Chronic Unpredictable Stress In Rats Research Articles

Higenamine exerts antidepressant effect by improving the astrocytic gap junctions and inflammatory response

BackgroundDepression is a refractory psychiatric disorder closely associated with dysfunction of the gap junctions (GJs) between astrocytes as well as neuroinflammation. Higenamine (Hig) is a potent cardiotonic ingredient in Fuzi (i.e., Aconitum carmichaeli Debx.) with anti-inflammatory and antioxidant effects, which has a significant protective effect on damaged nerve cells and has great potential for the treatment of neuropsychiatric diseases. MethodsRats were stimulated by chronic unpredictable stress (CUS) for 28 days while given Hig (5, 10, 20 mg/kg) and then analyzed behaviorally by the open field test, sucrose preference test, and forced swimming test. Changes in astrocyte GJs function and morphology were observed by dye transfer and transmission electron microscopy, respectively. Expression and phosphorylation of connexin 43 (Cx43) were analyzed by Western blot. Also, considering the close relationship between depression and neuroinflammation, we determined the inflammatory response in serum with ELISA kits and analyzed the expression of inflammation-related proteins with Western blot. ResultsHig ameliorated CUS-induced depression-like behavior in rats. Hig administration improved gap junctional dysfunction in astrocytes, reduced gap junctional gaps and elevated the expression of Cx43 and decreased the phosphorylation of Cx43. Meanwhile, Hig administration was also able to attenuate the inflammatory response that occurs after CUS in rats. LimitationsFor the role of Cx43 in depression, we did not validate it more deeply in animal models with knockout Cx43. In addition, GJs dysfunction might be associated with the inflammatory response seen in depression, but this needs to be further investigated. ConclusionsHig ameliorates depression and exerts its antidepressant effect possibly by improving the dysfunctional GJs between astrocytes and the inflammatory response.

Establishment of insomnia model of chronic unpredictable stress in rats

It is well known that stressful situation is one of the important factors causing insomnia, however, the underlying mechanism is still elusive. Therefore, the establishment of a suitable animal model of stress insomnia will be of great help to solve this problem. In this study, by combining with chronic unpredictable stress (multitude of stressors) and sleep deprivation, we attempted to establish a rat model of stress insomnia. It was observed that rats with stress insomnia showed significant weight loss, and less sleep quality in pentobarbital sodium induced sleep test and electroencephalogram detection. Moreover, rats with stress insomnia showed greater depression and anxiety detected by forced swimming, sucrose preference test and open field. Since oxidative stress has been reported to be involved in insomnia, we further evaluated the production of oxidative stress and found that the levels of lipid peroxidation product malondialdehyde (MDA) in liver, serum total bilirubin and urine biopyrrin were all significantly increased in rats with stress insomnia. In addition, we also found that the memory of these rats with stress insomnia was also obviously reduced in water maze. Taken together, these results demonstrate that the emotional behaviors, memory, oxidative and metabolism of the rats were all significantly changed after modeling, indicating a rat model of stress insomnia was successful establishment, and this animal model will provide basis to further explore the underlying mechanism of chronic stress in insomnia.

Study on effect of ethanolic extract of triticum aestivum in anxiety behaviour induced by chronic unpredictable stress in a rat model

Objectives- This study was undertaken to evaluate the effect of Ethanolic extract of Triticum aestivum (TAE) on different anxiety like behaviour induced by Chronic unpredictable stress in wistar albino rats. Materials and methods- Effect of TAE was studied on chronic unpredictable stress induced rats. The reference standard drug (Diazepam 1mg/kg po) and the test drug, TAE at doses of 150mg/kg and 200mg/kg b.w. were given to rats for 14 days. Anti-anxiety activity was assessed by using Light and Dark Box test. Then the locomotor activity of rats was assessed as indicator of anxiety. Animals were sacrificed at the end of this experiment..The adrenal and spleen weight, ulcer index as well as various biochemical parameters like Malondialdehyde (MDA) and Superoxide dismutase (SOD) were assessed. Results- The stay in Light box was increased, rearing activity was increased to a significant level in both Diazepam and TAE-200 mg/kg treated rats and this effect was comparable to that of normal non-stressed vehicle treated rats. Chronic stress caused elevation of MDA and depression of SOD level which is reversed by Ethanolic extract of Triticum aestivum (TAE).

