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Validity, reliability and utility of the chronic mild stress model of depression: A 10-year review and evaluation
Abstract
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.
... (Feyissa et al., 2017). In addition to anhedonia-Iike impairments in tests of rewarded behavior, the effects of CMS include a reduction of locomotion in the OFT during the rat's active period (Gorka et al., 1996), an effect reversed with antidepressant drugs (Willner, 1997). In this respect, psychomotor agitation or retardation symptoms have been reported in humans with MDD, which is a far more complex behavior than a simple decrease in locomotor activity. ...
... In this respect, psychomotor agitation or retardation symptoms have been reported in humans with MDD, which is a far more complex behavior than a simple decrease in locomotor activity. However, Willner (1997) suggests that: "a rat exposed to CMS could, in principle, legitimately attract a DSM-IV diagnosis of either major depressive disorder or major depressive disorder with melancholic features" (Willner, 1997). Nevertheless, hyperlocomotion has also been reported in the OFT in response to mild threats after rats were subject to a chronic unpredictable stress (CUS) model (Sequeira-Cordero et al., 2019). ...
... In this respect, psychomotor agitation or retardation symptoms have been reported in humans with MDD, which is a far more complex behavior than a simple decrease in locomotor activity. However, Willner (1997) suggests that: "a rat exposed to CMS could, in principle, legitimately attract a DSM-IV diagnosis of either major depressive disorder or major depressive disorder with melancholic features" (Willner, 1997). Nevertheless, hyperlocomotion has also been reported in the OFT in response to mild threats after rats were subject to a chronic unpredictable stress (CUS) model (Sequeira-Cordero et al., 2019). ...
Major depressive disorder (MDD) is a global public health issue that impacts the lives of millions of individuals, resulting in substantial disability and reduced quality of life. Despite the development of various categories of antidepressant medications, a significant number of patients fail to respond effectively to treatment, underscoring the need for new therapeutic options. In this chapter, we briefly describe and discuss the face, construct, and predictive validities of two animal models used with success to identify potentially helpful antidepressant medications: the forced swim test (FST) and the chronic mild stress (CMS) models.
... CMS exposure leads to the development of depression-like symptoms in animals, which we confirmed in our study. In this model, rats subjected for a prolonged period of time to a variety of mild stressors gradually decrease their responsiveness to rewarding stimuli, which is comparable to anhedonia, the core clinical symptom of the melancholic subtype of major depressive disorder (reviewed by [18]). After 3 weeks of CMS exposure, in addition to the generated stress-reactive group, we obtained a "stress nonreactive" group that failed to reduce their drinking of a palatable solution despite being under the Furthermore, no double immunofluorescence staining was found for HSP72 and HSP90B or for the astrocyte marker GFAP in either the PFC or HIP areas (Supplementary Figure S3). ...
... CMS exposure leads to the development of depression-like symptoms in animals, which we confirmed in our study. In this model, rats subjected for a prolonged period of time to a variety of mild stressors gradually decrease their responsiveness to rewarding stimuli, which is comparable to anhedonia, the core clinical symptom of the melancholic subtype of major depressive disorder (reviewed by [18]). After 3 weeks of CMS exposure, in addition to the generated stress-reactive group, we obtained a "stress nonreactive" group that failed to reduce their drinking of a palatable solution despite being under the influence of stress. ...
... We observed that IMI reversed anhedonia in the "stress IMI resp" group of rats; however, we also differentiated a "stress IMI nonresp" group in which IMI applied for 5 weeks did not reverse anhedonia. The group that failed to respond to IMI treatment, the "stress IMI nonresp" group, is in agreement with observations of other laboratories [18,19], and it is believed to reflect patients with treatment-resistant depression [20]. ...
The HSP70 and HSP90 family members belong to molecular chaperones that exhibit protective functions during the cellular response to stressful agents. We investigated whether the exposure of rats to chronic mild stress (CMS), a validated model of depression, affects the expression of HSP70 and HSP90 in the prefrontal cortex (PFC), hippocampus (HIP) and thalamus (Thal). Male Wistar rats were exposed to CMS for 3 or 8 weeks. The antidepressant imipramine (IMI, 10 mg/kg, i.p., daily) was introduced in the last five weeks of the long-term CMS procedure. Depressive-like behavior was verified by the sucrose consumption test. The expression of mRNA and protein was quantified by real-time PCR and Western blot, respectively. In the 8-week CMS model, stress alone elevated HSP72 and HSP90B mRNA expression in the HIP. HSP72 mRNA was increased in the PFC and HIP of rats not responding to IMI treatment vs. IMI responders. The CMS exposure increased HSP72 protein expression in the cytosolic fraction of the PFC and HIP, and this effect was diminished by IMI treatment. Our results suggest that elevated levels of HSP72 may serve as an important indicator of neuronal stress reactions accompanying depression pathology and could be a potential target for antidepressant strategy.
... CMS exposure leads to the development of depression-like symptoms in animals, which we confirmed in our study. In this model, rats subjected for a prolonged period of time to a variety of mild stressors gradually decrease their responsiveness to rewarding stimuli, which is comparable to anhedonia, the core clinical symptom of the melancholic subtype of major depressive disorder (reviewed by [18]). After 3 weeks of CMS exposure, in addition to the generated stress reactive group, we obtained a "stress nonreactive" group that failed to reduce their drinking of a palatable solution despite being under the influence of stress. ...
... After 3 weeks of CMS exposure, in addition to the generated stress reactive group, we obtained a "stress nonreactive" group that failed to reduce their drinking of a palatable solution despite being under the influence of stress. In the CMS paradigm, animals that do not develop anhedonia during the first 3 weeks of stress exposure are usually rejected from the next steps of the CMS paradigm [18]. Here, we utilized the "stress nonreactive" group to evaluate whether changes in the expression of HSP72, HSC70, HSP90A and HSP90B underlie anhedonic resilience. ...
... We observed that IMI reversed anhedonia in the "stress IMI resp" group of rats; however, we also differentiated a "stress IMI nonresp" group in which IMI applied for 5 weeks did not reverse anhedonia. Both behavioral responses after CMS and IMI treatment are in agreement with observations of other laboratories and reflect the clinical situation of patients' responses to antidepressant treatment [18,19]. The group that failed to respond to IMI treatment, the "stress IMI nonresp" group, is believed to reflect patients with treatment-resistant depression [20]. ...
The HSP70 and HSP90 family members belong to molecular chaperones that exhibit protective functions during the cellular response to stressful agents. We investigated whether the exposure of rats to chronic mild stress (CMS), a validated model of depression, affects the expression of HSP70 and HSP90 in the prefrontal cortex (PFC), hippocampus (HIP) and thalamus (Thal). Male Wistar rats were exposed to CMS for 3 or 8 weeks. The antidepressant imipramine (IMI, 10 mg/kg, i.p., daily) was introduced in the last five weeks of the long-term CMS procedure. Depressive-like behavior was verified by the sucrose consumption test. The expression of mRNA and protein was quantified by real-time PCR and Western blot, respectively. In the 8-week CMS model, stress alone elevated HSP72 and HSP90B mRNA expression in the HIP. HSP72 mRNA was increased in the PFC and HIP of rats not responding to IMI treatment vs. IMI responders. The CMS exposure increased HSP72 protein expression in the cytosolic fraction of the PFC and HIP, and this effect was diminished by IMI treatment. Our results suggest that elevated levels of HSP72 may serve as an important indicator of neuronal stress reactions accompanying depression pathology and could be a potential target for antidepressant strategy.
... Most models consist of physical stressors that are applied chronically to rodents with the intent of inducing a depressive phenotype, being the chronic unpredictable mild stress model the most widely applied. It causes a generalized reduction in reward sensitivity, as opposed to a specific effect on response to sweet tastes ( Willner, 1997 ). ...
... As anhedonia is a key feature of depression, there was a need to develop behavioural assessments that identified the presence of anhedonic-like phenotypes in rodents ( Irons and Ribot, 1898 ). For that purpose, the single-bottle sucrose test ( Willner, 1997 ) and the sucrose preference test (SPT) were developed based on the premise that a reduction in sucrose intake in the experimental group relative to controls is demonstrative of anhedonia , being commonly used in labs worldwide. The SPT is currently considered the most reliable method for the assessment of anhedonia in mice and the most frequently used approach to assess the capacity to experience pleasure (hedonic reaction) based on the interest of animals in normally palatable foods ( Scheggi et al., 2018 ). ...
... The SPT uses a two-bottle choice paradigm, in which the rodents can freely choose between a sugary solution (sucrose or saccharin) and plain water ( Tordoff and Bachmanov, 2003 ). A decreased sucrose preference is considered to reflect the development of anhedonia, and this decrease does not seem to be due to the caloric content and does not originate a reduction in overall consummatory behaviour ( Hoffman, 2016 ;Willner, 1997 ). ...
Anhedonia is described as a decreased ability to experience rewarding and enjoyable activities, a core symptom of major depressive disorder. The sucrose preference test (SPT) is a widely used and reliable behavioural test to assess anhedonia in rodents, based on a two-bottle choice paradigm. To date, different protocols are in use, inducing variability between researchers and hampering comparisons between studies. We performed a systematic review of the SPT protocols used in 2021 to identify the parameters in which they differ and their potential impact. We searched a total of four databases (PubMed, Scopus, Web of Science and Science Direct), from 1st January 2021 to 31st December 2021, and screened a total of 1066 articles. After screening by title and abstract, a total of 415 articles were included in this review. We extracted and analysed the different procedures used, the type of sweet solution and the habituation, deprivation , and testing protocols. The overall quality of the studies was considered very good, however, SPT protocols were extremely variable between studies with a total of 65 different habituation protocols and 104 combinations of food/water deprivation and preference testing European Neuropsychopharmacology 77 (2023) 80-92 duration. As the SPT is one of the most used tests to assess anhedonia in rodents, this work raises awareness of the great variability in SPT protocols being currently used. Furthermore, we call for standardization in the protocol used, and overall improvement of data reporting of methodologies and results, to increase the consistency between studies and allow a better comparison of results between different labs.
... Rats assigned to the CUS groups were exposed to two of the following eight stressors daily for consecutive 21 days: 1) 40 Hz 90 dB noise stimulation for 9 min; 2) swimming for 5 min in 4℃ cold water; 3) body restraint for 1 h; 4) pinching tail for 1 min; 5) food deprivation for 24 h; 6) water deprivation for 24 h; 7) nyctohemeral rhythm inversion, and 8) cage tilt at 45º [19]. To prevent the rats from adapting to the stress factors, we exerted two different stress factors on them daily, and the stressors varied within 48 h [19]. ...
... Rats assigned to the CUS groups were exposed to two of the following eight stressors daily for consecutive 21 days: 1) 40 Hz 90 dB noise stimulation for 9 min; 2) swimming for 5 min in 4℃ cold water; 3) body restraint for 1 h; 4) pinching tail for 1 min; 5) food deprivation for 24 h; 6) water deprivation for 24 h; 7) nyctohemeral rhythm inversion, and 8) cage tilt at 45º [19]. To prevent the rats from adapting to the stress factors, we exerted two different stress factors on them daily, and the stressors varied within 48 h [19]. We performed the cardiac surgery under cardiopulmonary bypass (CPB) on day 22. ...
Objective
Preoperative chronic stress (CS) is associated with postoperative brain injury in patients undergoing open heart cardiac surgery. This research is to explore the potential molecular biological mechanisms of brain damage following cardiac surgery in preoperative CS rats by the analyses combining proteomics and metabolomics.
Methods
We constructed the chronic unpredictable stress (CUS) and cardiac surgery models in adult rats. We proved the brain injury in CUS cardiac surgery rats by Hematoxylin–Eosin (H&E) staining, followed by separating the hippocampal tissue and investigating the potential mechanisms of brain injury by the methods of data-independent acquisition proteomics and untargeted metabolomics.
Results
The signaling pathways of glycoproteins and metabolism of amino acids were the main possible mechanisms of brain injury in CUS rats following cardiac surgery according to the proteomics and metabolomics. In addition, the pathways of animo acids metabolism such as the pathways of lysine degradation and β-alanine metabolism may be the main mechanism of cardiac surgery related brain injury in preoperative CUS rats.
Conclusions
The pathways of animo acids metabolism such as lysine degradation and β-alanine metabolism may be the potential mechanisms of brain injury in CUS rats following cardiac surgery. We should focus on the varieties of bioproteins and metabolites in these pathways, and related changes in other signaling pathways induced by the two pathways.
... It plays an important role in screening novel antidepressants and therapeutic strategies [5][6][7]. However, conflicting results have been reported throughout the years, casting doubts on the reliability of the CUS model and the SPT as an outcome measure [8][9][10]. To understand these concerns, a brief mention of the methodology of the test is warranted. ...
... Whereas 24 h of water deprivation resulted in a decreased preference, 5-8 h did not [16]. In a series of papers aimed at easing these concerns and reaffirming the premise that CUS causes a decreased sensitivity to rewards [10,18], Paul Willner, the originator of the model, made some concessions. The stressful component of fasting procedures, and their effects on body weight, may influence the test. ...
