Hippocampal cytogenesis correlates to escitalopram-mediated recovery in a chronic mild stress rat model of depression.

From clinical studies it is known that recurrent depressive episodes associate with a reduced hippocampal volume. Conversely, preclinical studies have shown that chronic antidepressant treatment increases hippocampal neurogenesis. Consequently, it has been suggested that a deficit in hippocampal neurogenesis is implicated in the pathophysiology of depression. To study a potential correlation between recovery and hippocampal cytogenesis, we established the chronic mild stress (CMS) rat model of depression. When rats are subjected to CMS, several depressive symptoms develop, including the major symptom anhedonia. Rats were exposed to stress for 2 weeks and subsequently to stress in combination with antidepressant treatment for 4 consecutive weeks. The behavioral deficit measured in anhedonic animals is a reduced intake of a sucrose solution. Prior to perfusion animals were injected with bromodeoxyuridine (BrdU), a marker of proliferating cells. Brains were sectioned horizontally and newborn cells positive for BrdU were counted in the dentate gyrus and tracked in a dorsoventral direction.CMS significantly decreased sucrose consumption and cytogenesis in the ventral part of the hippocampal formation. During exposure to the antidepressant escitalopram, given as intraperitoneally dosages of either 5 or 10 mg/kg/day, animals distributed in a bimodal fashion into a group, which recovered (increase in sucrose consumption), and a subgroup, which refracted treatment (no increase in sucrose consumption). Chronic treatment with escitalopram reversed the CMS-induced decrease in cytogenesis in the dentate gyrus of the ventral hippocampal formation, but in recovered animals only. Our data show a correlation between recovery from anhedonia, as measured by cessation of behavioral deficits in the CMS model, and an increase in cytogenesis in the dentate gyrus of the ventral hippocampal formation.     

Effects of the novel antidepressant milnacipran in a chronic mild stress model of depression

The chronic mild stress (CMS) model of depression may serve as a suitable research tool for studying the action of novel antidepressants (i.e., both efficacy and onset of action). The CMS‐induced sub‐sensitivity to reward is reversed by chronic treatment with antidepressant drugs. The effect of the serotonin and norepinephrine reuptake inhibitor (SNRI), milnacipran, was investigated on the CMS model in rats in comparison with imipramine. The CMS model of depression consisted in subjecting rats to several mild stressors for a prolonged period of time, which resulted in a decrease in their responsiveness to rewarding stimuli. This deficit was monitored by a decrease in the consumption of a 1% sucrose solution. Stressed and control animals received daily for 5 weeks injections of vehicle, imipramine (10 mg/kg) or milnacipran (3, 10, and 30 mg/kg). CMS caused a decrease in the consumption of the 1% sucrose solution. The deficit in sucrose consumption in stressed animals was reversed by imipramine and milnacipran. The effect of milnacipran was gradual, dose‐dependent, and was maintained for one week after stopping drug treatment. Neither imipramine nor milnacipran modified the behavior of control animals. Milnacipran is active in the CMS model of depression as expected from its clinically demonstrated antidepressant effect. Drug Dev. Res. 61:101–106, 2004. © 2004 Wiley‐Liss, Inc.     

BCPT对慢性应激抑郁大鼠脂质过氧化及免疫功能的影响

目的观察一种拟青霉代谢物提取物(BCPT)对慢性轻度不可预见性应激(CUMS)大鼠脂质过氧化及免疫功能的影响。方法采用CUMS法,造成大鼠抑郁模型,按试剂盒说明书要求测定大鼠血清GSH-PX、CAT、T-SOD活力和MDA、NO含量。采用MTT法检测CUMS大鼠血清对正常小鼠脾淋巴细胞转化的影响。结果BCPT提高CUMS大鼠血清GSH-PX、CAT、T-SOD活力,降低CUMS大鼠血清MDA、NO含量,改善CUMS大鼠血清对小鼠脾淋巴细胞的抑制作用。结论BCPT的抗抑郁作用可能与增强CUMS大鼠的抗氧化和免疫功能有关。     

