Mild Stress Model Of Depression Research Articles

Proteomic Investigation of the Ventral Rat Hippocampus Links DRP-2 to Escitalopram Treatment Resistance and SNAP to Stress Resilience in the Chronic Mild Stress Model of Depression

The development of depression as well as recovery from depression is most likely accompanied by a change in protein expression profiles. The purpose of the present study was to quantitatively investigate global protein expression differences independent of any hypothesis describing depression etiology and recovery. Thus two-dimensional differential in-gel electrophoresis was employed to compare the ventral hippocampal proteomes between different treatment groups in the chronic mild stress (CMS) model of depression. The CMS paradigm induces anhedonic behaviour, which is a major symptom of depression, by exposing rats to a series of mild stressors for 7 weeks, with antidepressant treatment during the last 4 weeks. In the CMS model, animals were split into six different groups at the end of treatment; unchallenged control escitalopram (n = 12), unchallenged control vehicle (n = 12), CMS vehicle (n = 12), CMS escitalopram responders (n = 11), CMS escitalopram non-responders (n = 13) and CMS resilient (stress resistant) (n = 12). Protein levels in the ventral rat hippocampus were compared between the groups to provide putative markers of anhedonia, escitalopram resistance, and stress resilience. Twenty-eight candidate protein spots were selected, of which 13 were successfully identified using tandem mass spectrometry. DRP-2 (dihydropyrimidinase-related protein-2) was a potential marker for escitalopram resistance, whereas alpha-SNAP and beta-SNAP were associated with stress resilience. Furthermore, several molecular chaperones and cytoskeleton organisers were identified as being differentially expressed. Our data indicate that neuronal adaptation is an essential element of depression etiology and recovery, suggesting the involvement of cellular plasticity in the underlying molecular mechanism.

Behavioral and biochemical studies of total furocoumarins from seeds of Psoralea corylifolia in the chronic mild stress model of depression in mice

Depression is related to alterations of the monoamine oxidase (MAO), hypothalamic-pituitary-adrenal (HPA) axis, and oxidative systems, and some antidepressants achieve their therapeutic effects through alteration of following biochemical markers of depression: MAO-A and MAO-B activities, cortisol levels, superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels. The seeds of Psoralea corylifolia, otherwise known as Buguzhi, have long been used for treatments of various symptoms associated with aging in China. Furocoumarins are the most widespread secondary metabolites in this species. The present study was designed to evaluate the potential antidepressant-like activity of total furocoumarins of P. corylifolia (TFPC) in the chronic mild stress (CMS) model of depression. Mice subjected to CMS exhibited a reduction in sucrose intake. Conversely, brain MAO-A and MAO-B activities, plasma cortisol levels, and liver SOD activity and MDA levels were increased following CMS exposures. The time-course for reversal of CMS-induced deficits in sucrose consumption by TFPC was dose-dependent. Thus, the statistically significant effect of the higher dose of TFPC (50 mg/kg body wt.) was observed after 3 days of treatment, while 6 days of treatment were required in the group receiving a lower dose (30 mg/kg body wt.) of TFPC. TFPC reversed these biochemical changes. These results suggest that TFPC may possess potent and rapid antidepressant properties that are mediated via MAO, the HPA axis and oxidative systems and these antidepressant actions could make TFPC a potentially valuable drug for the treatment of depression in the elderly.

P.2.b.008 Antidepressant-like activity of Wf-516, an antagonist of 5-HT1A receptors and inhibitor of 5-HT reuptake, in a chronic mild stress model of depression in rat

P.2.b.008 Antidepressant-like activity of Wf-516, an antagonist of 5-HT1A receptors and inhibitor of 5-HT reuptake, in a chronic mild stress model of depression in rat

Effects of desipramine and tramadol in a chronic mild stress model in mice are altered by yohimbine but not by pindolol