The sucrose preference test is a popular test for anhedonia in the chronic unpredictable stress model of depression. Yet, the test does not always produce consistent results. Long food and water deprivation before the test, while often implemented, confounds the results by introducing unwanted drives in the form of hunger and thirst. We assessed the reliability of the test when only short or no fasting was used. We searched PubMed, Embase, and Web of Science for studies in rats exposed to chronic unpredictable stress that used no more than 6 h of food and/or water deprivation before the test. Sweet consumptions, for stressed and control/antidepressant-treated animals, in 132 studies were pooled using random effects models. We found a decrease in sweet consumption in stressed rats, compared to controls, that was halved when a non-caloric sweetener was used and significantly reduced when sucrose consumption was corrected for body weight. What is more, the length of food and water deprivation was found to confound the effect. The effect was reversed when the stressed rats were treated with antidepressants. Methodological strategies meant to control for recognized sources of bias when conducting the test were often missing, and so was a clear and complete report of essential study information. Our results indicate that not only is food and water deprivation before the test unnecessary, but not recommended. Even in absence of long fasting, we found evidence of an additional effect on sweet consumption that is unrelated to anhedonia. Without properly controlling for non-hedonic drivers of consumption, the test is unreliable as a proxy measure of anhedonia. Strengthening the methodological rigor and addressing the confounding effect of metabolic factors in the sucrose preference test prevents misleading conclusions that harm the translatability of the associated research and perpetuates the use of animals for little gain.
... A chronic mild stress (CMS) animal model of depression was selected as a widely accepted and reliable model with the presence of depression-like behavior. Several weeks of exposure to various types of stressors with a different intensity which cannot be predicted by the animals result in behavioral, neurochemical, and neuroanatomical changes parallel to the symptoms of MDD [18,19]. Those symptoms may then be reversed by chronic treatment with different groups of antidepressants, which seems to have a positive effect on hippocampal neurogenesis [20]. ...
... Fisher's LSD post hoc analysis also showed that administration of 25 mg/kg SMe1EC2M3 in the stress group significantly changed sucrose preference (p ≤ 0.05) and thus normalized the effect of stress conditions. behavioral, neurochemical, and neuroanatomical changes parallel to the MDD [18,19]. Those symptoms may then be reversed by chronic treatment groups of antidepressants, which seems to have a positive effect on neurogenesis [20]. ...
Despite an accumulating number of studies, treatments for depression are currently insufficient. Therefore, the search for new substances with antidepressant potential is very important. In this study, we hypothesized that treatment with a newly synthesized pyridoindole derivative compound SMe1EC2M3 would result in protective and antidepressant-like effects on behavioral outcomes and reverse the impaired adult hippocampal neurogenesis caused by chronic mild stress (CMS). We found that chronic administration of 5 mg/kg and 25 mg/kg SMe1EC2M3 to adult Sprague Dawley rats ameliorated the consequences of CMS on immobility and swimming time in a forced swim test. A slight sedative effect of the highest dose of SMe1EC2M3 in the nonstress group was observed in the open field. SMe1EC2M3 in the highest dose ameliorated CMS-induced decreases in the sucrose preference test. Administration of SMe1EC2M3 significantly increased SOX2-positive cells in the hippocampal dentate gyrus (DG) in CMS compared to control animals. A significant reduction in glial fibrillary acid protein (GFAP)-positive cells in the DG of CMS compared to control animals was observed. Administration of both 5 and 25 mg/kg SMe1EC2M3 significantly increased signal of GFAP-positive cells in the DG of CMS animals. No such effects of SMe1EC2M3 were observed in the cornu ammonis hippocampal area. Additionally, we found that incubation of primary hippocampal neurons in the presence of 1.50 µM SMe1EC2M3 significantly stimulated the length of neurites. Overall, we found that the negative effects of CMS on depression-like behavior are partially reduced by the administration of SMe1EC2M3 and are associated with changes in hippocampal neurogenesis and neuronal differentiation. SMe1EC2M3 represents a potential drug candidate with positive neuroplastic effects and neurogenesis-associated effects in therapeutic approaches to depression.
... This model employs a variety of mild stressors to ensure high construct validity. Rodents who have experienced CUS consistently exhibit anhedonia, characterized by the inability to feel pleasure under normally pleasurable conditions, as a prominent feature alongside other depressive-like symptoms [10]. In addition, CUS-exposed mice often shown comprehensive physiological changes, including alterations in neurotransmitter systems [11][12][13][14]. ...
... Anhedonia, which is characterized by a diminished ability to experience pleasure, is a prominent behavioral feature of depression [10]. Lower reward responsiveness is a behavioral characteristic of CUS. ...
Mental health is influenced by the gut-brain axis; for example, gut dysbiosis has been observed in patients with major depressive disorder (MDD). Gut microbial changes by fecal microbiota transplantation or probiotics treatment reportedly modulates depressive symptoms. However, it remains unclear how gut dysbiosis contributes to mental dysfunction, and how correction of the gut microbiota alleviates neuropsychiatric disorders. Our previous study showed that chronic consumption of Lactobacillus reuteri ATG-F4 (F4) induced neurometabolic alterations in healthy mice. Here, we investigated whether F4 exerted therapeutic effects on depressive-like behavior by influencing the central nervous system. Using chronic unpredictable stress (CUS) to induce anhedonia, a key symptom of MDD, we found that chronic F4 consumption alleviated CUS-induced anhedonic behaviors, accompanied by biochemical changes in the gut, serum, and brain. Serum and brain metabolite concentrations involved in tryptophan metabolism were regulated by CUS and F4. F4 consumption reduced the elevated levels of serotonin (5-HT) in the brain observed in the CUS group. Additionally, the increased expression of Htr1a, a subtype of the 5-HT receptor, in the medial prefrontal cortex (mPFC) of stressed mice was restored to levels observed in stress-naïve mice following F4 supplementation. We further demonstrated the role of Htr1a using AAV-shRNA to downregulate Htr1a in the mPFC of CUS mice, effectively reversing CUS-induced anhedonic behavior. Together, our findings suggest F4 as a potential therapeutic approach for relieving some depressive symptoms and highlight the involvement of the tryptophan metabolism in mitigating CUS-induced depressive-like behaviors through the action of this bacterium.
... Rodent models are commonly used to investigate the mechanisms by which chronic stress exposure contributes to risk as they recapitulate many of the behavioral and physiological effects seen in humans. Most models involve a battery of psychological, sensory, and homeostatic stressors, and while effective in inducing stress responses, the type, duration, and timing of exposure varies widely across research labs and produces an array of behavioral and physiological changes that rely on the individual animal's perception of and response to the stress, often resulting in variability between cohorts of animals even within a single lab [39][40][41][42][43][44][45]. Even widely used models, such as chronic variable or unpredictable stress, are often modified to fit the needs of individual groups. ...
... While utilization of animal models to study the lasting effects of chronic stress has provided important insight into mechanisms underlying disease risk, variability in outcomes between and within labs, as well as the high labor effort required for such studies, can often be an obstacle for the utilization and interpretation of these models [37,[39][40][41][42][43][44][45][56][57][58][59][60][61]. We developed a model using transgenic mice expressing the Gq-coupled Designer Receptors Exclusively Activated by Designer Receptors (DREADD) hM3Dq in corticotropin-releasing factor (CRF) neurons, allowing us to activate the CRF system with the DREADD ligand clozapine-N-oxide (CNO) in a timing-selective and highthroughput manner [51,52]. ...
Trauma and chronic stress exposure are the strongest predictors of lifetime neuropsychiatric disease presentation. These disorders often have significant sex biases, with females having higher incidences of affective disorders such as major depression, anxiety, and PTSD. Understanding the mechanisms by which stress exposure heightens disease vulnerability is essential for developing novel interventions. Current rodent stress models consist of a battery of sensory, homeostatic, and psychological stressors that are ultimately integrated by corticotropin-releasing factor (CRF) neurons to trigger corticosteroid release. These stress paradigms, however, often differ between research groups in the type, timing, and duration of stressors utilized. These inconsistencies, along with the variability of individual animals’ perception and response to each stressor, present challenges for reproducibility and translational relevance. Here, we hypothesized that a more direct approach using chemogenetic activation of CRF neurons would recapitulate the effects of traditional stress paradigms and provide a high-throughput method for examining stress-relevant phenotypes. Using a transgenic approach to express the Gq-coupled Designer Receptor Exclusively Activated by Designer Drugs (DREADD) receptor hM3Dq in CRF-neurons, we found that the DREADD ligand clozapine-N-oxide (CNO) produced an acute and robust activation of the hypothalamic-pituitary-adrenal (HPA) axis, as predicted. Interestingly, chronic treatment with this method of direct CRF activation uncovered a novel sex-specific dissociation of glucocorticoid levels with stress-related outcomes. Despite hM3Dq-expressing females producing greater corticosterone levels in response to CNO than males, hM3Dq-expressing males showed significant typical physiological stress sensitivity with reductions in body and thymus weights. hM3Dq-expressing females while resistant to the physiological effects of chronic CRF activation, showed significant increases in baseline and fear-conditioned freezing behaviors. These data establish a novel mouse model for interrogating stress-relevant phenotypes and highlight sex-specific stress circuitry distinct for physiological and limbic control that may underlie disease risk.
... Stress has an important role in the development of human depression [8]. Laboratory animals subjected to chronic unpredictable mild stress (CUMS) develop depressive symptoms similar to human depression [9,10]. CUMS-induced increase in brain oxidative stress is considered as a major factor for neurotoxicity and neuronal death, which may be responsible for the development of chronic stressinduced depression [11]. ...
... This test is an indicator of anhedonia-like behavioral change, indicating loss of interest or pleasure. Anhedonia, a main symptom of human major depression, was modeled by inducing a decrease in responsiveness to reward reflected by reduced consumption and/or preference of sweetened solutions [10,44]. In our study, stressed mice showed a decrease in sucrose preference as compared to unstressed mice. ...
Objective: Flowers of Tecomella undulata have been reported to be a rich source of flavonoids such as rutin and quercetin. The present study was designed to evaluate the effect of ethanol extract of flowers of T. undulata on chronic unpredictable mild stress (CUMS)-induced depression in Swiss young male albino mice. Methods: The mice were subjected to CUMS for 21 successive days. Ethanol extract of the flowers (50, 100, and 200 mg/kg, p.o.) and fluoxetine (20 mg/kg, p.o.) per se was administered for 21 successive days to separate groups of unstressed and stressed mice. Tail suspension test (TST) and sucrose preference test were used to evaluate the effect of the extract on depression-like behavior in mice. Results: Extract of flowers of T. undulata (100 and 200 mg/kg) significantly decreased immobility period of stressed mice in TST, indicating significant antidepressant-like activity of the extract. Stress-induced reduced sucrose preference was significantly restored by the extract. There was no significant effect on locomotor activity of mice by the extract and fluoxetine. The extract significantly reversed stress-induced increase in brain malondialdehyde levels; plasma nitrite and corticosterone levels; and also significantly reversed the stress-induced decrease in reduced glutathione and catalase levels. There was no significant effect of the extract on brain MAO-A activity in both unstressed and stressed mice. Conclusion: These results indicated that ethanol extract of flowers of T. undulata showed significant antidepressant-like activity in mice subjected to CUMS, probably through alleviation of oxidative stress and decrease in plasma corticosterone levels.
... The unpredictable chronic mild stress (CUMS) is useful, well-validated and reliable in modelling human depressive disorders in rodents. [15] In accordance with previous studies, CUMS induces anhedonia and learned helplessness which are key symptoms of depression [16] as well as hypothalamicpituitary-adrenal axis (HPA) dysfunction, augmentation of inflammatory markers and oxidative stress, [17] endothelial dysfunction. [18] Moreover, the animal studies used CUMS procedure for at least 4 weeks have occured cardiovascular disturbances such as increased sympathetic cardiac tonus and impaired in vitro vascular reactivity to similar with clinical findings. ...
... This model reliably produces depression-like behaviour such as anhedonia and learned helplessness. [15] In our study, this chronic stress model was confirmed by increased serum corticosterone level and elevated immobility time in FST. Another reason for selecting this animal model is that CUMS model has been used in recent animal studies which investigated the changes in vascular function in depression. ...
Objectives:
Chronic stress may lead to depression and vascular endothelial dysfunction. We aimed to evaluate the effects of propolis on vascular functions and the possible mechanisms of its vascular effects in the rat model of chronic unpredictable mild stress (CUMS)-induced depression.
Methods:
Male Wistar rats were divided into control, stress (exposure to CUMS), control+propolis and stress+propolis groups (n = 8/each group). CUMS model was induced by exposing rats to various mild stressors daily for 5 weeks. The extract of propolis (100 mg/kg/day) was administered orally to propolis-treated groups for 5 weeks. The depression-like behaviours were assessed with the forced swimming test (FST). Chronic stress resulted in increased immobility response in FST and elevated serum corticosterone levels. Thoracic endothelial functions and expressions of endothelial nitric oxide synthase (eNOS), tumor necrosis factor-alpha (TNFα), interleukin-1beta (IL-1β), Heme oxygenase-1 (HO-1) and superoxide dismutase (SOD) level were assessed.
