Unpredictable Mild Stress Research Articles

Effect of Simotang on gastrointestinal motility and expression of vasoactive intestinal peptide in chronical stressed mice

Objective To explore effect of Simotang on gastrointestinal motility and expression of vasoactive intestinal peptide(VIP) in the hypothalamus, spinal cord and duodenum of chronical stressed mice. Methods Mice were randomly divided into normal, stress and Simotang group( n= 10 in each group), and given a variety of unpredictable chronic mild stress. After 21 days gastric emptying and intestinal propulsion function were measured,the expression of VIP was detected by immunohistochemistry and RT-PCR. Results Compared with mice in normal group( (49.81 ± 8.56)%; (51.02 ± 5.11 )% ), chronic stress increased gastric residual rate( (61.53 ±8.71 ) %; P ＜ 0.05 ) and reduced small intestine propulsion rate ( ( 31.79 ± 2.38 ) %; P ＜ 0. 05 ). There were differences in expressions of VIP positive cells and mRNA in duodenum( (8.8 ± 1.1 )/mm2 and(0. 58 ±0.03) ),hypothalamus ( ( 12.9 ± 1.5 )/mm2 and (0.81 ± 0. 07 ) ) and spinal cord ( ( 12.1 ± 1. 2)/mm2 and (0.76 ± 0.02) )in chronic stress group compared with normal group( (6.5 ± 0. 9)/mm2 and (0.43 ± 0. 04);( 10.8 ± 1.3 )/mm2and (0.57 ± 0.03 ); (9.3 ± 1.5 )/mm2 and (0.53 ± 0. 02 ) respectively). There was not difference in gastric residual rate (52.93 ± 9.15 )%, small intestine rate(48.98 ± 4.38 )% and expressions of VIP positive cells and mRNA in duodenum ( (6.7 ± 0.9)/mm2 and (0.48 ± 0. 05 ) ), hypothalamus ( ( 10. 6 ± 1.4 )/mm2 and ( 0. 61 ± 0. 05 ) )and spinal cord ( (9. 1 ± 1.3)/mm2 and(0.55 ± 0.05 ) ) in Simotang group compared with those in normal group (P ＞ 0.05 ), but there were decreased compared with those in chronic stress group (P ＜ 0.05 ). Conclusion Simotang can regulate expressions of VIP in duodenum, hypothalamusand spinal cord in chronically stressed mice. Key words: Chronic stress; Functional gastrointestinal disorders; Vasoactive intestinal peptide; Mouse; Simotang

Hypogonadism predisposes males to the development of behavioural and neuroplastic depressive phenotypes

The incidence of depression is 2-3× higher in women particularly during the reproductive years, an occurrence that has been associated with levels of sex hormones. The age-related decline of testosterone levels in men corresponds with the increased acquisition of depressive symptoms, and hormone replacement therapy can be efficacious in treating depression in hypogonadal men. Although it is not possible to model depression in rodents, it is possible to model some of the symptoms of depression including a dysregulated stress response and altered neuroplasticity. Among animal models of depression, chronic mild unpredictable stress (CMS) is a common paradigm used to induce depressive-like behaviours in rodents, disrupt the hypothalamic-pituitary adrenal axis and decrease hippocampal neuroplasticity. The purpose of this study was to assess the effect of hypogonadism, produced by gonadectomy, on the acquisition of depressive-like behaviours and changes in hippocampal neuroplasticity in adult male Sprague-Dawley rats. A 21-day unpredictable CMS protocol was used on gonadectomised (GDX) and sham-operated males which produced an attenuation of weight gain in the GDX males receiving CMS treatment (GDX-CMS). Behavioural analysis was carried out to assess anxiety- and depressive-like behaviours. The combination of GDX and CMS produced greater passive behaviours within the forced swim test than CMS exposure alone. Similarly, hippocampal cell proliferation, neurogenesis and the expression of the neuroplastic protein polysialated neural cell adhesion molecule (PSA-NCAM) were all significantly reduced in the GDX-CMS group compared to all other treatment groups. These findings indicate that testicular hormones confer resiliency to chronic stress in males therefore reducing the likelihood of developing putative physiological, behavioural or neurological depressive-like phenotypes.

