Search

Notwithstanding advances in understanding the pathophysiology of major depressive disorder (MDD), no single mechanism can explain all facets of this disorder. An expanding body of evidence indicates a putative role for the inflammatory response. Several meta-analyses showed an increase in systemic peripheral inflammatory markers in individuals with MDD. Numerous conditions and circumstances in the modern world may promote chronic systemic inflammation through mechanisms, including alterations in the gut microbiota. Peripheral cytokines may reach the brain and contribute to neuroinflammation through cellular, humoral, and neural pathways. On the other hand, antidepressant drugs may decrease peripheral levels of inflammatory markers. Anti-inflammatory drugs and nutritional strategies that reduce inflammation also could improve depressive symptoms. The present study provides a critical review of recent advances in the role of inflammation in the pathophysiology of MDD. Furthermore, this review discusses the role of glial cells and the main drivers of changes associated with neuroinflammation. Finally, we highlight possible novel neurotherapeutic targets for MDD that could exert antidepressant effects by modulating inflammation., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Susceptibility to psychiatric disorders seems to be influenced by environmental disturbances throughout all stages of life. Epigenetics is described as a key "bridge" between gene and environment, shaping gene expression and phenotype in response to environmental influences. For a long time, it was believed the epigenetic information could not be transmitted from one generation to the next, however, recent evidence has demonstrated that these acquired changes can be transmitted across generations in different species, with implications also for humans. The emerging evidence of epigenetic inheritance mechanisms is changing the concept of how and what information can be transferred across generations, rising as a promising theory to explain how psychiatric-related information can be inherited. In this review, we will discuss the main theory about epigenetic inheritance, present clinical evidence of its potential role in major psychiatric disorders, and how studies with patients and animal models have helped describe the epigenetic mechanisms and possible targets underlying this process in schizophrenia, bipolar disorder, depression, post-traumatic stress disorder, anxiety, substance use disorder and autism., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

This study aimed to evaluate the effects of environmental enrichment (EE) in Wistar rats subjected to maternal deprivation (MD). MD was performed in the first post-natal days (PND) ten for 3 h/day. The groups were: control; deprived without EE; and deprived with EE. The EE was applied for 3 h/day. Forced swimming test (FST) and open field test were performed, and histone deacetylase (HDAC) and DNA methyltransferase (DNMT) activities in the prefrontal cortex (PFC) and hippocampus were evaluated on 31, 41, and 61 PND. MD altered spontaneous locomotor activity and immobility time in FST, but the effects were sex- and developmental period dependent. In deprived females at PND 31, 41, and 61, HDAC and DNMT increased in the PFC and hippocampus. In females exposed to EE for 20 days, there was a decrease of HDAC in the hippocampus and DNMT in the PFC and hippocampus. Exposure of females to EE for 40 days can reverse HDAC and DNMT increase in all brain areas. In deprived males at PND 31, 41, and 61, HDAC and DNMT increased in the hippocampus, and in the group exposed to EE for 40 days, there was a decrease in hippocampal activity. In PFC of male deprived rats at PND 61 and EE for 40 days, there was a reduction of HDAC and DNMT. MD induced lifelong persistent behavioral and epigenetic changes, and such effects were more evident in female than male rats. EE can be considered an essential non-pharmacological strategy to treat long-term trauma-induced early life changes., (Copyright © 2021. Published by Elsevier Ltd.)

Bipolar disorder (BD) is a chronic condition characterized by severe mood swings alternating between episodes of mania and depression. Evidence indicates that protein kinase C (PKC) and oxidative stress are important therapeutic targets for BD. However, what PKC isoforms that are precisely involved in this effect are unknown. Therefore, we evaluated the effects of the intracerebroventricular (ICV) injection of PKC inhibitors (lithium (Li), tamoxifen (TMX), PKCα inhibitor (iPKCα), PKCγ inhibitor (iPKCγ), and PKCε inhibitor (iPKCε)) on the manic-like behaviors and oxidative stress parameters (4-hydroxy-2-nonenal (4-HNE), 8-isoprostane (8-ISO), carbonyl groups, 3-nitrotyrosine (3-NT), glutathione peroxidase (GPx) and glutathione reductase (GR)) in the brains of rats submitted to the model of mania induced by methamphetamine (m-AMPH). Animals received a single ICV infusion of artificial cerebrospinal fluid, Li, TMX, iPKCα, iPKCγ or iPKCε followed by an intraperitoneal injection of saline or m-AMPH before the behavioral analysis (open-field task). Oxidative stress was evaluated in the striatum, frontal cortex, and hippocampus. ICV injection of Li, TMX or iPKCε blocked the m-AMPH-induced increase in the manic-like behaviors - crossings, rearings, visits to the center, sniffing, and grooming. ICV infusion of iPKCα triggered a decrease in these behaviors induced by m-AMPH. Besides, the iPKCε administration significantly prevented the oxidative damage to lipids and proteins, as well as disturbances in the activity of antioxidant enzymes induced by m-AMPH. The findings of the present study suggest that PKCε isoform is strongly implied in the antimanic and antioxidant effects of Li, TMX, and the other PKC inhibitors in the model of mania., Competing Interests: Declaration of Competing Interest JQ has the following declarations of interest: Clinical research support: Janssen Pharmaceutical (Clinical Trial), Allergan (Clinical Trial); Advisory boards, speaker bureaus, expert witness, or consultant: Daiichi Sankyo (Speaker Bureau); Patent, equity, or royalty: Instituto de Neurociências Dr. João Quevedo (Stockholder); Other: Artmed Editora (Copyright), Artmed Panamericana (Copyright). All the other authors have no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The present study aimed to evaluate the effects of treatment with lithium (Li) and valproate (VPA) on behaviors and brain BDNF, NGF, NT-3, NT-4 and GDNF levels in mice submitted to paradoxical sleep deprivation (PSD), which induces an animal model of mania. Male C57BL/6J mice received an intraperitoneal (i.p.) injection of saline solution (NaCl 0.09%, 1 ml/kg), Li (47.3 mg/kg, 1 ml/kg) or VPA (200 mg/kg, 1 ml/kg) once a day for seven days. Animals were randomly distributed into six groups (n = 10 per group): (1) Control + Sal; (2) Control + Li; (3) Control + VPA; (4) PSD + Sal; (5) PSD + Li; or (6) PSD + VPA. Animals were submitted to 36 h of PSD, and then, they were submitted to the open field test. The frontal cortex and hippocampus were dissected from the brain. The manic-like behaviors in the mice were analyzed. Treatment with Li and VPA reversed the behavioral alterations induced by PSD. PSD decreased BDNF, NGF, and GDNF levels in the frontal cortex and hippocampus of mice. The administration of Li and VPA protected the brain against the damage induced by PSD. However, PSD and the administration of Li and VPA did not affect the levels of NT-3 and NT-4 in either brain structure evaluated. In conclusion, the PSD protocol induced manic-like behavior in rats and induced alterations in neurotrophic factor levels. It seems that neurotrophic factors and sleep are essential targets to treat BD., (Copyright © 2019. Published by Elsevier Ltd.)