Key findings:
Compared to control group, stress group exhibited a significant decrease in endothelium-dependent relaxations, and eNOS, SOD and HO-1 expressions, whereas a significant increase in the thoracic expressions of TNFα and IL-1β. Propolis ameliorated depression-like behaviours, vascular endothelial dysfunctions and alterations of protein expressions.
Conclusion:
Propolis exerted antidepressant-like and vasculoprotective effects in CUMS-induced depression in rats. Chronic propolis treatment may have a protective effect on CUMS-induced vascular endothelial dysfunction by its anti-inflammatory and antioxidant effects.
... Here, we provide compelling demonstrations that API could be a potent inhibitor of MAOA. In order to establish this, we proposed that since API has demonstrated potent in vitro inhibitory effects against MAOA in a previous study (Chaurasiya et al., 2014); subjecting the animals to the CUMS paradigm (a well validated test used in the context of chronic depression in animals) (Katz et al., 1981;Willner, 1997;Willner et al., 1987), as well as treating the animals with API for a longer time, could establish this. Our results showed that API attenuated CUMS-induced depression, and that this effect could be mediated through the inhibition of MAOA enzyme activity, reducing oxidative stress, inflammation and neuroendocrine signaling pathways in mice. ...
... CUMS is an experimental model used to mimic negative life occurrences that happen to humans which may result in anhedonia in rats (Willner, 1997). In this present study, SST, EPM, FST and TST were utilized to evaluate the effects of API on the behavioral performances of CUMS-induced mice. ...
Chronic stress is a risk factor for depression and is characterized by elevated levels of brain monoamine oxidase A (MAOA). Mounting evidence has shown that MAOA is a biochemical link between stress and depression. Apigenin (API), a natural flavonoid, as demonstrated in vitro inhibitory effect on MAOA, is suggestive of antidepressant-like activity. However, the in vivo inhibitory effect of API on MAOA and how it affects depression still remain unclear. Here, we report the probable mechanisms of action of API in chronic unpredictable mild stress (CUMS)-induced depression in mice. Treatment with API reversed anhedonia, and reduced anxiety and immobility time in behavioral studies. API reduced brain corticosterone and malondialdehyde (MDA) levels but increased brain levels of glutathione and superoxide dismutase. Furthermore, interleukin-6 and tumor necrosis factor-α were attenuated by API. It also restored cell loss and inhibited the activity of MAOA in the hippocampal brain regions and prefrontal cortex. Comparative binding affinity of API for MAOA (-7.7 kcal/mol) through molecular docking studies was greater than that of reference compound, clorgyline (-6.8 kcal/mol). Favorable hydrophobic interactions important to API binding at MAOA binding cavity was revealed to include conventional hydrogen bond (Cys323 and Tyr444), π-Sulfur (Cys323), π-π Stacked (Tyr407), π-π T-shaped (Phe208), π-lone pair and π-alkyl (Ile335, Ile180) interactions. These results suggest that API is a potent, selective, reversible inhibitor of MAOA with capability of attenuating CUMS-induced depression via inhibiting MAOA enzyme activity and altering other pathomechanisms.
... An approach to induce increased levels of circulating GCs in rodents is through the use of an Unpredictable Chronic Mild Stress (UCMS) model. UCMS has been shown to cause anxiety, depressive-like behavior, increased levels of corticotrophin releasing factor (CRF), increased circulating corticosterone, and glucose intolerance [22], and has been shown to be a valid and reliable model to examine the neurobiological consequences of chronic stress [23,24]. Therefore, the current study utilized the UCMS model to determine its effect on β-cell morphology and skeletal muscle signaling for atrophy and autophagy. ...
... A UCMS protocol with varying stressors that was modified from Willner [23] was used in the study (Fig. 2). The seven hours of stress consisted of short, 1-3.5 h changing blocks of stressors. ...
Purpose
To evaluate chronic stress and voluntary wheel running on murine beta-cell number, insulin-positive area, hind limb skeletal muscle morphology, autophagy protein abundance, and muscle atrophy gene expression.
Methods
Forty male Balb/c mice were randomized into four groups: sedentary (N = 10: Sed), sedentary stressed (N = 10: St), exercise (N = 10: Ex), and exercise stressed (N = 10: ExSt).
Results
Body weight increased more in ExST than Ex by week four of stress; Ex weighed less than Sed and St mice at study conclusion. Islet area was increased in ExSt (24,223 ± 2670 µm²) vs. Ex mice (16,811 ± 2704 µm²), (P < 0.05) Average β-cell number per islet was higher in ExSt (93.2 ± 5.7) and St (91.0 ± 5.2) mice when compared to Ex (68.6 ± 3.7) or Sed (70.7 ± 4.8), (P < 0.05). Exercise, with or without stress (Ex, ExSt), increased muscle mass vs. Sed and St mice, (P < 0.05). Both the total AKT and the pAKT protein levels were increased in ExSt vs. Sed. TOPORS mRNA expression was reduced in the Ex and ExST compared to both Sed and St; Nedd41 real-time mRNA expression was reduced in Ex vs. Sed, and St. Beclin-1 protein abundance was reduced in Ex and ExSt vs. Sed.
Conclusion
Eight weeks of chronic stress increased β-cell proliferation and islet area, but did not increase muscle ubiquitin-associated atrophy gene mRNA levels. Exercise coupled with stress appeared to improve muscle protein accumulation, and therefore could be a potential means to reduce muscle losses under conditions of mild stress or β-cell dysfunction.
... The most commonly used animal model of depression in the present studies was the UCMS paradigm, which is based on the development of anhedonia following exposure to chronic, variable stressors (Willner, 2017;Nollet, 2021). The model has strong theoretical appeal, based on the chronic onset of the antidepressant response, and performs well on key measures of validity (Willner, 1997). Nevertheless, the model has been criticized on both theoretical and practical grounds (Forbes et al., 1996;Barr and Phillips, 1998;Planchez et al., 2019;Markov and Novosadova, 2022), although a recent meta-analysis supported the utility of the model when specifically measuring anhedonia (Antoniuk et al., 2019). ...
One of the most important developments in psychopharmacology in the past decade has been the emergence of novel treatments for mood disorders, such as psilocybin for treatment-resistant depression. Psilocybin is most commonly found in different species of mushroom; however, the literature on mushroom and fungus extracts with potential antidepressant activity extends well beyond just psilocybin-containing mushrooms, and includes both psychedelic and non-psychedelic species. In the current review, we systematically review the preclinical literature on mushroom and fungus extracts, and their effects of animal models of depression and tests of antidepressant activity. The PICO structure, PRISMA checklist and the Cochrane Handbook for systematic reviews of intervention were used to guide the search strategy. A scoping search was conducted in electronic databases PubMed, CINAHL, Embase and Web of Science. The literature search identified 50 relevant and suitable published studies. These included 19 different species of mushrooms, as well as seven different species of other fungi. Nearly all studies reported antidepressant-like effects of treatment with extracts. Treatments were most commonly delivered orally, in both acute and chronically administered studies to predominantly male rodents. Multiple animal models of depression were used, the most common being unpredictable chronic mild stress, while the tail suspension test and forced swim test were most frequently used as standalone antidepressant screens. Details on each experiment with mushroom and fungus species are discussed in detail, while an evaluation is provided of the strengths and weaknesses of these studies.
... The control group and CUMS group were given 0.9% saline (10 mL/kg). Except for those in the control group, the rats in the other groups were exposed to CUMS for 4 weeks according to previous methods (15). The stressors included 5-min swimming in cold water (4 • C), 2-min electric foot shock (rats receive unavoidable 3 mA intensity electric foot shocks for a duration of 200 ms with a frequency of one shock per second), 2-min tail clamping, 3-h noise (100 dB), subject to a hot environment (45 • C) for 5 min, 24-h water deprivation, 24-h food deprivation. ...
The gut microbiota is thought to be an important factor that influences brain processes and behaviors through the gut–brain axis. Pogostemon cablin is used in traditional Chinese medicine (TCM) to treat gastrointestinal symptoms. Patchouli essential oil (PCO), the main active agent in P. cablin, is used in aromatherapy for stress relief. The aim of our study was to investigate the effects of orally administered PCO on anxiety- and depressive-like behaviors and the gut microbiota. We constructed a rat model of chronic unpredictable mild stress (CUMS) and explored the anxiolytic- and antidepressant-like effects of PCO using the open field test (OFT) and forced swim test (FST). Changes in the abundance of the gut microbiota, short-chain fatty acids (SCFAs), and other related molecules were assessed to determine the role of the gut microbiota. Our results showed that CUMS induced an anxiety-like phenotype in the OFT, which was reversed by PCO, and that PCO also significantly mitigated the depression-like behaviors caused by CUMS in the FST. Furthermore, we found that PCO increased the relative abundances of several probiotics, including Bacteroides and Blautia, and decreased the relative abundances of Ruminococcus_1 and Ruminococcus_2, which were increased by CUMS. Regarding SCFAs, the metabolites of the gut microbiota, PCO increased the concentration of propionic acid and decreased that of caproic acid. Finally, PCO restored the serotonin (5-hydroxytryptamine, 5-HT) level in the hippocampus, which had been decreased by CUMS. The results of this study suggested that PCO can improve stress-related anxiety- and depression-like behaviors and might exert its effects on the central nervous system through interactions with the gut microbiota.
... Chronic mild stress is the procedure, during which an animal is exposed to a variety of 2-3 mild stressors each day (i.e., random cage rotation, food or water deprivation, overnight illumination, cage tilt) for several weeks. This model brings possibility to explore the complex nature of depressive disorders with emphasis on anhedonia (Brotto et al. 2001;Willner 1997). Repeated restraint stress is another type of procedure employed to induce depressive-like behavior in rodents. ...
As major depressive disorder is becoming a more and more common issue in modern society, it is crucial to discover new possible grip points for its diagnosis and antidepressive therapy. One of them is endocannabinoid system, which has been proposed as a manager of emotional homeostasis, and thus, endocannabinoid alterations have been found in animals undergoing various preclinical models of depression procedures as well as in humans suffering from depressive-like disorders. In this review article, studies regarding those alterations have been summed up and analyzed. Another important issue raised by the researchers is the impact of currently used antidepressive drugs on endocannabinoid system so that it would be possible to predict reversibility of endocannabinoid alterations following stress exposure and, in the future, to be able to design individually personalized therapies. Preclinical studies investigating this topic have been analyzed and described in this article. Unfortunately, too few clinical studies in this field exist, what indicates an urgent need for collecting such data, so that it would be possible to compare them with preclinical outcomes and draw reliable conclusions.
... The protocol for CUMS consists of exposing the animals to continuous physical and environmental unpredictable stressful events of moderate intensity, always avoiding repeating the stress on the same day of the week [38][39][40][41][42]. At day 1, animals were kept in boxes tilted (45º) for a period of 5 h; at day 2, animals were subjected to a 5 h period of food and water deprivation (9am to 2 pm); at day 3, animals were subjected to confinement in tubes for a period of 1 h; at day 4, the pairing of animals from different boxes was performed for a period of 2 h; at day 5, animals were subjected to a 36 h period with intermittent light; at day 6, animals were exposed to a 4 h period under strobe light; and at day 7, shavings moistened with 300 mL of water were introduced in boxes for 17 h.. ...
Major Depressive Disorder (MDD) is a severe and multifactorial psychiatric condition. Evidence has shown that environmental factors, such as stress, significantly explain MDD pathophysiology. Studies have hypothesized that changes in histone methylation patterns are involved in impaired glutamatergic signaling. Based on this scenario, this study aims to investigate histone 3 involvement in depression susceptibility or resilience in MDD pathophysiology by investigating cellular and molecular parameters related to i) glutamatergic neurotransmission, ii) astrocytic functioning, and iii) neurogenesis. For this, we subjected male Wistar rats to the Chronic Unpredictable Mild Stress (CUMS) model of depression. We propose that by evaluating the sucrose consumption, open field, and object recognition test performance from animals submitted to CUMS, it is possible to predict with high specificity rats with susceptibility to depressive-like phenotype and resilient to the depressive-like phenotype. We also demonstrated, for the first time, that patterns of H3K4me3, H3K9me3, H3K27me3, and H3K36me3 trimethylation are strictly associated with the resilient or susceptible to depressive-like phenotype in a brain-region-specific manner. Additionally, susceptible animals have reduced DCx and GFAP and resilient animals present increase of AQP-4 immunoreactivity. Together, these results provide evidence that H3 trimethylations are related to the development of the resilient or susceptible to depressive-like phenotype, contributing to further advances in the pathophysiology of MDD and the discovery of mechanisms behind resilience.
... On day 1 was alteration of day-night cycle, on day 2 was exposure to cold water immersion stress and on day 3 was restraint stress. This cycle was repeated for a total of 21 days (in total 7 cycles of three stressors) and due to the alternating nature of the stressors, adaptation to stress did not occur (Willner, 1997). The details of the stressors are as follows: - ...
... The UCMS protocol is a well-defined model to induce a depressive state in rodents. 28 Rodents undergoing UCMS manifest with clinically relevant depressive symptoms such as anhedonia and learned helplessness 28 with alterations in brain structure and function parallel to clinical depression. 29 Rats were singly housed in UCMS groups and exposed to the following mild environmental stressors in randomly chosen sequences for 8 h each day, 5 days/ week, over the course of 8 weeks: Damp bedding-10 oz. of water was added to each standard cage, bath-all bedding was removed and ~0.5 inches of water was added to empty cage, water temperature was room temperature, ~24°C, cage Tilt-cage was tilted to 45 degrees without bedding, social stress-each rat was switched into a cage of a neighboring rat, no bedding-all bedding was removed from the cage, alteration of light/dark cycles-turning lights off/on in random increments for scheduled period. ...