Nicotine reverses anhedonic-like response and cognitive impairment in the rat chronic mild stress model of depression: comparison with sertraline

Smoking rates among depressed individuals are higher than is observed in the background population, and nicotine alleviates depressive symptoms. In rodents, nicotine shows antidepressant-like effects in the forced swim and learned helplessness paradigms. Clinical depression is associated with both anhedonia and cognitive impairments. In rats, chronic mild stress (CMS) decreases voluntary sucrose intake, reflecting an anhedonic-like state, and impairs performance in the spontaneous alternation behaviour (SAB) test, suggesting impaired cognitive function. Here, we examine the effect of chronic treatment of nicotine (0.4 mg/kg/day) and sertraline (5 mg/kg/day) on CMS-induced anhedonic-like behaviour and impairment in the SAB test. Nicotine and sertraline administered individually or in combination show significant and equally efficacious reversal of the CMS-induced decrease in sucrose intake, implying there is no additive or synergistic effect of the nicotine + sertraline combination. In the SAB test, nicotine, but not sertraline or nicotine + sertraline, reversed the CMS-induced impairment. The present results show that the effect of nicotine on a CMS-induced anhedonic-like state in rats is similar to that of a standard antidepressant drug. Moreover, the data suggest that nicotine alleviates CMS-induced cognitive disturbance. A treatment strategy involving the targeting of nicotinic acetylcholine receptors may prove beneficial for emotional and cognitive disturbances associated with depression.     

R-citalopram counteracts the antidepressant-like effect of escitalopram in a rat chronic mild stress model

The selective serotonin (5-HT) reuptake inhibitor, citalopram, is a racemic mixture of the stereoisomers, S-(+)-citalopram (escitalopram) and R-(-)-citalopram (R-citalopram). R-citalopram has been shown to counteract the 5-HT enhancing properties of escitalopram in acute studies in animals. In the present study we report, for the first time, on an interaction between R-citalopram and escitalopram after repeated dosing in a rat chronic mild stress (CMS) model of depression. The effect of escitalopram (2.0, 3.9 and 7.8 mg/kg per day), R-citalopram (7.8 mg/kg per day) and escitalopram 3.9 mg/kg per day plus R-citalopram 7.8 mg/kg per day were studied and compared to the effect of citalopram (8.0 mg/kg per day), imipramine and R-fluoxetine (8.9 mg/kg per day). Significant effects relative to a vehicle-treated group were achieved from week 1 for escitalopram (3.9 and 7.8 mg/kg per day), from week 2 for citalopram (8.0 mg/kg per day), from week 3 for R-fluoxetine (8.9 mg/kg per day) and from week 4 for escitalopram (2.0 mg/kg per day) and imipramine (8.9 mg/kg per day). R-citalopram (7.8 mg/kg per day) and escitalopram (3.9 mg/kg per day) plus R-citalopram (7.8 mg/kg per day) did not differ significantly from vehicle. There were no drug-induced effects in non-stressed control groups. In conclusion, escitalopram showed a shorter time to response in the rat CMS model of depression than citalopram, which was faster acting than R-fluoxetine and imipramine. R-citalopram counteracted the effect of escitalopram. The mechanism of action of R-citalopram is, at the moment unclear, but may be relevant to the improved clinical antidepressant activity seen with escitalopram in comparison with citalopram, and may also indicate an earlier response to escitalopram compared to other selective serotonin reuptake inhibitors (SSRIs).     