There is accumulating evidence demonstrating that dysfunction of glutamatergic neurotransmission, particularly via N-methyl-d-aspartate (NMDA) receptors, is involved in the pathophysiology of major depressive disorder (MDD). Several studies have revealed an altered expression of NMDA receptor subtypes and impaired NMDA receptor-mediated intracellular signaling pathways in brain circuits of patients with MDD. Clinical studies have demonstrated that NMDA receptor antagonists, particularly ketamine, have rapid antidepressant effects in treatment-resistant depression, however, neurobiological mechanisms are not completely understood. Growing body of evidence suggest that signal transduction pathways involved in synaptic plasticity play critical role in molecular mechanisms underlying rapidly acting antidepressant properties of ketamine and other NMDAR antagonists in MDD. Discovering the molecular mechanisms underlying the unique antidepressant actions of ketamine will facilitate the development of novel fast acting antidepressants which lack undesirable effects of ketamine. This review provides a critical examination of the NMDA receptor involvement in the neurobiology of MDD including analyses of alterations in NMDA receptor subtypes and their interactive signaling cascades revealed by postmortem studies. Furthermore, to elucidate mechanisms underlying rapid-acting antidepressant properties of NMDA receptor antagonists we discussed their effects on the neuroplasticity, mostly based on signaling systems involved in synaptic plasticity of mood-related neurocircuitries., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A relationship between neuroinflammation and the development of psychiatric disorder have been revealed by many studies in the past decade. Although studies have shown that stressors can induce long-term changes that may be related to behavioral responses, these alterations have been poorly studied soon after a stressor, such as maternal deprivation (MD). Thus, this study was designed to investigate the acute effect of experimental induction of MD on inflammatory and microglial activation markers in the brain of infant rats. Early MD was induced from postnatal day (PND) 1-10. On PND 10 the prefrontal cortex (PFC) and hippocampus from MD and control groups were removed to investigate microglial activation and neuroinflammatory markers. In the PFC the expressions of cluster of differentiation molecule 11B (CD11B), toll-like receptor (TLR)-2, and TLR-4 were increased in rats subjected to MD. The arginase expression was elevated in the PFC and hippocampus of maternally deprived rats. The cytokines interleukin-5 (IL-5), -6, -7, -10, tumor necrosis factor (TNF-α), and interferon gamma (INF-γ) were increased in the PFC of MD rats group. In the PFC the macrophage inflammatory proteins (MIP)-1α levels were reduced in MD rats group. In the hippocampus only the levels of TNF-α and INF-γ were elevated in infant rats subjected to MD. In conclusion, our results support the hypothesis that neuroinflammation and microglial activation, mainly in the PFC, could be involved with changes in the brain resident cells following MD, and these alterations could be associated to the development of psychiatric conditions late in life., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Studies have suggested the involvement of oxidative stress in the physiopathology of bipolar disorder. Preclinical data have shown that PKC inhibitors may act as mood-stabilizing agents and protect the brain in animal models of mania. The present study aimed to evaluate the effects of Lithium (Li) or tamoxifen (TMX) on behavioral changes and oxidative stress parameters in an animal model of mania induced by ouabain (OUA). Wistar rats received a single intracerebroventricular (ICV) injection of OUA or artificial cerebrospinal fluid (ACSF). From the day following ICV injection, the rats were treated for seven days with intraperitoneal injections of saline, Li or TMX twice a day. On the 7th day after OUA injection, locomotor activity was measured using the open-field test, and the oxidative stress parameters were evaluated in the hippocampus and frontal cortex of rats. The results showed that OUA induced hyperactivity in rats, which is considered a manic-like behavior. Also, OUA increased lipid peroxidation and oxidative damage to proteins, as well as causing alterations to antioxidant enzymes in the frontal cortex and hippocampus of rats. The Li or TMX treatment reversed the manic-like behavior induced by OUA. Besides, Li, but not TMX, reversed the oxidative damage caused by OUA. These results suggest that the manic-like effects induced by OUA and the antimanic effects of TMX seem not to be related to the oxidative stress., (Copyright © 2019. Published by Elsevier Ltd.)

Major depressed patients show increased bacterial translocation with elevated plasma levels of lipopolysaccharide (LPS), which may trigger immune-inflammatory and neuro-oxidative responses. Recently, an animal model based on chronic LPS administration was developed which was associated with long-lasting depressive-like and neuro-oxidative alterations in female mice. The aim of the current study was to investigate behavioral, neuroimmune and neuroprogressive alterations in female mice 6 weeks after LPS chronic exposure. Female mice received increasing doses of LPS during 5 days at one-month intervals repeated for 4 consecutive months. Six weeks after the last LPS-exposure, we assessed behavioral despair and anhedonia, microglial activation, alterations in tryptophan, 5-HT, kynurenine, quinolinic acid (QUIN) levels and spermidine/spermine N1-acetyltransferase (SAT1) expression in the hippocampus, both with and without fluoxetine administration. Our results show that six weeks post-LPS, mice present behavioral despair and anhedonia in association with increased IBA1 expression (a microglia activation marker), NF-kB p65 and IL-1β levels, indoleamine 2,3-dioxygenase (IDO1) mRNA expression, kynurenine, QUIN levels and QUIN/tryptophan ratio, and lowered tryptophan, 5-HT levels and SAT1 mRNA expression. Fluoxetine reversed the behavioral and neuroimmune alterations but had no effect in the reversal of IDO1 increased expression, QUIN levels and QUIN/tryptophan ratio. In conclusion, our results support the validity of the chronic LPS model of major depression and additionally shows its translational relevance with respect to neuroimmune and neuroprogressive pathways., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Major depressive disorder (MDD) is a highly debilitating condition that is drawing considerable attention due to its high global prevalence and to the fact that treatments are still far from reaching the total number of patients affected. Among available treatment strategies, quetiapine is an important research target, due to antidepressant responses in patients resistant to classical treatments and in animals submitted to protocols that induce depressive-like behaviours. Quetiapine has a broad spectrum of action, within which are many mechanisms that seem to be related to the most effective antidepressant therapeutic responses. In this review, research results related to the pharmacokinetic profile, neurotransmitters, receptors and signalling molecular targets involved in the functional and structural plasticity of key brain regions in MDD are reported and discussed. Moreover, the physiological mechanisms, which are targets of quetiapine and are involved in both MDD and poor therapeutic response, are reported. The main adverse effects observed from therapeutic dosages and overdose are also described. Finally, the main mechanisms underlying the therapeutic response are highlighted., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Evidence has shown that the kynurenine pathway (KP) plays a role in the onset of oxidative stress and also in the pathophysiology of schizophrenia. The aim of this study was to use a pharmacological animal model of schizophrenia induced by ketamine to investigate if KP inhibitors could protect the brains of Wistar rats against oxidative stress and behavioral changes. Ketamine, injected at the dose of 25mg/kg, increased spontaneous locomotor activity. However, the inhibitors of tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase (IDO) and kynurenine-3-monooxygenase (KMO) were able to reverse these changes. In addition, the IDO inhibitor prevented lipid peroxidation, and decreased the levels of protein carbonyl in the prefrontal cortex (PFC), hippocampus and striatum. It also increased the activity of superoxide dismutase (SOD) in the hippocampus, as well as increasing the levels of catalase activity in the PFC and hippocampus. The TDO inhibitor prevented lipid damage in the striatum and reduced the levels of protein carbonyl in the hippocampus and striatum. Also, the TDO inhibitor increased the levels of SOD activity in the striatum and CAT activity in the hippocampus of ketamine-induced pro-oxidant effects. Lipid damage was not reversed by the KMO inhibitor. The KMO inhibitor increased the levels of SOD activity in the hippocampus, and reduced the levels of protein carbonyl while elevating the levels of CAT activity in the striatum of rats that had been injected with ketamine. Our findings revealed that the KP pathway could be a potential mechanism by which a schizophrenia animal model induced by ketamine could cause interference by producing behavioral disturbance and inducing oxidative stress in the brain, suggesting that the inhibition of the KP pathway could be a potential target in treating schizophrenia., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To determine the prevalence of food addiction in a large Brazilian non-clinical sample. Sociodemographic and psychopathological correlates of food addiction as well as associations with quality (QoL) domains were also investigated., Methods: This cross-sectional study obtained data from a Brazilian anonymous web-based research platform (N = 7639; 71.3% females). Participants provided sociodemographic data and completed the modified Yale Food Addiction Scale 2.0, PHQ-9, hypomania checklist (HCL-32), Fagerström Test for Nicotine Dependence, AUDIT, modified Skin picking-Stanford questionnaire, Minnesota impulsive disorders interview, Symptom Checklist-90-Revised inventory (SCL-90R), early trauma inventory self report-short form, and the WHO Quality of Life instrument-Abbreviated version (WHOQOL-Bref). Associations were adjusted to potential confounders through multivariable models., Results: The prevalence of food addiction was 4.32% (95%CI: 3.89-4.80%), and was more common among females. Food addiction was associated with a positive screen for a major depressive episode (OR = 4.41; 95%CI: 3.46-5.62), bipolar spectrum disorder (OR = 1.98; 95%CI: 1.43-2.75), and skin picking disorder (OR = 2.02; 95%CI: 1.31-3.09). Food addiction was also independently associated with exposure to early life psychological and sexual abuse (P = 0.008) as well as with reduced physical, psychological, social, and environment QoL (all P < 0.001)., Conclusions: Food addiction may be common in low and middle-income countries, though possibly less prevalent than in the US. Food addiction was associated with co-occurring mood disorders and skin picking disorder as well as with early life psychological and sexual abuse. Finally, food addiction was independently associated with broad reductions in QoL. Public health efforts towards the early recognition and management of food addiction are warranted., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