Beneficial effects of Dendrobium nobile Lindl. Alkaloids (DNLA) on anxiety and depression induced by chronic unpredictable stress in rats

Dendrobium nobile Lindl. alkaloid (DNLA) is effective against animal models of Alzheimer's disease. This study further examined its effect on anxiety and depression produced by chronic unpredictable stress (CUS). Rats were subjected to CUS for 42 days, followed by DNLA treatment (20 mg/kg/day, po) for 28 days. The behavioral tests, histopathology, neurotransmitters and RNA-Seq were examined. DNLA attenuated body weight loss and CUS-induced anxiety/depressive-like behaviors, as evidenced by the elevated-plus-maze test, open-field test and sucrose preference. DNLA alleviated neuronal damage and loss and increased Nissl bodies in the hippocampus CA2 region and cortex. DNLA decreased CUS-elevated 5-hydroxytryptamine, dopamine and monoamine oxidase and catechol-O-methyltransferase activities in the brain. DNLA attenuated HPA activation by decreasing adrenocorticotropic hormones and the expression of corticotropin-releasing hormone receptor-1, and increased the expression of glucocorticoid receptor in the brain. RNA-Seq revealed distinct gene expression patterns among groups. Gene ontology revealed the cell projection assembly, postsynapse and centrosome as top biological processes, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment showed the cAMP, cGMP-PKG, glutamatergic synapse and circadian as major pathways for DNLA effects. Using DESeq2, CUS modulated 1700 differentially expressed genes (DEGs), which were prevented or attenuated by DNLA. CUS-induced DEGs were highly correlated with the Gene Expression Omnibus (GEO) database for anxiety and depression and were ameliorated by DNLA. Taken together, DNLA attenuated anxiety/depression-like behavior and neuronal damage induced by CUS in rats. The mechanisms could be related to regulation of the monoamine neurotransmitters and the HPA axis, and modulation of gene expression in the hippocampus.

GW117: A novel serotonin (5-HT2C ) receptor antagonist and melatonin (MT1 /MT2 ) receptor agonist with potential antidepressant-like activity in rodents.

AimsTo evaluate the antidepressant‐like effect of compound GW117 in rodents using in vitro binding and uptake assays as well in vivo behavioral tests.MethodsWe investigated the target profile of GW117 using [35S]‐GTPγS and [3H]PIP binding. Using the forced swimming test and chronic unpredictable stress in rats, tail suspension test in mice and rats, and learned helplessness model in mice, we further revealed the antidepressant‐like and anxiolytic‐like effects of GW117.ResultsThe current study suggests that GW117 displays serotonin 2C (5‐HT2C) receptor antagonist and melatonin type 1 and 2 (MT1/MT2) receptor agonist properties, as well as evident antidepressant and anxiolytic effects.ConclusionThese data suggest that GW117 is probably a potent antidepressant.

RAGE Signaling pathway in hippocampus dentate gyrus involved in GLT-1 decrease induced by chronic unpredictable stress in rats

A pivotal role of glutamatergic neurotransmission in the pathophysiology of major depressive disorder (MDD) has been supported in preclinical and clinical studies. Glutamate transporters are responsible for rapid uptake of glutamate to maintain glutamate homeostasis. Down-regulation of glutamate transporters has been reported in MDD patients and animal models. However, the mechanism for stress-induced modulation of glutamate transporter expression is poorly understood. Receptor for advanced glycosylation end products (RAGE), a member of immunoglobulin family, is found expressed widely in brain and play important roles in neuronal development, neurite growth, neurogenesis and neuroinflammation. Our study showed chronic unpredictable stress (CUS) induced depressive-like behaviors and reduced RAGE expression in hippocampus DG, CA1 and CA3 areas. The protein levels of GLT-1, p-CREB and p-p65 decreased in hippocampus DG as well. Knockdown of RAGE expression in hippocampus DG with RAGE shRNA lentivirus particles induced depressive-like behaviors. Meanwhile, the protein and mRNA levels of GLT-1 were significantly decreased as well as phosphorylation of CREB and p65. Neither CUS nor RAGE knockdown altered GLAST protein and mRNA levels. These findings suggested that RAGE/CREB-NF-κB signaling pathway in hippocampus DG involved in modulation of GLT-1 expression, which possibly contributed to the depressive-like behavior induced by CUS.

