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Coffee intake is increasingly recognized as a life-style factor associated with the preservation of health, but there is still a debate on the relative effects of caffeinated and decaffeinated coffee. We now tested how the regular drinking of caffeinated and decaffeinated coffee for 3 weeks impacted on the behavior of male and female adult mice. Males drinking caffeinated coffee displayed statistically significant lower weight gain, increased sensorimotor coordination, greater motivation in the splash test, more struggling in the forced swimming test, faster onset of nest building, more marble burying and greater sociability. Females drinking caffeinated coffee displayed statistically significant increased hierarchy fighting, greater self-care and motivation in the splash test and faster onset of nest building. A post-hoc two-way ANOVA revealed sex-differences in the effects of caffeinated coffee ( p values for interaction between the effect of caffeinated coffee and sex) on the hierarchy in the tube test ( p = 0.044; dominance), in the time socializing ( p = 0.044) and in the latency to grooming ( p = 0.048; selfcare), but not in the marble burying test ( p = 0.089). Intake of decaffeinated coffee was devoid of effects in males and females. Since caffeine targets adenosine receptors, we verified that caffeinated but not decaffeinated coffee intake increased the density of adenosine A 1 receptors (A 1 R) and increased A 1 R-mediated tonic inhibition of synaptic transmission in the dorsolateral striatum and ventral but not dorsal hippocampus, the effects being more evident in the ventral hippocampus of females and striatum of males. In contrast, caffeinated and decaffeinated coffee both ameliorated the antioxidant status in the frontal cortex. It is concluded that caffeinated coffee increases A 1 R-mediated inhibition in mood-related areas bolstering wellbeing of both males and females, with increased sociability in males and hierarchy struggling and self-care in females.

The CACNA1C gene encodes the alpha-1c subunit of the Ca v 1.2 calcium channel, a regulator of neuronal calcium influx involved in neurotransmitter release and synaptic plasticity. Genetic data show a role for CACNA1C in depressive symptoms underlying different psychiatric diagnoses. However, the mechanisms involved still require further exploration. This study aimed to investigate sex and region-specific changes in the Cacna1c gene and behavioral outcomes in mice exposed to chronic stress. Moreover, we evaluated the Nuclear factor of activated T-cells 5 (Nfat5) and the Brain-derived neurotrophic factor (Bdnf) as potential upstream and downstream Cacna1c targets and their correlation in stressed mice and humans with depression. Male and female Swiss mice were exposed to chronic unpredictable stress (CUS) for 21 days. Animal-integrated emotionality was assessed using the sucrose splash test, the tail suspension, the open-field test, and the elevated-plus-maze. Gene expression analysis was performed in the amygdala, prefrontal cortex, and hippocampus. Human data for in silico analysis was obtained from the Gene Expression Omnibus. CUS-induced impairment in integrated emotional regulation was observed in males. Gene expression analysis showed decreased levels of Cacna1c and Nfat5 and increased levels of Bdnf transcripts in the amygdala of stressed male mice. In contrast, there were no major changes in behavioral responses or gene expression in female mice after stress. The expression of the three genes was significantly correlated in the amygdala of mice and humans. The strong and positive correlation between Canac1c and Nfat5 suggests a potential role for this transcription factor in Canac1c expression. These changes could impact amygdala reactivity and emotional responses, making them a potential target for psychiatric intervention., Competing Interests: Declaration of Competing Interest none. FundingThis study was supported by the Brazilian National Council for Scientific and Technological Development (CNPq) and the Coordination for the Improvement of Higher Education (CAPES, Brazil). MPK and GG are CNPq Research Productivity Fellows. CRB had a CNPq Postdoctoral Fellowship (PDJ) and LMB had a CNPq Master Fellowship., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background Suicide is one of the leading global causes of death. Behavior patterns from suicide ideation to completion are complex, involving multiple risk factors. Advances in technologies and large-scale bioinformatic tools are changing how we approach biomedical problems. The "omics" field may provide new knowledge about suicidal behavior to improve identification of relevant biological pathways associated with suicidal behavior. Methods We reviewed transcriptomic, proteomic, and metabolomic studies conducted in blood and post-mortem brains from individuals who experienced suicide or suicidal behavior. Omics data were combined using systems biology in silico, aiming at identifying major biological mechanisms and key molecules associated with suicide. Results Post-mortem samples of suicide completers indicate major dysregulations in pathways associated with glial cells (astrocytes and microglia), neurotransmission (GABAergic and glutamatergic systems), neuroplasticity and cell survivor, immune responses and energy homeostasis. In the periphery, studies found alterations in molecules involved in immune responses, polyamines, lipid transport, energy homeostasis, and amino and nucleic acid metabolism. Limitations We included only exploratory, non-hypothesis-driven studies; most studies only included one brain region and whole tissue analysis, and focused on suicide completers who were white males with almost none confounding factors. Conclusions We can highlight the importance of synaptic function, especially the balance between the inhibitory and excitatory synapses, and mechanisms associated with neuroplasticity, common pathways associated with psychiatric disorders. However, some of the pathways highlighted in this review, such as transcriptional factors associated with RNA splicing, formation of cortical connections, and gliogenesis, point to mechanisms that still need to be explored., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Psychosocial stress has profound effects on the body, including the immune system and the brain 1,2 . Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD) 3 , the underlying mechanisms are not well understood. Here we show that expression of a circulating myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is increased in the serum of humans with MDD as well as in stress-susceptible mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), as well as altered social behaviour. Using a combination of mass cytometry and single-cell RNA sequencing, we performed high-dimensional phenotyping of immune cells in circulation and in the brain and demonstrate that peripheral monocytes are strongly affected by stress. In stress-susceptible mice, both circulating monocytes and monocytes that traffic to the brain showed increased Mmp8 expression following chronic social defeat stress. We further demonstrate that circulating MMP8 directly infiltrates the NAc parenchyma and controls the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders., (© 2024. The Author(s).)

