Combination of low doses of mirtazapine plus venlafaxine produces antidepressant-like effects in rats, without affecting male or female sexual behavior.

RATIONALE: Pharmacological treatments for depression are not always effective and produce unwanted side effects. Male and female sexual dysfunction is one of these side effects, which can lead to treatment withdrawal. Combination of two antidepressants with different mechanisms of action, like mirtazapine (MTZ) and venlafaxine (VLF) have been shown to be effective for treatment-resistant depression in humans. Combination of low doses of these drugs may still exert antidepressant-like effects without altering sexual behavior. OBJECTIVES: To investigate the potential antidepressant-like effect of the chronic administration of low doses of MTZ plus VLF combined, as well as its impact on male and female sexual behavior in rats. METHODS: The antidepressant-like effect of a 14-day treatment with combinations of MTZ plus VLF (0/0, 2.5/3.75 or 5/7.5 mg/kg) was assessed in young adult male and female rats in the forced swim test (FST). The 5/7.5 mg/kg MTZ/VLF combination was also tested in the chronic mild stress (CMS) test, in both males and females treated for 21 days. The sexual effects of this last treatment were assessed in sexually experienced males and in gonadally-intact females during proestrus. RESULTS: The 5/7.5 mg/kg MTZ/VLF combination produced an antidepressant-like effect in the FST and reversed the CMS-induced anhedonia in both male and female rats. This combination did not alter male sexual behavior, female proceptive and receptive behaviors or the regularity of the estrous cycle. CONCLUSION: The combination of low doses of MTZ and VLF might be a promising therapeutic alternative to treat depression without affecting the sexual response.

Antidepressant-like and antioxidant effects of Morus nigra L. in rats subjected to the unpredictable chronic mild stress model.

This study aimed to evaluate the antidepressant-like and antioxidant potential of the aqueous leaf extract of Morus nigra L. in rats subjected to unpredictable chronic mild stress (UCMS). Male Wistar rats were divided into four groups, control and stressed, and treated with saline or aqueous extract of M. nigra. The dose administered was 10 mg/kg daily by gavage for 5 weeks concurrently with UCMS. M. nigra extract which showed syringic acid, quercetin, and rutin, as major phenolic compounds decreased the immobility time without changes in locomotor activity of stressed rats, in the forced swimming and open field tests, respectively. In addition, the extract diminished carbonylated proteins, lipid peroxidation, and nitrite levels in the brains of rats subjected to UCMS. These data reinforced antidepressant-like properties with the involvement of oxidative stress modulation by M. nigra extract pointing it as a possible new adjuvant treatment for depression.

Effects of chronic mild stress induced from peripuberty on sexual behavior in male rats, with or without escitalopram treatment.

BACKGROUND: After the Coronavirus Disease pandemic, depression became more present, including in adolescents. Escitalopram, a selective serotonin reuptake inhibitor, was approved in 2009 for treatment of the major depressive disorder, both in children and adolescents. The undesirable effects of antidepressants on sexual dysfunction are usually underestimated. AIMS: To investigate the effects of chronic mild stress, induced from peripuberty up to adulthood, on male sexual behavior parameters, with or without the escitalopram treatment, using rats as experimental model in a translational study. MATERIALS AND METHODS: Forty-four peripubertal male rats were distributed into four groups: Sham control, escitalopram, stress, and stress + escitalopram. The chronic mild stress consisted of nine different stressors randomly applied one per day, for 8 weeks (from 41 to 97 days postpartum). Escitalopram therapy by gavage (10 mg/kg) started at 70 days postpartum and lasted for 4 weeks. The male sexual behavior parameters were evaluated at 114 days postpartum. After that, euthanasia was performed for blood and testis collection. Histopathology of the testes and plasmatic testosterone level were carried out. RESULTS: There was a reduction in sexual activity and motivation in rats exposed to the stress protocol, which were treated or not with escitalopram, as well as an increase in the total number of mounts in animals exposed to the stress and treated with escitalopram. The testosterone levels were lower in animals exposed to the stress, which were or not treated with escitalopram (stress and stress + escitalopram). The frequency of histologically normal seminiferous tubule sections was lower in animals that were exposed to the stress and/or received escitalopram (escitalopram, stress, and stress + escitalopram). CONCLUSION: Chronic mild stress induced from peripuberty, associated or not to escitalopram treatment, altered the testosterone levels and testicular histoarchitecture and seems to be related to the reduction in male sexual motivation.