This study used an animal model of depression induced by maternal care deprivation (MCD) to investigate whether depressive behaviour, neuroinflammation and oxidative stress were underlying factors in developmental programming after early life stress. At postnatal days (PND) 20, 30, 40, and 60, individual subsets of animals were evaluated in behavioural tests and then euthanized to assess cytokine levels and oxidative stress parameters in the prefrontal cortex (PFC), hippocampus and serum. The results showed that MCD did not induce behavioural changes at PND 30 and 40. However, at PND 20 and 60, the rats displayed a depressive-like behaviour in the forced swimming test, without changes in locomotor spontaneous activity. In the brain and serum, the levels of pro-inflammatory cytokines (interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α)) were increased, and the anti-inflammatory cytokine (interleukin-10) level was reduced throughout developmental programming (PND 20, 30, 40 and 60). Protein carbonyl levels increased in the brain at PND 30, 40 and 60. Superoxide dismutase (SOD) activity was decreased during all developmental programming phases evaluated in the brain. Catalase (CAT) activity was decreased at PND 20, 40 and 60 in the brain. Our results revealed that "critical episodes" in early life stressful events are able to induce behavioural alterations that persist into adulthood and can stimulate inflammation and oxidative damage in both central and peripheral systems, which are required for distinct patterns of resilience against psychiatric disorders later in life., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The present study was created to investigate the effects of chronic mild stress (CMS) on the depressive behavior and neurochemical parameters of rats that were subjected to sepsis. Wistar rats were subjected to a CMS protocol, and sepsis was induced by cecal ligation and perforation (CLP). The animals were then divided into 4 separate groups; Control + Sham (n = 20), Control + CLP (n = 30), CMS + Sham (n = 20) and CMS + CLP (n = 30). Body weight, food and water intake and mortality were measured on a daily basis for a period of 10 days after the induction of sepsis. Locomotor activity, splash and forced swimming tests were performed ten days after CLP. At the end of the test period, the animals were euthanized, and the prefrontal cortex and hippocampus were removed to determine the levels of cytokines and oxidative damage. Our results show that there was no significant interaction between CMS and CLP in relation to locomotor activity and the forced swimming test. However, we did observe a significant decrease in total grooming time in the Control + CLP and CMS + Sham groups, with the CMS + CLP group showing behavior similar to that of the control animals. This was found to be related to a decrease in the levels of brain cytokines, and not to oxidative damage parameters. Collectively, our results suggest that a previous stress caused by CMS can protect the brain against the systemic acute and severe stress elicited by sepsis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Bipolar disorder (BD) is a neuropsychiatric disorder that is characterized by a phasic course of affective episodes interspersed with a euthymic state. Epidemiological, clinical, genetic, post-mortem and preclinical studies have shown that inflammatory reactions and immune modulation play a pivotal role in the pathophysiology of BD. It is conceptualized that biomarkers of inflammation and immune responses should be employed to monitor the disease process in bipolar patients. The objective of this systematic review is to analyse the inflammatory markers involved in human studies and to explore each individual marker for its potential clinical application and summarize evidence regarding their role in BD. A systematic review of human studies to measure inflammatory markers was conducted, and the studies were identified by searching PubMed/MEDLINE, PsycINFO, EMBASE, and Web of Science databases for peer-reviewed journals that were published until September 2015. In this review, we included peripheral markers, genetic, post-mortem and cell studies with inflammatory biomarker analysis in BD. One hundred and two (102) papers met the inclusion criteria. The pro-inflammatory cytokines were elevated and the anti-inflammatory cytokines were reduced in BD patients, particularly during manic and depressive phases when compared to the controls. These changes tend to disappear in euthymia, indicating that inflammation may be associated with acute phases of BD. Even though there are promising findings in this field, further clinical studies using more established detection techniques are needed to clearly show the benefit of using inflammatory markers in the diagnosis, follow-up and prognosis of patients with BD., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The present study aimed to investigate the effects of mood stabilizers, specifically lithium (Li) and valproate (VPA), on the PI3K/Akt signaling pathway in the brains of rats subjected to the ouabain (OUA)-induced animal model of mania. In addition, the effects of AR-A014418, a GSK-3β inhibitor, on manic-like behavior induced by OUA were evaluated. In the first experimental protocol Wistar rats received a single ICV injection of OUA or artificial cerebrospinal fluid (aCSF). From the day following ICV injection, the rats were treated for 6 days with intraperitoneal injections of saline, Li or VPA twice a day. In the second experimental protocol, rats received OUA, aCSF, OUA plus AR-A014418, or aCSF plus AR-A014418. On the 7th day after OUA injection, locomotor activity was measured using the open-field test. In addition, we analyzed the levels of p-PI3K, p-MAPK, p-Akt, and p-GSK-3β in the brain of rats by immunoblot. Li and VPA reversed OUA-related hyperactivity. OUA decreased p-PI3K, p-Akt and p-GSK-3β levels. Li and VPA improved these OUA-induced cellular dysfunctions; however, the effects of the mood stabilizers were dependent on the protein and brain region analyzed. In addition, AR-A014418 reversed the manic-like behavior induced by OUA. These findings suggest that the manic-like effects of ouabain are associated with the activation of GSK-3β, and that Li and VPA exert protective effects against OUA-induced inhibition of the GSK-3β pathway., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Cigarette smoking during the prenatal period has been investigated as a causative factor of obstetric abnormalities, which lead to cognitive and behavioural changes associated with schizophrenia. The aim of this study was to investigate behaviour and AChE activity in brain structures in adult rats exposed to cigarette smoke during the prenatal period. Pregnant rats were divided into non-PCSE (non-prenatal cigarette smoke exposure) and PCSE (prenatal cigarette smoke exposure) groups. On post-natal day 60, the rats received saline or ketamine for 7days and were subjected to behavioural tasks. In the locomotor activity task, the non-PCSE+ketamine and PCSE+ketamine groups exhibited increased locomotor activity compared with the saline group. In the social interaction task, the non-PCSE+ketamine and PCSE+ketamine groups exhibited an increased latency compared with the control groups. However, the PCSE+ketamine group exhibited a decreased latency compared with the non-PCSE+ketamine group, which indicates that the cigarette exposure appeared to decrease, the social deficits generated by ketamine. In the inhibitory avoidance task, the non-PCSE+ketamine, PCSE, and PCSE+ketamine groups exhibited impairments in working memory, short-term memory, and long-term memory. In the pre-pulse inhibition (PPI) test, cigarette smoke associated with ketamine resulted in impaired PPI in 3 pre-pulse (PP) intensity groups compared with the control groups. In the biochemical analysis, the AChE activity in brain structures increased in the ketamine groups; however, the PCSE+ketamine group exhibited an exacerbated effect in all brain structures. The present study indicates that exposure to cigarette smoke during the prenatal period may affect behaviour and cerebral cholinergic structures during adulthood., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Recent studies show that activation of the mTOR signaling pathway is required for the rapid antidepressant actions of glutamate N-methyl-D-aspartate (NMDA) receptor antagonists. A relationship between mTOR kinase and the endoplasmic reticulum (ER) stress pathway, also known as the unfolded protein response (UPR) has been shown. We evaluate the effects of ketamine administration on the mTOR signaling pathway and proteins of UPR in the prefrontal cortex (PFC), hippocampus, amygdala and nucleus accumbens, after the inhibiton of mTOR signaling in the PFC. Male adult Wistar rats received pharmacological mTOR inhibitor, rapamycin (0.2 nmol), or vehicle into the PFC and then a single dose of ketamine (15 mg/kg, i.p.). The immunocontent of mTOR, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), eukaryotic elongation factor 2 kinase (eEF2K) homologous protein (CHOP), PKR-like ER kinase (PERK) and inositol-requiring enzyme 1 (IRE1) - alpha were determined in the brain. The mTOR levels were reduced in the rapamycin group treated with saline and ketamine in the PFC; p4EBP1 levels were reduced in the rapamycin group treated with ketamine in the PFC and nucleus accumbens; the levels of peEF2K were increased in the PFC in the vehicle group treated with ketamine and reduced in the rapamycin group treated with ketamine. The PERK and IRE1-alpha levels were decreased in the PFC in the rapamycin group treated with ketamine. Our results suggest that mTOR signaling inhibition by rapamycin could be involved, at least in part, with the mechanism of action of ketamine; and the ketamine antidepressant on ER stress pathway could be also mediated by mTOR signaling pathway in certain brain structures., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Recent studies have shown benefits for the supplementation of folic acid in schizophrenic patients. The aim of this study was to evaluate the effects of folic acid addition on adult rats, over a period of 7 or 14 days. It also sets out to verify any potential protective action using an animal model of schizophrenia induced by ketamine, in behavioral and biochemical parameters. This study used two protocols (acute and chronic) for the administration of ketamine at a dose of 25 mg/kg (i.p.). The folic acid was given by oral route in doses of 5, 10 and 50 mg/kg, once daily, for 7 and/or 14 days in order to compare the protective effects of folic acid. Thirty minutes after the last administration of ketamine, the locomotor and social interaction activities were evaluated, and immediately the brain structure were removed for biochemical analysis. In this study, ketamine was administered in a single dose or in doses over the course of 7 days increasing the animal's locomotion. This study showed that the administration of folic acid over 7 days was unable to prevent hyper locomotion. In contrast, folic acid (10 and 50 mg/kg) administrated over a period of 14 days, was able to partially prevent the hyper locomotion. Our data indicates that both acute and chronic administrations of ketamine increased the time to first contact between the animals, while the increased latency for social contact was completely prevented by folic acid (5, 10 and 50 mg/kg). Chronic and acute administrations of ketamine also increased lipid peroxidation and protein carbonylation in brain. Folic acid (10 and 50 mg/kg) supplements showed protective effects on the oxidative damage found in the different brain structures evaluated. All together, the results indicate that nutritional supplementation with folic acid provides promising results in an animal model of schizophrenia induced by ketamine., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Bipolar disorder (BD) is a chronic psychiatric illness characterized by severe and biphasic changes in mood. Several pathophysiological mechanisms have been hypothesized to underpin the neurobiology of BD, including the presence of mitochondrial dysfunction. A confluence of evidence points to an underlying dysfunction of mitochondria, including decreases in mitochondrial respiration, high-energy phosphates and pH; changes in mitochondrial morphology; increases in mitochondrial DNA polymorphisms; and downregulation of nuclear mRNA molecules and proteins involved in mitochondrial respiration. Mitochondria play a pivotal role in neuronal cell survival or death as regulators of both energy metabolism and cell survival and death pathways. Thus, in this review, we discuss the genetic and physiological components of mitochondria and the evidence for mitochondrial abnormalities in BD. The final part of this review discusses mitochondria as a potential target of therapeutic interventions in BD., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The exact pathophysiology of major depressive disorder (MDD) remains elusive. The monoamine theory, which hypothesizes that MDD emerges as a result of dysfunctional serotonergic, dopaminergic and noradrenergic pathways, has guided the therapy of this illness for several decades. More recently, the involvement of activated immune, oxidative and nitrosative stress pathways and of decreased levels of neurotrophic factors has provided emerging insights regarding the pathophysiology of MDD, leading to integrated theories emphasizing the complex interplay of these mechanisms that could lead to neuroprogression. In this review, we propose an integrative model suggesting that T helper 17 (Th17) cells play a pivotal role in the pathophysiology of MDD through (i) microglial activation, (ii) interactions with oxidative and nitrosative stress, (iii) increases of autoantibody production and the propensity for autoimmunity, (iv) disruption of the blood-brain barrier, and (v) dysregulation of the gut mucosa and microbiota. The clinical and research implications of this model are discussed., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The neurotrophic hypothesis of major depressive disorder (MDD) postulates that the pathology of this illness incorporates a down-regulation of neurotrophin signaling. Brain-derived neurotrophic factor (BDNF) is the most studied neurotrophic mediator regarding the neurobiology of MDD. Nevertheless, emerging evidence has implicated the multi-competent angiogenic and neurogenic molecule - vascular endothelial growth factor (VEGF) - in hippocampal neurogenesis and depression pathophysiology., Objective: To compare peripheral levels of VEGF between individuals with MDD and healthy controls., Methods: We performed a systematic review and meta-analysis of original studies measuring peripheral levels of VEGF in participants with MDD compared to healthy controls. We searched the Pubmed/MEDLINE, EMBASE and PsycInfo databases for studies published in any language through December 16th, 2014., Results: Fourteen studies met eligibility criteria (N=1633). VEGF levels were significantly elevated in individuals with MDD when compared to healthy controls (Hedges's g=0.343; 95% CI: 0.146-0.540; P<0.01). Funnel plot inspection and the Egger's test did not provide evidence of publication bias. A significant degree of heterogeneity was observed (Q=38.355, df=13, P<0.001; I(2)=66.1%), which was explored through meta-regression and subgroup analyses. Overall methodological quality, sample for assay (plasma versus serum), as well as the matching of MDD and control samples for age and gender emerged as significant sources of heterogeneity., Conclusions: Taken together, extant data indicate that VEGF shows promise as a biomarker for MDD, and supports that this mediator may be involved in neuroplasticity mechanisms underlying the pathophysiology of MDD., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Treatment-resistant depression affects up to 20% of individuals suffering from major depressive disorder (MDD). The medications currently available to treat depression, including serotonin re-uptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs), fail to produce adequate remission of depressive symptoms for a large number of patients. The monoamine hypothesis upon which these medications are predicated should be expanded and revised as research elucidates alternative mechanisms of depression and effective methods to treat the underlying pathologic consequences. Research into the role of tryptophan degradation and the kynurenine pathway in the setting of inflammation has brought new insight into potential etiologies of MDD. Further investigation into the connection between inflammatory mediators, tryptophan degradation, and MDD can provide many targets for novel antidepressant therapies. Thus, this review will highlight the role of the kynurenine pathway in the pathophysiology of depression, as well as a novel therapeutic target to classic and new modulators to treat depression based on findings from preclinical and clinical studies., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Progression of bipolar disorder (BD) has been associated with cognitive impairment and changes in neuroplasticity, including a decrease in serum brain-derived neurotrophic factor (BDNF). However, no study could examine BDNF levels directly in different brain regions after repeated mood episodes to date. The proposed animal model was designed to mimic several manic episodes and evaluate whether the performance in memory tasks and BDNF levels in hippocampus, prefrontal cortex, and amygdala would change after repeated amphetamine (AMPH) exposure. Adult male Wistar rats were divided into subchronic (AMPH for 7 days) and chronic groups (35 days), mimicking manic episodes at early and late stages of BD, respectively. After open field habituation or inhibitory avoidance test, rats were killed, brain regions were isolated, and BDNF mRNA and protein levels were measured by quantitative real-time PCR and ELISA, respectively. AMPH impaired habituation memory in both subchronic and chronic groups, and the impairment was worse in the chronic group. This was accompanied by increased Bdnf mRNA levels in the prefrontal cortex and amygdala region, as well as reduced BDNF protein in the hippocampus. In the inhibitory avoidance, AMPH significantly decreased the change from training to test when compared to saline. No difference was observed between subchronic and chronic groups, although chronically AMPH-treated rats presented increased Bdnf mRNA levels and decreased protein levels in hippocampus when compared to the subchronic group. Our results suggest that the cognitive impairment related to BD neuroprogression may be associated with BDNF alterations in hippocampus, prefrontal cortex, and amygdala., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The present study aimed to investigate the effects of mood stabilizers, specifically lithium (Li) and valproate (VPA), on mitochondrial superoxide, lipid peroxidation, and proteins involved in cell death signaling pathways in the brains of rats subjected to the ouabain-induced animal model of mania. Wistar rats received Li, VPA, or saline twice a day for 13 days. On the 7th day of treatment, the animals received a single intracerebroventricular injection of ouabain or aCSF. After the ICV injection, the treatment with mood stabilizers continued for 6 additional days. The locomotor activity of rats was measured using the open-field test. In addition, we analyzed oxidative stress parameters, specifically levels of phosphorylated p53 (pp53), BAX and Bcl-2 in the brain of rats by immunoblot. Li and VPA reversed ouabain-related hyperactivity. Ouabain decreased Bcl-2 levels and increased the oxidative stress parameters BAX and pp53 in the brains of rats. Li and VPA improved these ouabain-induced cellular dysfunctions; however, the effects of the mood stabilizers were dependent on the protein and brain region analyzed. These findings suggest that the Na(+)/K(+)-ATPase can be an important link between oxidative damage and the consequent reduction of neuronal and glial density, which are both observed in BD, and that Li and VPA exert protective effects against ouabain-induced activation of the apoptosis pathway., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Bipolar disorder (BD) is a severe psychiatric disorder associated with social and functional impairment. Some studies have strongly suggested the involvement of oxidative stress in the pathophysiology of BD. Paradoxal sleep deprivation (PSD) in mice has been considered a good animal model of mania because it induces similar manic-like behavior, as well as producing the neurochemical alterations which have been observed in bipolar patients. Thus, the objective of the present study was to evaluate the effects of the antioxidant agent's n-acetylcysteine (Nac) and/or deferoxamine (DFX) on behavior and the oxidative stress parameters in the brains of mice submitted to the animal model of mania induced by PSD. The mice were treated for a period of seven days with saline solution (SAL), Nac, DFX or Nac plus DFX. The animals were subject to the PSD protocol for 36 h. Locomotor activity was then evaluated using the open-field test, and the oxidative stress parameters were subsequently evaluated in the hippocampus and frontal cortex of mice. The results showed PSD induced hyperactivity in mice, which is considered a manic-like behavior. In addition to this, PSD increased lipid peroxidation and oxidative damage to proteins, as well as causing alterations to antioxidant enzymes in the frontal cortex and hippocampus of mice. The Nac plus DFX adjunctive treatment prevented both the manic-like behavior and oxidative damage induced by PSD. Improving our understanding relating to oxidative damage in biomolecules, and the antioxidant mechanisms presented in the animal models of mania are important in helping to improve our knowledge concerning the pathophysiology and development of new therapeutical treatments for BD., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Bipolar Disorder (BD) is one of the most severe psychiatric disorders. Despite adequate treatment, patients continue to have recurrent mood episodes, residual symptoms, and functional impairment. Some preclinical studies have shown that histone deacetylase inhibitors may act on manic-like behaviors. Neurotrophins have been considered important mediators in the pathophysiology of BD. The present study aims to investigate the effects of lithium (Li), valproate (VPA), and sodium butyrate (SB), an HDAC inhibitor, on BDNF, NGF and GDNF in the brain of rats subjected to an animal model of mania induced by ouabain. Wistar rats received a single ICV injection of ouabain or artificial cerebrospinal fluid. From the day following ICV injection, the rats were treated for 6 days with intraperitoneal injections of saline, Li, VPA or SB twice a day. In the 7th day after ouabain injection, locomotor activity was measured using the open-field test. The BDNF, NGF and GDNF levels were measured in the hippocampus and frontal cortex by sandwich-ELISA. Li, VPA or SB treatments reversed ouabain-related manic-like behavior. Ouabain decreased BDNF, NGF and GDNF levels in hippocampus and frontal cortex of rats. The treatment with Li, VPA or SB reversed these impairment induced by ouabain. In addition, Li, VPA and SB per se increased NGF and GDNF levels in hippocampus of rats. Our data support the notion that neurotrophic factors play a role in BD and in the mechanisms of the action of Li, VPA and SB., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Studies have pointed to a relationship between MAPK kinase (MEK) signaling and the behavioral effects of antidepressant drugs. So, in the present study we examined the behavioral and molecular effects of ketamine, an antagonist of the N-methyl-d-aspartate receptor (NMDA), which has been shown to have an antidepressant effect after the inhibition of MEK signaling in Wistar rats. Our results showed that acute administration of the MEK inhibitor PD184161, produced depressive-like behavior and stopped antidepressant-like effects of ketamine in the forced swimming test. The phosphorylation of extracellular signal-regulated kinase 1/2 (pERK 1/2) was decreased by PD184161 in the amygdala and nucleus accumbens, and the effects of ketamine on pERK 1/2 in the prefrontal cortex and hippocampus were inhibited by PD184161. The ERK 2 levels were decreased by PD184161 in the nucleus accumbens; and the effects of ketamine were blocked in this brain area. The p38 protein kinase (p38MAPK) and proBDNF were inhibited by PD184161, and the MEK inhibitor prevented the effects of ketamine in the nucleus accumbens. In addition, ketamine increased pro-BDNF levels in the hippocampus. In conclusion, our findings demonstrated that an acute blockade of MAPK signaling lead to depressive-like behavior and stopped the antidepressant response of ketamine, suggesting that the effects of ketamine could be mediated, at least in part, by the regulation of MAPK signaling in these specific brain areas., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Lisdexamfetamine dimesylate (LDX) is a prodrug that requires conversion to d-amphetamine (d-AMPH) for bioactivity. Treatment with d-AMPH induces hyperlocomotion and is regarded as a putative animal model of bipolar mania. Therefore, we sought to determine the behavioral and oxidative stress alterations induced by sub-chronic LDX administration as well as their reversal and prevention by lithium in rats. A significant increment in locomotor behavior was induced by LDX (10 and 30 mg/kg). To determine Li effects against LDX-induced alterations, in the reversal protocol rats received LDX (10 or 30 mg/kg) or saline for 14 days. Between days 8 and 14 animals received Li (47.5 mg/kg, i.p.) or saline. In the prevention paradigm, rats were pretreated with Li or saline prior to LDX administration. Glutathione (GSH) levels and lipid peroxidation was determined in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) of rats. Lithium prevented LDX-induced hyperlocomotion at the doses of 10 and 30 mg/kg, but only reversed LDX-induced hyperlocomotion at dose of 10mg/kg. In addition, both doses of LDX decreased GSH content (in ST and PFC), while Li was able to reverse and prevent these alterations mainly in the PFC. LDX (10 and 30 mg/kg) increased lipid peroxidation which was reversed and prevented by Li. In conclusion, LDX-induced hyperlocomotion along with associated increments in oxidative stress show promise as an alternative animal model of mania., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Prenatal cigarette smoke exposure (PCSE) has been associated with physiological and developmental changes that may be related to an increased risk for childhood and adult neuropsychiatric diseases. The present study investigated locomotor activity and cholinesterase enzyme activity in rats, following PCSE and/or ketamine treatment in adulthood. Pregnant female Wistar rats were exposed to 12 commercially filtered cigarettes per day for a period of 28 days. We evaluated motor activity and cholinesterase activity in the brain and serum of adult male offspring that were administered acute subanesthetic doses of ketamine (5, 15 and 25 mg/kg), which serves as an animal model of schizophrenia. To determine locomotor activity, we used the open field test. Cholinesterase activity was assessed by hydrolysis monitored spectrophotometrically. Our results show that both PCSE and ketamine treatment in the adult offspring induced increase of locomotor activity. Additionally, it was observed increase of acetylcholinesterase and butyrylcholinesterase activity in the brain and serum, respectively. We demonstrated that animals exposed to cigarettes in the prenatal period had increased the risk for psychotic symptoms in adulthood. This also occurs in a dose-dependent manner. These changes provoke molecular events that are not completely understood and may result in abnormal behavioral responses found in neuropsychiatric disorders, such as schizophrenia., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Several evidences have demonstrated that oxidative stress has a central role in bipolar disorder (BD). Recently, studies have been suggested histone deacetylases (HDAC) as a possible target for new medications in treatment of mood disorders. In this study, we investigated the effects of sodium butyrate (SB, a histone deacetilase inhibitor) on oxidative stress in rats submitted to an animal model of mania induced by d-amphetamine (d-AMPH). Wistar rats were first given d-AMPH or saline (Sal) for 14 days, and then, between days 8 and 14, rats were treated with SB or Sal. Locomotor activity and risk-taking behavior were assessed by open-field test and oxidative stress was measured in prefrontal cortex, amygdala, hippocampus and striatum. The results showed that SB reversed and prevented d-AMPH-induced behavioral effects. The d-AMPH administration induced oxidative damage in all brain structures analyzed. Depending on the cerebral area and technique, SB was able to reverse this impairment. The present study reinforces the need for more studies of HDAC inhibitors as possible target for new medications in treatment for BD., (Copyright © 2013. Published by Elsevier Ltd.)