Behavioral flexibility permits the appropriate behavioral adjustments in response to changing environmental demands. The present study aimed to evaluate if variability in baseline flexibility can enable differences in coping strategies, changes in neuroplasticity, and behavioral outcomes in responses to chronic social defeat stress (CSDS). Male C57BL6 mice were submitted to the Morris Water Maze (MWM) using an extended protocol for reversal learning to assess. The animals were divided into low and high behavioral flexibility groups based on their performance on the last day of acquisition versus the four days of reversal learning. The CSDS was applied for ten consecutive days, and coping strategies were evaluated during the physical interaction on the first and last day of stress. A battery of behavioral tests to assess social and emotional behavior was conducted 24 h after the CSDS protocol. The complexity of prefrontal cortex (PFC) neuronal morphology was evaluated by the Golgi-Cox method. Animals with High Flexibility exhibited changes in their CSDS coping strategies, from active to passive coping, during the CSDS protocol. Low Flexibility mice had no alterations in the coping strategies during CSDS. After social stress, High Flexibility was associated with reduced social interaction with an aggressive Swiss mouse, higher latency to immobility in the tail suspension test, and reduced latency to self-care in the sucrose splash test. High Flexibility mice also displayed higher dendritic complexity on pyramidal neurons from the prelimbic and infralimbic prefrontal cortex compared to Low Flexibility mice. These results suggest That High Flexibility is associated with increased neuroplasticity in cortical areas and better emotional responses related to behavioral despair and motivation. However, exposure to CSDS reversed the beneficial effects of High Flexibility in male mice. Thus, this study suggests that baseline variability in behavioral flexibility, even in inbred strains, might be associated with differences in coping strategies, PFC morphology, and behavioral responses to social stress., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The CACNA1C gene encodes the pore-forming alpha-1c subunit of L-type voltage-gated calcium channels. The calcium influx through these channels regulates the transcription of the brain-derived neurotrophic factor (BDNF). Polymorphisms in this gene have been consistently associated with psychiatric disorders, and alterations in BDNF levels are a possible biological mechanism to explain such associations. Here, we sought to investigate the effect of the CACNA1C rs1006737 and rs4765913 polymorphisms and their haplotypes on serum BDNF concentration. We further aim to investigate the regulatory function of these SNPs and the ones linked to them. The study enrolled 641 young adults (362 women and 279 men) in a cross-sectional population-based survey. Linear regression was used to test the effects of polymorphisms and haplotypes on BDNF levels adjusted for potential confounders. Moreover, regulatory putative functional roles were assessed using in silico approach. BDNF levels were not associated with CACNA1C polymorphisms/haplotype in the total sample. When the sample was stratified by sex, checking the effect of polymorphisms on men and women separately, the A-allele of rs4765913 was associated with lower BDNF levels in women compared with the TT genotype (p = 0.010). The AA (rs1006737-rs4765913) haplotype was associated with BDNF levels in opposite directions regarding sex, with lower levels of BDNF in women (p = 0.040) compared to those without this haplotype, while with higher levels in men (p = 0.027). These findings were supported by the presence of regulatory marks only on the male fetal brain. Our results suggest that the BDNF levels regulation may be a potential mechanism underpinning the association between CACNA1C and psychiatric disorders, with a differential role in women and men., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Anhedonia is a critical symptom of major depressive disorder that is defined as the reduced ability to experience pleasure. The Temporal Experience of Pleasure Scale (TEPS) is commonly used to measure anhedonia and has exhibited satisfactory reliability., Objectives: We aim to perform cross-cultural adaptation of a Brazilian version of the TEPS and evaluate its psychometric properties., Method: The cross-cultural adaptation was performed according to previously established protocols. Cronbach's alpha coefficient of internal consistency was used to establish the degree of interrelation and coherence of items. Also, we calculated the intraclass correlation coefficient to determine the stability of the scale after a proposed interval had elapsed and used exploratory factor analysis to evaluate the scale's factor structure and content validity. Principal component analysis was used to determine the factors to be retained in the factor model., Results: The participants reported that the Brazilian version of the TEPS had good comprehensibility and applicability. The results revealed a statistically significant correlation between measures. The intraclass correlation coefficient calculated was significant. The Cronbach's alpha value calculated indicated that the scale's overall internal consistency was adequate., Conclusion: The Portuguese version of the TEPS scale proposed achieved good comprehensibility for the Brazilian population and its psychometric characteristics demonstrated good reliability and validity., Competing Interests: No conflicts of interest declared concerning the publication of this article.

Objectives: This study investigated the involvement of heme oxygenase-1 (HO-1) in the antidepressant-like effects of ursolic acid (UA), a plant-derived compound with neuroprotective and antidepressant-like properties., Methods: Mice received intracerebroventricular injections of zinc protoporphyrin IX (ZnPP) or cobalt protoporphyrin IX (CoPP) to inhibit or induce HO-1, respectively, together with effective (0.1 mg/kg, p.o.) or sub-effective (0.01 mg/kg, p.o.) doses of UA or fluoxetine (10 mg/kg, p.o.). Immobility time was assessed using the tail suspension test (TST) and the ambulatory behaviour with the open field test. HO-1 immunocontent was evaluated in mice hippocampus and prefrontal cortex., Key Findings: ZnPP prevented the anti-immobility effects of UA and fluoxetine. Combined treatment with a sub-effective dose of CoPP and UA synergistically exerted antidepressant-like effects in the TST. Acute administration of UA or CoPP, but not fluoxetine, increased the HO-1 immunocontent in the hippocampus. None of the treatments altered the HO-1 immunocontent in the prefrontal cortex., Conclusions: In conclusion, this work shows that increased hippocampal HO-1 content and activity mediate the antidepressant-like effect of UA in the TST., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Ketamine has emerged as a prophylactic agent against depressive-like behavior induced by stress. However, the possible pro-resilience effects of ketamine against inflammatory stressors-induced depressive-like behavior and the signaling pathways associated with this response remain to be determined. Therefore, this study investigated the ability of prophylactic ketamine administration to produce a pro-resilience effect against the depressive-like behavior induced by lipopolysaccharide (LPS - 0.83 mg/kg, i.p.) and tumor necrosis factor-alpha (TNF-α - 0.1 fg/site, i.c.v.) administration in mice. The possible contribution of the NLRP3 inflammasome-driven signaling pathway to this effect was evaluated in the ventral hippocampus. A single administration of ketamine (5 mg/kg, i.p.) given 1 week before the LPS or TNF-α administration prevented the depressive-like behavior induced by these inflammatory stressors in the tail suspension test (TST) and splash test (SPT). On the other hand, a lower dose of ketamine (1 mg/kg, i.p.) failed to produce a similar effect. The administration of LPS, but not TNF-α, increased the immunocontent of the microglial marker Iba-1 in the ventral hippocampus. LPS increased the immunocontent of all proteins related to NLRP3 signaling, namely ASC, NLRP3, TXNIP, cleaved caspase-1, and IL-1β in this brain region, while TNF-α only increased ASC and NLRP3 immunocontent. Ketamine administered at the dose of 5 mg/kg, but not at 1 mg/kg, prevented the increase on the immunocontent of NLRP3 inflammasome complex components and regulators induced by LPS or TNF-α administration. Collectively, these findings suggest that ketamine elicits a pro-resilient phenotype against inflammatory stressors-induced depressive-like behavior, an effect associated with the suppression of the NLRP3 inflammasome-driven signaling pathway., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Social hierarchy formation is strongly evolutionarily conserved. Across species, rank within social hierarchy has large effects on health and behavior. To investigate the relationship between social rank and stress susceptibility, we exposed ranked male and female mice to social and non-social stressors and manipulated social hierarchy position. We found that rank predicts same sex social stress outcomes: dominance in males and females confers resilience while subordination confers susceptibility. Pre-existing rank does not predict non-social stress outcomes in females and weakly does so in males, but rank emerging under stress conditions reveals social interaction deficits in male and female subordinates. Both history of winning and rank of cage mates affect stress susceptibility in males: rising to the top rank through high mobility confers resilience and mice that lose dominance lose stress resilience, although gaining dominance over a subordinate animal does not confer resilience. Overall, we have demonstrated a relationship between social status and stress susceptibility, particularly when taking into account individual history of winning and the overall hierarchy landscape in male and female mice., Competing Interests: KL, KC, MK, LP, CB, SR No competing interests declared, (© 2021, LeClair et al.)