The involvement of neuroinflammation in an animal model of dementia and depression.

Alzheimer's disease (AD) and depression are inflammatory pathologies, leading to increased inflammatory response and neurotoxicity. Therefore, this study aimed to evaluate the effect of the treatment with fluoxetine and/or galantamine and/or donepezil on the levels of proinflammatory and anti-inflammatory cytokines in a mixed animal model of depression and dementia. Adult male Wistar rats underwent chronic mild stress (CMS) protocol for 40 days and were subjected to stereotaxic surgery for intra-hippocampal administration of amyloid-beta (Aꞵ) peptide or artificial cerebrospinal fluid (ACSF) to mimic the dementia animal model. On the 42nd day, animals were treated with water, galantamine, donepezil, and/or fluoxetine, orally for 17 days. On the 57th and 58th days, the Splash and Y-maze tests for behavior analysis were performed. The frontal cortex and hippocampus were used to analyze the tumor necrosis factor alfa (TNF-α), interleukin 1 beta (IL-1ꞵ), IL-6, and IL-10 levels. The results of this study show that animals subjected to CMS and administration of Aꞵ had anhedonia, cognitive impairment, increased TNF-α and IL-1ꞵ levels in the frontal cortex, and reduced IL-10 levels in the hippocampus. All treatment groups were able to reverse the cognitive impairment. Only donepezil did not decrease the TNF-α levels in the hippocampus. Fluoxetine + galantamine and fluoxetine + donepezil reversed the anhedonia. Fluoxetine reversed the anhedonia and IL-1ꞵ levels in the frontal cortex. In addition, fluoxetine + donepezil reversed the reduction of IL-10 levels in the hippocampus. The results indicate a pathophysiological interaction between AD and depression, and the association of medications in the future may be a possible therapeutic strategy to reduce inflammation, especially the fluoxetine-associated treatments.

Behavioral and inflammatory changes in rats induced by a three-hit stress model: Implications for psychiatric disorders.

Many aspects of the impact of childhood trauma remain unknown, such as the age at which individuals are most vulnerable to trauma, whether traumatic experiences have more severe and lasting effects when experienced early in life, and whether early life trauma causes psychiatric conditions such as anxiety and major depressive disorder (MDD) that persist over time or evolve into other disorders. Thus, this study aimed to investigate the impact of traumatic experiences in childhood on susceptibility to mood disorders in adulthood, particularly MDD. Animal models were used to address these questions, and different stressor protocols at various stages of the offspring's life were used. Three-hit starting with injections of Poly: IC was performed on the 9th day of gestation and then considered the first stressor. After birth, the animals were exposed to the maternal deprivation (MD) protocol, which separated the pups from the mother 3 h a day during the first ten days of life. From the 60th day of life, the animals were divided to receive the chronic mild stress (CMS) protocol over 21 days. The stressors can induce anxiety-like behaviors, such as increased locomotor activity through a maternal immune activation protocol using Poly: IC and demonstrating depressive-like behaviors through the MD and CMS protocols. It also showed changes in brain structures for pro-inflammatory parameters, IL-1ß and TNF-α, and alterations in anti-inflammatory parameters, IL-4 and IL-10, at different ages of life. The study also found that regulating pro- and anti-inflammatory cytokines is necessary for appropriate neuronal behavior, and stress responses can be both friendly and enemy, with costs and benefits balanced to provide the best-fit result. In conclusion, phenotypic characteristics of animals' life history are shaped by signals transmitted directly or indirectly to developing animals, known as "predictive adaptive responses."

Antidepressant Effect of Sodium Butyrate is Accompanied by Brain Epigenetic Modulation in Rats Subjected to Early or Late Life Stress.