A growing body of evidence has pointed to a relationship between oxidative stress and depression. Thus, the present study was aimed at evaluating the effects of the antioxidants n-acetylcysteine (NAC), deferoxamine (DFX) or their combination on sweet food consumption and oxidative stress parameters in rats submitted to 40days of exposure to chronic mild stress (CMS). Our results showed that in stressed rats treated with saline, there was a decrease in sweet food intake and treatment with NAC or NAC in combination with DFX reversed this effect. Treatment with NAC and DFX decreased the oxidative damage, which include superoxide and TBARS production in submitochondrial particles, and also thiobarbituric acid reactive substances (TBARS) levels and carbonyl proteins in the prefrontal cortex, amygdala and hippocampus. Treatment with NAC and DFX also increased the activity of the antioxidant enzymes, superoxide dismutase and catalase in the same brain areas. Even so, a combined treatment with NAC and DFX produced a stronger increase of antioxidant activities in the prefrontal cortex, amygdala and hippocampus. The results described here indicate that co-administration may induce a more pronounced antidepressant activity than each treatment alone. In conclusion, these results suggests that treatment with NAC or DFX alone or in combination on oxidative stress parameters could have positive effects against neuronal damage caused by oxidative stress in major depressive disorders., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Bipolar disorder (BD) is a chronic, prevalent, and highly debilitating psychiatric illness characterized by recurrent manic and depressive episodes. Mood stabilizing agents such as lithium and valproate are two primary drugs used to treat BD. To develop a novel animal model of mania (hallmark of BD), it is important to assess the therapeutic and prophylactic effect of these mood stabilizers on the new candidate target animal model. The present work investigates the therapeutic and prophylactic value of lithium and valproate in a novel preclinical animal model of mania, induced by ketamine. In the prevention protocol, wistar rats were pretreated with lithium (47.5 mg/kg, i.p., twice a day), valproate (200 mg/kg, i.p., twice a day), or saline (i.p., twice a day) for 14 days. Between days 8 and 14, the rats were treated with ketamine (25 mg/kg, i.p.) or saline. In the reversal protocol, rats first received ketamine (25 mg/kg, i.p.) or saline. After, the administration of lithium, valproate, or saline was carried out for seven days. Our results indicated that lithium and valproate reversed and prevented ketamine-induced hyperlocomotion. Moreover, lithium and valproate reversed (prefrontal cortex, hippocampus, and striatum) and prevented (prefrontal cortex, hippocampus, striatum, and amygdala) the increase of the TBARS level induced by ketamine. The protein carbonyl formation, induced by ketamine, was reversed by lithium and valproate in the prefrontal cortex, hippocampus, and striatum, and prevented only in the amygdala. These findings support the notion that the administration of ketamine might be a promising pharmacological animal model of mania, which could play a role in the pathophysiology of BD., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Recently, several studies have emerged suggesting a role of the intracellular survival pathways in the treatment of mood disorders. In addition, the beneficial effects of using a combination of antipsychotics and antidepressants have been shown. With this in mind, we evaluated the effects of the acute administration of fluoxetine (FLX), olanzapine (OLZ) and the combination of fluoxetine/olanzapine on the brain-derived-neurotrophic factor (BDNF), cAMP response element-binding (CREB), Protein Kinase B (PKB, Akt), B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated death promoter (BAD) in the rat brain. Adult Wistar rats received an acute injection of OLZ (3 or 6 mg/kg) and/or FLX (12.5 or 25 mg/kg), and were evaluated for Akt, BDNF, CREB, Bcl-2 and BAD protein levels in the prefrontal cortex, hippocampus and striatum. Our results showed that treatment with FLX and OLZ alone or in combination increased the Akt, CREB, BDNF, Bcl-2 and BAD levels in the prefrontal cortex, hippocampus and striatum. However, the combination of FLX and OLZ at high doses was associated with a greater increase in the levels of Akt in the prefrontal cortex, and did not have an effect on the levels of BAD in any of the brain areas that we evaluated. Finally, these findings further support the hypothesis that treatment with FLX and OLZ alone or in combination exert neuroprotective effects, and that intracellular survival pathways could be involved in the therapeutic effects of combining antipsychotic and antidepressant drugs in mood disorders., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The present study was aimed to investigate the behavioral and molecular effects of lamotrigine. To this aim, Wistar rats were treated with lamotrigine (10 and 20 mg/kg) or imipramine (30 mg/kg) acutely and chronically. The behavior was assessed using forced swimming test. Brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), Proteina Kinase B (PKB, AKT), glycogen synthase kinase 3 (GSK-3) and B-cell lymphoma 2 (Bcl-2) levels, citrate synthase, creatine kinase and mitochondrial chain (I, II, II-III and IV) activities were assessed in the brain. The results showed that both treatments reduced the immobility time. The BDNF were increased in the prefrontal after acute treatment with lamotrigine (20 mg/kg), and the BDNF and NGF were increased in the prefrontal after chronic treatment with lamotrigine in all doses. The AKT increased and Bcl-2 and GSK-3 decreased after both treatments in all brain areas. The citrate synthase and creatine kinase increased in the amygdala after acute treatment with imipramine. Chronic treatment with imipramine and lamotrigine (10 mg/kg) increased the creatine kinase in the hippocampus. The complex I was reduced and the complex II, II-III and IV were increased, but related with treatment and brain area. In conclusion, lamotrigine exerted antidepressant-like, which can be attributed to its effects on pathways related to depression, such as neurotrophins, metabolism energy and signaling cascade., (Copyright © 2011. Published by Elsevier Ltd.)