Leptin is an anorexigenic hormone well recognized by its role in mediating energy homeostasis. Recently, leptin has been associated with psychiatric disorders and interestingly, leptin treatment has shown antidepressant and anxiolytic effects. We examined the association of leptin levels and leptin (LEP) gene rs3828942 polymorphism with anxiety disorders considering sex differences. A cross-sectional population-based study, including 1067 young adults, of whom 291 presented anxiety disorders diagnosed by the Mini International Neuropsychiatric Interview (MINI 5.0). The rs3828942 polymorphism was genotyped by real-time PCR and ELISA measured leptin levels. Leptin levels were not associated with anxiety disorders after adjusting for sex and body mass index (BMI) [ß = - 0.009 (- 0.090-0.072); p = 0.832]. The distribution of rs3828942 genotypes was not associated with anxiety disorders. However, in a sex-stratified sample, the A-allele of rs3828942 polymorphism was associated with risk for GAD in women even when adjusting for confounding variables [OR = 1.87 (1.17-2.98); p = 0.008]. In a subsample of 202 individuals with GAD and control matched by sex and BMI, results suggest an interaction between genotypes and GAD diagnosis based on leptin levels only in the male group [F (1, 54) = 6.464; p = 0.0139]. Leptin is suggested to be related with the neurobiology of anxiety disorders in a sex-dependent manner since women carrying the A-allele of LEP rs3828942 present a higher risk for GAD, while leptin levels seem to be lower in men with GAD carrying A-allele. Studies on the relationship between leptin polymorphisms and levels are scarce and, therefore, further research is necessary., (© 2019. Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Guanosine has been shown to potentiate ketamine's antidepressant-like actions, although its ability to augment the anxiolytic effect of ketamine remains to be determined., Objective: This study investigated the anxiolytic-like effects of a single administration with low doses of ketamine and/or guanosine in mice subjected to chronic administration of corticosterone and the role of NLRP3-driven signaling., Methods: Corticosterone (20 mg/kg, p.o.) was administered for 21 days, followed by a single administration of ketamine (0.1 mg/kg, i.p.), guanosine (0.01 mg/kg, p.o.), or ketamine (0.1 mg/kg, i.p.) plus guanosine (0.01 mg/kg, p.o.). Anxiety-like behavior and NLRP3-related targets were analyzed 24 h following treatments., Results: Corticosterone reduced the time spent in the open arms and the central zone in the elevated plus-maze test and open-field test, respectively. Corticosterone raised the number of unsupported rearings and the number and time of grooming, and decreased the latency to start grooming in the open-field test. Disturbances in regional distribution (increased rostral grooming) and grooming transitions (increased aborted and total incorrect transitions) were detected in corticosterone-treated mice. These behavioral alterations were accompanied by increased immunocontent of Iba-1, ASC, NLRP3, caspase-1, TXNIP, and IL-1β in the hippocampus, but not in the prefrontal cortex. The treatments with ketamine, guanosine, and ketamine plus guanosine were effective to counteract corticosterone-induced anxiety-like phenotype, but not disturbances in the hippocampal NLRP3 pathway., Conclusions: Our study provides novel evidence that low doses of ketamine and/or guanosine reverse corticosterone-induced anxiety-like behavior and shows that the NLRP3 inflammasome pathway is likely unrelated to this response., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Glibenclamide is a second-generation sulfonylurea used in the treatment of Type 2 Diabetes Mellitus. The primary target of glibenclamide is ATP-sensitive potassium channels inhibition; however, other possible targets include the control of inflammation and blood-brain barrier permeability, which makes this compound potentially interesting for the management of brain-related disorders. Here, we showed that systemic treatment with glibenclamide (5 mg/kg, p.o., for 21 days) could prevent the behavioral despair and the cognitive dysfunction induced by chronic unpredictable stress (CUS) in mice. In nonhypoglycemic doses, glibenclamide attenuated the stress-induced weight loss, decreased adrenal weight, and prevented the increase in glucocorticoid receptors in the prefrontal cortex, suggesting an impact in hypothalamic-pituitary-adrenal (HPA) axis function. Additionally, we did not observe changes in Iba-1, NLRP3 and caspase-1 levels in the prefrontal cortex or hippocampus after CUS or glibenclamide treatment. Thus, this study suggests that chronic treatment with glibenclamide prevents the emotional and cognitive effects of chronic stress in female mice. On the other hand, the control of neuroinflammation and NLRP3 inflammasome pathway is not the major mechanism mediating these effects. The behavioral effects might be mediated, in part, by the normalization of glucocorticoid receptors and HPA axis., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Amyloid beta (Aβ), one of the main hallmarks of Alzheimer's Disease (AD), may stimulate pattern recognition receptors (PRR) such as the NLRP3 inflammasome, inducing a pro-inflammatory state in the brain that contributes to disease development. Physical exercise can have multiple beneficial effects on brain function, including anti-inflammatory and neuroprotective roles. The objective of this study was to investigate the prophylactic effect of moderate treadmill exercise for 4 weeks on inflammatory events related to NLRP3 signaling in the hippocampus of mice after intracerebroventricular Aβ 1-40 administration. Our results show that Aβ 1-40 administration (400 pmol/mouse, i.c.v.) significantly increased the immunocontent Iba-1 (a microglial reactivity marker), NLRP3, TXNIP, and caspase-1 in the hippocampus of mice. However, physical exercise prevented the hippocampal increase in Iba-1, TXNIP, and activation of the NLRP3 inflammasome pathway caused by Aβ 1-40 . Moreover, physical exercise per se reduced the TXNIP and caspase-1 immunocontent in the hippocampus. No alterations were observed on the immunocontent of GFAP, ASC, and IL-1β in the hippocampus after Aβ 1-40 and/or physical exercise. These results reinforce the role of NLRP3 inflammasome pathway in AD and point to physical exercise as a possible non-pharmacological strategy to prevent inflammatory events triggered by Aβ 1-40 in mice.

Generalized Anxiety Disorder (GAD) presents a high prevalence in the population, leading to distress and disability. Immune system alterations have been associated with anxiety-related behaviors in rodents and GAD patients. CD300f immune receptors are highly expressed in microglia and participate not only in the modulation of immune responses but also in pruning and reshaping synapses. It was recently demonstrated that CD300f might be influential in the pathogenesis of depression in a sex-dependent manner. Here, we evaluated the role of CD300f immune receptor in anxiety, using CD300f knockout mice (CD300f-/-) and patients with GAD. We observed that male CD300f-/- mice had numerous behavioral changes associated with a low-anxiety phenotype, including increased open field central locomotion and rearing behaviors, more exploration in the open arms of the elevated plus-maze test, and decreased latency to eat in the novelty suppressed feeding test. In a cross-sectional population-based study, including 1111 subjects, we evaluated a common single-nucleotide polymorphism rs2034310 (C/T) in the cytoplasmatic tail of CD300f gene in individuals with GAD. Notably, we observed that the T allele of the rs2034310 polymorphism conferred protection against GAD in men, even after adjusting for confounding variables. Overall, our data demonstrate that CD300f immune receptors are involved in the modulation of pathological anxiety behaviors in a sex-dependent manner. The biological basis of these sex differences is still poorly understood, but it may provide significant clues regarding the neuropathophysiological mechanisms of GAD and can pave the way for future specific pharmacological interventions., Competing Interests: None., (© 2020 The Authors.)