The selective sigma2 ligand Lu 28-179 has an antidepressant-like profile in the rat chronic mild stress model of depression

The selective sigma2 (sigma2) ligand Lu 28-179, or 1'-[4[1-(4-fluorophenyl)-1H-indol-3-yl]-l-butyl]spiro[isobenzofuran++ +-1(3H),4'-piperidine], was studied in the chronic mild stress (CMS) model of depression. The CMS test procedure consists of sequential exposures to a variety of mild stressors for a prolonged period of time and results in behavioural hedonic deficits, which can be measured as decreased consumption of a palatable sucrose solution. In rats, exposure to CMS treatment with citalopram or imipramine for 2 or 4 weeks, respectively, normalized the sucrose intake. Similarly, Lu 28-179 (1.0 mg/kg subcutaneously per day) normalized sucrose intake in rats exposed to CMS. This effect was found in two separate experiments and was achieved after 3 and 4 weeks of treatment, respectively. This suggests an antidepressant potential for Lu 28-179. Doses of 0.01 and 0.1 mg/kg were inactive. Groups exposed to CMS and treated with 0.5, 2.0 or 3.0 mg/kg showed a significantly increased sucrose intake compared with vehicle-treated stressed animals at week 5. However, this effect was confounded by decreased intake in the vehicle controls. Lu 28-179 did not affect sucrose intake in non-stressed rats at any of the doses tested.     

Neuropsychopharmacological effect of sesamol in unpredictable chronic mild stress model of depression: behavioral and biochemical evidences

Rationale  

A complex relationship exists among stressful situations, body's reaction to stress, and the onset of clinical depression. Chronic unpredictable stressors can produce a situation similar to clinical depression, and such animal models can be used for the preclinical evaluation of antidepressants. Many findings have shown that the levels of proinflammatory cytokines (e.g., TNF-α) and oxidative stress (increased lipid peroxidation, decreased glutathione levels, and endogenous antioxidant enzyme activities) are increased in patients with depression. Sesamol, a phenolic derivative with a methylenedioxy group, is a potent inhibitor of cytokine production as well as an antioxidant.     

Behavioural and biochemical studies of citalopram and WAY 100635 in rat chronic mild stress model

Reversal of chronic mild stress (CMS)-induced decrease of sucrose consumption has been studied in rats after 2, 7, 14, and 35 days treatment with imipramine, citalopram (both 10 mg/kg per day, i.p.), WAY 100635 (0.2 mg/kg sc, b.i.d.), and citalopram plus WAY 100635. Bmax, Kd, and functional status [cyclic AMP (cAMP) generation] of beta1-adrenoceptors were assessed in cortical tissue at the same time points. Citalopram reversed CMS-induced reduction of sucrose intake at an earlier time point than imipramine. WAY 100635 was not effective and did not potentiate the effect of citalopram. CMS produced increase of Bmax. Imipramine decreased Bmax in controls (Days 2, 7, 14, and 35) and normalised Bmax in stressed animals (Day 35). Citalopram, WAY 100635, and the combination increased Bmax in stressed animals and controls (Days 14 and 35). Inconsistent changes of Kd values and of cAMP responses to noradrenaline (NA) stimulation were observed. Thus stress- and drug-induced effects on beta1-adrenoceptors do not appear to be a common biochemical marker of antidepressant-like activity in the CMS model.     

Influence of hyperhomocysteinemia on behavioral and neurochemical alterations in a chronic mild unconditioned stress rat model

目的 研究高同型半胱氨酸血症(Hhcy)对慢性不可预见应激模型大鼠行为学、神经递质及神经营养因子水平的影响.方法 以高蛋氨酸饮食喂养大鼠制作Hhcy模型(Hhcy组,12只);另选24只大鼠,均分为普食组和对照组,均给予普通饮食喂养;Hhcy组与普食组给予慢性不可预见性刺激.比较三组的学习记忆能力、海马组织5-羟色胺(5-HT)和5-羟基吲哚乙酸(5-HIAA)含量以及脑脊液中神经营养因子(BDNF)水平.结果 水迷宫实验中,Hhcy组目的象限停留时间比普食组短(P＜0.05);Hhcy组海马5-HIAA含量和脑脊液中BDNF含量均较普食组低(P＜0.05).结论 Hhcy可致慢性应激模型大鼠学习记忆能力的下降,加重神经递质及生长因子水平的异常,可能为抑郁症的危险因素之一.     