This study investigated the antidepressant-like effects of a chronic treatment with either tramadol (20 mg/kg, i.p.) or desipramine (10 mg/kg, i.p.) in the unpredictable chronic mild stress model of depression in BALB/c mice. Mice were first submitted to a 2 week drug-free unpredictable chronic mild stress before the onset of the treatments. The unpredictable chronic mild stress regimen induced a degradation of the state of the coat and decreased the grooming behaviour in the splash test. These physical and behavioural abnormalities were counteracted by tramadol and desipramine. Furthermore, we observed neither a significant acceleration nor diminution by pindolol (5-HT 1A/1B receptor antagonist, 10 mg/kg, i.p.) on the antidepressant-like actions of desipramine and tramadol whereas yohimbine (α 2-adrenergic receptor antagonist, 2 mg/kg, i.p.) antagonized the antidepressant-like effects of both drugs during the unpredictable chronic mild stress regimen. The results of the study support the suggestion that antidepressant-like effect of tramadol and desipramine in mice in the unpredictable chronic mild stress model is mediated by the noradrenergic system rather than the serotonergic system.

Chronic mild stress impact: Are females more vulnerable?

Despite the knowledge that women are more susceptible than men to stress-related mental illness, such as major depression, there is no comprehensive estimation of the role of gender in the detrimental effects of chronic stress that might cause depression. Sex differences regarding the association of behavioral parameters with serotonergic and hypothalamic–pituitary–adrenal axis activities were investigated in the chronic mild stress model of depression. Additionally, the impact of chronic mild stress exposure on an additional/novel short-term stressful procedure, such as the forced swim test was examined in male and female rats. Female rats were found to be more vulnerable to chronic mild stress and that was depicted with disruption of sucrose intake, decreases in open field activity, increased corticosterone levels, alteration in estrous cycle and decreased serotonergic activity in hippocampus and hypothalamus. On the contrary, in males the current chronic mild stress protocol elicited only behavioral changes, such as disruption in sucrose intake and decreased open field activity. Interestingly, in response to forced swim test, females previously subjected to chronic mild stress, were found to cope better by exhibiting increased active behavior in the second forced swim test session and higher hypothalamic serotonergic activity in comparison with corresponding males. On the other hand, males were more affected by previous chronic mild stress exposure and that was manifested by decreased active behavior in the first forced swim test session and increased corticosterone levels following second forced swim test session. These data indicate that although females are more vulnerable in the application of chronic mild stress than males, in response to an additional-novel stressor (forced swim test) they show better response. Therefore, both sex/gender and combination of stressful procedures should be carefully considered in the study of the pathophysiology of stress-related mental illnesses.

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

AbstractThe 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.

Impaired T-cell dependent humoral response and its relationship with T lymphocyte sensitivity to stress hormones in a chronic mild stress model of depression

The humoral response and the role of catecholamines and corticosterone were analyzed in a chronic mild stress (CMS) model of depression. Mice subjected for more than 6 weeks to CMS showed a significant decrease in T-cell dependent antibody production. However, T-cell independent humoral response was not altered. Serum corticosterone levels and splenic norepinephrine (NE) contents showed an early increase but they were not altered after prolonged CMS exposure. Nevertheless, hormonal inhibitory effect on T lymphocyte reactivity was higher in 6-week CMS mice compared to non-exposed animals. Thus, our results suggest that the impaired T-cell dependent humoral response in a CMS model of depression is neither related to changes in glucocorticoids nor in NE levels but is correlated with an increment of T-cell sensitivity to stress hormones. These findings would underlie the involvement of catecholamines and glucocorticoid lymphocyte receptors in the immune alterations observed in stress and depression.

Behavioral and cardiovascular changes in the chronic mild stress model of depression

Depression is a multifaceted psychological disorder that involves changes in behavior, neuroendocrine function, and physiological responses. The present study investigated multiple behavioral and cardiovascular consequences in the chronic mild stress (CMS) rodent model of depression. Rats were exposed to 4 weeks of CMS followed by 4 weeks of a stress-free recovery period. Sucrose intake, a measure of anhedonia, and spontaneous locomotor activity were measured weekly throughout the study, and cardiovascular function tests were conducted at the completion of the protocol. The results indicate that CMS results in anhedonia and reduced locomotor activity, as well as elevated heart rate (HR), reduced HR variability, and elevated sympathetic cardiac tone. The behavioral effects of CMS recovered to baseline (prestress) levels during the recovery period; however, cardiovascular changes were observed following the recovery of sucrose intake and activity levels. The present findings suggest that behavioral changes that are indicative of anhedonia and locomotor alterations associated with depression are dissociable from long-term cardiovascular changes induced by CMS.