BACKGROUND: Major depression has a complex and multifactorial etiology constituted by the interaction between genetic and environmental factors in its development. OBJECTIVE: The aim of this study was to evaluate the effects of sodium butyrate (SD) on epigenetic enzyme alterations in rats subjected to animal models of depression induced by maternal deprivation (MD) or chronic mild stress (CMS). METHODS: To induce MD, male Wistar rats were deprived of maternal care during the first 10 days of life. To induce CMS, rats were subjected to the CMS for 40 days. Adult rats were then treated with daily injections of SD for 7 days. Animals were subjected to the forced swimming test (FST), and then, histone deacetylase (HDAC), histone acetyltransferase (HAT), and DNA methyltransferase (DNMT) activities were evaluated in the brain. RESULTS: MD and CMS increased immobility time in FST and increased HDAC and DNMT activity in the animal brains. SD reversed increased immobility induced by both animal models and the alterations in HDAC and DNMT activities. There was a positive correlation between enzyme activities and immobility time for both models. HDAC and DNMT activities also presented a positive correlation between themselves. CONCLUSION: These results suggest that epigenetics can play an important role in major depression pathophysiology triggered by early or late life stress and its treatment.

Quetiapine effect on depressive-like behaviors, oxidative balance, and inflammation in serum of rats submitted to chronic stress.

Major depressive disorder (MDD) etiology is still not completely understood, and many individuals resist the traditional treatments. Chronic exposure to stressful events can contribute to development and progression and be involved in biological changes underlying MDD. Among the biological mechanisms involved, inflammatory changes and oxidative balance are associated with MDD pathophysiology. Quetiapine, a second-generation antipsychotic, induces a better therapeutic response in individuals refractory to traditional treatments. The main objectives of this research were as follows: to evaluate the effect of chronic mild stress (CMS) on depressive-like behaviors, oxidative stress, and inflammation in adult rats; to evaluate the possible antidepressant, antioxidant, and anti-inflammatory effects of quetiapine. The animals were submitted to CMS protocols. At the end of the CMS, the animals were submitted to a chronic treatment for 14 days with the following drugs: quetiapine (20 mg/kg), imipramine (30 mg/kg), and escitalopram (10 mg/kg). At the end of the treatments, the animals were evaluated in the open field tests, anhedonia (splash test), and forced swimming. The animals were euthanized after the behavioral tests, and serum samples were collected. Myeloperoxidase (MPO) activity and interleukin-6 (IL-6) levels were analyzed. CMS induced an increase in depressive-like behaviors, and quetiapine significantly reduced these behaviors. MPO activity and IL-6 levels increased in the serum of animals submitted to CMS. Quetiapine significantly reduced MPO activity and IL-6 levels. These results corroborate other evidence, indicating that chronic stress is a relevant phenomenon in the etiology of depression and suggesting that quetiapine induces an antidepressant effect because it reduces oxidative and inflammatory mechanisms.

Hydroalcoholic Extract of Rabbiteye Blueberry (Vaccinium ashei) Leaves Mitigates Unpredictable Chronic Mild Stress Model Inducing Depressive-Like Behavior in Rats.

Several studies reported that rabbiteye blueberry (Vaccinium ashei Reade) leaves present promising biological properties. To the best of our knowledge, no study investigated the possible application of their hydroalcoholic extract for treating mood disorders. Herein, we evaluated if the hydroalcoholic extract of rabbiteye blueberry (Vaccinium ashei Reade) leaves (HEV) promotes an antidepressant-like effect in rodents using chronic experimental approaches. The effect of repeated administration of HEV (50 mg/kg, p.o.) on the immobility time was assessed in the forced swimming test (FST) in an unpredictable chronic mild stress (UCMS) model. Repeated treatment with HEV reversed the depressive-like behavior induced by UCMS by reducing the immobility time. Besides, the exposure to HEV caused no changes in relative organ weights in rats submitted to UCMS. The results indicated that HEV administration presented antidepressant-like action devoid of toxic effects. Thus, it is possible to suggest its potential as a safe and accessible therapeutic tool in the management of depression and other related mood disorders.

Effects of escitalopram treatment and chronic mild stress induced from peripuberty on spermatic parameters of adult rats.