Autophagy is a process of degradation and recycling of cytoplasmatic components by the lysosomes. In the central nervous system (CNS), autophagy is involved in cell surveillance, neuroinflammation, and neuroplasticity. Neuropsychiatric conditions are associated with functional disturbances at molecular and cellular levels, causing significant impairments in cell homeostasis. Additionally, emerging evidence supports that dysfunctions in autophagy contribute to the pathophysiology of neurological diseases. However, the studies on autophagy in psychiatric disorders are highly heterogeneous and have several limitations, mainly to assess causality and determine the autophagy flux in animals and human samples. Besides, the role of this mechanism in non-neuronal cells in the CNS is only recently being explored. Thus, this review summarizes and discusses the changes in the autophagy pathway in animal models of psychiatric disorders and the limitations underlying the significant findings. Moreover, we compared these findings with clinical studies. Understanding the involvement of autophagy in psychiatric conditions, and the limitation of our current models may contribute to the development of more effective research approaches and possibly pharmacological therapies., (Copyright © 2020. Published by Elsevier Inc.)

We investigated the ability of agmatine to potentiate the antidepressant-like and synaptic effects of ketamine in mice. Agmatine (0.1 and 1 mg/kg, p.o.) and ketamine (1 and 10 mg/kg, i.p.) produced an antidepressant-like effect in the tail suspension test. The combination of agmatine (0.01 mg/kg, p.o.) and ketamine (0.1 mg/kg, i.p.), at subthreshold doses, produced an antidepressant-like effect 1 h, 24 h and 7d after treatment. Western blot analysis from prefrontal cortex tissue showed that the combined treatment, after 1 h, increased p70S6K and GluA1, and reduced synapsin 1 phosphorylation. Additionally, after 24 h, Akt, p70S6K, GluA1, and synapsin 1 phosphorylation; and PSD95 immunocontent increased (which persisted for up to 7d). Dendritic architecture analysis of the prefrontal cortex revealed that the combined treatment improved dendritic arbor complexity (after 24 h, up to 7d), and increased spine density (after 1 h, up to 24 h). Morphometric analysis revealed a filopodia-shaped dendrite spine upregulation after 1 h. A predominance of stubby, mushroom, branched and filopodia; and a reduction in thin protrusions were observed after 24 h. Finally, mushroom-shaped dendritic spines predominance increased after 7d. Agmatine potentiated ketamine's antidepressant, and dendritic arbors and spines remodeling effects in a time-dependent manner. Our data indicate Akt/p70S6K signaling as a likely target for these effects., Competing Interests: Declaration of Competing Interest All the authors declare that have no biomedical financial interests or conflict of interest in this study., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Early life stressors, such as childhood trauma, have been associated to alterations in immune response that can last until adulthood. In this context, interleukin 1β (IL-1β) emerges as a pro-inflammatory cytokine with a pivotal role. Also, considering the temperament differences in stress susceptibility, and even immune dysfunction, studies investigating the complex interaction between these factors are scarce. Thus, the aim of the present study was to evaluate the moderating role of temperament traits in the relationship between childhood trauma and serum IL-1β levels. This cross-sectional study consisted of 325 individuals, men and women, aged 18-35, enrolled from a population-based study in the city of Pelotas, Southern Brazil. Our main results indicate that higher serum levels of IL-1β were associated with trauma severity (p < 0.01), and the variance of anger could explain 29% of IL-1β increase in individuals who suffered severe trauma (p < 0.05). The effect of anger was considerably stronger in men than in women (46% and 25%, respectively). Moreover, the variance of sensitivity also explained 15% of IL-1β increase (p < 0.05) as well as the variance of volition explained 11% of IL-1β decrease (p < 0.05) in individuals who suffered severe trauma in the general population. Our results indicate that emotional individual differences can moderate the impact of childhood trauma on low-grade inflammation in young adults., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Bipolar Disorder is a disorder characterized by alternating episodes of depression, mania or hypomania, or even mixed episodes. The treatment consists on the use of mood stabilizers, which imply serious adverse effects. Therefore, it is necessary to identify new therapeutic targets to prevent or avoid new episodes. Evidence shows that individuals in manic episodes present a purinergic system dysfunction. In this scenario, inosine is a purine nucleoside known to act as an agonist of A 1 and A 2A adenosine receptors. Thus, we aimed to elucidate the preventive effect of inosine on locomotor activity, changes in purine levels, and adenosine receptors density in a ketamine-induced model of mania in rats. Inosine pretreatment (25 mg/kg, oral route) prevented the hyperlocomotion induced by ketamine (25 mg/kg, intraperitoneal route) in the open-field test; however, there was no difference in hippocampal density of A 1 and A 2A receptors, where ketamine, as well as inosine, were not able to promote changes in immunocontent of the adenosine receptors. Likewise, no effects of inosine pretreatments or ketamine treatment were observed for purine and metabolic residue levels evaluated. In this sense, we suggest further investigation of signaling pathways involving purinergic receptors, using pharmacological strategies to better elucidate the action mechanisms of inosine on bipolar disorder. Despite the limitations, inosine administration could be a promising candidate for bipolar disorder treatment, especially by attenuating maniac phase symptoms, once it was able to prevent the hyperlocomotion induced by ketamine in rats., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A role for microglia in neuropsychiatric diseases, including major depressive disorder (MDD), has been postulated. Regulation of microglial phenotype by immune receptors has become a central topic in many neurological conditions. We explored preclinical and clinical evidence for the role of the CD300f immune receptor in the fine regulation of microglial phenotype and its contribution to MDD. We found that a prevalent nonsynonymous single-nucleotide polymorphism (C/T, rs2034310) of the human CD300f receptor cytoplasmic tail inhibits the protein kinase C phosphorylation of a threonine and is associated with protection against MDD, mainly in women. Interestingly, CD300f -/- mice displayed several characteristic MDD traits such as augmented microglial numbers, increased interleukin 6 and interleukin 1 receptor antagonist messenger RNA, alterations in synaptic strength, and noradrenaline-dependent and persistent depressive-like and anhedonic behaviors in females. This behavioral phenotype could be potentiated inducing the lipopolysaccharide depression model. RNA sequencing and biochemical studies revealed an association with impaired microglial metabolic fitness. In conclusion, we report a clear association that links the function of the CD300f immune receptor with MDD in humans, depressive-like and anhedonic behaviors in female mice, and altered microglial metabolic reprogramming., Competing Interests: The authors declare no competing interest.

Neuronal hippocampal death can be induced by exacerbated levels of cortisol, a condition usually observed in patients with Major depressive disorder (MDD). Previous in vitro and in vivo studies showed that ursolic acid (UA) elicits antidepressant and neuroprotective properties. However, the protective effects of UA against glucocorticoid-induced cytotoxicity have never been addressed. Using an in vitro model of hippocampal cellular death induced by elevated levels of corticosterone, we investigated if UA prevents corticosterone-induced cytotoxicity in HT22 mouse hippocampal derived cells. Concentrations lower than 25 µM UA did not alter cell viability. Co-incubation with UA for 48 h was able to protect HT22 cells from the reduction on cell viability and from the increase in apoptotic cells induced by corticosterone. Inhibition of protein kinase A (PKA), protein kinase C (PKC) and, Ca 2+ /calmodulin-dependent protein kinase II (CaMKII), but not phosphoinositide 3-kinase(PI3K), by using the pharmacological the inhibitors: H-89, chelerythrine, KN-62, and LY294002, respectively totally abolished the cytoprotective effects of UA. Finally, UA abrogated the reduction in phospho-extracellular signal-regulated kinases 1 and 2 (ERK1/2) but not in phospho-c-Jun kinases induced by corticosterone. These results indicate that the protective effect of UA against the cytotoxicity induced by corticosterone in HT22 cells may involve PKA, PKC, CaMKII, and ERK1/2 activation. The cytoprotective potential of UA against corticosterone-induced cytotoxicity and its ability to modulate intracellular signaling pathways involved in cell proliferation and survival suggest that UA may be a relevant strategy to manage stress-related disorders such as MDD.