Behavior of Rats in a Forced Swimming Test Is Not an Unambiguous Predictor for the Development of Anhedonia in Chronic Stress

Anhedonia is one of the central features of the development of depression. Chronic stress leads to the development of depression-like behavior in experimental animals, which in particular is expressed as impairments to the consumption of and/or preference for tasty meals or drinks, i.e., anhedonia. We report here studies of the development of chronic unpredictable stress-induced anhedonia in animals previously separated into groups on the basis of activity in the forced swimming test. Anhedonia was assessed weekly in terms of the level of consumption and at the end of the experiment in terms of the preference for sucrose solution. Chronic unpredictable stress in rats led to the development of anhedonia, apparent as a decrease in the preference for sucrose solution. The link between the animals’ initial behavior in the forced swimming test and the development of anhedonia was not straightforward. Despite the fact that the probability of developing anhedonia was higher in rats with initially higher levels of activity in the forced swimming test (assessed in terms of the number of animals demonstrating anhedonia), groups of animals resistant and sensitive to chronic stress as assessed in terms of anhedonia showed no significant differences in their initial behavioral characteristics in the forced swimming test.

Ovarian failure induced by 4-vinylcyclohexene diepoxide worsens the autonomic cardiovascular response to chronic unpredictable stress in rats

AimsAfter menopause, women are more responsive to stress and more prone to exhibit hypertension, which elevates the risk of cardiac diseases. This vulnerability is due, in part, to the decline of ovarian steroids plasma levels. The 4-vinylciclohexane diepoxide (VCD) causes a gradual depletion of ovarian follicles causing loss of the normal ovarian function and a hormonal profile comparable to menopause in humans. We aimed to verify whether the ovarian failure (OF) worsens the cardiovascular autonomic response to stress. Main methodsRats were treated with VCD (160 mg/kg) or oil for 15 days, exposed to chronic unpredictable stress (CUS) for 10 days and studied 80 and 180 days after VCD treatment. Key findings80 days after VCD-treatment, stressed rats showed increased sympathetic nerve activity, reduced parasympathetic activity and an increase in the overall spontaneous baroreflex sensitivity (BRS). 180 days after VCD treatment, BRS was impaired and the vascular sympathetic activity was increased, independently of stress exposure. SignificanceNeither 80 nor 180 days after the onset of VCD-treatment the hypertensive effects of stress were enhanced in rats. However, OF led to a worsening on different aspects of the cardiovascular response to stress, which can cause cardiovascular complications when associated with ovarian aging.

The anxiolytic-like effects of ginsenoside Rg3 on chronic unpredictable stress in rats

The present study is to evaluate the anxiolytic-like activities underlying ginsenoside Rg3 (GRg3). The anxiolytic-like activities were induced by GRg3 (20 and 40 mg/kg, i.g), evidenced by blocking the decreased time and entries in the open arms in elevated plus maze test and by reversing the increased latency to feed in novelty-suppressed feeding test. In addition, the decreased levels on progesterone, allopregnanolone, serotonin (5-HT) in the prefrontal cortex and hippocampus of chronic unpredictable stress (CUS) were blocked by GRg3 (20 and 40 mg/kg, i.g). Furthermore, the increased corticotropin releasing hormone, corticosterone and adrenocorticotropic hormone were blocked by GRg3 (20 and 40 mg/kg, i.g). Collectively, the anxiolytic-like effects produced by GRg3 were associated with the normalization of neurosteroids biosynthesis, serotonergic system as well as HPA axis dysfunction.

Up-regulation of GluR1 in paraventricular nucleus and greater expressions of synapse related proteins in the hypothalamus of chronic unpredictable stress-induced depressive rats

Converging evidence indicates that abnormal glutamatergic and synaptic systems may be associated with the pathophysiology of depression. Over-activation of corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) plays a key role in the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity and is a prominent feature in depression. In this study, we examined the effect of chronic unpredictable stress (CUS) in rats on the expression of AMPA subunit GluR1 protein in the hypothalamic PVN as well as on the expression of GluR1 and several synapse-related proteins in the hypothalamus. We found that CUS in rats induced CRH over-expression accompanied by significant GluR1 up-regulation in the hypothalamic PVN and GluR1 co-localized with CRH in the PVN area. The expression of GluR1 and three synapse-related proteins (PSD95, SYP and MAP2) in the hypothalamus were also increased at both mRNA and protein levels in CUS rats. Correlation analysis showed that the levels of the above proteins are directly correlated with depression-like behaviors of rats in sucrose preference test, open field test and forced swim test. These findings suggest that the augmented glutamatergic and synaptic signaling might be a potential mechanism underlying CRH over-activation in the hypothalamic PVN and contribute to CUS-induced depression-like behaviors in rats.

Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviors

BackgroundIn recent years, proinflammatory cytokine interleukin-1β (IL-1β) was considered to play a critical role in the pathogenesis of depression. In addition, P2X7 receptor (P2X7R), a member of the purinergic receptor family, which is predominantly present on microglia, as well as on astrocytes and neurons in lesser amounts in the central nervous system, was suggested to be involved in the processing and releasing of IL-1β. Here, we investigated the role of P2X7R in the pathogenesis of depression.MethodsMale Sprague-Dawley rats were subjected to chronic unpredictable stressors (CUS) for 3 weeks. At the end of week 1, 2, and 3, extracellular ATP, caspase 1, IL-1β, and components and activation of NLRP3 inflammasome (nucleotide-binding, leucine-rich repeat, pyrin domain containing 3) were evaluated as biomarker of neuroinflammation. In separate experiments, the rats were microinjected with P2X7R agonists ATP, BzATP, and saline into the hippocampus, respectively, or exposed to CUS combined with hippocampal microinjection with P2X7R antagonist, BBG and A438079, and saline, respectively, for 3 weeks, followed by exposed to forced swimming test and open-field test. Moreover, we also evaluated the depressive and anxiety-like behavior of P2X7-null mice in forced swimming test, open-field test, and elevated plus maze.ResultsAlong with stress accumulation, extracellular ATP, cleaved-caspase 1, IL-1β, and ASC were significantly enhanced in the hippocampus, but P2X7R and NLRP3 were not. Immunoprecipitation assay indicated that along with the accumulation of stress, assembly of NLRP3 inflammasome and cleaved caspase 1 in NLRP3 inflammasome were significantly increased. Moreover, antagonists of P2X7R, either BBG or A438079, prevented the development of depressive-like behaviors induced by chronic unpredictable stress in rats. Meanwhile, we could not observe any depressive-like or anxiety-like behaviors of P2X7-null mice after they had been exposed to CUS. The results implied that P2X7 knockout could impede the development of depressive-like and anxiety-like behaviors induced by CUS. In contrast, chronic administration of agonists of P2X7R, either ATP or BzATP, could induce depressive-like behaviors.ConclusionsThe activation of P2X7R and subsequent NLRP3 inflammasome in hippocampal microglial cells could mediate depressive-like behaviors, which suggests a new therapeutic target for the prevention and treatment of depression.

CAMP/PKA/CREB/GLT1 signaling involved in the antidepressant-like effects of phosphodiesterase 4D inhibitor (GEBR-7b) in rats.

ObjectivesGEBR-7b, a potential phosphodiesterase 4D inhibitor, has been shown to have memory-enhancing effects in rodents. However, it is still unknown whether GEBR-7b also has the antidepressant-like effects in rats. Herein, we examined the potential of GEBR-7b to attenuate depression-like behaviors in the rat model of depression induced by chronic unpredictable stress (CUS). Next, we also investigated the alterations of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA) catalytic subunit (PKAca), cAMP response element-binding (CREB), and glutamate transporter 1 (GLT1) levels produced by GEBR-7b in the rats model of depression.MethodsEffects of GEBR-7b on CUS (35 days)-induced depression-like behaviors were examined by measuring immobility time in the forced swimming test (FST). Hippocampal cAMP levels were examined by enzyme-linked immunosorbent assay, whereas PKAca, phosphorylation of CREB (pCREB), CREB, and GLT1 in the hippocampus of rats were subjected to Western blot analysis.ResultsCUS exposure caused a depression-like behavior evidenced by the increased immobility time in FST. Depression-like behavior induced by CUS was accompanied by a significant increased GLT, decreased cAMP, PKAca, pCREB activities in hippocampus. However, repeated GEBR-7b administration significantly reversed CUS-induced depression-like behavior and changes of cAMP/PKA/CREB/GLT1 signaling. No alteration was observed in locomotor activity in open field test.ConclusionThese findings indicate that GEBR-7b reversed the depression-like behaviors induced by CUS in rats, which is at least in part mediated by modulating cAMP, PKAca, pCREB, and GLT1 levels in the hippocampus of rats, supporting its neuroprotective potential against behavioral and biochemical dysfunctions induced by CUS.