Obesity is driven by an imbalance between caloric intake and energy expenditure, causing excessive storage of triglycerides in adipose tissue at different sites around the body. Increased visceral adipose tissue (VAT) is associated with diabetes, while pericardial adipose tissue (PAT) is associated with cardiac pathology. Adipose tissue can expand either through cellular hypertrophy or hyperplasia, with the former correlating with decreased metabolic health in obesity. The aim of this study was to determine how VAT and PAT remodel in response to obesity, stress, and exercise. Here we have used the male obese Zucker rats, which carries two recessive fa alleles that result in the development of hyperphagia with reduced energy expenditure, resulting in morbid obesity and leptin resistance. At 9 weeks of age, a group of lean (Fa/Fa or Fa/fa) Zucker rats (LZR) and obese (fa/fa) Zucker rats (OZR) were treated with unpredictable chronic mild stress or exercise for 8 weeks. To determine the phenotype for PAT and VAT, tissue cellularity and gene expression were analyzed. Finally, leptin signaling was investigated further using cultured 3T3‐derived adipocytes. Tissue cellularity was determined following hematoxylin and eosin (H&E) staining, while qPCR was used to examine gene expression. PAT adipocytes were significantly smaller than those from VAT and had a more beige‐like appearance in both LZR and OZR. In the OZR group, VAT adipocyte cell size increased significantly compared with LZR, while PAT showed no difference. Exercise and stress resulted in a significant reduction in VAT cellularity in OZR, while PAT showed no change. This suggests that PAT cellularity does not remodel significantly compared with VAT. These data indicate that the extracellular matrix of PAT is able to remodel more readily than in VAT. In the LZR group, exercise increased insulin receptor substrate 1 (IRS1) in PAT but was decreased in the OZR group. In VAT, exercise decreased IRS1 in LZR, while increasing it in OZR. This suggests that in obesity, VAT is more responsive to exercise and subsequently becomes less insulin resistant compared with PAT. Stress increased PPAR‐γ expression in the VAT but decreased it in the PAT in the OZR group. This suggests that in obesity, stress increases adipogenesis more significantly in the VAT compared with PAT. To understand the role of leptin signaling in adipose tissue remodeling mechanistically, JAK2 autophosphorylation was inhibited using 5 μM 1,2,3,4,5,6‐hexabromocyclohexane (Hex) in cultured 3T3‐derived adipocytes. Palmitate treatment was used to induce cellular hypertrophy. Hex blocked adipocyte hypertrophy in response to palmitate treatment but not the increase in lipid droplet size. These data suggest that leptin signaling is necessary for adipocyte cell remodeling, and its absence induces whitening. Taken together, our data suggest that leptin signaling is necessary for adipocyte remodeling in response to obesity, exercise, and psychosocial stress.
... In this context, nitric oxide (NO) has been implicated in modulating physiological functions, such as depression response (KOUROSH-ARAMI et al., 2020) related to the stress (WILLNER, 1997;BROOKS et al., 2018) . ...
Learned helplessness is the condition of humans or animals that have learned to behave helplessly, failing to respond even though there are opportunities to help themselves by avoiding unpleasant circumstances. It was investigated the participation of nitric oxide (NO) in female Wistar rats in learned helplessness tests. The animals received acute treatment with N–nitro-l-arginine methyl ester (L-NAME, 10 mg/kg or 100 mg/kg), an inhibitor of NO synthase, 30 minutes before random inescapable shock sessions lasting 25 minutes. On the test day, the animals that received L-NAME of 10 mg/kg or 100 mg/kg 24 hours beforehand, demonstrated reduced difference between stress and non-stress groups compared with control groups. The activity of the neuronal nitric oxide synthase was lower in animals pretreated with L-NAME, especially at a dose of 100 mg/kg. These results indicate that acute inhibition of NO synthase improved learned helplessness response, suggesting that NO is involved with stress and depression.
... The principle behind this model is to induce behavioral changes in rats that are similar to the clinical manifestations of MDD by subjecting them to chronic mild and unpredictable stimulation. According to Willner, the chronic mild stress model is often used as an effective model for studying the pathogenesis of MDD and the mechanisms of antidepressant drugs due to its rationality as an animal model and its similarity to the mental symptoms of MDD and response to antidepressant drugs [46][47][48]. Guo (Table 1). Similar findings were reported by Hua et al. and Fan et al. [28,29]. ...
With the development of society and changes in lifestyle, major depressive disorder (MDD) has become a significant disease that plagues many people. Licorice, an excellent natural medicine with a long history of cultivation and application, is found in classical antidepressant prescriptions such as Chaihu Shugan Powder, Ganmai Dazao Decoction, Suanzaoren Decoction, etc. Licorice mainly contains triterpenoids and flavonoids, among which licorice total flavonoids (LF) and liquiritin are the main active components with good antidepressant effects. The pharmacological effects of licorice have been extensively investigated in current studies. However, a review of the antidepressant effects of LF and liquiritin has not been conducted. This article reviews the antidepressant effects of LF and liquiritin, including the biological characteristics of licorice and the pharmacological mechanism of LF and liquiritin in treating MDD. Studies have shown that LF and liquiritin can exert their antidepressant effects by improving depressive behavior, regulating endocrine and hypothalamic-pituitary-adrenal (HPA) axis function, affecting the brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB) signaling pathway, enhancing synaptic plasticity, increasing monoamine neurotransmitter levels, protecting nerve cells, reducing inflammation, preventing apoptosis, reducing oxidation and other ways. This lays a theoretical foundation for the development of antidepressant drugs.
... The design and execution of the CUMS procedure referred to preceding studies with suitable changes [32,33]. During the CUMS procedure, except for the CON group, the rats were exposed to stressors, consisting of water and food deprivation (12 h), restraint (2 h), tilt cage (45 • , 12 h), day and night reversal (Light off/on 12 h), wet location (24 h), horizontal shaking (10 min), clip tail (2 min), single cage (24 h), noise (30 min) and ice water stimulation (4 • C, 15 min), which were illustrated in Fig. 1. ...
Depression is a complex and prevalent mental illness. Cherry leaf is a traditional Chinese herbal medicine, which has confirmed to exert a certain antidepressant effect, but its potential neural regulation mechanism is not clear. This paper aims to investigate the improved action of cherry leaf decoction (CLD) on chronic unpredictable mild stress (CUMS) rats and its potential neural regulation mechanism by verifying the role and function of NMDAR regulatory target α2δ-1 in depression due to CUMS. Male SD rats were subjected to random stressors persisting for 5 weeks to establish the CUMS depression rat model. CLD could effectively alleviate depression-like behaviors of CUMS rats in behavioral tests including sucrose preference test, forced swimming test, tail suspension test and open field test. After the administration of the CLD, the expression of corticotropic-releasing hormone (CRH) in the hypothalamus was inhibited. Moreover, the levels of CRH, adrenal cortical hormone (ACTH) and corticosterone (CORT) in serum also decreased significantly. CUMS upregulated the expressions of α2δ-1, N-methyl-d-aspartate receptor 1 (NR1), NR2A and NR2B, and enhanced the binding ability to of α2δ-1 and NR1, which were reversed by CLD. The results demonstrated that CLD could ameliorate depression-like behaviors due to CUMS, which was related to the fact that CLD down-regulated α2δ-1 level and interfered with α2δ-1 binding to NR1, thereby reducing NMDAR expression and ultimately inhibiting HPA axis activity.
... Harding et al. (2004) have developed a cognitive bias method for determining affective state in animals, based on measuring emotionally induced biases in decision making. Their findings indicated that rats in unpredictable housing, inducing a mild negative affective state (Willner, 1997), were more pessimistic in response to ambiguous stimuli than controls. The method has been applied successfully to a number of other species, including starlings (Matheson et al., 2008), sheep (Doyle et al., 2010) and dogs (Mendl et al., 2010a). ...
... From adaptive feeding to the end of the trial, body weights were conducted once a week. Sucrose preference test (SPT) (Willner 1997), forced swimming test (FST) (Zhao et al. 2018) and open field test (OPT) (Guo et al. 2019) were carried out at one week before modeling, fourth and senveth week after modeling. ...
Introduction
Chaigui granules are a novel manufactured traditional Chinese antidepressant medicine, which is originated from the ancient classical prescription of Xiaoyaosan. It ameliorated depression-like behavior and concomitant symptoms in animal models. But its antidepressant mechanism is still unclear. Therefore, network pharmacology and molecular biology were used to explore underlying antidepressant mechanism in this study.
Methods
Firstly, network pharmacology was used to screen main active ingredients and potential targets in the treatment of depression with Chaigui granules, and to perform pathway enrichment analysis. Secondly, chronic and unpredictable mild stress-induced depression model rats were used, and behavioral tests were used to evaluate the antidepressant effect of Chaigui granules. Finally, the core targets and key pathways predicted by network pharmacology were validated by qRT-PCR and Western blot to determine the relevant gene and protein expression levels in rat hippocampus.
Results
The results of network pharmacology indicated that the PI3K/Akt signaling pathway may play a key role in antidepressant of Chaigui granules. The results of animal experiments showed that Chaigui granules significantly modulated behavioral indicators. Subsequently, the upregulation of relative mRNA levels of mTOR, Akt and PI3K and downregulation of GSK-3β and FoxO3a were observed in rat hippocampus by molecular biology diagnosis. In addition, the decreased expression of Akt and mTOR in CUMS rats hippocampus was significantly reversed, and the expression levels of GSK-3β and FoxO3a were upregulated.
Conclusions
Based on the results of network pharmacology and animal experiment validation, Chaigui granules may reverse CUMS-induced depression-like behavior in rats through PI3K/Akt/mTOR signaling pathway.
... T he origins of the unpredictable chronic stress (UCS) protocol go back to the early 1980s, when researchers proposed the chronic administration of a variety of stressors to rodents to induce behavioral alterations relevant to the study of depression [1][2][3][4] . Construct, face and predictive validities of this model are supported by many studies, showing that rodents exposed to the UCS protocol develop anhedonia-like behavior, cognitive deficits, hormonal and neurochemical imbalances, weight loss and other changes that can be reversed by using antidepressant treatments 5 . Given its translational potential, there has been an exponential growth in the implementation of this protocol across laboratories as it has become an important tool for the study of the neurobiological basis of depression and antidepressant action 6,7 . ...
The zebrafish (Danio rerio) is a model animal that is being increasingly used in neuroscience research. A decade ago, the first study on unpredictable chronic stress (UCS) in zebrafish was published, inspired by protocols established for rodents in the early 1980s. Since then, several studies have been published by different groups, in some cases with conflicting results. Here we conducted a systematic review to identify studies evaluating the effects of UCS in zebrafish and meta-analytically synthetized the data of neurobehavioral outcomes and relevant biomarkers. Literature searches were performed in three databases (PubMed, Scopus and Web of Science) with a two-step screening process based on inclusion/exclusion criteria. The included studies underwent extraction of qualitative and quantitative data, as well as risk-of-bias assessment. Outcomes of included studies (n = 38) were grouped into anxiety/fear-related behavior, locomotor function, social behavior or cortisol level domains. UCS increased anxiety/fear-related behavior and cortisol levels while decreasing locomotor function, but a significant summary effect was not observed for social behavior. Despite including a substantial number of studies, the high heterogeneity and the methodological and reporting problems evidenced in the risk-of-bias analysis made it difficult to assess the internal validity of most studies and the overall validity of the model. Our review thus evidences the need to conduct well-designed experiments to better evaluate the effects of UCS on diverse behavioral patterns displayed by zebrafish.
... The procedure for TST was reported as previously described [16]. Mice were assessed in the TST, which was performed with a computerized device allowing four animals to be tested at one time. ...
A response surface methodology was applied to optimize the variables affecting
the supercritical fluid carbon dioxide extraction of oil from the fruit of Gardenia jasminoides
using the Box–Behnken design. The optimum extraction parameters were an extraction
temperature of 49.94 °C, an extraction pressure of 29.89 MPa and an extraction time of
93.82 min. Through a GC/MS analysis, we revealed 16 major components of the oil
extract, which showed potent antidepressant effects in both of two behavior despair models
in mice: tail suspension test and forced swimming test. Our results suggest that the oil
extract of Gardenia jasminoides prepared using the supercritical fluid carbon dioxide
extraction may contain effective constituents to be used for depression therapy.
... Chronic stress is a major risk factor for psychiatric illnesses (Mazure, 1998;Tennant, 2002). Previous trauma exposure increases attentional bias towards a new threat (Blekić et al., 2021) and experimentally, chronic stress in animal models has been shown to alter valence behaviors, increasing negative valence processing (Monteiro et al., 2015;Willner et al., 1987) (for review see (Tran and Gellner, 2023;Willner, 1984Willner, , 1997Willner, , 2017Willner et al., 1992)). The circuits implicated in valence process overlap with those implicated in stress (for review see (Daviu et al., 2019)). ...