Vitamin D, a fat-soluble vitamin, plays a role not only in calcium and phosphate homeostasis but also in several other functions, including cell growth and neuromuscular and immune function. The deficiency of vitamin D is highly prevalent throughout the world and has been suggested to be associated with an enhanced risk of major depressive disorder (MDD) and anxiety disorders. Therefore, vitamin D supplementation has been investigated for the prevention and treatment of these disorders. This review presents preclinical and clinical evidence of the effects of vitamin D supplementation in these disorders. Although preclinical studies provide limited evidence on the possible mechanisms underlying the beneficial effects of vitamin D for the management of these disorders, most of the clinical studies have indicated that vitamin D supplementation is associated with the reduction of symptoms of depression and anxiety, particularly when the supplementation was carried out in individuals with an MDD diagnosis (of the 13 studies in which MDD diagnosis was established, 12 had positive results with vitamin supplementation). However, some heterogeneity in the outcomes was observed and might be associated with an absence of overt psychiatric symptoms in several studies, genetic polymorphisms that alter vitamin D metabolism and bioavailability, differences in the supplementation regimen (monotherapy, adjunctive therapy, or large bolus dosing), and levels of 25-hydroxyvitamin D 3 (25(OH)D) at baseline (individuals with low vitamin D status may respond better) and attained after supplementation. Additionally, factors such as sex, age, and symptom severity also need to be further explored in relation to the effects of vitamin D. Therefore, although vitamin D may hold significant potential for mental health, further preclinical and clinical studies are clearly necessary to better understand its role on mood/affect modulation.

Growing evidence support the role of vitamin D in brain function and behavior. This study investigated the relationship between 25-hydroxyvitamin D 3 [25(OH)D 3 ] levels, biochemical profile and symptoms of depression and anxiety in healthy individuals. Symptoms of depression were assessed by the Beck Depression Inventory (BDI) and anxiety was evaluated with the State-Trait Anxiety Inventory (STAI). Our sample included 36 individuals, mostly women 27(75%), 36.39 ± 9.72 years old, non-smokers 31(86.1%), body mass index of 26.57 ± 3.92 kg/m 2 , 27.95 ± 7.50% body fat. Participants were divided into those with 25(OH)D 3 levels lower than 40 ng/mL (mean 28.16 ± 7.07) and equal or higher than 40 ng/mL (mean 53.19 ± 6.32). Those with lower 25(OH)D 3 had higher levels of triacylglycerol, triacylglycerol/high density lipoprotein (HDL) ratio, high glucose and homeostatic model assessment of insulin resistance (HOMA-IR) index. No changes were observed in sociodemographic variables, body composition, inflammatory parameters and cortisol. Additionally, in the groups with low and high 25(OH)D 3 levels, STAI state, STAI trait and BDI scores were not statistically different. Levels of 25(OH)D 3 were inversely and independently associated with glucose and HOMA-IR, but not associated with triacylglycerol, depression and anxiety scores. Lower levels of 25(OH)D 3 were associated with dysfunction in glucose metabolism but not with depression and anxiety in healthy individuals.

Genetic variants involved in adenosine metabolism and its receptors were associated with increased risk for psychiatric disorders, including anxiety, depression, and schizophrenia. Here, we examined an association between a single nucleotide polymorphism in A 2A receptor gene (ADORA2A, rs2298383 SNP) with current depressive episode and symptom profile. A total of 1253 individuals from a cross-sectional population-based study were analyzed by the Mini International Neuropsychiatric Interview 5.0. Our data showed that the TT genotype of ADORA2A rs2298383 SNP was associated with reduced risk for depression when compared to the CC/CT genotypes (p = 0.020). This association remained significant after adjusting for confounding variables such as smoking, gender, socioeconomic class, and ethnicity (OR = 0.631 (95% CI 0.425-0.937); p = 0.022). Regarding the symptoms associated with depression, we evaluated the impact of the ADORA2A SNP in the occurrence of sad/discouraged mood, anhedonia, appetite changes, sleep disturbances, motion changes, energy loss, feelings of worthless or guilty, difficulty in concentrating, and presence of bad thoughts. Notably, the TT genotype was independently associated with reduced sleep disturbances (OR = 0.438 (95% CI 0.258-0.743); p = 0.002) and less difficulty in concentrating (OR = 0.534 (95% CI 0.316-0.901; p = 0.019). The cross-sectional design cannot evaluate the cause-effect relationship and did not evaluate the functional consequences of this polymorphism. Our data support an important role for ADORA2A rs2298383 SNP in clinical heterogeneity associated with depression. The presence of the TT genotype was associated with decrease risk for current depression and disturbances in sleep and attention, two of the most common symptoms associated with this disorder.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most robust neurobiological findings in the pathophysiology of major depressive disorder (MDD) over the last 40 years. The persistent increase in glucocorticoids levels induces morphological and anatomical changes in the brain, especially in the hippocampus. Ketamine represents a major advance for the treatment of MDD, however the psychotomimetic effects of this compound limit its widespread use. Agmatine is a neuromodulator that has been shown to be a putative novel and well-tolerated antidepressant/augmenter drug. In this study, the exposure of HT22 hippocampal neuronal cell line to corticosterone (50 μM) induced a significant neuronal cell death. Interestingly, the incubation of HT22 cells with the fast-acting antidepressant drug ketamine (1 μM) prevented the corticosterone-induced toxicity. Similarly, agmatine caused a significant cytoprotection at the concentration of 0.1 μM against corticosterone (50 μM) cell damage. Notably, the incubation with a subthreshold concentration of ketamine (0.01 μM) in combination with a subthreshold concentration of agmatine (0.001 μM) prevented the neuronal damage elicited by corticosterone (50 μM). A 24 h co-incubation with subthreshold concentrations of ketamine (0.01 μM) and agmatine (0.001 μM) was able to cause a significant increase in the phosphorylation levels of Akt (Ser 473 ) and p70S6 kinase (Thr 389 ) as well as PSD95 immunocontent. Neither glycogen synthase kinase-3β (Ser 9 ) phosphorylation nor β catenin immunocontent were altered by a 24 h co-incubation period. Finally, the co-incubation of cells for 30 min did not produce any effect in the phosphorylation or immunocontent of any protein investigated. Taken together, our results support the notion that the combination of subthreshold concentrations of ketamine and agmatine has cytoprotective effects against corticosterone-induced cell death. This effect is accompanied by its ability to activate Akt and mTOR/S6 kinase signaling pathway, and increase the expression of synaptic proteins., (Copyright © 2018. Published by Elsevier Ltd.)

