNF signaling pathway in hippocampus. Importantly, the usage of TrkB shRNA fully blocked the antidepressant effects of Rg2 in mice. Collectively, these results suggest that Rg2 produces an antidepressant-like effect in mice which is mediated, at least in part, through promoting the hippocampal BDNF signaling pathway.

Fluoxetine coupled with zinc in a chronic mild stress model of depression: Providing a reservoir for optimum zinc signaling and neuronal remodeling

BackgroundRecently, depression has been envisioned as more than an alteration in neurotransmitters centered around receptor signaling pathways. Consequently, the precise mechanisms of selective serotonin reuptake inhibitor (SSRI) antidepressant drugs such as fluoxetine are being revisited. Zinc is a trace element that has been long implicated in the psychopathology and therapy of depression. Zinc has been found to be sequestered and dispensed during stress and inflammation through a family of proteins called metallothioneins (MTs). In addition, MTs are well known for their antioxidant and therefore cytoprotective action. Changes in MTs, their upstream regulators and downstream effectors in response to fluoxetine have not been yet studied. The aim of the present study is to examine whether depression-induced changes in protein levels and mRNA levels of nuclear factor-erythroid 2-related factor 2 (Nrf2), MTs, antioxidant defensive enzyme heme oxygenase (HO-1), zinc-specific receptor GPR39 and brain derived neurotrophic factor (BDNF) in the hippocampus can be reversed by fluoxetine treatment, zinc supplementation or a combination of the two. Material and methodsThe present study investigated the effect of chronic (4weeks) combined treatment with zinc hydroaspartate (15mg/kg) and fluoxetine (10mg/kg) on a chronic mild stress model (CMS) in male Sprague–Dawley rats. ResultsHippocampal mRNA and protein levels of Nrf2, HO-1, MTs, GPR39 (protein level only) and BDNF were significantly higher in response to a combined therapy of fluoxetine and zinc than to either monotherapy. Additionally, HO-1 and MTs gene expression was correlated with that of Nrf2 in the FLX-only group. ConclusionFluoxetine therapy activated the expression of MTs and HO-1 through an Nrf2-dependent pathway. When FLX was escorted by zinc, activated MTs had a positive impact on BDNF through the zinc signaling receptor GPR39, resulting in general improvement in neuronal plasticity as well as reduction of neuronal atrophy and neuronal cell loss.