Epidemiological studies have indicated that prenatal exposure to environmental insults can bring an increased risk of schizophrenia. The objective of our study was to determine biochemical parameters in rats exposed to cigarette smoke (CS) in the prenatal period, evaluated in adult offspring submitted to animal model of schizophrenia induced by acute subanaesthetic doses of ketamine (5 mg/kg, 15 mg/kg and 25 mg/kg). Pregnant female Wistar rats were exposed to 12 commercially filtered cigarettes per day, daily for a period of 28 days. We evaluated the oxidative damage in lipid and protein in the rat brain, and DNA damage in the peripheral blood of male adult offspring rats. To determine oxidative damage in the lipids, we measured the formation of thiobarbituric acid reactive species (TBARS) and the oxidative damage to the proteins was assessed by the determination of carbonyl groups content. We also evaluated DNA damage using single-cell gel electrophoresis (comet assay). Our results showed that rats exposed to CS in the prenatal period presented a significant increase of the lipid peroxidation, protein oxidation and DNA damage in adult age. We can observe that the animals submitted at acute doses of ketamine also presented an increase of the lipid peroxidation and protein oxidation at different doses and structures. Finally, we suggest that exposure to CS during the prenatal period affects two essential cerebral processes during development: redox regulation and DNA integrity, evaluated in adult offspring. These effects can leads to several neurochemical changes similar to the pathophysiology of schizophrenia., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Lack of dystrophin in brain structures have been involved with impaired cognitive functions. Acethylcolinesterase (AChE) is implicated in many cognitive functions and probably plays important roles in neurodegenerative disorders. In the present study, we investigated AChE activity in the prefrontal cortex, hippocampus, striatum and cortex of mdx mice. To this aim, brain tissues from male dystrophic mdx and normal control mice were used. We observed that mdx mice display a reduction in AChE activity of 40-60% in all brain structures evaluated. In conclusion, dystrophin deficiency may be affecting AChE activity and contributing negatively, in part, to memory storage and restoring., (Copyright © 2011 Elsevier B.V. All rights reserved.)