This narrative review will present and discuss clinical data from 16 cross-sectional and 6 longitudinal studies examining the relationship between body mass index (BMI), symptoms of depression and peripheral inflammation. Our aim is to determine which of obesity and depression contributes best to the peripheral low-grade inflammation frequently associated to both conditions. Studies including a complete evaluation of inflammatory markers are scarce and high levels of interleukin-6 (IL-6) and C-reactive protein (CRP) are the most consistent findings associated with obesity and symptoms of depression. Among the cross-sectional studies, seven studies, including a total of 9421 individuals, pointed to BMI as the major factor associated with systemic low-grade inflammation. However, in four studies, including 16,837 individuals, CRP levels remained associated with the symptoms of depression even after correction for BMI, suggestion that in the absence of overweight or obesity other sources of peripheral inflammation might contribute to presence of depressive symptoms. Additionally, another five studies, including 5569 individuals failed to find an association between depression and peripheral inflammation, reinforcing the heterogeneity of this condition. In the longitudinal data, changes in BMI were associated with a reduction in depressive scores at follow-up, after bariatric surgery or after diet. In four longitudinal studies, high levels of CRP were found to be associated with depression even after adjustment for BMI and weight loss, further corroborating the idea that other sources of peripheral inflammation might contribute to depressive symptoms. Thus it seems that both obesity and depressive symptoms can contribute to peripheral inflammation, and once installed the presence of inflammation can contribute to several behavioral alterations that reinforce the cyclic pattern of co-occurrence observed in patients with obesity and MDD. Future clinical studies should focus on strategic efforts to collect new data and to improve or standardize methods for the evaluation of depression, body composition and a more complete inflammatory profile. These approaches are essential for the development of pharmacological and/or non-pharmacological strategies designed to break this cyclic pattern of co-occurrence., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Ursolic acid has been shown to display antidepressant-like effects in mice through the modulation of monoaminergic systems. In this study, we sought to investigate the involvement of signaling pathways on the antidepressant-like effects of ursolic acid., Methods: Mice were treated orally with ursolic acid (0.1mg/kg) and, 45min later they received the followings inhibitors by intracerebroventricular route: H-89 (PKA inhibitor, 1μg/mouse), KN-62 (CAMK-II inhibitor, 1μg/mouse), chelerythrine (PKC inhibitor, 1μg/mouse), U0126 (MEK1/2 inhibitor, 5μg/mouse), PD98059 (MEK1/2 inhibitor, 5μg/mouse), wortmannin (PI3K irreversible inhibitor, 0.1μg/mouse) or LY294002 (PI3K inhibitor, 10 nmol/mouse). Immobility time of mice was registered in the tail suspension test (TST)., Results: The anti-immobility effect of ursolic acid in the TST was abolished by the treatment of mice with H-89, KN-62, chelerythrine, U0126 or PD98059, but not with wortmannin or LY294002., Conclusions: These results suggest that activation of PKA, PKC, CAMK-II, MEK1/2 may underlie the antidepressant-like effects of ursolic acid., (Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Ursolic acid is a pentacyclic triterpenoid found in several plants. Despite its initial use as a pharmacologically inactive emulsifier in pharmaceutical, cosmetic and food industries, several biological activities have been reported for this compound so far, including anti-tumoural, anti-diabetic, cardioprotective and hepatoprotective properties. The biological effects of ursolic acid have been evaluated in vitro, in different cell types and against several toxic insults (i.e. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, amyloid-β peptides, kainic acid and others); in animal models of brain-related disorders (Alzheimer disease, Parkinson disease, depression, traumatic brain injury) and ageing; and in clinical studies with cancer patients and for muscle atrophy. Most of the protective effects of ursolic acid are related to its ability to prevent oxidative damage and excessive inflammation, common mechanisms associated with multiple brain disorders. Additionally, ursolic acid is capable of modulating the monoaminergic system, an effect that might be involved in its ability to prevent mood and cognitive dysfunctions associated with neurodegenerative and psychiatric conditions. This review presents and discusses the available evidence of the possible beneficial effects of ursolic acid for the management of neurodegenerative and psychiatric disorders. We also discuss the chemical features, major sources and potential limitations of the use of ursolic acid as a pharmacological treatment for brain-related diseases.

Glutamatergic system and mTOR signaling pathway have been proposed to be important targets for pharmacological treatment of major depressive disorder. Previous studies have shown that inosine, an endogenous purine, is able to exert a remarkable antidepressant-like effect in mice. Nevertheless, the role of glutamatergic system and mTOR in this effect was not previously determined. This study was designed to investigate the possible modulation of NMDA receptors (NMDAR), AMPA receptors (AMPAR) and mTOR complex 1 (mTORC1) signaling pathway in the inosine anti-immobility effect in the tail suspension test (TST) in mice. Pre-treatment of mice with NMDA (0.1 pmol/mouse, NMDAR agonist, i.c.v.) and D-serine (30 μg/mouse, NMDAR co-agonist, i.c.v.) prevented inosine (10 mg/kg, i.p.) anti-immobility effect in the TST. In addition, a synergistic antidepressant-like effect was observed when a sub-effective dose of inosine (0.1 mg/kg, i.p.) was combined with sub-effective doses of NMDAR antagonists MK-801 (0.001 mg/kg, p.o.) or ketamine (0.1 mg/kg, i.p.). Conversely, the antidepressant-like effect elicited by inosine was not altered by pre-treatment with AMPAR antagonist, DNQX (2.5 μg/mouse, i.c.v.). The mTORC1 inhibitor rapamycin (0.2 nmol/mouse, i.c.v.) prevented the inosine anti-immobility effect in the TST. Noteworthy, inosine treatment did not change the immunocontent of the synaptic proteins PSD95, GluA1 and synapsin I. Mice locomotor activity assessed by open-field test, was not altered by treatments. Taken together, this study shows a pivotal role of NMDAR inhibition and mTORC1 activation for inosine antidepressant-like effect and extends the knowledge concerning the molecular mechanism and potential of inosine for antidepressant strategies.

Over the past three decades, an intricate interaction between immune activation, release of pro-inflammatory cytokines and changes in brain circuits related to mood and behavior has been described. Despite extensive efforts, questions regarding when inflammation becomes detrimental or how we can target the immune system to develop new therapeutic strategies for the treatment of psychiatric disorders remain unresolved. In this context, novel aspects of the neuroinflammatory process activated in response to stressful challenges have recently been documented in major depressive disorder (MDD). The Nod-like receptor pyrin containing 3 inflammasome (NLRP3) is an intracellular multiprotein complex responsible for a number of innate immune processes associated with infection, inflammation and autoimmunity. Recent data have demonstrated that NLRP3 activation appears to bridge the gap between immune activation and metabolic danger signals or stress exposure, which are key factors in the pathogenesis of psychiatric disorders. In this review, we discuss both preclinical and clinical evidence that links the assembly of the NLRP3 complex and the subsequent proteolysis and release of the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) in chronic stress models and patients with MDD. Importantly, we also focus on the therapeutic potential of targeting the NLRP3 inflammasome complex to improve stress resilience and depressive symptoms., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Inosine is a purine nucleoside formed by the breakdown of adenosine that elicits an antidepressant-like effect in mice through activation of adenosine A 1 and A 2A receptors. However, the signaling pathways underlying this effect are largely unknown. To address this issue, the present study investigated the influence of extracellular-regulated protein kinase (ERK)1/2, Ca 2+ /calmoduline-dependent protein kinase (CaMKII), protein kinase A (PKA), phosphoinositide 3-kinase (PI3K)/Akt, and glycogen synthase kinase 3beta (GSK-3β) modulation in the antiimmobility effect of inosine in the tail suspension test (TST) in mice. In addition, we attempted to verify if inosine treatment was capable of altering the immunocontent and phosphorylation of the transcription factor cyclic adenosine monophosphatate (cAMP) response-binding element protein (CREB) in mouse prefrontal cortex and hippocampus. Intracerebroventricular administration of U0126 (5 μg/mouse, MEK1/2 inhibitor), KN-62 (1 μg/mouse, CaMKII inhibitor), H-89 (1 μg/mouse, PKA inhibitor), and wortmannin (0.1 μg/mouse, PI3K inhibitor) prevented the antiimmobility effect of inosine (10 mg/kg, intraperitoneal (i.p.)) in the TST. Also, administration of a sub-effective dose of inosine (0.1 mg/kg, i.p.) in combination with a sub-effective dose of AR-A014418 (0.001 μg/mouse, GSK-3β inhibitor) induced a synergic antidepressant-like effect. None of the treatments altered locomotor activity of mice. Moreover, 24 h after a single administration of inosine (10 mg/kg, i.p.), CREB phosphorylation was increased in the hippocampus. Our findings provided new evidence that the antidepressant-like effect of inosine in the TST involves the activation of PKA, PI3K/Akt, ERK1/2, and CaMKII and the inhibition of GSK-3β. These results contribute to the comprehension of the mechanisms underlying the purinergic system modulation and indicate the intracellular signaling pathways involved in the antidepressant-like effect of inosine in a preclinical test of depression.