Effects of the selective nonpeptide corticotropin-releasing factor receptor 1 antagonist antalarmin in the chronic mild stress model of depression in mice

Several recent studies on corticotropin-releasing factor (CRF) have suggested that this neuropeptide may play a role in depression. Consequently, CRF receptor antagonists have been proposed as potential new agents for the treatment of this condition. This study investigated the effects of a 4-week treatment with the well-known CRF 1 receptor antagonist, antalarmin, and the prototypical selective serotonin reuptake inhibitor (SSRI), fluoxetine, in the chronic mild stress (CMS) model in BALB/c mice. Animals were exposed to 9 weeks of CMS which rapidly (within 2 weeks) produced decrease of physical state (PS), body weight gain and blunted emotional response in the light/dark test. Chronic treatment with antalarmin (10 mg/kg ip) and fluoxetine (10 mg/kg ip) led to an improvement of CMS-induced modifications. These results suggest that CRF 1 receptor antagonists may represent potential antidepressants.

Altered Expression of Autonomic Neurotransmitter Receptors and Proliferative Responses in Lymphocytes from a Chronic Mild Stress Model of Depression: Effects of Fluoxetine

We studied β-adrenergic and muscarinic cholinergic receptor (MR) expression and proliferative response in lymphocytes from animals under chronic mild stress (CMS) model of depression (CMS animals). Animals were subjected to CMS (periods of food or water deprivation, changes in lighting conditions, tilted cage, etc.) for 12 weeks. CMS lymphocytes showed an altered mitogen-induced proliferation. CMS-B and -T lymphocytes showed an increment on β-adrenoceptor number and on intracellular responses to a β-agonist. CMS-T cells showed higher MR expression and lower cGMP responses than normal lymphocytes. MR were not detectable in normal B cells while CMS-B cells showed both MR expression and cGMP response. Beta and muscarinic stimulation influenced lymphocyte proliferative responses, in accordance with cAMP and cGMP responses. After 12 weeks of the CMS procedure, animals were treated with fluoxetine while the CMS procedure continued. Fluoxetine treatment reverted the alterations induced by CMS. These findings suggest a possible mechanism for the immune alterations found in depressive disorders and for the effect of fluoxetine treatment on immune response.

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.

Prolonged desipramine treatment increases the production of interleukin-10, an anti-inflammatory cytokine, in C57BL/6 mice subjected to the chronic mild stress model of depression

Background: Depression is associated with activation of the inflammatory response system (IRS). In humans, antidepressants significantly increase the production of interleukin-10 (IL-10), a negative immunoregulatory cytokine. The aims of the present study were to examine the effects of desipramine, a tricyclic antidepressant, on the IRS in C57BL/6 mice with and without exposure to chronic mild stress (CMS). Methods: We examined the effects of desipramine on the cytotoxic activity of natural killer (NK) cells, the proliferative responses of lymphocytes after stimulation with IL-1, IL-2, lipopolysaccharide (LPS), concanavaline-A (Con-A), phytohaemagglutinin-P (PHA), pokeweed mitogen (PWM), and anti-CD3 monoclonal antibodies, the production of IL-2, IL-4, IL-10 and interferon-γ (IFNγ) by T lymphocytes and the ability of B cells to proliferate after stimulation by lipopolysaccharide (LPS). Results: Prolonged treatment of C57BL/6 mice subjected to CMS with desipramine increases the ability of T cells to produce IL-10 and the ability of B cells to proliferate after stimulation with LPS; and significantly decreases the cytotoxic activity of NK cells and the proliferative responses of lymphocytes after stimulation with Con-A, PHA and anti-CD3 monoclonal antibodies. Repeated administration of desipramine to non-stressed mice increases the activity of T lymphocytes, lowers that of B lymphocytes, increases the production of IL-10 by T cells and has no significant effect on the activity of NK cells. Conclusion: Prolonged desipramine treatment of stressed and non-stressed C57BL/6 mice induces an increase in the production of IL-10, an anti-inflammatory cytokine.