Effect of Chaihu Shugan San and its components on expression of ERK1/2 mRNA in the hippocampus of rats with chronic mild unpredicted stress depression.

To explore the antidepressant effect and mechanism of Chaihu Shugan San (CHSGS) composition, a compound traditional Chinese herb medicine and its components. Rats were randomly divided into 6 groups: normal control group, model control group, a CHSGS group, a component I group, a component II group and a fluoxetine control group. The depression model was replicated by chronic unpredictable mild stress and single house for 28 d. Behavioral scores of the rats were detected by Open-field test and sucrose solution consumption test, and ERK1/2 mRNA expression in the hippocampus tissue was assayed by real-time fluorescent quantitative PCR. ERK1/2 mRNA expression was down-regulated in the depression model group compared with the normal control group (P<0.01). Compared with the model group, ERK1/2 mRNA expression in the CHSGS group and fluoxetine group was both up-regulated (P<0.05 or P<0.01); and only ERK1 mRNA expression in the component I group was up-regulated (P<0.05). No significant difference existed between the component II group and the model group (P>0.05). Isolated-living condition and chronic mild unpredictable stress can down-regulate the expression of ERK1/2 mRNA in the hippocampus tissue. CHSGS may exert an antidepressant effect through increasing the expression of ERK1/2 mRNA in the hippocampus, component I may play an important role in its antidepression effect, while compatibility of the use of component II can enhance the antidepressant efficacy.

P.3.d.003 Effects of olanzapine on structure and function of brain tissue biomolecules during unpredictable chronic mild stress: an Fourier transform mid-infrared spectroscopic study

P.3.d.003 Effects of olanzapine on structure and function of brain tissue biomolecules during unpredictable chronic mild stress: an Fourier transform mid-infrared spectroscopic study

Of Depressed Mice and Men: Similar Genetic Expression in the Amygdala

Mice subjected to unpredictable chronic mild stress (UCMS) develop a depression-like syndrome (e.g., progressively worsened coat, reduced weight gain,

Analysis of the determination of NO and NOS in brain and myocardium of depression model rats

Objective To study nitric oxide (NO) and nitric oxide synthase (NOS) in brain and myocar-dium of depression model rats and to explore the mechanism of brain and myocardium injuryed. Methods The de-pression model rats were produced by chronic mild unpredictable stress and separation. The behavior of rats were detected by open field test and sucrose consumption test. The contents of NO and NOS were determined with spec-trophotometric method. Results Compared with the normal control, the contents of NO [Brain ( 8.97±2.22 )μmol/g prot vs ( 1.86±1.28 )μmol/g prot; Myocardium (9.67±1.53) μmol/g prot vs (2.67±1.08)μmol/g prot] and NOS[Brain(9. 50±1.89) U/mg prot vs (2.31±0. 97) U/mg prot; Myocardium( 11.20±1.47) U/mg prot vs(2.53±0.97)U/mg prot] in brain and myocardium were significantly increased (P<0.01)of depression model rats. Conclusion The contents of NO and NOS increase significantly in brain and myocardi-um of depression model rats and it may induce the injury on brain and myecardium of them. Key words: Depression; Brain; Myocardium; Nitric oxide; Nitric oxide synthase

Proatherosclerotic effects of chronic stress in male rats: Altered phenylephrine sensitivity and nitric oxide synthase activity of aorta and circulating lipids

The aim of this study was to analyze the effects of chronic mild unpredictable stress (CMS) on the vasoconstrictor response and morphology of the thoracic aorta and serum lipid profiles in rats. Male Sprague–Dawley rats were submitted to CMS, which consisted of the application of different stressors for 7 days per week across 3 weeks. The rats were sacrificed 15 days after CMS expsoure. CMS induced supersensitivity to the vasoconstrictor effect of phenylephrine in endothelium-intact thoracic aortic rings without changes in aortic rings without endothelium, or pre-incubated with nitric oxide (NO) synthesis inhibitor. Rats submitted to CMS showed hypertrophy of the intima and tunica media of thoracic aorta, increased serum levels of triglycerides, total cholesterol, very low-density lipoprotein cholesterol, low-density lipoprotein cholesterol and atherogenic index, without changes in high-density lipoprotein cholesterol levels, when compared with control rats. These data indicate that CMS induces physiological and morphological changes that may contribute to the development of atherosclerosis by mechanisms related to deficiency in NO production and dyslipidemia.