In this study, we assessed the oxidative stress parameters in rats submitted to an animal model of mania induced by ouabain (OUA), which included the use of lithium (Li) and valproate (VPA). Li and VPA treatment reversed and prevented the OUA-induced damage in these structures, however, this effect varies depending on the brain region and treatment regimen. Moreover, the activity of the antioxidant enzymes, namely, superoxide dismutase (SOD) and catalase (CAT) was found to be increased and decreased, respectively, in the brain of OUA-administered rats. Li and VPA modulated SOD and CAT activities in OUA-subjected rats in both experimental models. Our results support the notion that Li and VPA exert antioxidant-like properties in the brain of rats submitted to animal model of mania induced by ouabain., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Recent evidence suggests that peripheral markers related to oxidative stress, inflammation and neurotrophins may be altered during mood episodes in bipolar disorder. These can be seen as proxies of peripheral toxicity or markers of illness activity. Here we report an en bloc assessment of a set of previously described biomarkers in different mood states (n = 60) as well as in healthy subjects (n = 80). To make the point that these are ominous changes, we obtained the same measures from a group of septic patients (n = 15) as a "positive" control group. In this sample, we measured serum levels of brain derived neurotrophic factor, neurotrophin 3, tumor necrosis factor α, interleukin 6, interleukin 10, total reactive antioxidant potential, thiobarbituric acid reactive substances and protein carbonyl content. Several of the markers discriminated between the bipolar and control groups, especially when patients were in acute episodes. In some cases, toxicity was as high in bipolar disorder as that seen in patients with sepsis. We believe these findings highlight the potential of using biomarkers to assess illness activity in bipolar disorder., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Bipolar disorder (BD) is a devastating major mental illness associated with high rates of suicide and work loss. There is an emerging body of data suggesting that bipolar disorder is associated with mitochondrial dysfunction. In this context, the present study aims to investigate the effects of mood stabilizers lithium (Li) and valproate (VPT) on mitochondrial respiratory chain activity in brain of rats undergoing treatment with the pro-manic agent d-AMPH d-amphetamine (d-AMPH). In the reversal treatment, Wistar rats were first given d-AMPH or saline for 14 days, and then, between days 8 and 14, rats were treated with Li, VPA or saline (Sal). In the prevention treatment, rats were pretreated with Li, VPA or Sal. Locomotor behavior was assessed using the open-field task and mitochondrial chain activity complexes I, II, III and IV were measured in brain structures (hippocampus, striatum and prefrontal). Li and VPA reversed and prevented d-AMPH-induced hyperactivity. In both experiments, d-AMPH inhibited mitochondrial respiratory chain activity in all analyzed structures. In the reversal treatment, VPA reversed d-AMPH-induced dysfunction in all brain regions analyzed. In the prevention experiment, the effects of Li and VPA on d-AMPH-induced mitochondrial dysfunction were dependent on the brain region analyzed. These findings suggested that dopamine can be an important link for the mitochondrial dysfunction seen in BD and, Li and VPA exert protective effects against this d-AMPH-induced mitochondrial dysfunction, but this effect varies depending on the brain region and the treatment regimen., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