SIRT2 is involved in the modulation of depressive behaviors.

Exposure to chronic stress produces negative effects on mood and hippocampus-dependent memory formation. SIRT2 alteration has been reported in mood disorders; however, the role of SIRT2 in depression remains unclear. Therefore, we aimed to determine whether SIRT2 can restore stress-induced suppression of neurogenesis in a rat chronic unpredictable stress (CUS) model of depression. Sucrose preference test, home-cage locomotion, forced swim test, and elevated plus maze were used to determine the role of SIRT2 in CUS model. To further determine the hippocampal neurogenesis contributes to the role of SIRT in mediating the antidepressant-like behavior, rats were exposed to X-irradiation to disrupt the process of hippocampal neurogenesis. CUS decreased expression of the SIRT2 protein in the hippocampus. Treatment with the antidepressant fluoxetine reversed the CUS-induced SIRT2 change. Furthermore, inhibiting SIRT2 by tenovin-D3 resulted in depression-like behaviors and impaired hippocampal neurogenesis in rats. Conversely, overexpression of SIRT2 by the intra-hippocampal infusion of recombinant adenovirus vector expressing mouse SIRT2 reversed the CUS-induced depressive-like behaviors, and promoted neurogenesis. Disrupting neurogenesis in the dentate gyrus by X-irradiation abolished the antidepressant-like effect of Ad-SIRT2-GFP. These findings indicate that hippocampal SIRT2 is involved in the modulation of depressant-like behaviors, possibly by regulating neurogenesis.

BICC1 expression is elevated in depressed subjects and contributes to depressive behavior in rodents.

Major depressive disorder (MDD) is a debilitating and widespread illness that exerts significant personal and socioeconomic consequences. Recent genetic and brain-imaging studies suggest that bicaudal C homolog 1 gene (BICC1), which codes for an RNA-binding protein, may be associated with depression. Here, we show that BICC1 mRNA is upregulated in the dorsolateral prefrontal cortex and dentate gyrus of human postmortem MDD patients. We also show that BICC1 is increased in the prefrontal cortex and hippocampus in the rat chronic unpredictable stress (CUS) model of depression. In addition, we show in vivo that a single acute antidepressant dose of ketamine leads to a rapid decrease of BICC1 mRNA, while in vitro, we show that this is likely due to neuronal activity-induced downregulation of BICC1. Finally, we show that BICC1 knockdown in the hippocampus protects rats from CUS-induced anhedonia. Taken together, these findings identify a role for increased levels of BICC1 in the pathophysiology of depressive behavior.

Exercise prevents raphe nucleus mitochondrial overactivity in a rat depression model

Monoamine deficit and mitochondrial dysfunction may underlie depression. Serotoninergic neurons from raphe nuclei project widely and may be involved in depression. This study used chronic unpredictable stress (CUS) in rats as a model of depression to assess the effects of CUS, exercise and fluoxetine on mitochondrial function and serotonin levels in the raphe nuclei. Rats were divided into 4 groups (6 per group): control (C); depression (D), CUS for 28days; depression+exercise (DE), treadmill exercises from days 11–28 of CUS; depression+fluoxetine (DF), fluoxetine (5mg/kg/d i.g.) from days 11 to 28 of CUS. Behavioral changes were assessed using body weight, sucrose consumption tests (anhedonia) and open field tests (locomotor/exploratory behavior). Raphe nucleus mitochondrial function was determined using the respiratory control ratio, ATP synthesis rate, and activities of superoxide dismutase and glutathione peroxidase. Serotonin levels were measured in the raphe nuclei and hippocampus. On day 28 of CUS, body weight was higher in group C than in groups D, DE and DF (P<0.001), and higher in group DE than in group D or DF (P<0.05). Sucrose consumption was higher in group C than in groups D, DE and DF (P<0.001), higher in group DE than in groups D (P<0.001) or DF (P<0.05), and higher in group DF than in group D (P<0.05). All measures of mitochondrial function were increased in group D compared with the other groups (P<0.01). Hippocampal serotonin was lower in group D than in the other groups (P<0.01); levels in the raphe nuclei were elevated in group DE compared with the remaining groups (P<0.001). CUS in rats may cause overactivation of the mitochondria in the raphe nuclei, and exercise training may suppress these changes.