The aim of this study was to investigate the effect of blueberry (Vaccinium virgatum) fruit extract on metabolic, behavioral and oxidative stress parameters in the hippocampus and cerebral cortex of mice submitted to an experimental model of metabolic syndrome induced by a highly palatable diet (HPD). Mice C57BL/6 were divided into 4 experimental groups: (1) received standard chow and saline orally, (2) received standard chow and blueberry hydroalcoholic extract, (3) received HPD and saline orally, (4) received HPD and blueberry hydroalcoholic extract. The animals were treated for 150days. Our results showed that the animals fed with HPD presented insulin resistance, increased body weight, visceral fat, glucose, triglycerides, and total cholesterol when compared to the control group. The blueberry extract prevented the increase of these metabolic parameters. Also, the extract was able to reduce the levels of thiobarbituric acid reactive substances in the cerebral cortex and hippocampus of animals submitted to HPD. In contrast, no differences were observed in the total thiol content, activity of the antioxidant enzymes catalase and superoxide dismutase. In addition, the HPD fed animals showed a significant increase in immobility time in the forced swimming test and blueberry prevented this alteration, although no changes were observed in the ambulatory behavior, as well as in the anxiolytic profile of these animals. Overall, our findings suggest that chronic consumption of blueberry extract exhibits hypoglycemic, hypolipidemic, antidepressant-like and antiperoxidative effects in an animal model of metabolic syndrome., (Copyright © 2017. Published by Elsevier Masson SAS.)

Caffeine prophylactically prevents mood and memory impairments through adenosine A 2A receptor (A 2A R) antagonism. A 2A R antagonists also therapeutically revert mood and memory impairments, but it is not known if caffeine is also therapeutically or only prophylactically effective. Since depression is accompanied by mood and memory alterations, we now explored if chronic (4 weeks) caffeine consumption (0.3 g/L) reverts mood and memory impairment in helpless mice (HM, 12 weeks old), a bred-based model of depression. HM displayed higher immobility in the tail suspension and forced swimming tests, greater anxiety in the elevated plus maze, and poorer memory performance (modified Y-maze and object recognition). HM also had reduced density of synaptic (synaptophysin, SNAP-25), namely, glutamatergic (vGluT1; -22 ± 7 %) and GABAergic (vGAT; -23 ± 8 %) markers in the hippocampus. HM displayed higher A 2A R density (72 ± 6 %) in hippocampal synapses, an enhanced facilitation of hippocampal glutamate release by the A 2A R agonist, CGS21680 (30 nM), and a larger LTP amplitude (54 ± 8 % vs. 21 ± 5 % in controls) that was restored to control levels (30 ± 10 %) by the A 2A R antagonist, SCH58261 (50 nM). Notably, caffeine intake reverted memory deficits and reverted the loss of hippocampal synaptic markers but did not affect helpless or anxiety behavior. These results reinforce the validity of HM as an animal model of depression by showing that they also display reference memory deficits. Furthermore, caffeine intake selectively reverted memory but not mood deficits displayed by HM, which are associated with an increased density and functional impact of hippocampal A 2A R controlling synaptic glutamatergic function.

The consumption of caffeine modulates working and reference memory through the antagonism of adenosine A 2A receptors (A 2A Rs) controlling synaptic plasticity processes in hippocampal excitatory synapses. Fear memory essentially involves plastic changes in amygdala circuits. However, it is unknown if A 2A Rs in the amygdala regulate synaptic plasticity and fear memory. We report that A 2A Rs in the amygdala are enriched in synapses and located to glutamatergic synapses, where they selectively control synaptic plasticity rather than synaptic transmission at a major afferent pathway to the amygdala. Notably, the downregulation of A 2A Rs selectively in the basolateral complex of the amygdala, using a lentivirus with a silencing shRNA (small hairpin RNA targeting A 2A R (shA 2A R)), impaired fear acquisition as well as Pavlovian fear retrieval. This is probably associated with the upregulation and gain of function of A 2A Rs in the amygdala after fear acquisition. The importance of A 2A Rs to control fear memory was further confirmed by the ability of SCH58261 (0.1 mg/kg; A 2A R antagonist), caffeine (5 mg/kg), but not DPCPX (0.5 mg/kg; A 1 R antagonist), treatment for 7 days before fear conditioning onwards, to attenuate the retrieval of context fear after 24-48 h and after 7-8 days. These results demonstrate that amygdala A 2A Rs control fear memory and the underlying process of synaptic plasticity in this brain region. This provides a neurophysiological basis for the association between A 2A R polymorphisms and phobia or panic attacks in humans and prompts a therapeutic interest in A 2A Rs to manage fear-related pathologies.