There is a body of evidence suggesting that BDNF is involved in bipolar disorder (BD) pathogenesis. Intracerebroventricular (ICV) injection of ouabain (OUA), a specific Na(+)/K(+) ATPase inhibitor, induces hyperlocomotion in rats, and has been used as an animal model of mania. The present study aims to investigate the effects of the lithium (Li) and valproate (VPT) in an animal model of mania induced by ouabain. In the reversal model, animals received a single ICV injection of OUA or cerebrospinal fluid (aCSF). From the day following the ICV injection, the rats were treated for 6 days with intraperitoneal (IP) injections of saline (SAL), Li or VPT twice a day. In the maintenance treatment (prevention model), the rats received IP injections of Li, VPT, or SAL twice a day for 12 days. In the 7th day of treatment the animals received a single ICV injection of either OUA or aCSF. After the ICV injection, the treatment with the mood stabilizers continued for more 6 days. Locomotor activity was measured using the open-field test and BDNF levels were measured in rat hippocampus and amygdala by sandwich-ELISA. Li and VPT reversed OUA-related hyperactive behavior in the open-field test in both experiments. OUA decreased BDNF levels in first and second experiments in hippocampus and amygdala and Li treatment, but not VPT reversed and prevented the impairment in BDNF expression after OUA administration in these cerebral areas. Our results suggest that the present model fulfills adequate face, construct and predictive validity as an animal model of mania., ((c) 2009 Elsevier Ltd. All rights reserved.)

The intracerebroventricular (ICV) administration of ouabain (a Na(+)/K(+)-ATPase inhibitor) in rats has been suggested to mimic some symptoms of human bipolar mania. Clinical studies have shown that bipolar disorder may be related to mitochondrial dysfunction. Herein, we investigated the behavioral and biochemical effects induced by the ICV administration of ouabain in rats. To achieve this aim, the effects of ouabain injection immediately after and 7 days following a single ICV administration (at concentrations of 10(-2) and 10(-3)M) on locomotion was measured using the open-field test. Additionally, thiobarbituric acid reactive substances (TBARSs) and superoxide production were measured in submitochondrial particles of the prefrontal cortex, hippocampus, striatum and amygdala. Our findings demonstrated that ouabain at 10(-2) and 10(-3)M induced hyperlocomotion in rats, and this response remained up to 7 days following a single ICV injection. In addition, we observed that the persistent increase in the rat spontaneous locomotion is associated with increased TBARS levels and superoxide generation in submitochondrial particles in the prefrontal cortex, striatum and amygdala. In conclusion, ouabain-induced mania-like behavior may provide a useful animal model to test the hypothesis of the involvement of oxidative stress in bipolar disorder.

Dystrophin is a protein found at the plasmatic membrane in muscle and postsynaptic membrane of some neurons, where it plays an important role on synaptic transmission and plasticity. Its absence is associated with Duchenne's muscular dystrophy (DMD), in which cognitive impairment is found. Oxidative stress appears to be involved in the physiopathology of DMD and its cognitive dysfunction. In this regard, the present study investigated oxidative parameters (lipid and protein peroxidation) and antioxidant enzymes activities (superoxide dismutase and catalase) in prefrontal cortex, cerebellum, hippocampus, striatum and cortex tissues from male dystrophic mdx and normal C57BL10 mice. We observed (1) reduced lipid peroxidation in striatum and protein peroxidation in cerebellum and prefrontal cortex; (2) increased superoxide dismutase activity in cerebellum, prefrontal cortex, hippocampus and striatum; and (3) reduced catalase activity in striatum. It seems by our results, that the superoxide dismutase antioxidant mechanism is playing a protective role against lipid and protein peroxidation in mdx mouse brain.