Peripheral insulin-like growth factor-I produces antidepressant-like behavior and contributes to the effect of exercise

Growth factors in the brain are important to depression and it's treatment and we assessed the ability of peripherally administered insulin-like growth factor-I (IGF-I) to influence behavior related to depression. We found that mice that received chronic IGF-I treatment showed antidepressant-like behavior in forced-swim and novelty-induced hypophagia (NIH) tests and increased sucrose consumption after chronic mild unpredictable stress exposure. Additionally, peripheral anti-IGF-I administration blocked exercise-induced antidepressant effects in the forced-swim test (FST). These results support the functional relevance of neurotrophic mechanisms to depression and extend this idea to include neurotrophic factors in the periphery.

Stress modifies the vaginal flora in cyclic female rats*

The understanding of the pathogenesis of vaginitis is directly dependent upon the factors which promote the colonization by bacterial genital microflora. Disruption of the bacterial barrier function afforded by the predominant microflora can lead to colonization by pathogenic or opportunistic pathogenic subdominant species. The present study focused on the effects of stress on the bacteria of the vaginal flora. For this purpose two types of psychological stress were employed: acute and subacute mild unpredictable stress. Estimation of the vaginal flora of 22 Wistar rats was performed according to the distinct phases of the estrous cycle: PE (proestrous), E (estrous), ME (metestrous), and DE (diestrous). Bacteria isolated from the vaginal flora were identified following Bergey’s Manual criteria. Escherichia coli, Clostridium , and Clostridium perfringens (vegetative and spore forms), showed increased numbers at PE-E after acute and subacute stress. Enterococcus was increased after acute stress, in all stages, while S treptococcus was increased after acute stress only at ME-DE. Staphylococcus aureus was detected at ME-DE only after stress. Staphylococcus epidermidis seemed to be predominant, but not influenced by stress at PE-E. However, it was detected in increased numbers at ME-DE after stress. Fusobacterium was detected at low levels in all phases and remained unaffected after exposure to stress. Both types of stress increased the numbers of Bacteroides at PE-E. Finally, the absence of Lactobacillus was noticed at PE-E 24 h after acute and subacute mild unpredictable stress, while Lactobacillus was decreased at ME-DE 72 h after stress. Hormonal fluctuations during the different phases of the estrous cycle may be associated with alterations in the vaginal flora. The data showed that stress acting on the vaginal flora and its immunity potential may contribute to disturbances of the natural balance in the area by altering the numbers of several bacteria that belong to the vaginal microflora. Continuous research on the factors that regulate the vaginal microflora is considered as essential, to prevent complications in infections that may be caused by indigenous microorganisms. Key words: stress, vaginal flora, clostridium, lactobacillus

Stress modulates the enzymatic inducibility by benzo[α]pyrene in the rat liver

The role of stress on the inducibility by benzo[ α ]pyrene (B[ α ]P), a representative polycyclic aromatic hydrocarbon, of several drug-metabolizing enzymes was investigated in rats, using restraint stress and mild unpredictable stress as models of psychological stress. Restraint stress was found to significantly suppress basal ethoxyresorufin 7-dealkylase (EROD) and pentoxyresorufin 7-dealkylase (PROD) activities (two-fold). In contrast, mild unpredictable stress markedly increased basal EROD activity, while PROD activity was not affected. In addition, both types of stress resulted in a significant reduction of basal p -nitrophenol hydroxylation (PNP). It is worth noting that restraint stress greatly enhanced the inducibility of EROD, methoxyresorufin 7-dealkylase (MROD) and to a lesser extent PROD activities by B[ α ]P, while mild unpredictable stress had no, or only a mild effect on the inducibility of cytochrome P450s (CYPs) by B[ α ]P. In conclusion, psychological stress may modulate different enzymatic systems which are vital elements of the detoxification mechanisms of the body. The two distinct types of psychological stress used in this study appear to affect the enzymatic systems under investigation in a stress-specific manner at the basal level and at the induced state by B[ α ]P.