BACKGROUND: The prevalence of depression in adolescents has significantly increased worldwide. Escitalopram is a selective serotonin reuptake inhibitor approved for treatment of psychiatric disorders in children and adolescents by the Food and Drugs Administration. AIMS: This study aimed to evaluate the sperm parameters of adult rats exposed to chronic mild stress (CMS), from peripuberty to adulthood, treated or not with escitalopram. MATERIALS AND METHODS: Sixty-two male rats were distributed into four groups: S - submitted to CMS; E - Escitalopram (10 mg / kg, via gavage); ES - CMS + ES; SC - Sham control. The induced depression protocol consisted of the exposure of the animals to nine different stressors (one stressor/day), randomly for 8 weeks, from peripuberty (41 days postpartum, dpp) to adulthood (97 dpp). The escitalopram treatment period started at 70 dpp and lasted 4 weeks. The euthanasia was performed for biological material collection at 114 dpp. Morphometric, biometric, sperm parameters, oxidative stress analyses, and corticosterone dosage were carried out. RESULTS: There was a reduction of the sperm daily production and sperm concentration in the epididymis of rats treated and/or submitted to CMS. These groups (E, S, ES) also showed reduction of the mitochondrial activity; acrosome integrity; sperm chromatin compaction; sperm motility and vitality, besides an increased frequency of morphologically abnormal sperm. The sperm transit time through the epididymis was significantly higher in the escitalopram-treated rats (E, ES). No differences were observed regarding the sperm DNA fragmentation. The lipid peroxidation was significantly increased at the epididymal (E, S, and ES group) and testicular levels (S group). CONCLUSION: The CMS with or without escitalopram treatment altered the oxidative status in sperm and male organs, worsening the qualitative and quantitative sperm parameters, which can probably compromise the male fertility.

High and fluctuating levels of ovarian hormones induce an anxiogenic effect, which can be modulated under stress conditions: Evidence from an assisted reproductive rodent model.

Elevated levels of endogenous ovarian hormones are conditions commonly experienced by women undergoing assisted reproductive technologies (ART). Additionally, infertility-associated stress and treatment routines are factors that together may have a highly negative impact on female emotionality, which can be aggravated when several cycles of ART are needed to attempt pregnancy. This study aimed to investigate the effect of high and fluctuating levels of gonadal hormones induced by repeated ovarian stimulation on the stress response in rodents. To mimic the context of ART, female rats were exposed to an unpredictable chronic mild stress (UCMS) paradigm for four weeks. During this time, three cycles of ovarian stimulation (superovulation) (150 IU/Kg of PMSG and 75 IU/Kg of hCG) were applied, with intervals of two estrous cycles between them. The rats were distributed into four groups: Repeated Superovulation/UCMS; Repeated Superovulation/No Stress; Saline/UCMS; and Saline/No Stress. Anxiety-like and depressive-like behaviors were evaluated in a light-dark transition box and by splash test, respectively. Corticosterone, estradiol, progesterone, and biometric parameters were assessed. Data were analyzed using a two-way Generalized Linear Model (GzLM). Our results showed that repeated ovarian stimulation exerts by itself an expressive anxiogenic effect. Surprisingly, when high and fluctuating levels of ovarian hormones were combined with chronic stress, anxiety-like behavior was no longer observed, and a depressive-like state was not detected. Our findings suggest that females subjected to emotional overload induced by repeated ovarian stimulation and chronic stress seem to trigger the elaboration of adaptive coping strategies.

Short Daily Exposure to Environmental Enrichment, Fluoxetine, or Their Combination Reverses Deterioration of the Coat and Anhedonia Behaviors with Differential Effects on Hippocampal Neurogenesis in Chronically Stressed Mice.