Harmine is a beta-carboline alkaloid that inhibits monoamine reuptake systems. Findings point to an antidepressant effect of the compounds that increases the levels of monoamines after monoamine oxidase inhibition. The present study aims to compare the behavioral effects and the BDNF hippocampus levels of acute administration of harmine and imipramine in rats. To this aim, rats were acutely treated with harmine (5, 10 and 15 mg/kg) and imipramine (10, 20 and 30 mg/kg) and animal behavior was assessed in the forced swimming and open-field tests. Afterwards, hippocampal BDNF protein levels were assessed in imipramine- and harmine-treated rats by ELISA-sandwich assay. We observed that harmine at doses of 10 and 15 mg/kg, and imipramine at 20 and 30 mg/kg reduced immobility time, and increased both climbing and swimming time of rats compared to saline group, without affecting locomotor activity. Acute administration of harmine at the higher dose, but not imipramine, increased BDNF protein levels in the rat hippocampus. Finally, these findings further support the hypothesis that harmine could be a new pharmacological target for the treatment of mood disorders.

Chronic ingestion of caffeine causes dependence and sleep disturbance in children and adolescents. In rodents, the administration of caffeine may produce behavioral cross-sensitization to some psychostimulants, such as dopaminergic psychoactive drugs. Methylphenidate (MPH; Ritalin) is a psychostimulant used in pediatric- and adult human populations to manage the symptoms associated with attention-deficit hyperactivity disorder (ADHD). Previous studies have suggested that dopamine- and cAMP-regulated phosphoproteins of 32 kDa (DARPP-32) participate in the manifestation of behavioral activity following ingestion of caffeine or MPH. The aim of the present study was to evaluate whether long-term administration of low doses of caffeine in rodents during their adolescence induces cross-sensitization to MPH challenge in their adulthood and investigate the involvement of DARPP-32 in this model. Young rats (P25) consumed water or caffeine (0.3 g/L; mean consumption was 7.5 mg/day/kg) for 28 days. The caffeine consumption was then suspended for 14 days (washout period) when the animals received saline solution or MPH (1, 2, or 10 mg/kg) (P67) intraperitoneally. The locomotor activity of these rats was assessed using the open-field test, following which the immunocontent of DARPP-32 was evaluated in samples of their prefrontal cortex, striatum, or hippocampus. Rats chronically exposed to caffeine in their adolescent period and to inactive doses of MPH (1mg/kg) in adulthood showed augmented locomotor activity. The behavioral effect observed was accompanied by increased levels of DARPP-32 in the striatum and prefrontal cortex compared to control groups (saline or caffeine). However, no alteration caused by these treatments was noted in the hippocampus. In conclusion, chronic caffeine exposure induces likely long-term cross-sensitization to MPH in a DARPP-32-dependent pathway.

Schizophrenia is a complex neuropsychiatric disorder in which symptoms can be classified as either positive, such as delusions and hallucinations, or negative, such as blunted affect and social withdrawal. However, the mechanisms underlying this disease are poorly understood. There is evidence that reactive oxygen species (ROS) play an important role in the pathogenesis of many diseases, particularly those which are neurological and psychiatric in nature. Ketamine has been used to induce a schizophrenia-like condition as an animal model in which to study this condition. In the present study we tested the effects of sub-anesthetic doses of ketamine on various parameters of oxidative stress in the brain of rats. Our results indicate that lipid peroxidation and tissue protein oxidation were affected by varying sub-anesthetic doses of ketamine in multiple cerebral structures. Additionally, the activity of the antioxidant enzymes CAT and SOD was measured and was also found to be altered in most of the structures tested. In conclusion, we observe an increase in oxidative damage marked by an increase in lipid peroxidation, oxidative protein damage and a decrease in enzymatic defenses, in an animal model of schizophrenia. Given that oxidative stress could be related to schizophrenia, these findings may explain, at least in part, the mechanisms underlying in this disease.

Major depression is a common, serious and recurrent disorder, characterized by symptoms at the psychological, behavioral and physiological levels. Recent studies have suggested that reactive oxygen species (ROS) may play a role in the pathophysiology of bipolar disorder. The chronic mild stress (CMS) rat model has been used as an animal model of depression, since it induces some symptoms of a major depressive episode in humans (i.e. anhedonia). We investigated behavioral, physiological and neurochemical aspects of rats exposed for 40 days to CMS. Sweet food consumption, locomotor activity and body weight were assessed in stressed and control rats. We also investigated the potential involvement of ROS in the CMS model. Superoxide generation in submitochondrial particles from the rat hippocampus, prefrontal cortex and cortex was measured through superoxide-dependent oxidation of epinephrine to adrenochrome in a submitochondrial extract. We report that sweet food intake was reduced in rats subjected to CMS compared to controls. Further, CMS animals failed to gain body weight compared with non-stressed rats. Locomotor activity was not affected in stressed rats. An increase in superoxide production was detected in all brain structures analyzed. However, thiobarbituric acid reactive substances were increased only in cortex. In conclusion, these observations support the view that the CMS model of depression mimics alterations observed in depressed patients. The model affords a useful system in which to test the hypothesis that altered brain energy metabolism is associated with neuropsychiatric disorders.

Major depression is characterized for symptoms at the psychological, behavioral and physiological levels. The chronic mild stress model has been used as an animal model of depression. The consumption of sweet food, locomotor activity, body weight, lipid and protein oxidation levels and superoxide dismutase and catalase activities in the rat hippocampus, prefrontal cortex and cortex were assessed in rats exposed to chronic mild stress. Our findings demonstrated a decrease on sweet food intake, no effect on locomotor activity, lack of body weight gain, increase in protein (prefrontal, hippocampus, striatum and cortex) and lipidic peroxidation (cerebellum and striatum), and an increase in catalase (cerebellum, hippocampus, striatum, cortex) and a decrease in superoxide dismutase activity (prefrontal, hippocampus, striatum and cortex) in stressed rats. In conclusion, our results support the idea that stress produces oxidants and an imbalance between superoxide dismutase and catalase activities that contributes to stress-related diseases, such as depression.

Several studies have supported the idea that ionotropic glutamate N-methyl-d-aspartate receptor (NMDA) is an important player in the etiology of psychopathologies, such as anxiety disorders and major depression. Additionally, studies have shown that ketamine induces antidepressant effects in humans as well as in rodents subjected to animal models of depression. In this context, the present study was aimed to evaluate behavioral and physiological effects of acute and chronic administration of ketamine, a NMDA receptor antagonist, in rats exposed to chronic mild stress (CMS). After 40 days of CMS, rats were treated with ketamine (15 mg/kg) and sweet food consumption, body and adrenal gland weight, corticosterone and adrenocorticotropic (ACTH) hormone levels, and hippocampal BDNF protein levels were assessed. Our findings demonstrated that CMS evoked anhedonia, induced hypertrophy of adrenal gland, impaired gain of body weight and increased corticosterone and ACTH circulating levels in rats. Acute and chronic treatment with ketamine reversed the increase in adrenal gland weight, promoted regain of body weight, and normalized corticosterone and ACTH circulating levels. Repeated, but not acute, administration of ketamine reversed anhedonia-like behavior, although the treatment with ketamine per se increased sweet food consumption in non-stressed rats. Finally, acute and chronic ketamine treatment did not alter hippocampal BDNF protein levels in stressed rats. In conclusion, these findings support the idea of a putative role of NMDA receptors in mood-related symptoms, and rapid and robust effects of ketamine in reverting mainly physiological alterations induced by chronic mild stressful situations in rats.