Chronic unpredictable stress regulates visceral adipocyte-mediated glucose metabolism and inflammatory circuits in male rats

Chronic psychological stress is a prominent risk factor involved in the pathogenesis of many complex diseases, including major depression, obesity, and type II diabetes. Visceral adipose tissue is a key endocrine organ involved in the regulation of insulin action and an important component in the development of insulin resistance. Here, we examined for the first time the changes on visceral adipose tissue physiology and on adipocyte‐associated insulin sensitivity and function after chronic unpredictable stress in rats. Male rats were subjected to chronic unpredictable stress for 35 days. Total body and visceral fat was measured. Cytokines and activated intracellular kinase levels were determined using high‐throughput multiplex assays. Adipocyte function was assessed via tritiated glucose uptake assay. Stressed rats showed no weight gain, and their fat/lean mass ratio increased dramatically compared to control animals. Stressed rats had significantly higher mesenteric fat content and epididymal fat pad weight and demonstrated reduced serum glucose clearing capacity following glucose challenge. Alterations in fat depot size were mainly due to changes in adipocyte numbers and not size. High‐throughput molecular screening in adipocytes isolated from stressed rats revealed activation of intracellular inflammatory, glucose metabolism, and MAPK networks compared to controls, as well as significantly reduced glucose uptake capacity in response to insulin stimulation. Our study identifies the adipocyte as a key regulator of the effects of chronic stress on insulin resistance, and glucose metabolism, with important ramifications in the pathophysiology of several stress‐related disease states.

MGluR2/3 blockade produces rapid and long-lasting reversal of anhedonia caused by chronic stress exposure.

BackgroundDepression is a prevalent neuropsychiatric disorder that affects an estimated 350 million people worldwide. Currently available treatments for depression are lacking in both speed of onset and efficacy. Recent pharmacological efforts have targeted the glutamatergic neurotransmitter system using the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine to produce rapid and robust antidepressant effects, however the widespread clinical use of ketamine is limited due to side effects and abuse liability. More recently, work evaluating metabotropic mGluR2/3 receptor antagonists has demonstrated many similarities with ketamine.MethodsMale, Sprague–Dawley rats were exposed to a chronic unpredictable stress paradigm, which produces decreased sucrose preference, a measure of anhedonia. Rats were then treated with vehicle or a single injection of the mGluR2/3 antagonist LY341495 (3 mg/kg, i.p.) and tested at 24 hrs, 48 hrs or 10 days after a single treatment.ResultsWe demonstrate that a single treatment with LY341495 produces a rapid (within 1–2 days) and long-lasting (10 days) reversal of anhedonia caused by chronic unpredictable stress in rats. This model provides a rigorous test of rapid-acting agents as typical antidepressants require several weeks of treatment to produce a response.ConclusionsThese data suggest that LY341495 has the ability to produce rapid and robust antidepressant effects similar to ketamine. Together, the results highlight the potential for similar compounds to produce rapid and lasting efficacy for the treatment of depression.

Leptin restores adult hippocampal neurogenesis in a chronic unpredictable stress model of depression and reverses glucocorticoid-induced inhibition of GSK-3β/β-catenin signaling