Depression is a neuropsychiatric disorder with a high impact on the worldwide population. To overcome depression, antidepressant drugs are the first line of treatment. However, pre-clinical studies have pointed out that antidepressants are not entirely efficacious and that the quality of the living environment after stress cessation may play a relevant role in increasing their efficacy. As it is unknown whether a short daily exposure to environmental enrichment during chronic stress and antidepressant treatment will be more effective than just the pharmacological treatment, this study analyzed the effects of fluoxetine, environmental enrichment, and their combination on depressive-associated behavior. Additionally, we investigated hippocampal neurogenesis in mice exposed to chronic mild stress. Our results indicate that fluoxetine reversed anhedonia. Besides, fluoxetine reversed the decrement of some events of the hippocampal neurogenic process caused by chronic mild stress. Conversely, short daily exposure to environmental enrichment changed the deterioration of the coat and anhedonia. Although, this environmental intervention did not produce significant changes in the neurogenic process affected by chronic mild stress, fluoxetine plus environmental enrichment showed similar effects to those caused by environmental enrichment to reverse depressive-like behaviors. Like fluoxetine, the combination reversed the declining number of Ki67, doublecortin, calretinin cells and mature newborn neurons. Finally, this study suggests that short daily exposure to environmental enrichment improves the effects of fluoxetine to reverse the deterioration of the coat and anhedonia in chronically stressed mice. In addition, the combination of fluoxetine with environmental enrichment produces more significant effects than those caused by fluoxetine alone on some events of the neurogenic process. Thus, environmental enrichment improves the benefits of pharmacological treatment by mechanisms that need to be clarified.

Ayahuasca prevents oxidative stress in a rat model of depression elicited by unpredictable chronic mild stress

ABSTRACT Background: Depression is a highly disabling common mental disorder and, due to its multifactorial nature, the development of effective therapies is challenging and of great relevance. Ayahuasca (AYA), an entheogenic traditional beverage, has emerged as an alternative for antidepressant treatment, however, AYA preclinical and clinical trials are still incipient. Objectives: This investigation aimed to evaluate some behavioral and biochemical effects of AYA subchronic administration in rats submitted to a model of depression elicited by unpredictable chronic mild stress (UCMS). Methods: 500 mg/kg of AYA was administered in adult male rats once a day for 15 days before submitting the animals to UCMS. Anhedonia-like and locomotion behavior, lipid peroxidation, antioxidant enzyme activities, and sulfhydryl/nitrite content were evaluated. Results: AYA intake failed to prevent anhedonia-like behavior. Locomotion was not altered by AYA consumption or by the experimental condition. UCMS increased TBARS and nitrites levels, decreased the levels of catalase in the cerebral cortex and of Sulfhydryl in the hippocampus. AYA treatment counteracted these biochemical alterations but did not display any alterations in non-stressed rats. Conclusions: Taken together, results indicate an adaptogenic antioxidant molecular mechanism of AYA in relation to depression induced by stress.

Behavior and oxidative stress parameters in rats subjected to the animal's models induced by chronic mild stress and 6-hydroxydopamine.

Major depressive disorder (MDD) is one of the most prevalent forms of mental illness also affecting older adults. Recent evidence suggests a relationship between MDD and neurodegenerative diseases, including Parkinson's disease (PD). Individuals with PD have a predisposition to developing MDD, and both neurobiological conditions are associated with oxidative stress. Thus, we conducted this study to investigate depressive-like behavior and oxidative stress parameters using both animal models of PD and stress. Adult Wistar rats were subjected to chronic mild stress (CMS) protocol by 40 days and then it was used 6-hydroxydopamine (6-OHDA) as a model of PD, into the striatum. The experimental groups were: Control + Sham, Stress + Sham, Control+6-OHDA, and Stress+6-OHDA. Depressive like-behavior was evaluated by the forced swimming test (FST) and spontaneous locomotor activity by open-field test. Oxidative stress parameters were measured in the striatum, hippocampus, and prefrontal cortex (PFC). The results showed effects to increase immobility and decrease climbing times in the FST in Stress + Sham, Control+6-OHDA, and Stress+6-OHDA groups. The number of crossings and rearings were decreased in the Stress+6-OHDA group. The lipid peroxidation was increased in the PFC of Stress + Sham, and the hippocampus and striatum of Stress + Sham and Control+6-OHDA groups. Carbonyl protein levels increased in the PFC of Stress + Sham and striatum in Control+6-OHDA. Nitrite/Nitrate concentration was elevated in the PFC of Stress + Sham, in the hippocampus of Control+6-OHDA, the striatum of Stress + Sham, and Control+6-OHDA groups. Myeloperoxidase (MPO) activity was increased in the PFC and hippocampus of Stress + Sham and Control+6-OHDA groups. The activity of catalase decreased in the PFC of the Stress + Sham group. The activity of the superoxide dismutase (SOD) was decreased in the PFC of the Stress + Sham group, in the hippocampus of Stress + Sham and Control+6-OHDA groups, and the striatum of Control+6-OHDA group. These findings suggest that both stress and 6-OHDA induce depressive-like behavior and oxidative stress in the brain. The joining models have little evidence of the effects. Thus these findings suggest that other pathways are involved in the common point of the pathophysiology of PD and MDD.