Altered function of peripheral organ systems in rats exposed to chronic mild stress model of depression.

1. In depression, psychiatric symptoms are frequently associated with impaired cardiovascular function and perhaps also increased risk for cancer diseases. Pathophysiological basis of this comorbidity is not clearly understood. Molecular events involved, particularly factors modified by chronic stress exposure, may only be evaluated in animal models of depression. 2. Present experiments were aimed to study parameters related to cardiovascular system (tyrosine hydroxylase (TH) gene expression in adrenal glands) and carcinogenesis (retinoic acid receptors in the liver) in the chronic mild stress model of depression. 3. Chronic mild stress induced a rise in adrenal TH gene expression in both male and female rats. Gender dependent changes were found in retinoic acid receptor binding with stress-induced activation in females but not males. Ovariectomized animals exhibited higher retinoic acid receptor binding. slightly elevated TH mRNA levels and failed to respond to chronic mild stress exposure with further increase in TH mRNA levels. Similarly, chronic mild stress induced an anhedonic state manifested by decreased sucrose preference in control but not ovariectomized rats. 4. Presented data document that central neurochemical and behavioral changes in animals exposed to chronic mild stress model of depression are associated with changes in adrenal TH gene expression and with gender dependent changes in retinoic acid receptor status in the liver. Such alterations may participate in the development of pathological changes and could participate on increased risk for cardiovascular and oncologic comorbidity in depressive patients.

Pharmacological validation of the chronic mild stress model of depression

Pharmacological validation of the chronic mild stress model of depression

Escitalopram has potent and rapid effect in a chronic mild stress model of depression in rats

Escitalopram has potent and rapid effect in a chronic mild stress model of depression in rats

Corticotropin-releasing hormone mRNA levels in response to chronic mild stress rise in male but not in female rats while tyrosine hydroxylase mRNA levels decrease in both sexes.

Corticotropin-releasing hormone (CRH) and catecholamines are suggested to play a significant role in the pathophysiology of depression. In the present study we investigated gene expression of CRH in the hypothalamic paraventricular nucleus (PVN) and tyrosine hydroxylase (TH) in the locus coeruleus (LC) in an experimental model of depression. A chronic mild stress model was applied in rats of both genders for a three-week period. Anhedonic behaviour, a typical sign of depression-like state, was measured by a sucrose preference test. The chronic mild stress induced a decrease in sucrose preference in both genders. The body weight gain was reduced in males only. The total activity in the open field test was unchanged, however, male rats exposed to chronic mild stress showed enhanced locomotor activity during the first minute of the session, suggesting increased anxiety. Basal plasma corticosterone levels, thymus and adrenal weights measured on the third day after cessation of the stress regimen, were not affected by the stress procedure. Evaluation of CRH mRNA levels in the PVN by in situ hybridisation revealed a significant rise in response to chronic mild stress in males. In females, the basal CRH mRNA levels were higher compared to those in males, but the stress-induced rise was absent. Chronic mild stress resulted in a decrease in TH mRNA levels in the LC. These data demonstrate that chronic mild stress model of depression induces a specific stress response with a reduction of TH gene expression in the LC and clear gender differences in gain of body weight, anxiety-like behaviour, and CRH mRNA levels in the PVN.