The basolateral amygdala (BLA) is an emotional processing hub and is well-established to influence both positive and negative valence processing. Selective engagement of a heterogeneous cell population in the BLA is thought to contribute to this flexibility in valence processing. However, how this process is impacted by previous experiences which influence valence processing is unknown. Here we demonstrate that previous positive (EE) or negative (chronic unpredictable stress) experiences differentially influence the activity of specific populations of BLA principal neurons projecting to either the nucleus accumbens core or bed nucleus of the stria terminalis. Using chemogenetic manipulation of these projection-specific neurons we can mimic or occlude the effects of chronic unpredictable stress or enriched environment on valence processing to bidirectionally control avoidance behaviors and stress-induced helplessness. These data demonstrate that previous experiences influence the responsiveness of projection-specific BLA principal neurons, biasing information routing through the BLA, to govern valence processing.
... 11 Unpredictable chronic mild stress (UCMS) is an important behavioral model that resembles human depression. 14 The hippocampus and its connections within limbic-cortical networks may play a crucial role in the pathogenesis of major depression. Acute stress and chronic stress disturb hippocampal-dependent memory and prevent the formation of longterm potentialization, which plays a role in the formation of synaptic plasticity and memory. ...
... In the USA, depression affects adolescents and accounts for one-third of adolescent fatalities [10]. There are many animal models that mimic human depression, but the chronic mild stress (CMS) model is the most widely used model that replicates the main symptoms of human depression [11]. In this model, rats are exposed to multiple stressors, which alters their behavior and biochemistry by altering the chemistry, plasticity, expression, and function of their neurons, neuroreceptors, and neurotrophin [12]. ...
Background:
Stress can lead to emotional and mental symptoms such as anxiety, sadness, panic attacks, and depression. Malic acid was chosen due to malic acid has the ability to improve antioxidant activity and improves liver damage. This study evaluates malic acid anti-depressant activity in the hypothalamus of stressed rats.
Methods:
Thirty-six male albino rats were divided into 2 equal groups; Normal and chronic mild stress (CMS) rats. Normal rats were divided into 3 equal groups; control, malic acid, and venlafaxine drug groups: normal rats were administered orally with 1 mL of saline solution, 250 mg/kg of malic acid, and 20 mg/kg of venlafaxine drug, respectively. CMS rats were divided into 3 equal groups; CMS, CMS + malic acid, and CMS + venlafaxine drug: CMS rats were administered orally with 1 mL of saline solution, 250 mg/kg of malic acid, and 20 mg/kg of venlafaxine drug, respectively. All the above-mentioned treatments were administered once a day by oral gavage for 6 weeks.
Results:
The obtained results revealed that the animal behavioral tests such as forced swimming test, tail suspension test, sucrose preference test, and open-field test (center square entries test, center square duration test, and distance travelled test), norepinephrine, dopamine, serotonin, γ-aminobutyric acid, nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity, oxidative index, conjugated dienes, catalase, glutathione peroxidase, superoxide dismutase, malondialdehyde, interleukin-6, tumor necrosis factor-α, interleukin-10, interleukin-1β, sodium/potassium-ATPase activity, and histamine-N-methyl transferase (Hnmt) and tyrosine hydroxylase (TH) enzymes in the hypothalamus of stressed rats, were returned to approaching the normal state in the stressed group after treating with malic acid for 6 weeks.
Conclusions:
Malic acid ameliorated stressed-related symptoms and it inhibited superoxide anion and neuro-inflammation in the hypothalamus of stressed rats.
... Play is also a 'low resilience' behaviour, being energetic and yet relatively non-essential to survival, and such behaviours are often early indicators of poor welfare, because stressed or diseased animals conserve their energy to prioritise the essential behaviours [44]. Additionally, if the ear problems cause a depression-like state, then lack of responsiveness to a treat and lack of binkying could indicate anhedonia in the rabbits [52]. ...
The impacts of ear disease on animal welfare and behaviour are little documented. Ear disease may be common in rabbits, but difficult to recognise, and lop-ears have previously been indicated as a risk factor for ear disease. We aimed to better understand the range of ear conditions in pet rabbits, signalment risk factors, and impacts on welfare and behaviour. Through an online questionnaire, we investigated owner-reported signalment, veterinary diagnosis of ear conditions, impaired hearing, and ear pain for UK pet rabbits. Relationships between ear condition measures and ear conformation, quality of life, and behaviour were analysed using logistic regression. Of 551 valid responses, 28.5% of rabbits reportedly had experienced ear conditions; 21.2% diagnosed or mentioned by vets, with otitis and excess cerumen most common. Approximately 25% of lop-eared rabbits had ear conditions indicated by a vet versus 10% of erect-eared rabbits. Lop-eared, half-lop, and older rabbits were most at risk (P<0.050). Rabbits reported as showing ear pain responses had reduced owner-reported quality of life compared with other rabbits (P<0.050). Rabbits with ear problems were less likely to be responsive to relevant sounds, and performed binky behaviour (joy jumps) less frequently, than rabbits without such issues. Understanding prevalence and risk factors for ear conditions is critical to improving welfare standards across this widely owned pet species. The findings suggest that improved recognition and treatment of ear conditions, and avoiding breeding from rabbits with early signs, or a family history, of ear disease are necessary to help combat this animal welfare issue.
... However, various tests of different depression-like behaviors based on exposure to stressful stimuli have been developed, including the learned helplessness model (Seligman et al. 1980), the FST (Porsolt et al. 1977) and the tail suspension test (Steru et al. 1985) to be used with different animal models of depression, e.g. rodents subjected to chronic mild stress (Willner 1997) or FSL rats. The forced swim test is the most widely used test of behavioral despair, i.e. the despair elicited by the exposure to animals to an inescapable situation, and it is based on assumption that rodents will try to escape an aversive stimulus. ...
Background:
Major depressive disorder (MDD) is defined as a complex mental disorder which is characterized by a pervasive low mood and aversion to activity. Several types of neurotransmitter systems e.g. serotonergic, glutamatergic and noradrenergic systems have been suggested to play an important role in the origination of depression, but neurotrophins such as brain derived neurotrophic factor (BDNF) have also been implicated in the disease process.
Objectives:
The purpose of this study was to examine the effects of a newly developed class of molecules, characterized as positive allosteric modulators of neurotrophin/Trk receptor mediated signaling (Trk-PAM), on neurotransmitter release and depression-like behavior in vivo.
Methods:
The effect of and possible interaction of neurotrophin/Trk signaling pathways with serotonergic and glutamatergic systems in the modulation of depression-related responses was studied using newly developed Trk-PAM compounds (ACD855, ACD856 and AC26845), as well as ketamine and fluoxetine in the forced swim test (FST) in rodents. Moreover, in vivo microdialysis in freely moving rats was used to assess changes in neurotransmitter levels in the rat.
Results:
The results from the study show that several different compounds, which all potentiate Trk-receptor mediated signaling, display antidepressant-like activity in the FST. Moreover, the data also indicate that the effects of both fluoxetine and ketamine in the FST, both used in clinical practice, are mediated via BDNF/TrkB signaling, which could have implications for novel therapies in MDD.
Conclusions:
Trk-PAMs could provide an interesting avenue for the development of novel therapeutics in this area.
... Psychopathologies are frequently correlated with repeated or chronic exposure to stressors (Pasternac and Talajic, 1991;Chrousos and Gold, 1992;McEwen, 1998McEwen, , 2000McEwen, , 2004Chrousos, 2000;Morrison, 2001), which over time, is believed to facilitate or sensitize stress responses (Morris et al., 2010;Herman, 2013;Ursin, 2014;Belda et al., 2015;Post, 2016). Several animal paradigms of chronic intermittent stress also sensitize stress-associated responses and model some human pathological symptoms (Ortiz et al., 1996;Willner, 1997;Bielajew et al., 2002;Grippo et al., 2005;Ostrander et al., 2006;Bondi et al., 2008;Hill et al., 2010;Cox et al., 2011;Belda et al., 2015). However, not all repeated stress regimens lead to response sensitization, but instead produce response reductions defined as habituation, especially when the recurrent intermittent threat is moderate and nearly always the same or homotypic (Grissom and Bhatnagar, 2009;Rabasa et al., 2015;McCarty, 2016;Hughes B. M. et al., 2018;Radley and Herman, 2022). ...
Chronic stress is epidemiologically correlated with physical and psychiatric disorders. Whereas many animal models of chronic stress induce symptoms of psychopathology, repeated homotypic stressors to moderate intensity stimuli typically reduce stress-related responses with fewer, if any, pathological symptoms. Recent results indicate that the rostral posterior hypothalamic (rPH) region is a significant component of the brain circuitry underlying response reductions (habituation) associated with repeated homotypic stress. To test whether posterior hypothalamic transcriptional regulation associates with the neuroendocrine modifications induced by repeated homotypic stress, RNA-seq was performed in the rPH dissected from adult male rats that experienced either no stress, 1, 3, or 7 stressful loud noise exposures. Plasma samples displayed reliable increases of corticosterone in all stressed groups, with the smallest increase in the group exposed to 7 loud noises, indicating significant habituation compared to the other stressed groups. While few or no differentially expressed genes were detected 24-h after one or three loud noise exposures, relatively large numbers of transcripts were differentially expressed between the group exposed to 7 loud noises when compared to the control or 3-stress groups, respectively, which correlated with the corticosterone response habituation observed. Gene ontology analyses indicated multiple significant functional terms related to neuron differentiation, neural membrane potential, pre- and post-synaptic elements, chemical synaptic transmission, vesicles, axon guidance and projection, glutamatergic and GABAergic neurotransmission. Some of the differentially expressed genes (Myt1l, Zmat4, Dlx6, Csrnp3) encode transcription factors that were independently predicted by transcription factor enrichment analysis to target other differentially regulated genes in this study. A similar experiment employing in situ hybridization histochemical analysis in additional animals validated the direction of change of the 5 transcripts investigated (Camk4, Gabrb2, Gad1, Grin2a and Slc32a) with a high level of temporal and regional specificity for the rPH. In aggregate, the results suggest that distinct patterns of gene regulation are obtained in response to a repeated homotypic stress regimen; they also point to a significant reorganization of the rPH region that may critically contribute to the phenotypic modifications associated with repeated homotypic stress habituation.
Leptadenia hastata (Pers) Decne is a tropical herb widely used in the phytotherapy of neuropsychiatric disorders, including depression. Despite the availability of synthetic antidepressant drugs, depression remains a major medical problem. The study aimed to evaluate the effect of methanol leaf extract of Leptadenia hastata (LHME) on chronic unpredictable mild stress-induced depression.
Behavioral testing constitutes the primary method to measure the emotional states of nonhuman animals in preclinical research. Emerging as the characteristic tool of the behaviorist school of psychology, behavioral testing of animals, particularly rodents, is employed to understand the complex cognitive and affective symptoms of neuropsychiatric disorders. Following the symptom-based diagnosis model of the DSM, rodent models and tests of depression and anxiety focus on behavioral patterns that resemble the superficial symptoms of these disorders. While these practices provided researchers with a platform to screen novel antidepressant and anxiolytic drug candidates, their construct validity—involving relevant underlying mechanisms—has been questioned. In this review, we present the laboratory procedures used to assess depressive- and anxiety-like behaviors in rats and mice. These include constructs that rely on stress-triggered responses, such as behavioral despair, and those that emerge with nonaversive training, such as cognitive bias. We describe the specific behavioral tests that are used to assess these constructs and discuss the criticisms on their theoretical background. We review specific concerns about the construct validity and translational relevance of individual behavioral tests, outline the limitations of the traditional, symptom-based interpretation, and introduce novel, ethologically relevant frameworks that emphasize simple behavioral patterns. Finally, we explore behavioral monitoring and morphological analysis methods that can be integrated into behavioral testing and discuss how they can enhance the construct validity of these tests.
The primary risk factor for the onset of depression is social stress. In a clinical study, experience to daily social stress has been connected to the occurrence of major depressive disorder. To investigate the underlying mechanisms, animal depressive models have been proposed. In this study, we comprehensively summarized the different methodologies used to induce social-related stress in animals, including the most commonly used resident-intruder model, housing condition, social isolation, early life social event as well as social hierarchy model. Meanwhile, we investigated the behavioral readout adopted in this field. Moreover, we systematically summarized the molecular changes that have been associated with behavior observation. We found that most of the studies were performed on male animals. However, in humans, depression happens 2–3 times greater in females than males, thus we discussed the potential model that has been adopted to study social stress in females as well. We hope this study could provide a good summary for the field to have a comprehensive view of the social stress-related depression model as a foundation for the development of corresponding therapeutic approaches.
The psychedelic prodrug psilocybin has shown therapeutic benefits for the treatment of numerous psychiatric conditions. Despite positive clinical end points targeting depression and anxiety, concerns regarding the duration of the psychedelic experience produced by psilocybin, associated with enduring systemic exposure to the active metabolite psilocin, pose a barrier to its therapeutic application. Our objective was to create a novel prodrug of psilocin with similar therapeutic benefits but a reduced duration of psychedelic effects compared with psilocybin. Here, we report the synthesis and functional screening of 28 new chemical entities. Our strategy was to introduce a diversity of cleavable groups at the 4-hydroxy position of the core indole moiety to modulate metabolic processing. We identified several novel prodrugs of psilocin with altered pharmacokinetic profiles and reduced pharmacological exposure compared with psilocybin. These candidate prodrugs have the potential to maintain the long-term benefits of psilocybin therapy while attenuating the duration of psychedelic effects.