高同型半胱氨酸血症对慢性应激模型大鼠行为学及神经生化的影响

目的研究高同型半胱氨酸血症(Hhcy)对慢性不可预见应激模型大鼠行为学、神经递质及神经营养因子水平的影响。方法以高蛋氨酸饮食喂养大鼠制作Hhcy模型(Hhcy组,12只);另选24只大鼠,均分为普食组和对照组,均给予普通饮食喂养;Hhcy组与普食组给予慢性不可预见性刺激。比较三组的学习记忆能力、海马组织5-羟色胺(5-HT)和5-羟基吲哚乙酸(5-HIAA)含量以及脑脊液中神经营养因子(BDNF)水平。结果水迷宫实验中,Hhcy组目的象限停留时间比普食组短(P<0.05);Hhcy组海马5-HIAA含量和脑脊液中BDNF含量均较普食组低(P<0.05)。结论Hhcy可致慢性应激模型大鼠学习记忆能力的下降,加重神经递质及生长因子水平的异常,可能为抑郁症的危险因素之一。     

Anxiolytic profile of fluoxetine as monitored following repeated administration in animal rat model of chronic mild stress

Background: Fluoxetine, a selective serotonin re-uptake inhibitor (SSRI), has been proposed to be more effective as an antidepressive drug as compared to other SSRIs. After chronic SSRI administration, the increase in synaptic levels of 5-HT leads to desensitization of somatodentritic 5-HT autoreceptors in the raphe nuclei. Chronic stress may alter behavioral, neurochemical and physiological responses to drug challenges and novel stressors. Methods: Twenty four male rats were used in this study. Animals of CMS group were exposed to CMS. Animals of stressed and unstressed group were administrated with fluoxetine at dose of 1.0 mg/kg s well as 5.0 mg/kg repeatedly for 07 days 1 h before exposed to CMS. The objective of the present study was to evaluate that repeated treatment with fluoxetine could attenuate CMS-induced behavioral deficits. Results: Treatment with fluoxetine attenuated CMS-induced behavioral deficits. Fluoxetine administration induced hypophagia in unstressed as well as CMS rats. Acute and repeated administration of fluoxetine increased motor activity in familiar environment but only repeated administration increased exploratory activity in open field. Anxiolytic effects of fluoxetine were greater in unstressed rats. These anxiolytic effects were produced as result of repeated administration not on acute administration of fluoxetine at 1.0 mg/kg as well as 5.0 mg/kg. Conclusion: The present study demonstrated that CMS exposure resulted into behavioral deficits and produced depressive-like symptoms. Fluoxetine, an SSRI, administration attenuated behavioral deficits induced by CMS. Anxiolytic effects of repeated fluoxetine administration were greater in unstressed than CMS animals.     

Antidepressant-like action of AGN 2979, a tryptophan hydroxylase activation inhibitor, in a chronic mild stress model of depression in rats.

Chronic mild stress (CMS) procedure was used to study an antidepressant-like activity of AGN 2979, a selective inhibitor of tryptophan hydroxylase (TH) activation. At the dose of 4 mg/kg, AGN 2979 fully reversed the CMS-induced reduction in the consumption of 1% sucrose solution. This effect was maintained for at least 1 week after cessation of treatment and no signs of withdrawal were observed in either stressed or control animals receiving AGN 2979. The lower (1 mg/kg) and higher (16 mg/kg) doses were ineffective. The magnitude of action of AGN 2979 in the CMS model was comparable to that of imipramine (10 mg/kg) but its onset of action appears to be faster since the inhibition of sucrose intake in stressed animals was already reversed after the 1st week of AGN 2979 administration while imipramine required 3 weeks of treatment to cause similar effect. These results provide support for the hypothesis that inhibition of TH activation may result in a potent antidepressant activity.     

Involvement of norepinephrine and serotonin system in antidepressant-like effects of hederagenin in the rat model of unpredictable chronic mild stress-induced depression

Abstract

Context: Previous studies from our laboratory indicated that both acute and subchronic administration of Fructus Akebiae (FAE) [the fruit of Akebiae quinata (Thunb.) Decne, (Lardizabalaceae)] produce antidepressant-like effects in animal depressive behavior tests. FAE contains approximately 70% of hederagenin (HG) as its main chemical component.