Chronic mild unpredictable stress after noradrenergic denervation: attenuation of behavioural and biochemical effects of DSP-4 treatment

Chronic mild unpredictable stress, which reduces rewarded behaviour in rats, is becoming increasingly popular as an animal model of depression. The effect of chronic mild stress (applied to animals housed five per cage for 15 days) on forced swimming and open field behaviour, and on β-adrenoceptor binding was studied in naive rats and after the denervation of the locus coeruleus projections by DSP-4 (50 mg kg −1) treatment. In the forced swimming test, chronic mild stress reduced the immobility time on the second day of testing in both vehicle- and DSP-4-treated rats, indicating rather an antidepressant-like effect. This antidepressant-like effect of chronic mild stress in the forced swimming test was not present in individually housed rats which suggests that this paradigm is sensitive to housing conditions. Stress had no clear effect on the open field locomotion in naive animals (but caused a reduction in defecations), but completely blocked the DSP-4-induced decrease in the exploratory activity. As measured by 3H-dihydroalprenolol binding, DSP-4 treatment increased the β-adrenoceptor affinity in the frontal cortex and the number of binding sites in the hippocampus and in the cerebral cortex (total-frontal cortex). Stress had no effect on the β-adrenoceptor binding in the frontal cortex and cerebral cortex, but prevented the increase in affinity caused by DSP-4 treatment in the frontal cortex. In the hippocampus, chronic mild stress and DSP-4 treatment increased the number of β-adrenoceptor binding sites. Neither chronic mild stress nor DSP-4 treatment had any effect on CCK B receptor binding in the cerebral cortex and striatum. These results show that chronic mild stress applied to group-housed rats can prevent the development of certain behavioural and biochemical changes caused by the denervation of the locus coeruleus projection areas.

496 Psychophysiology of interrelation between sleep and stress: possible role of some peptides

Chronic exposure to mild unpredictable stress causes subsensitivity to rewards (anhedonia). These effects are reversible by chronic treatment with antidepressant drugs, and have been proposed as an animal model of depression. In the present study, sleep architecture, particularly the rapid eye movement (REM) component, was mapped in rats following exposure to chronic mild stress. The study used a unique large scale automated sleep system to record and analyze the sleep signals from 32 rats simultaneously. The effects of stress on sleep were maximal following 21 days of stress, at which time the stressed animals demonstrated decreases in active waking and deep sleep, and disruptions of REM sleep. The changes in REM sleep included increases in the duration of and transitions into REM sleep over the sleep part of the sleep-wake cycle, and most importantly, a reduced latency to the onset of the first REM period. These sleep abnormalities, and in particular the decrease in REM latency, are consistent with those reported in endogenous depression. The results provide further support for the validity of the chronic mild stress paradigm as an animal model to study the mechanisms underlying endogenous depression.

Behavioural, neurochemical and endocrine responses after chronic mild unpredictable stress in two different rat strains : S. Bekris a, N. Kioukia b, K. Antoniou a, I. Christofidis b and Z. Papadopoulou-Daifoti a. aDepartment of Experimental Pharmacology, Medical School, University of Athens, Goudi, 115 27 Athens, Greece. bImmunoassay Quality Control Lab., I.R.R.P, NCSR Demokritos, Ag. Paraskevi, 153 10 Athens, Greece

Behavioural, neurochemical and endocrine responses after chronic mild unpredictable stress in two different rat strains : S. Bekris a, N. Kioukia b, K. Antoniou a, I. Christofidis b and Z. Papadopoulou-Daifoti a. aDepartment of Experimental Pharmacology, Medical School, University of Athens, Goudi, 115 27 Athens, Greece. bImmunoassay Quality Control Lab., I.R.R.P, NCSR Demokritos, Ag. Paraskevi, 153 10 Athens, Greece

Anti-anhedonic actions of the novel serotonergic agent flibanserin, a potential rapidly-acting antidepressant

Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions and to block the formation of conditioned place preferences; these effects are reversed by chronic treatment with tricyclic or atypical antidepressant drugs. The present study was designed to evaluate the antidepressant-like activity in this model of flibaserin (BIMT-17), a novel serotonergic agent with 5-HT 1A receptor agonist and 5-HT 2 receptor antagonist properties. Two experiments were conducted, using rats (experiment 1) and mice (experiment 2). In experiment 1, decreases in sucrose intake were seen in rats exposed to chronic mild stress, but the effect was unreliable in this study, and sucrose testing was terminated after 7 weeks of stress. Beginning after 5 weeks of stress, groups of control and stressed animals were treated daily with vehicle, fluoxetine (5 mg/kg) or flibanserin (5, 10 or 20 mg/kg). After 6 weeks of treatment, all animals were tested for acquisition of food-reinforced place preference conditioning. Conditioning was seen in all groups other than the vehicle-treated stressed animals. We also tested the locomotor stimulant effect of a single injection of the dopamine D 2/D 3 receptor agonist quinpirole (0.2 mg/kg). The effect of quinpirole was potentiated by fluoxetine in control animals, and by both fluoxetine and flibanserin (all doses) in stressed animals. In experiment 2, long-lasting decreases in sucrose intake were seen in mice exposed to chronic mild stress. The effects were reversed by chronic (4 weeks) treatment with fluoxetine (5 mg/kg) or flibanserin (2.5 or 5 mg/kg); the full effect of flibanserin was seen after the first injection. All animals received a single injection of raclopride (0.1 mg/kg) immediately prior to a sucrose intake test on day 27 of drug treatment. Raclopride decreased sucrose intake only in the three drug-treated stressed groups. The results support a rapid antidepressant-like action of flibanserin, and suggest that this effect involves sensitization of dopamine D 2/D 3 receptor-mediated transmission.

The attenuation of morphine-conditioned place preference following chronic mild stress is reversed by a CCKB receptor antagonist.

Chronic exposure to mild unpredictable stress has been found to abolish the acquisition of preference for a distinctive environment paired with morphine, whereas morphine induced conditioning place preference in non-stressed rats. Chronic treatment for 21 days with the tricyclic antidepressant imipramine reversed the motivational effects produced by chronic mild stress, and animals showed a place preference for the morphine-paired compartment. When the CCKB receptor antagonist PD-134,308 was co-administered with morphine in stressed animals during the conditioning period, the preference for the morphine-paired compartment was also re-established. The CCKB receptor antagonist given alone did not induce rewarding effects in this paradigm. These findings indicate that the administration of a CCKB receptor antagonist reversed the effects of chronic mild stress on opiate rewarding properties.

Changes in sleep architecture following chronic mild stress

Chronic exposure to mild unpredictable stress causes subsensitivity to rewards (anhedonia). These effects are reversible by chronic treatment with antidepressant drugs, and have been proposed as an animal model of depression. In the present study, sleep architecture, particularly the rapid eye movement (REM) component, was mapped in rats following exposure to chronic mild stress. The study used a unique large scale automated sleep system to record and analyze the sleep signals from 32 rats simultaneously. The effects of stress on sleep were maximal following 21 days of stress, at which time the stressed animals demonstrated decreases in active waking and deep sleep, and disruptions of REM sleep. The changes in REM sleep included increases in the duration of and transitions into REM sleep over the sleep part of the sleep-wake cycle, and most importantly, a reduced latency to the onset of the first REM period. These sleep abnormalities, and in particular the decrease in REM latency, are consistent with those reported in endogenous depression. The results provide further support for the validity of the chronic mild stress paradigm as an animal model to study the mechanisms underlying endogenous depression.

The Effect of Selective Serotonin Releasing Agents in the Chronic Mild Stress Model of Depression in Rats