Pharmacological treatments that improve mood were first identified serendipitously, but more than half a century later, how these drugs induce their antidepressant effects remains largely unknown. With the help of animal models, a detailed understanding of their pharmacological targets and acute and chronic effects on brain chemistry and neuronal function has been achieved, but it remains to be elucidated how these effects translate to clinical efficacy. Whilst the field has been dominated by the monoamine and neurotrophic hypotheses, the idea that the maladaptive cognitive process plays a critical role in the development and perpetuation of mood disorders has been discussed since the 1950s. Recently, studies using objective methods to quantify changes in emotional processing found acute effects with conventional antidepressants in both healthy volunteers and patients. These positive effects on emotional processing and cognition occur without a change in the subjective ratings of mood. Building from these studies, behavioural methods for animals that quantify similar cognitive affective processes have been developed. Integrating these behavioural approaches with pharmacology and targeted brain manipulations, a picture is beginning to emerge of the underlying mechanisms that may link the pharmacology of antidepressants, these neuropsychological constructs and clinical efficacy. In this chapter, we discuss findings from animal studies, experimental medicine and patients investigating the neuropsychological effects of antidepressant drugs. We discuss the possible neural circuits that contribute to these effects and discuss whether a neuropsychological model of antidepressant effects could explain the temporal differences in clinical benefits observed with conventional delayed-onset antidepressants versus rapid-acting antidepressants.
A visible light induced C-3 thiocyanation of imidazo[1,2-a]pyridines by using naphthalimide based photo redox catalyst has been reported. Tolerance of electron withdrawing and donating groups on different positions of imidazo[1,2-a]pyridine...
The prevalence of depression is increasing, and geriatric depression, in particular, is difficult to recognize and treat. Depression in older adults is often accompanied by neuroinflammation in the central nervous system (CNS). Neuroinflammation affects the brain’s physiological and immune functions through several pathways and induces depressive symptoms. This study investigated the relationship among depression, neuroinflammation, and fish oil supplementation. Thirty-six male Sprague−Dawley rats were used in an aging-related depression animal model to simulate geriatric depression. Cognitive function, depressive-like symptoms, peripheral nervous system and CNS inflammation status, and the tryptophan-related metabolic pathway were analyzed. The geriatric depression animal model was associated with depressive-like behaviors and cognitive impairment. The integrity of the blood−brain barrier was compromised, resulting in increased expression of ionized calcium-binding adapter molecule 1 and the glial fibrillary acidic protein in the brain, indicating increased neuroinflammation. Tryptophan metabolism was also negatively affected. The geriatric-depressive-like rats had high levels of neurotoxic 5-hydroxyindoleacetic acid and kynurenine in their hippocampus. Fish oil intake improved depressive-like symptoms and cognitive impairment, reduced proinflammatory cytokine expression, activated the brain’s glial cells, and increased the interleukin-10 level in the prefrontal cortex. Thus, fish oil intervention could ameliorate abnormal neurobehaviors and neuroinflammation and elevate the serotonin level in the hippocampus.
Background:
Exposing rats to repeated unpredictable stressors is a popular method for modelling depression. The sucrose preference test is used to assess the validity of this method, as it measures a rat´s preference for a sweet solution as an indicator of its ability to experience pleasure. Typically, if stressed rats show a lower preference compared to unstressed rats, it is concluded they are experiencing stress-induced anhedonia.
Methods:
While conducting a systematic review, we identified 18 studies that used thresholds to define anhedonia and to distinguish "susceptible" from "resilient" individuals. Based on their definitions, researchers either excluded "resilient" animals from further analyses or treated them as a separate cohort. We performed a descriptive analysis to understand the rationale behind these criteria.
Results:
we found that the methods used for characterizing the stressed rats were largely unsupported. Many authors failed to justify their choices or relied exclusively on referencing previous studies. When tracing back the method to its origins, we converged on a pioneering article that, although employed as a universal evidence-based justification, cannot be regarded as such. What is more, through a simulation study, we provided evidence that removing or splitting data, based on an arbitrary threshold, introduces statistical bias by overestimating the effect of stress.
Conclusion:
Caution must be exercised when implementing a predefined cut-off for anhedonia. Researchers should be aware of potential biases introduced by their data treatment strategies and strive for transparent reporting of methodological decisions.
Brain metabolism is a fundamental process involved in the proper development of the central nervous system and in the maintenance of the main higher functions in humans. As consequence, energy metabolism imbalance has been commonly associated to several mental disorders, including depression. Here, by employing a metabolomic approach, we aimed to establish if differences in energy metabolite concentration may underlie the vulnerability and resilience in an animal model of mood disorder named chronic mild stress (CMS) paradigm. In addition, we have investigated the possibility that modulation of metabolite concentration may represent a pharmacological target for depression by testing whether repeated treatment with the antidepressant venlafaxine may normalize the pathological phenotype by acting at metabolic level. The analyses were conducted in the ventral hippocampus (vHip) for its key role in the modulation of anhedonia, a core symptom of patients affected by depression. Interestingly, we showed that a shift from glycolysis to beta oxidation seems to be responsible for the vulnerability to chronic stress and that vHip metabolism contributes to the ability of the antidepressant venlafaxine to normalize the pathological phenotype, as shown by the reversal of the changes observed in specific metabolites. These findings may provide novel perspectives on metabolic changes that could serve as diagnostic markers and preventive strategies for the early detection and treatment of depression as well as for the identification of potential drug targets.
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.
Amphetamine and tranylcypromine are structurally related chemical isomers with pharmacologically distinctive activity profiles. Since they are equimolar and structurally similar they may be used to assess the pharmacologically distinctive activity profiles. Since they are equimolar and structurally similar they may be used to assess the pharmacological specificity of a proposed animal model of depression. Adult male Sprague-Dawley rats were exposed to a chronic stress regimen or remained undisturbed. They were then acutely stressed with white noise. The monoamine oxidase inhibitor tranylcypromine was effective in restoring otherwise reduced stress elicited open field activity in chronically stressed rats. Amphetamine did not resemble tranylcypromine or other antidepressants, and produced a variety of effects at least some of which indicated a potential increase rather than reduction in depression consequent to chronic administration.
The initial activity of a rat placed in novel surroundings (i.e., open field activity) has been taken as an indicator of its emotional state. We have investigated the effects of immediately antecedent stress upon open field activity in comparison with basal (i.e., unstressed) activity, and additionally, the effects of a history of chronic stress upon the above behavioral patterns. Acute exposure to a non-traumatic, non-debilitating stress (noise and light) consistently increased activity in comparison with basal activity. A history of chronic stress on the other hand reduced basal activity from control levels, and eliminated the activation response to acute stress. This lack of acute activation may bear some resemblance to depression on several grounds. Behaviorally it represents a "refractory loss of interest." Also, chronically stressed rats showed endocrine changes similar to those seen in human depressives. Finally, antidepressant treatment with the monoamine oxidase inhibitor pargyline restored the ability of chronically stressed rats to respond actively to stress.
Benzodiazepines have been prescribed for the treatment of Generalized Anxiety Disorder (GAD) for nearly three decades due to their proven anxiolytic efficacy, despite a considerable side effect and abuse liability profile. A new class of compounds, the azapirones, have been developed as an alternative to benzodiazepine treatment. Ipsapirone is a novel anxiolytic azapirone which has high specificity for the 5-HT1A receptor and which has the potential for offering certain advantages over buspirone. The present 5-week study investigated three doses of ipsapirone (2.5mg, 5.0mg and 7.5mg tid) versus placebo in 267 GAD outpatients. Efficacy was evaluated using the Hamilton Anxiety Rating Scale (HAM-A), Zung Anxiety Scale (Zung-A), and Clinical Global Impression (CGI). The study design consisted of a 1-week placebo run-in, a 4-week double-blind treatment period, and a 1-week placebo washout. The 5.0mg group demonstrated consistently superior improvement in all efficacy variables during the treatment period, with significant differences (p < 0.05) from placebo and, at times, the 2.5mg and 7.5mg groups. Incidence of adverse events, primarily dizziness, nausea, sedation, and asthenia, was found to be dose proportional, with significant increase in the 7.5mg group, which may account for the diminished effectiveness seen with this dose. Our results suggest that ipsapirone may represent a viable treatment for GAD.
: In addition to their "classic" actions at serotonergic and noradrenergic terminals, long-term administration of antidepressants increases behavioral responses to the stimulation of D2/D3 receptors in the nucleus accumbens. The functional significance of these effects has been investigated within the context of a novel animal model of depression, chronic mild stress-induced anhedonia. In this model, long-term sequential exposure of rats to a variety of mild stressors causes a decrease in responsiveness to rewards, which is reversed by long-term administration (3-5 weeks) of antidepressants. This article reviews studies that have investigated the role of the mesoaccumbens dopamine projection in these behavioral changes. The data suggest that sensitization of D2/D3 receptors in the nucleus accumbens represents a final common pathway that is both necessary and sufficient for the antianhedonic action of antidepressant drugs.
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.
The consumption of, and preference for, a rewarding 0.9% sucrose solution was examined in rats subjected chronically (8 wk) to a regimen of unpredictable mild stressors. Intake of sucrose was reduced in stressed animals compared to controls after 3 wk. However, correction for body weight changes revealed no significant difference in sucrose consumption between the groups. A comparison of the mean sucrose intakes of matched low-weight rats, with low weight a function of either immaturity or stress, failed to differentiate between the groups. Total sucrose consumption and total fluid intake correlated significantly with body weight of stressed animals and controls. Percentage preference for sucrose solution did not differ between controls and stressed animals. It is concluded that the validity and reliablity of sucrose consumption as an hedonic measure within the context of exposure to chronic unpredictable mild stress must be questioned.
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 various 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 throughout 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) 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 per day) 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.
In 2 experiments, the consumption of palatable weak sucrose solutions by 10 rats was reduced by chronic exposure to mild unpredictable stress. Increases in the levels of dopamine and 5-hydroxytryptamine (5-HT) and their metabolites were found in the limbic forebrain of stressed rats; these changes were not present in the caudate nucleus or septal area, or in the brains of meal-fed control animals. In the 1st experiment (7 wks of stress), specific binding to dopamine D2 receptors was decreased in limbic forebrain; this change was not seen in the 2nd experiment (3 wks of stress). A discussion is included on the possible role of these changes in mesolimbic dopamine function in the reduced sensitivity to reward that follows exposure to chronic mild stress. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Chronic exposure to very mild unpredictable stress has previously been found to depress the consumption of, and preference for, highly palatable sweet solutions. The present study used the place conditioning procedure to investigate whether these effects result from a decreased sensitivity to reward. Rats were subjected to chronic mild unpredictable stress for a total of 4 weeks. During weeks 3 and 4, they received four training trials, in which rewards were presented in a distinctive environment, and four further non-rewarded trials in a different environment. The rewards used in different experiments were food pellets, dilute (0.7%) and concentrated (34%) sucrose solutions, anddl-amphetamine sulphate (0.5 and 1.0 mg/kg). In all experiments, non-stressed animals showed an increase in preference for the environment associated with reward; in stressed animals, these effects were abolished or greatly attenuated. Chronic unpredictable mild stress, which may be comparable in intensity to the difficulties people encounter in their daily lives, appears to cause a generalized decrease in sensitivity to rewards.
Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions. In the present study this effect was reversed by chronic (9 weeks) treatment with the atypical antidepressants, fluoxetine and maprotiline (5 mg/kg/day); the non-antidepressant chlordiazepoxide was ineffective. Stressed animals were also subsensitive to food reward in the place conditioning procedure; however, fluoxetine and maprotiline treated animals showed normal place preference conditioning. Acute pretreatment with raclopride (100 g/kg) selectively reversed the recovery of sucrose drinking in antidepressant-treated stressed animals. These results extend previous reports of the efficacy of tricyclic antidepressants in this paradigm, and support the hypothesis of a dopaminergic mechanism of antidepressant action.
Rats exposed for 6 weeks to a variety of mild unpredictable stressors showed reduced consumption of a preferred sucrose solution. The deficit was apparent after 1 week of stress and was maintained for at least 2 weeks after termination of the stress regime. Sucrose preference was unaffected by 2 weeks of treatment with the tricyclic antidepressant DMI but returned to normal after 3 weeks of DMI treatment. Subsensitivity to the anorexic effect of a low dose of apomorphine was seen in vehicle-treated stressed animals, and in unstressed animals following withdrawal from DMI. In both cases, the changes resulted from a failure of apomorphine to reduce eating time (rather than from changes in eating rate); this effect is assumed to represent a subsensitive response to stimulation of dopamine cell body autoreceptors. As the same effect is seen in anhedonic stressed animals and in animals withdrawn from DMI, it is concluded that dopamine autoreceptor desensitization probably does not contribute to clinical improvement following chronic antidepressant treatment.