Objective: This study compared the antidepressant ability of FAE with that of HG in mice and further investigated the antidepressant-like effects and potential mechanisms of HG in rats subjected to unpredictable chronic mild stress (UCMS).

Materials and methods: Mice received FAE (50?mg/kg) and HG (20?mg/kg) once a day via intragastric administration (i.g.) for 3?weeks. The anxiolytic and antidepressant activities of FAE and HG were compared using elevated plus maze (EPM) and behavioral despair tests including tail suspension test (TST) and forced swimming test (FST), respectively. Antidepressant effects of HG (5?mg/kg) were assessed using the UCMS depressive rat model. Moreover, the levels of monoamine neurotransmitters and relevant gene expression in UCMS rats’ hippocampi were determined through high-performance liquid chromatography with electrochemical detection and real-time polymerase chain reaction techniques.

Results: The results of our preliminary screening test suggest that HG at 20?mg/kg, while not FAE at 50?mg/kg, significantly decreased the immobility in both TST and FST compared with the vehicle group when administered chronically; however, there were no significant differences observed between the HG and the FAE group. Chronic administration of HG failed to significantly reverse the altered crossing and rearing behavioral performance, time spent in the open arm and closed entries in the EPM, even if they showed an increased tendency, but HG significantly increased the percent of sucrose preference in the sucrose preference test (SPT) and decreased the immobility time in the FST. HG showed that significant increases of norepinephrine and serotonin levels and exhibited a tendency to increase the expression of 5-hydroxytryptamine (serotonin) 1A receptor mRNA, and to significantly decrease the expression of the mRNA for the serotonin transporter (5-HTT). However, there were no significant differences in the expression of the brain-derived neurotrophic factor.

Conclusion: These findings confirm the antidepressant-like effects of HG in a behavioral despair test and UCMS rat model, which may be associated with monoamine neurotransmitters and 5-HTT mRNA expression.     

Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation

This paper evaluates the validity, reliability and utility of the chronic mild stress (CMS) model of depression. In the CMS model, rats or mice are exposed sequentially, over a period of weeks, to a variety of mild stressors, and the measure most commonly used to track the effects is a decrease in consumption of a palatable sweet solution. The model has good predictive validity (behavioural changes are reversed by chronic treatment with a wide variety of antidepressants), face validity (almost all demonstrable symptoms of depression have been demonstrated), and construct validity (CMS causes a generalized decrease in responsiveness to rewards, comparable to anhedonia, the core symptom of the melancholic subtype of major depressive disorder). Overall, the CMS procedure appears to be at least as valid as any other animal model of depression. The procedure does, however, have two major drawbacks. One is the practical difficulty of carrying out CMS experiments, which are labour intensive, demanding of space, and of long duration. The other is that, while the procedure operates reliably in many laboratories, it can be difficult to establish, for reasons which remain unclear. However, once established, the CMS model can be used to study problems that are extremely difficult to address by other means. Received: 15 January 1997 / Final version: 18 August 1997     

褪黑激素对慢性应激性抑郁症大鼠海马细胞的影响

目的 探讨褪黑激素(MT)对慢性应激性抑郁症大鼠海马细胞的作用及可能机制.方法 36只SD大鼠随机均分为生理盐水(NS)组、抑郁(DM)组和治疗(MT)组.采用Morris水迷宫实验观察MT对大鼠智力行为的影响,用免疫组织化学法测定海马区细胞神经生长因子(NGF)、肿瘤坏死因子α(TNF-α)、MT受体1(MTR-1)、MTR-2及白细胞介素6(IL-6)的表达.结果 MT组大鼠逃避潜伏期和穿越站台次数较DM组减少(P＜0.05或P＜0.01).与NS组和DM组相比,MT组TNF-α和IL-6表达减少,而NGF、MTR-1、MTR-2表达增加(P＜0.05或P＜0.01).结论 MT可能通过增强神经营养素的作用,抑制炎性因子,从而起到抑制抑郁症发作的作用.