Melatonin Reverses the Depression-associated Behaviour and Regulates Microglia, Fractalkine Expression and Neurogenesis in Adult Mice Exposed to Chronic Mild Stress.

Depression may be precipitated by the negative impact of chronic stress, which is considered to play a key role in this neuropsychiatric disorder. Interestingly, depressed patients show decreased levels of melatonin. This hormone acts pro-neurogenic and exhibits anti-depressant effects in rodent models of predictive antidepressant-like effects. However, the benefits of melatonin in reversing the deleterious effects of chronic mild stress on the alterations in behaviour and in the neurogenic niche of the hippocampus in male BALB/c mice are unknown. In this study, we compared the effects of melatonin (2.5 mg/kg) and citalopram (5 mg/kg), an antidepressant drug belonging to the selective serotonin reuptake inhibitors, in male BALB/c mice exposed to chronic mild stress (CMS). We also investigated the potential effects of melatonin and citalopram on microglial cells, hippocampal neurogenesis and peripheral cytokine profiles. Melatonin and citalopram induced similar antidepressant-like activities that occurred with some of the the following findings: (1) reversal of the morphological alterations in microglia; (2) reversal of the decreased immunoreactivity to CX3CL1 and CX3CR1 in the dentate gyrus; (3) positive regulation of cell proliferation, survival and complexity of the dendritic trees of doublecortin-cells; and (4) modifications of peripheral CX3CL1 expression. This outcome is consistent with the hypothesis about the antidepressant-like effect of melatonin and supports its relevance as a modulator of the niche in the dentate gyrus.

Hypothalamic-pituitary-adrenal axis responsivity to an acute novel stress in female rats subjected to the chronic mild stress paradigm.

The chronic mild stress (CMS) paradigm is the most frequently investigated animal model for major depression. The hypothalamic-pituitary-adrenal (HPA) axis participates in the generation of depressive symptomatology. We examined whether the depression-like state induced by CMS is associated with immediate changes in HPA axis activation in response to a novel acute stress and whether this response could be modified by hormonal status. Adult female Wistar rats were ovariectomized and received estrogen or vehicle pellets. After 2 weeks, rats were subjected to CMS (or control) conditions for 2.5 or 4.5 weeks. Rats were subsequently subjected to restraint stress for 1 h, and plasma corticosterone (CT) levels were determined before (2:00 p.m.) and after acute stress induction (3:00 and 4:00 p.m.). CT levels and FOS expression were measured in the medial parvocellular subdivision of the PVN (PaMP), central (CeA) and medial amygdala (MeA) and ventral subiculum of the hippocampus (vSub). Plasma CT levels in animals treated with 6.5 weeks of estrogen were elevated before and 1 h after restraint stress induction. Results indicate that the estrogen chronicity and CMS exposure impacted CT secretion. Neuronal PaMP, CeA, MeA and vSub activity decreased after 4.5 weeks of CMS in all groups. No differences were detected between CMS and non-CMS groups. These data suggest that the HPA central hyporesponsiveness observed in the experimental groups subjected to a longer protocol period was independent to CMS paradigm and estrogen treatment restored partially its activity. These data suggest that additional stressors could be responsible for the observed alterations of the HPA axis.

Brazilin Treatment Produces Antidepressant- and Anxiolytic-Like Effects in Mice.