Rats subjected chronically (12 weeks) to a variety of mild, unpredictable stressors showed a reduced consumption of sucrose or a sucrose/saccharin mixture in two-bottle consumption tests (sweet solution versus water). The deficit was apparent within 2 weeks of stress; normal behaviour was restored by chronic (7 weeks) treatment with the tricyclic antidepressants desmethylimipramine (DMI) or amitriptyline (AMI). Acute administration of the dopamine D1 receptor antagonist SCH-23390 1 week after withdrawal, or the dopamine D2 receptor antagonist sulpiride 2 weeks after withdrawal, were without effect in vehicle-treated stressed animals, and in non-stressed animals. However, the DA antagonists selectively reversed the improvement of performance in DMI- or AMI-treated stressed animals. This suggests that an increase in functional activity at DA synapses is the mechanism of action of DMI and AMI in this model.
Chronic sequential exposure to a variety of mild unpredictable stressors has previously been found to depress the consumption of a dilute (1%) sucrose solution and to inhibit food-induced place preference conditioning. In the present study, using a simplified version of the mild stress procedure, the decreased sucrose intake was reversed by chronic (4 weeks) treatment with the atypical antidepressant mianserin. The racemic compound ()-mianserin (5 mg/kg per day) and one of its enantiomers, (+)-mianserin (2.5 mg/kg) were effective in this model; a lower dose of ()-mianserin (2.5 mg/kg), and the other enantiomer, (–)-mianserin (2.5 mg/kg), were ineffective. Vehicle-treated stressed animals were also subsensitive to food reward in the place conditioning procedure: normal place preference conditioning was reinstated by chronic treatment with ()-mianserin (5 mg/kg) or (+)-mianserin, but not by the lower dose of ()-mianserin (2.5 mg/kg) or by (–)-mianserin. Raclopride (100 g/kg) reinstated the decrease in sucrose intake in stressed animals successfully treated with ()- or (+)-mianserin. The results suggest that (+)-mianserin is the active enantiomer in reversing chronic mild stress-induced anhedonia, and further support the hypothesis of a dopaminergic mechanism of antidepressant action in this paradigm.
Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of a palatable (1%) sucrose solution, and to attenuate food-induced place preference conditioning. In this study the effects of pramipexole (SND-919), a dopamine D2 agonist, were studied during 7–9 weeks of chronic treatment. Pramipexole (1.0 mg/kg per day) reversed the suppression of sucrose intake in stressed animals, increasing sucrose intakes above the levels seen in untreated nonstressed controls. Pramipexole also increased sucrose intake in nonstressed animals; these effects were accompanied by increases in water intake and tended to correlate with weight loss. Drug-treated stressed animals also lost weight, but in this case water intake was unaffected. A second group of animals received a higher dose of pramipexole (2.0 mg/kg per day). The effects of the two doses were very similar. After three weeks of treatment, these animals were switched to a lower dose of pramipexole (0.1 mg/kg per day). Increases in sucrose intake were maintained over three weeks of treatment at the lower dose, with significant recovery of body weight. Two further groups received the same doses of pramipexole (1.0 mg/kg for 6 weeks or 2.0 mg/kg for 3 weeks followed by 0.1 mg/kg thereafter), but received intermittent (twice-weekly) drug treatment. Intermittent pramipexole treatments also tended to increase sucrose intakes, but the results were less consistent from week to week. Following 6–8 weeks of pramipexole treatment, food-induced place preference conditioning was studied in all animals. Untreated stressed animals showed no evidence of place conditioning. Normal conditioning was seen in both groups of stressed animals treated daily with pramipexole (at 1.0 and 0.1 mg/kg) and in the group treated twice weekly at the higher dose (1.0 mg/kg); intermittent treatment at the lower dose (0.1 mg/kg) was ineffective. The results indicate that pramipexole exerts rapid anti-anhedonic effects in the chronic mild stress model. This conclusion is complicated, but not undermined, by drug-induced weight loss and by the presence of significant drug effects in nonstressed control animals.
Chronic sequential administration of a variety of mild stressors causes a decrease in responsiveness to rewards in rats, which is reversed by chronic administration of antidepressant drugs. This paper reviews the validity of chronic mild stress-induced anhedonia as an animal model of depression, and the evidence that changes in hedonic responsiveness in this model are mediated by changes in the sensitivity of dopamine D2 receptors in the nucleus accumbens. The review opens with an analysis of the design features of animal models of depression, and ends with a brief account of other animal models of anhedonia.
Complement proteins and fragments participate in the induction and modulation of specific and nonspecific immune reactions. We have examined the effect of 4 weeks of chronic mild stress (CMS) on complement sheep red blood cell hemolytic activity measured in CH50 units in two selectively bred lines of rats, the Flinders resistant line (FRL) and the Flinders sensitive line (FSL), that differ in cholinergic sensitivity and behavioral characteristics. Additionally, CMS-induced hedonic deficit (decreased preference for 0.02% saccharin over water) and serum corticosterone levels were compared in FRL and FSL rats. CMS caused a significantly (p < 0.01) greater decline in CH50 responses in FSL (−15%) than in FRL (−7%) rats. This was accompanied by a significant (p < 0.01) suppression of saccharin preference over a 24 h period in both FRL and FSL rats. Both lines showed a similar, more than 2-fold (p < 0.01) increase in corticosterone levels following CMS. These results further confirm that CMS induces a depressive-like state in rats as well as the validity of the FSL rat as a genetic model of depression. They also indicate that the effect of stress on the immune system can be monitored by measuring the complement CH50 response.
The effects of acute and chronic stressors on saccharin intake and preference in the hypercholinergic Flinders Sensitive Line (FSL) rat, a putative genetic animal model of depression, were studied and compared to the control Flinders Resistant Line (FRL) rats. Overall, the FRL rats drank significantly less saccharin and water than the FSL rats when compared over a wide range of saccharin concentrations (0.01–5%) under baseline conditions. A 0.02% saccharin concentration was used in subsequent experiments. We observed a significant suppression of saccharin intake/preference at 1 h following a single 5-min exposure to cold swim stress only in FSL rats. There was a tendency to increase saccharin intake in both lines at 1 h following a scrambled foot shock stress. These effects of acute stressors disappeared upon retesting for saccharin consumption/preference 23 h after the stress. Chronic 4-week exposure to unpredictable mild stressors significantly (p < 0.01) decreased saccharin consumption in the FSL rats, but not in the FRL rats. The FSL rats also exhibited a significantly greater decrease in saccharin preference (−24% vs. prestress baseline, as compared to −7% in FRL controls, p < 0.05). In conclusion, FSL rats appear more prone than the FRL rats to chronic, as well as immediate acute, stress-induced anhedonic effects. This outcome further supports the notion that the FSL rat is a useful model of a genetic predisposition to depressive-like reactions.
Chronic exposure to very mild unpredictable stress has previously been found to reduce or abolish the acquisition of place preference conditioning. In the present study, chronic mild stress was found to abolish the acquisition of preferences for a distinctive environment paired with morphine (0.7 mg/kg). However, chronic mild stress did not impair the acquisition of place aversion conditioning induced by naloxone (0.7 mg/kg) or picrotoxin (2.0 mg/kg). The results demonstrate that chronic stress does not cause a general impairment of associative learning but, rather, a specific impairment of rewarded behaviour.
1. The present study assessed the potential antidepressant action of gepirone hydrochloride, an azapirone serotonin (5-HT1A) partial agonist in patients with major depression. 2. Overall, gepirone demonstrated a significant antidepressant activity within the entire patient group (p less than 0.001). However, when subjects were stratified based upon the presence or absence of DSM III-R melancholic features, the melancholic depressives showed little change in weekly depression ratings compared to patients without melancholic symptoms (p less than 0.001). 3. Similarly, patients who were more severely ill at the pretreatment period had less improvement compared to those with more modest illness severity (p less than 0.001). 4. These observations compliment those of prior studies suggesting antidepressant activity for gepirone. 5. However, a consistent efficacy comparable to conventional neuronal reuptake inhibitor antidepressants remains to be established in patients with more severe depression characterized by melancholic features.
Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions. In the present study this effect was reversed by chronic (9 weeks) treatment with the atypical antidepressants, fluoxetine and maprotiline (5 mg/kg/day); the non-antidepressant chlordiazepoxide was ineffective. Stressed animals were also subsensitive to food reward in the place conditioning procedure; however, fluoxetine and maprotiline treated animals showed normal place preference conditioning. Acute pretreatment with raclopride (100 micrograms/kg) selectively reversed the recovery of sucrose drinking in antidepressant-treated stressed animals. These results extend previous reports of the efficacy of tricyclic antidepressants in this paradigm, and support the hypothesis of a dopaminergic mechanism of antidepressant action.
Chronic sequential administration of a variety of mild stressors causes a decrease in responsiveness to rewards in rats, which is reversed by chronic administration of antidepressant drugs. This paper reviews the validity of chronic mild stress-induced anhedonia as an animal model of depression, and the evidence that changes in hedonic responsiveness in this model are mediated by changes in the sensitivity of dopamine D2 receptors in the nucleus accumbens. The review opens with an analysis of the design features of animal models of depression, and ends with a brief account of other animal models of anhedonia.
Consumption of a palatable wet mash was examined in rats subjected chronically (4-10 weeks) to unpredictable mild stress. Intake of mash containing 0, 10%, or 20% additional sucrose was normal in stressed animals. In control animals, the addition of 30% or 40% sucrose caused a decrease in the quantity of mash consumed, but increased the rate of eating. Both the increase in eating rate and the decrease in intake, at high sucrose concentration, were markedly attenuated in stressed animals (which therefore had higher intakes of very sweet mash and lower rates of eating, relative to control animals). Like chronic mild stress, the dopamine receptor antagonist pimozide (0.2 mg/kg) also increased the intake of a wet mash with 30% added sucrose, while decreasing the rate of consumption. Stressed animals were relatively insensitive to pimozide, though there were significant additive effects on duration of eating (increased) and on postprandial resting (suppressed). The failure of stressed animals to adapt their intake to increases in sweetness, and the similarities between the effects of chronic mild stress and acute pimozide, are compatible with the hypothesis that animals exposed to chronic mild stress are anhedonic.
Previous studies have demonstrated that chronic exposure of rats to a melange of ultra-mild stressors causes an antidepressant-reversible decrease in the intake of palatable weak sucrose solutions, as well as other evidence of insensitivity to rewards. In the present study, we analyzed some of the behavioral requirements for the suppression of consummatory behaviour by chronic mild stress. Rats exposed to our standard chronic mild stress protocol and tested following 20 h food and water deprivation showed a decrease in intake of 1% sucrose, but not of water or chow. The effect on sucrose intake was also present, but smaller, in non-deprived animals, and wa seen in both singly- and pair-housed animals. Experiments designed to identify the crucial elements of the stress procedure showed that one element, paired housing (in animals normally housed singly) was particularly potent. However, no one element was either necessary to cause the decrease in sucrose intake, or sufficient to maintain the impairment for longer than 4 weeks: Variety and frequency of microstressors appeared to be the essential features of procedures causing a prolonged anhedonia.
Exposure to acute inescapable shock caused reductions in the consumption of a highly palatable diet. The magnitude and duration of the reduction varied across strains of mice. With repeated exposure to footshock, consumption of the diet returned to baseline levels, although alterations of weight appeared to be more persistent. The course of the adaptation varied across strains of mice; however, the rate of adaptation was unrelated to the extent of the alterations of consumption induced by the acute stressor. When mice were exposed to a series of different stressors, the adaptation progressed less readily, and reductions of diet consumption were apparent in strains that had not shown such an effect following acute stressor application or when repeatedly exposed to a single type of stressor. Data were discussed with respect to the mechanisms that might be operative in subserving stressor-induced anhedonia.
The effect of chronic unpredictable mild stress on sensitivity to reward was evaluated using the brain self-stimulation procedure. Rats were allowed to electrically self-stimulate the ventral tegmental area, one of the main cerebral structures subserving positive reinforcement. Stimulation thresholds (frequency of stimuli) for self-stimulation responses were determined prior to, during, and following a 19-day period of exposure to a variety of mild unpredictable stressors. Stimulation threshold was increased in stressed rats, suggesting a decrease in the rewarding properties of brain stimulation. This deficit became evident after about 1 week of mild stress, lasted throughout the stress period, and progressively diminished following termination of the stress regime. In stressed rats concomitantly treated with the tricyclic antidepressant desipramine (5 mg/kg b.i.d.), no stress-induced increase in self-stimulation threshold was observed. However, desipramine did not modify self-stimulation threshold in non-stressed animals. Thus, the increased threshold for brain self-stimulation produced by a period of chronic unpredictable mild stress can be completely prevented by concomitant antidepressant treatment and may provide an heuristic animal model of depression.