Chronic exposure to mild unpredictable stress has been found to depress the consumption of, and preference for, highly palatable sucrose solution in rats. Stress-induced behavioral deficits may be maintained for a long time, however chronic administration of clinically effective antidepressants can restore normal behavior. This is the first report showing that Sprague-Dawley rats can be used in this model. A preference deficit in this strain of rats took at least 7 weeks to develop; about twice the time required when hooded Lister or Wistar rats are used in this model. Water consumption was not effected by chronic exposure to the mild stress regime and/or by chronic administration of the selective serotonin (5-HT) releasing agent MMAI (5-methoxy-6-methyl-2-aminoindan). The stress-induced deficit in sucrose intake was completely reversed by chronic treatment with MMAI (5 mg/kg, 2 × day) over 3 weeks in the two-bottle tests. In single-bottle tests, chronic treatment with the selective 5-HT releasers, MMAI (5 mg/kg, 2 × day) or MTA (p-methylthioamphetamine; 5 mg/kg, 2 × day), reversed the deficit in rewarded behavior (anhedonia) measured as a decrease in the consumption of 1% sucrose solution in the chronic mild stress model of depression in rats. With the experimental procedure employed, and at a dose of 10 mg/kg/day of 5-HT releasers, the magnitude and onset of this effect were greater than observed following similar administration of the selective 5-HT reuptake inhibitor (SSRI) sertraline (10 mg/kg/day), used as a standard anti-depressant drug.

Decreased hedonic responsiveness following chronic mild stress is not secondary to loss of body weight

Chronic exposure to mild unpredictable stress (CMS) has previously been found to decrease hedonic responsiveness, as measured by the consumption of palatable sweet solutions or sensitivity to brain stimulation reward. These effects are reversed by chronic treatment with antidepressant drugs, and the CMS procedure has been proposed as a relatively valid animal model of depression. It has recently been suggested that the behavioural effects of CMS may be secondary to loss of body weight. This article collates data from five laboratories using the CMS procedure. Data are presented from seven studies using five different rat strains, as well as CD1 mice. Three-week exposure to CMS significantly decreased sucrose consumption by Lister hooded, PVG hooded, Wistar, and Wistar WU rats, and by CD1 mice, and sensitivity to brain stimulation reward in Ibm:Ro Ro rats. Weight loss in different experiments varied between 0 and 10%. Hedonic sensitivity relative to body weight (e.g., mg sucrose/g body weight) decreased significantly in all experiments. Animals maintained on a restricted feeding regime lost weight but did not show decreases in sucrose intake. It is concluded that decreased hedonic sensitivity following chronic mild stress cannot be attributed to loss of body weight.

Pharmacological validation of the chronic mild stress model of depression

Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions, and this effect was reversed by chronic treatment with a variety of antidepressant drugs. The present study reports three experiments examining the effects in this model of further antidepressant agents, a number of non-antidepressants, and some compounds of indeterminate clinical status. Male Wistar rats were exposed sequentially to a variety of mild stressors, which continued throught the experiments. Drug treatments commenced after 3 weeks of stress, by which time intake of a 1% sucrose solution (measured in a 1-h weekly test) was significantly depressed. No drug effects were seen after 1 week of treatment. Normal levels of sucrose drinking were seen following chronic (3–5 weeks) of treatment with the antidepressants imipramine (10 mg/kg per day), brofaromine (20 mg/kg per day), and buspirone (5 mg/kg per day). Positive effects were also seen following chronic treatment with atropine (1 mg/kg per day) and mepyramine (5 mg/kg per day). d-Amphetamine (1 and 3 mg/kg per day), the neuroleptics haloperidol and chlorprothixene (1 mg/kg per day), and morphine (administered at doses rising to 110 mg/kg per day) were ineffective; amphetamine (3 mg/kg) and morphine decreased sucrose intake in control animals. No inferences can be drawn from the effects of atropine and mepyramine, which are of indeterminate clinical status; data from the other seven agents tested support the hypothesis that the chronic mild stress model responds appropriately to antidepressant and non-antidepressant agents.

Effects of chronic mild stress on performance in behavioural tests relevant to anxiety and depression

Chronic exposure to mild unpredictable stress (CMS) has previously been found to depress the consumption of a weak (1%) sucrose solution by rats. This effect was confirmed in each of three experiments in the present study, following which behaviour was examined in other tests relevant to either depression or anxiety. CMS did not significantly affect behaviour in the social interaction test and caused an anxiolytic-like profile in the elevated plus-maze. CMS increased submissive behaviour in the resident-intruder test, and decreased male sexual behaviour. The latter effect was more pronounced in animals reared in isolation from the time of weaning; isolation rearing did not influence sexual behaviour in nonstressed animals. Isolation rearing also potentiated the effect of CMS on sucrose drinking, in both male and female rats. These results support the relevance of the CMS procedure as a potential animal model of depression.