Increasing evidence shows depression relevant to oxidative stress and inflammation. Anti-inflammatory strategies or antioxidants have led to the development of new antidepressants. Brazilin is a natural product from the Chinese traditional medicine Caesalpinia sappan L., exerting anti-inflammatory, antioxidant, anti-platelet concentration, and anti-cancer effects. While the antidepressant effect of brazilin is largely unknown. In present study, we investigated the effects of brazilin on H2O2-induced oxidative injury in PC12 cells and on depression- and anxiety-like behaviors of chronically mild stressed (CMS)-induced depression mice. It was found that brazilin pre-treatment (both 10 and 20 µM) significantly increased cell viability and decreased cell apoptosis in H2O2-treated PC12 cells. Furthermore, repetitive administration of brazilin to CMS-induced depression mice by intraperitoneal injection (10 mg/kg) made the mice significantly lose their latency of feeding in novelty-suppressed feeding test (NSF), have more the sucrose preference in sucrose preference test (SPT), and more time spent in the central zone without affecting their crossing activity in open field test (OFT). These results suggested that brazilin can play a role in antidepressant and anxiolytic-like behaviors for CMS-induced depression mice probably through inhibiting the oxidative stress. Therefore, brazilin is worth to be further explored for treating depressive and anxiety disorders.

Efeitos do Estresse Crônico Moderado sobre o Desempenho de Ratos Wistar em Tarefas de Aprendizagem / Effects of Chronic Mild Stress on Performance of Wistar Rats in Learning Tasks

As pesquisas sobre o efeito do estresse crônico moderado (CMS) sobre a aprendizagem de não humanos apresentam resultados contraditórios. Este estudo investigou os efeitos do CMS sobre o desempenho de ratos em duas tarefas de aprendizagem: uma discriminação visual simultânea e uma aprendizagem espacial em labirinto aquático. Oito ratos Wistar machos foram divididos em grupo experimental (GE, exposto ao CMS) e grupo controle (GC). Após exposição do GE ao protocolo de CMS por três semanas, ambos os grupos passaram por uma tarefa de discriminação visual e pela tarefa de aprendizagem espacial no labirinto aquático de Morris (MWM), além de testes de preferência por solução de sacarose. O GE continuou sendo exposto ao CMS durante a tarefa de discriminação visual. Os resultados sugerem que o CMS pode ter reduzido o ganho de peso e dificultado a aprendizagem de discriminação visual do GE, sem alterações na preferência por sacarose e no MWM. De acordo com os resultados do presente estudo e da literatura em geral, os efeitos do CMS sobre a aprendizagem podem depender de sua duração e da complexidade da tarefa.

Researches on the effect of chronic mild stress (CMS) on non-human learning present contradictory results. This study investigated the effects of CMS on rats' performance in two learning tasks: a simultaneous visual discrimination and a spatial learning task in a water maze. Eight Wistar rats were divided into experimental group (GE, exposed to CMS) and control group (GC). After the GE group had been submitted to the CMS protocol for three weeks, both groups were exposed to a visual discrimination task and spatial learning task in the Morris Water Maze (MWM), in addition to preference tests for a sucrose solution. GE continued to be exposed to CMS for visual discrimination task. Results suggested that CMS may reduce weight gain and make the visual discrimination learning more difficult for the GE, without changes on the sucrose preference and MWM. According to the results of the present study and the literature in general, the effects of CMS on learning may depend on the duration and complexity of the task.

Is chronodisruption a vulnerability factor to stress?

Since the circadian system seems to modulate stress responses, this study aimed to evaluate if the combination of circadian strain and stress amplifies changes expected from each factor alone. Control Balb/c mice (12:12-NS) kept in standard 12:12 light:dark cycles (LD) and submitted to no stress procedures (NS) were compared to groups submitted to shortened LD (10:10-NS), chronic mild stress (CMS) but no circadian strain (12:12-CMS), or shortened LD followed by CMS (10:10-CMS). Rest-activity/temperature rhythms and body weight were assessed throughout the experiments. In Experiment 1 mice were submitted to 3 weeks of CMS; in Experiment 2 sucrose preference and light-dark tests were performed. Also, blood samples were collected at the end of Experiment 2 to assess metabolic parameters. Relative amplitude of temperature after CMS was increased only in the 10:10-CMS group, while body weight change was reduced during CMS regardless of LD intervention. During the CMS, the relative amplitude of temperature was negatively correlated with body weight gain. No differences in behavior and metabolic parameters were seen among groups. Identifying suitable research designs to investigate our hypothesis that circadian disturbances may increase vulnerability to stress-induced depression and anxiety is warranted.