Previous studies have reported that dopamine receptor antagonists increase the intake of solid or liquid diets containing high concentrations of sucrose. In Experiment 1, different groups of rats were trained in two-bottle tests (sweet solution vs. water), using three concentrations of either sucrose (0.7, 7 or 34%) or saccharin (0.02, 0.2 or 0.8%). Both sweeteners showed an inverted-U-shaped concentration-intake function. Raclopride increased intake of 34% sucrose, but not of 0.8% saccharin. In Experiment 2, raclopride had similar effects in three-bottle tests (all 3 concentrations available concurrently). However, whereas 34% was the most preferred sucrose solution, 0.2% saccharin was preferred to 0.8%. Thus, 0.8% saccharin differs from 34% sucrose in two ways, being not only noncaloric, but also aversive. In Experiment 3, 34% sucrose was rendered aversive by the addition of 0.08% quinine. Intake of this cocktail was not increased by raclopride. These results suggest that the difference between sucrose and saccharin in the effects of raclopride is related to the aversive properties of a concentrated solution of saccharin, rather than to its lack of calories.
Rats subjected chronically (12 weeks) to a variety of mild, unpredictable stressors showed a reduced consumption of sucrose or a sucrose/saccharin mixture in two-bottle consumption tests (sweet solution versus water). The deficit was apparent within 2 weeks of stress; normal behaviour was restored by chronic (7 weeks) treatment with the tricyclic antidepressants desmethylimipramine (DMI) or amitriptyline (AMI). Acute administration of the dopamine D1 receptor antagonist SCH-23390 1 week after withdrawal, or the dopamine D2 receptor antagonist sulpiride 2 weeks after withdrawal, were without effect in vehicle-treated stressed animals, and in non-stressed animals. However, the DA antagonists selectively reversed the improvement of performance in DMI- or AMI-treated stressed animals. This suggests that an increase in functional activity at DA synapses is the mechanism of action of DMI and AMI in this model.
Chronic exposure to very mild unpredictable stress has previously been found to depress the consumption of, and preference for, highly palatable sweet solutions. The present study used the place conditioning procedure to investigate whether these effects result from a decreased sensitivity to reward. Rats were subjected to chronic mild unpredictable stress for a total of 4 weeks. During weeks 3 and 4, they received four training trials, in which rewards were presented in a distinctive environment, and four further non-rewarded trials in a different environment. The rewards used in different experiments were food pellets, dilute (0.7%) and concentrated (34%) sucrose solutions, and dl-amphetamine sulphate (0.5 and 1.0 mg/kg). In all experiments, non-stressed animals showed an increase in preference for the environment associated with reward; in stressed animals, these effects were abolished or greatly attenuated. Chronic unpredictable mild stress, which may be comparable in intensity to the difficulties people encounter in their daily lives, appears to cause a generalized decrease in sensitivity to rewards.
The most familiar usage of animal models of depression is as antidepressant screening tests. Paul Willner reviews their usage in a different context--as simulations of depression. The behavioural features of animal models of depression are compared with clinical symptomatology, and the contribution of animal models to understanding the following aspects of depression are reviewed: sources of population variability, natural history, psychological aspects, symptomatology and mechanisms of antidepressant action. Finally, the role of animal models of depression is considered as a critical interface between basic behavioural neuroscience and the clinic.
The depressive Attributional Style Questionnaire (Peterson et al., 1982) and the Hassles and Uplifts Questionnaire (Kanner et al., 1981) were administered to melancholic and non-melancholic depressed patients (matched for severity according to a doctors/nurses rating scale), and to non-depressed volunteers. Compared to the other two groups, melancholic patients had higher internality and stability scores for negative attributions, and reported a greater intensity of 'hassles' and a lower frequency of 'uplifts'. The intensity of 'uplifts' was reduced in both depressed groups. On all other cognitive measures, the reactive patients were indistinguishable from non-depressed volunteers. The results suggest that the 'depressive attributional style' may be specific to melancholic patients, and underline the importance of studying well-defined diagnostic subgroups.
Rats, subjected chronically (10-12 weeks) to a variety of mild, unpredictable stressors, showed a decrease in their consumption of weak sucrose solutions; normal behavior was restored by chronic (5-9 weeks) treatment with the tricyclic antidepressant imipramine. Acute administration of the dopamine receptor antagonist pimozide or the specific dopamine D2 receptor antagonist raclopride had no effect in nonstressed animals and in vehicle-treated stressed animals, but both drugs selectively reversed the improvement of performance in imipramine-treated stressed animals. The 5HT antagonist metergoline increased sucrose consumption in all groups. The data suggest that the mechanism of action of imipramine in this model is an increase in functional activity at dopamine (DA) synapses.
The direction and extent of weight change during two separate episodes of severe, unipolar depression were assessed in 53 (unmedicated) outpatients in the Pittsburgh (Pa) study of maintenance therapy of depression. There was a high concordance (45 of 53 patients) of direction of self-reported weight change during the two episodes. Twenty-three patients lost weight during both episodes, 17 gained weight, and 5 showed no change. The extent of weight change between the two episodes was highly correlated. Self-reported weight change corresponded closely to measured weight changes in a large sample of the study population. Changes in appetite paralleled those in body weight. Duration of the episode and body mass index were related to the weight change, but two features of depression with which weight loss in depression has been associated (the endogenous character of the depression and it severity) were not. Direction and extent of weight change in unipolar depression appear to be stable patient characteristics across episodes and are thus potential markers for subtypes of depression. This stability of weight change is in sharp contrast to the lack of stability of the endogenous subtype in consecutive episodes of major depression.
Revue des «modeles animaux» de la depression. Les modeles proposes sont du moins connu aux modeles couramment utilises. La revue est centree sur la validite de ces modeles, sur les informations qu'ils ont permis de produire et sur les contributions qu'ils sont susceptibles d'apporter dans le futur
Twenty-six strains of mice were tested for their reaction to four different sweet substances; saccharin, acesulfame, dulcin and sucrose. There was considerable strain variation in the degree to which they found the sweet substances preferable to water. The variation in preference for any one sweet substance is very highly correlated with the variation in preference for the other sweet substances. This is interpreted to mean that there is only one sweetness receptor, although an alternative explanation in terms of variation in psychological motivation is not discounted. The difference between C57BL/6Ty and DBA/2Ty is largely due to a single gene, Sac.
Rats exposed chronically (5-9 weeks) to a variety of mild unpredictable stressors showed a reduced consumption of and preference for saccharin or sucrose solutions. Preference deficits took at least 2 weeks to develop and were maintained for more than 2 weeks after termination of the stress regime. Sucrose preference was unaffected by 1 week of treatment with the tricyclic antidepressant DMI but returned to normal after 2-4 weeks of DMI treatment. DMI did not alter sucrose preference in unstressed animals. No significant changes were seen in saline preference either during stress or following drug treatment. DMI reduced blood corticosterone and glucose levels, but stress did not significantly alter either measure. The results are discussed in terms of an animal model of endogenous depression.
Rats exposed for 6 weeks to a variety of mild unpredictable stressors showed reduced consumption of a preferred sucrose solution. The deficit was apparent after 1 week of stress and was maintained for at least 2 weeks after termination of the stress regime. Sucrose preference was unaffected by 2 weeks of treatment with the tricyclic antidepressant DMI but returned to normal after 3 weeks of DMI treatment. Subsensitivity to the anorexic effect of a low dose of apomorphine was seen in vehicle-treated stressed animals, and in unstressed animals following withdrawal from DMI. In both cases, the changes resulted from a failure of apomorphine to reduce eating time (rather than from changes in eating rate); this effect is assumed to represent a subsensitive response to stimulation of dopamine cell body autoreceptors. As the same effect is seen in anhedonic stressed animals and in animals withdrawn from DMI, it is concluded that dopamine autoreceptor desensitization probably does not contribute to clinical improvement following chronic antidepressant treatment.
DSM-III lifetime diagnoses were assessed in 52 patients with a lifetime history of anorexia nervosa or bulimia by means of a standardised diagnostic interview. It was found that 44.2% had a lifetime diagnosis of DSM-III major affective disorder, with abstaining anorectics having a lower rate of depression than those with bulimic symptoms. In the great majority of cases, the onset of affective disorder post-dated the onset of the eating disorder by at least one year. In patients whose eating disorder was in remission, the rate of depressive symptoms was lower than in those in the acute stage of their illness. These findings, combined with recent studies on biological changes in eating disorders, and psychological theories of depression, suggest that in most cases in which the two conditions are associated, the depression is secondary to the eating disorder.
Thirty-three bulimic and 14 restrictive anorexics were compared on DSM-III diagnoses of affective and anxiety disorders, observer-rated and self-rated measures of depression and anxiety, and family history. A subgroup of 18 eating disorder subjects was administered the dexamethasone suppression test. The same 18 subjects were compared to 13 subjects with affective disorder on the Schedule for Affective Disorders and Schizophrenia. It was found that a large group with bulimia and restrictive anorexia nervosa was subject to a depressive disorder. Thirty-eight percent of the sample fulfilled criteria for a major depressive episode. The dysphoric experience seemed as intense in the bulimic and restricter group. There was a high incidence of dexamethasone nonsuppression (55%), which was found to be related to various measures of depression. Bulimics and restricters differed in their family history of affective disorder. While 61% of bulimics had a positive history of depression, this was found in only 23% of restricters (p less than .03).
Eighteen animal models of depression are reviewed in relation to three sets of validating criteria. Of the 18 models, five could only be assessed for predictive validity, seven could be assessed for predictive and face validity, and six could potentially have predictive, face and construct validity. Some traditional models (reserpine reversal, amphetamine potentiation) are rejected as invalid; the models with the highest overall validity are the intracranial self-stimulation, chronic stress and learned helplessness models in rats, and the primate separation model.
Stressors influence the activity of biogenic amines and provoke a variety of behavioral disturbances which have been considered as models of human depression. To evaluate the effects of stressors on reward processes, responding for electrical brain stimulation was assessed after acute or chronic shock, and the modification of performance by desmethylimipramine was determined. While escapable shock did not affect performance, inescapable shock reduced responding from the nucleus accumbens and medial forebrain bundle, but not from the substantia nigra. These deficits were were antagonized by repeated stressor application or by desmethylimipramine. Uncontrollable stressors may influence motivational processes subserved by some brain regions, and may thus influence affective state. Chronic stress or desmethylimipramine may induce adaptive neurochemical changes, thereby preventing the behavioral disturbances otherwise produced by stressors.
Rates of responding for intracranial self-stimulation from the medial forebrain bundle, nucleus accumbens and substantia nigra were evaluated in mice that had been exposed to either escapable shock, yoked inescapable shock or no shock treatment. Whereas performance was unaffected by escapable shock, marked reductions of responding from the medial forebrain bundle and nucleus accumbens were evident following the uncontrollable shock treatment. Responding from the substantia nigra was unaffected by the stress treatment. Uncontrollable shock is thought to reduce the rewarding value of responding for electrical brain stimulation from those brain regions in which stressors are known to influence dopamine activity.
In two studies of depressed, manic, schizophrenic, and normal subjects, a scale for measuring the intensity of subjects' pleasureable responses to normally emjoyable situations (the Pleasure Scale) evidenced good internal reliability and moderate agreement with the Chapman Anhedonia Scale and Indexes of depressive symptom severity. Only the depressed patients showed extremely anhedonic responses. Although more than half the depressed patients evidenced pleasure scores in the normal range, about 185 of them seemed more anhedonic than any norma subject. A mixture analysis resolved depressed patient scores into two distinct distributions: a normal-range distribution (88% of depressives) and an extremely anhedonic distribution (12%). The findings provide some support for the existence of a qualitatively distinct subtype of major depression that has been variously defined an "endogenomorphic" or "melancholic."
Adult male Sprague-Dawley rats were subjected to acute (95 dB white noise) or chronic stress, or their combination. In comparison with unstressed controls, stressed rats were more active upon several measures of open field activity. A history of chronic stress eliminated the acute stress induced activation. Concurrent treatment of chronically stressed rats with amitriptyline or scopolamine, or with a combination of both drugs resulted in selective behavioral improvement (i.e., in motor activity, latency, defecation) for amitriptyline and combined treatment rats, with significant restoration of the normal behavioral response. Scopolamine however was only marginally effective. A higher dose of scopolamine proved effective, but only with a marked disruption of baseline activity. Examination of plasma corticosterone titers indicated that chronic stress induced an elevation of basal levels and that this was reversed by amitriptyline, scopolamine, and combined drug treatment. Thus while behavioral depression and elevated corticosteroids may covary they are not identically mediated.
We have proposed that chronic stress may produce motivational, behavioral, and neuroendocrine symptoms in rats resembling endogenous depression in humans. The chronic stress model has proved responsive to chronic treatment by antidepressant drugs. Two issues concerning this effect remain unresolved, these being; the requirement of drug chronicity, and treatment outcome to different drug doses. The present experiment examined both issues in a factorial design in which vehicle and two doses of the tricyclic antidepressant imipramine were varied across 2 treatment periods; acute (1 hr) and chronic (3 weeks). Both factors were found to significantly interact with treatment outcome, suggesting that chronic treatment is necessary for recovery and that this outcome is dependent upon drug level.
A reduction in sucrose and saccharine consumption following chronic stress is reported for the rat. This deficit may be related to consummatory deficits seen in endogenous depression. To further examine this state pharmacologically, stressed rats were treated with the antidepressant imipramine. Despite a general absence of appetitive effects (or in some cases mild anorexia) imipramine significantly restored saccharine consumption in a variety of tests. The pharmacological similarity of the deficit to the changes accompanying affective disorders further supports the potential applicability of the chronic stress model.