Stress and glucocorticoid stress hormones inhibit neurogenesis, whereas antidepressants increase neurogenesis and block stress-induced decrease of neurogenesis. Our previous studies have shown leptin, an adipocyte-derived hormone with antidepressant-like properties 1, promotes baseline neurogenesis in the adult hippocampus 2. The present study aimed to determine whether leptin is able to restore stress-induced suppression of neurogenesis in a rat chronic unpredictable stress (CUS) model of depression. Chronic treatment with leptin reversed the CUS-induced reduction of hippocampal neurogenesis and depression-like behaviors. Leptin treatment elicited delayed long-lasting antidepressant-like effects in the behavioral despair test, and this effect was blocked by ablation of neurogenesis with X-irradiation. The functional isoform of the leptin receptor, LepRb, and the glucocorticoid receptor (GR) were colocalized in hippocampal neural stem/progenitor cells in vivo and in vitro. Leptin treatment reversed the GR agonist dexamethasone (DEX)-induced reduction of proliferation of cultured neural stem/progenitor cells from adult hippocampus. Further mechanistic analysis revealed that leptin and DEX converged on GSK3β and β-catenin. DEX decreased Ser9 phosphorylation and increased Tyr216 phosphorylation of GSK3β, while leptin increased Ser9 phosphorylation and attenuated the effects of DEX at both Ser9 and Tyr216 phosphorylation sites of GSK3β. Moreover, leptin increased total level and nuclear translocation of β-catenin, a primary substrate of GSK3 β and a key regulator in controlling neural progenitor proliferation, and reversed the inhibitory effects of DEX on β-catenin. Together, our results suggest that adult neurogenesis is involved in the delayed long-lasting antidepressant-like behavioral effects of leptin, and leptin treatment counteracts chronic stress and glucocorticoid-induced suppression of hippocampal neurogenesis via activating the GSK3β/β-catenin signaling pathway.

Regional alterations in the endocannabinoid system in an animal model of depression: effects of concurrent antidepressant treatment

It has been suggested that disturbances in endocannabinoid signaling contribute to the development of depressive illness; however, at present there is insufficient evidence to allow for a full understanding of this role. To further this understanding, we performed an analysis of the endocannabinoid system in an animal model of depression. Male rats exposed to chronic, unpredictable stress (CUS) for 21 days exhibited a reduction in sexual motivation, consistent with the hypothesis that CUS in rats induces depression-like symptoms. We determined the effects of CUS, with or without concurrent treatment with the antidepressant imipramine (10 mg/kg), on CP55940 binding to the cannabinoid CB(1) receptor; whole tissue endocannabinoid content; and fatty acid amide hydrolase (FAAH) activity in the prefrontal cortex, hippocampus, hypothalamus, amygdala, midbrain and ventral striatum. Exposure to CUS resulted in a significant increase in CB(1) receptor binding site density in the prefrontal cortex and a decrease in CB(1) receptor binding site density in the hippocampus, hypothalamus and ventral striatum. Except in the hippocampus, these CUS-induced alterations in CB(1) receptor binding site density were attenuated by concurrent antidepressant treatment. CUS alone produced a significant reduction in N-arachidonylethanolamine (anandamide) content in every brain region examined, which was not reversed by antidepressant treatment. These data suggest that the endocannabinoid system in cortical and subcortical structures is differentially altered in an animal model of depression and that the effects of CUS on CB(1) receptor binding site density are attenuated by antidepressant treatment while those on endocannabinoid content are not.

The antidepressant effect of an antiulcer pentadecapeptide BPC 157 in Porsolt's test and chronic unpredictable stress in rats. A comparison with antidepressants

Various antidepressants have antiulcer activity. Likewise, the models currently used in ulcers and depression disorders research have a considerable degree of similarity. Therefore, the possibility that depression disorders could be effectively influenced by a primary antiulcer agent with a cyto/organoprotective activity, such as the novel stomach pentadecapeptide BPC 157, was investigated in two rat depression assays. First, a forced swimming test (a Porsolt's procedure) was used. As a more severe procedure, chronic unpredictable stress (after 5 d of unpredictable stress protocol, once daily drug application during stress procedure, open field-immobility test assessment at fourth or sixth day of medication) was used. In a forced swimming test, a reduction of the immobility time in BPC 157 (10 μg, 10 ng.kg –1 i.p.) treated rats corresponds to the activity of the 15 mg or 40 mg (i.p.) of conventional antidepressants, imipramine or nialamide, respectively, given according to the original Porsolt's protocol. In chronic unpredictable stress procedure, particular aggravation of experimental conditions markedly affected the conventional antidepressant activity, whereas BPC 157 effectiveness was continuously present. The effect of daily imipramine (30 mg) medication could be seen only after a more prolonged period, but not after a shorter period (i.e., 4-d protocol). In these conditions, no delay in the effectiveness was noted in BPC 157 medication and a reduction of the immobility of chronically stressed rats was noted after both 4 and 6 d of BPC 157 (10 μg, 10 ng) medication.