Blockade of AT1 type receptors for angiotensin II prevents cardiac microvascular fibrosis induced by chronic stress in Sprague-Dawley rats.

To test the effects of chronic-stress on the cardiovascular system, the model of chronic mild unpredictable stress (CMS) has been widely used. The CMS protocol consists of the random, intermittent, and unpredictable exposure of laboratory animals to a variety of stressors, during 3 consecutive weeks. In this study, we tested the hypothesis that exposure to the CMS protocol leads to left ventricle microcirculatory remodeling that can be attenuated by angiotensin II receptor blockade. Male Sprague-Dawley rats were randomly assigned into four groups: Control, Stress, Control + losartan, and Stress + losartan (N = 6, each group, losartan: 20 mg/kg/day). The rats were euthanized 15 days after CMS exposure, and blood samples and left ventricle were collected. Rats submitted to CMS presented increased glycemia, corticosterone, noradrenaline and adrenaline concentration, and losartan reduced the concentration of the circulating amines. Cardiac angiotensin II, measured by high-performance liquid chromatography (HPLC), was significantly increased in the CMS group, and losartan treatment reduced it, while angiotensin 1-7 was significantly higher in the CMS losartan-treated group as compared with CMS. Histological analysis, verified by transmission electron microscopy, showed that rats exposed to CMS presented increased perivascular collagen and losartan effectively prevented the development of this process. Hence, CMS induced a state of microvascular disease, with increased perivascular collagen deposition, that may be the trigger for further development of cardiovascular disease. In this case, CMS fibrosis is associated with increased production of catecholamines and with a disruption of renin-angiotensin system balance, which can be prevented by angiotensin II receptor blockade.

Acute treatment with ketamine and chronic treatment with minocycline exert antidepressant-like effects and antioxidant properties in rats subjected different stressful events.

Despite decades of research, the fundamental neurochemical and molecular mechanisms underlying the major depressive disorder (MDD) are still poorly understood, and current antidepressant treatments have limited clinical efficacy. In clinical conditions, the rapprochement between the disease and the corrective actions of drugs in laboratory animals is essential for developing effective therapies. Thus, the aim of this study was to evaluate the antidepressant effects of ketamine (N-metil-d-asparte (NMDA) receptor antagonist), minocycline (tetracycline antibiotic), and amitriptyline (classical antidepressant), on behavior and oxidative stress parameters in animals submitted to the chronic mild stress (CMS) and maternal deprivation protocols. For this aim, male Wistar rats were submitted to maternal deprivation or CMS. To induce maternal deprivation, Wistar rats were deprived of maternal care during the first 10 days of life. To induce CMS, Wistar rats were submitted to the CMS for 40 days. To reverse the effects of stress, treatment was done intraperitoneally with a single dose of ketamine (15 mg/kg), and minocycline (25 mg/kg) and amitriptyline (10 mg/kg) by 20 days. After treatment, the animals were submitted to the forced swimming test and then analyzed oxidative stress parameters in the prefrontal cortex (PFC), hippocampus, amygdala and nucleus accumbens (NAc). Treatment with ketamine, minocycline and amitriptyline were able to exert antidepressant effects in the forced swimming test. However, these antidepressant effects were dependent on the stress model by which the animals were exposed. In certain brain regions some treatment strategies had a pro-oxidant effect. Though, most of the strategies used in this study had antioxidant effects, as reported by a decrease on protein and lipid damage, nitrite/nitrate concentration and myeloperoxidase activity. In addition, an increase in the antioxidant superoxide dismutase (SOD) and catalase (CAT) enzymes activities were also evident after treatments. In conclusion, the antidepressant effects of ketamine and minocycline, in the present study, may be associated, at least in part, with its antioxidant and neuroprotective effects in animals subjected to maternal deprivation or CMS.