The NK1-receptor antagonist NKP608 has an antidepressant-like effect in the chronic mild stress model of depression in rats

The chronic mild stress (CMS) model of depression was used to study the potential antidepressant-like activity of NKP608, a non-peptidic, specific, potent and orally active NK1 receptor antagonist. In this model, a substantial decrease in consumption of a 1% sucrose solution is observed in rats continously subjected to a variety of mild stressors. This effect can be reversed by chronic administration of various classes of antidepressant drugs. Chronic, oral treatment with NKP608 (once daily for 5 weeks) gradually reversed CMS-induced reductions in sucrose consumption and, the magnitude of this effect was comparable to that observed following administration of imipramine (10 mg/kg). The time-course of action of NKP608 in the CMS model was dose-dependent. At the dose of 0.03 mg/kg, NKP608 caused a full reversal of the CMS-induced deficit in sucrose consumption after 4 weeks of treatment (comparable to 5 weeks required for imipramine), while only 1 week of treatment was required in the group receiving the dose of 0.1 mg/kg NKP608. Lower (0.003 mg/kg) and higher (1.0 mg/kg) doses of the compound were ineffective. These results suggest that NKP608 has antidepressant-like properties in the CMS model in rats; the effect was comparable to conventional drugs, but the onset of action was faster than with the representative tricyclic antidepressant imipramine.

Comparison of antidepressant-like activity of Lu 28-179, a selective σ 2 ligand, citalopram and imipramine in a chronic mild stress model of depression in rats

Many patients who remit fully/partially or recover from an episode of major depression continue to suffer from sleep problems, mainly insomnia. Our study assesses the frequency and types of ongoing or re-emerging subjective insomnia symptoms and their relationship to subsequent depressive relapse or recurrence in a group of full/partial remitters or recoverers.Sixty patients, 18 to 65 years of age, with current MDD defined using DSM-IV-TR criteria were participated in the study. They began a 24-week course of open-label acute plus continuation phase treatment mainly with SSRIs. Maintenance treatment was not planned for not affecting natural relapse or recurrence rates. All participants were evaluated by CGI-S, BDI, HAMD-17, PSQI, and ISI at weeks 0, 4, 12, 24, and 52.Majority of the participants (83.33%) had subjective sleep disturbance, insomnia prior to relapse or recurrence. Repeated measures ANOVA was used to evaluate changes in scores of depression and sleep scales over time between recurred (N = 12) and non-recurred groups (N = 48). Differences between means were calculated with post hoc Bonferroni comparison test. The changes in scores of entire clinical scales over time between recurred and non-recurred groups were statistically significant.The limitations of this study include the use of a relatively small, mostly young female sample and the lack of an objective sleep measure to corroborate self-report scales.Early recognition and treatment of disturbances of the sleep–wake cycle may be important for treatment and prevention of recurrence of depression.

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.

Alnespirone (S 20499), an Agonist of 5-HT 1A Receptors, and Imipramine Have Similar Activity in a Chronic Mild Stress Model of Depression

MUÑOZ, C. AND M. PAPP. Alnespirone (S 20499), an agonist of 5-HT 1A receptors, and imipramine have similar activity in a chronic mild stress model of depression . PHARMACOL BIOCHEM BEHAV 63(4) 647–653, 1999.—A chronic mild stress (CMS) model of depression was used to study an antidepressant-like activity of alnespirone (S 20499), a selective agonist of 5-HT 1A receptors. In this model, a substantial decrease in consumption of a palatable sucrose solution over time is observed in rats subjected to a variety of mild stressors. This effect can be reversed by chronic administration of various classes of antidepressant drugs. Chronic (5 weeks) treatment with alnespirone, in a dose range between 1–5 mg/kg/day, gradually and dose dependently reversed the CMS-induced reductions in sucrose consumption without any significant effects in the nonstressed control animals. The onset of action of the most active doses (2.5 and 5 mg/kg/day) and the overall efficacy of alnespirone in the CMS model were comparable to those observed following similar administration of imipramine (10 mg/kg/day). At the lower (0.5 mg/kg/day) and higher (10 and 20 mg/kg/day) doses, alnespirone was ineffective against the CMS-induced deficit in sucrose consumption. These data provide further support for previous suggestions, based on both the clinical observations and animal data, that agonism at 5-HT 1A receptors may result in antidepressant action.