The aim of the present study was to evaluate the protective effects of blueberry extract on oxidative stress and inflammatory parameters in a model of mania induced by ketamine administration in rats. Male rats were pretreated with blueberry extract (200mg/kg, once a day for 14days), lithium chloride (45mg/kg, mood stabilizer used as a positive control, twice a day for 14days), or vehicle. Between the 8th and 14th days, rats also received an injection of ketamine (25mg/kg) or vehicle. In the 15th day, thirty minutes after ketamine administration the hyperlocomotion of the animals was assessed in the open - field apparatus. Immediately after the behavioral analysis brain and blood were collected for biochemical determinations. ketamine treatment induced hyperlocomotion and oxidative damage in cerebral cortex, hippocampus and striatum such as an increase in lipid peroxidation and a decrease in the antioxidant enzymes activities (superoxide dismutase, catalase e glutatione peroxidase). Ketamine administration also increased the IL-6 levels in serum in rats. Pretreatment of rats with blueberry extract or lithium prevented the hyperlocomotion, pro - oxidant effects and inflammation induced by ketamine. Our findings suggest that blueberry consumption has a neuroprotective potential against behavioral and biochemical dysfunctions induced in a preclinical model that mimic some aspects of the manic behavior., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Considering the high prevalence of psychiatric disorders, its social burden and the limitations of currently available treatments, alternative therapeutic approaches targeting different biological pathways have been investigated. Curcumin is a natural compound with multi-faceted pharmacological properties, interacting with several neurotransmitter systems and intracellular signaling pathways involved in mood regulation. Also, curcumin has anti-inflammatory, antioxidant and neurotrophic effects, suggesting a strong potential to manage conditions associated with neurodegeneration, such as psychiatric disorders. Most literature data focused on the potential of curcumin to counteract behavioral and neurochemical alterations in preclinical models of depression. The findings still need to be further explored and clinical reports share some controversial results that might be associated with its low systemic bioavailability following oral administration. Other psychiatric disorders also have neurochemical alterations similar to those found in depression, including neurotoxicity, oxidative stress and neuroinflammation. Despite the limited number of reports, preclinical models investigated the potential role for curcumin in anxiety, bipolar disorder, post-traumatic stress disorder and autism spectrum disorders. Here, we will summarize the cellular targets of curcumin relevant to psychiatric disorders and its effects in preclinical and clinical studies with depression, anxiety disorders and other psychiatric related conditions., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Major depressive disorder is a disabling psychiatric condition that causes a significant burden on individuals and society. There is still a lack of a clear understanding of the neuropathological changes associated with this illness and the efficacy of antidepressants is still far from optimal. Research into antidepressant therapies has evolved from serendipitous observation in human trials, but more than 60 years after the first monoaminergic antidepressants emerged they remain the mainstay for treating depression. However, glutamatergic modulators such as ketamine became the forefront of antidepressant exploration, especially for treatment-resistant depression and suicidal ideation. The glutamatergic hypothesis of depression is not new, however other NMDA receptor modulators do not seem to share the rapid and sustained effects of ketamine, suggesting that a unique combination of intracellular targets might be involved in its effect. Interestingly, inflammation can impact the glutamatergic system enhancing excitotoxicity and decreasing neuroplasticity. The points of convergence between the inflammatory and glutamatergic hypotheses of depression are not completely established, especially regarding the effects of fast-acting antidepressants. In this review, we discuss the most recent research surrounding glutamatergic fast-acting antidepressants, capable of modulating cellular plasticity and synaptogenesis and the potential of anti-inflammatory compounds evaluated from a different perspective. The combination of innovative ideas plus improvements on the discoveries made so far might lead to advances in antidepressant research with the promise of finding compounds that are both effective and fast-acting, even in patients who have tried other therapies with limited success., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Stress has been considered determinant in the etiology of depression. The adrenal medulla plays a key role in response to stress by releasing catecholamines, which are important to maintain homeostasis. We aimed to study the adrenal medulla in a mouse model of depression induced by 21 days of unpredictable chronic stress (UCS). We observed that UCS induced a differential and time-dependent change in adrenal medulla. After 7 days of UCS, mice did not show depressive-like behavior, but the adrenal medullae show increased protein and/or mRNA levels of catecholamine biosynthetic enzymes (TH, DβH and PNMT), Neuropeptide Y, the SNARE protein SNAP-25, the catecholamine transporter VMAT2 and the chromaffin progenitor cell markers, Mash1 and Phox2b. Moreover, 7 days of UCS induced a decrease in the chromaffin progenitor cell markers, Sox9 and Notch1. This suggests an increased capacity of chromaffin cells to synthesize, store and release catecholamines. In agreement, after 7 days, UCS mice had higher NE and EP levels in adrenal medulla. Opposite, when mice were submitted to 21 days of UCS, and showed a depressive like behavior, adrenal medullae had lower protein and/or mRNA levels of catecholamine biosynthetic enzymes (TH, DβH, PNMT), catecholamine transporters (NET, VMAT1), SNARE proteins (synthaxin1A, SNAP25, VAMP2), catecholamine content (EP, NE), and lower EP serum levels, indicating a reduction in catecholamine synthesis, re-uptake, storage and release. In conclusion, this study suggests that mice exposed to UCS for a period of 21 days develop a depressive-like behavior accompanied by an impairment of adrenal medullary function., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

Background: Generalized anxiety disorder (GAD) is a common psychiatric disorder characterized by long-term worry, tension, nervousness, fidgeting, and symptoms of autonomic system hyperactivity. The neurobiology of this disorder is still unclear, although it has been shown consistently that the environment and the genetic profile could increase its risk. We examined whether a polymorphism in the brain-derived neurotrophic factor (BDNF) gene, which plays a role in neuroplasticity and memory, could increase the vulnerability to this disorder., Participants and Methods: In our study, 816 participants from a population-based study were genotyped by qPCR for the BDNF functional variant rs6265 (Val66Met) and the BDNF serum levels were measured by ELISA., Results: Our results showed a significant association between the Met allele and risk for GAD (P=0.014), but no differences were observed in the serum levels of BDNF according to diagnosis (P=0.531) or genotype distribution (P=0.197). However, after stratification according to the GAD diagnosis, the Met allele was associated significantly with an increase in serum BDNF levels compared with the Val/Val genotype in GAD participants (F=3.93; P=0.048). The logistic regression analysis confirmed the independent association of Met allele as a risk factor for development of GAD after adjusting for confounder variables (β=0.528; 95% confidence interval: 0.320-0.871; P=0.012)., Conclusion: These results suggest that BDNF could be involved in the neurobiology of GAD and might represent a useful marker associated with the disease.

Objective: To investigate peripheral levels of interleukin-10 (IL-10) in patients with major depressive disorder (MDD) and bipolar disorder (BD) and evaluate the relationship between IL-10, age of disease onset, and duration of illness., Methods: Case-control study nested in a population-based cohort of 231 individuals (age 18-24 years) living in Pelotas, state of Rio Grande do Sul, Brazil. Participants were screened for psychopathology using the Mini-International Neuropsychiatric Interview (MINI) and the Structured Clinical Interview for DSM-IV (SCID-I). Serum IL-10 was measured using commercially available immunoassay kits., Results: Peripheral levels of IL-10 were not significantly different in individuals with MDD or BD as compared to controls. However, higher IL-10 levels were found in MDD patients with a later disease onset as compared with controls or early-onset patients. In addition, IL-10 levels correlated negatively with illness duration in the MDD group. In the BD group, age of onset and duration of illness did not correlate with IL-10 levels., Conclusion: Higher levels of IL-10 are correlated with late onset of MDD symptoms. Moreover, levels of this cytokine might decrease with disease progression, suggesting that an anti-inflammatory balance may be involved in the onset of depressive symptoms and disease progression in susceptible individuals.

Introduction: Studies have already pointed out the contribution of oxidative stress in the pathophysiology of major depressive disorder (MDD). The aim of the present study was to investigate the oxidative-antioxidative systems in MDD and in response to cognitive psychotherapies. Oxidative stress were analyzed in 49 MDD patients at baseline, post-treatment, and follow-up; and 49 control subjects without history of psychiatric disorders., Results: MDD subjects presented an increase in oxidative damage related to control subjects for thiobarbituric acid reactive species (TBARS), nitric oxide, and a decrease in total thiol content. Cognitive psychotherapies were able to counteract peripheral oxidative stress in MDD patients, reducing TBARS levels (p<0.001) in the follow-up, nitric oxide (p<0.001) in the post-treatment and follow-up, and increasing the total thiol content (p<0.01) in the post-treatment and follow-up., Conclusion: Oxidative stress was associated with MDD and the regulation of these parameters might represent an important mechanism associated with the clinical improvement of cognitive psychotherapy., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: Depressive symptoms have been frequently observed in association with immune activation. We prospectively evaluate depressive symptoms and risk factors for major depression in patients with hepatitis C virus treated with antiviral combined therapy., Methods: Fifty patients were assessed during 1 year; the structured diagnostic interview - Mini International Neuropsychiatric Interview - was used to screen psychiatric disorders at the baseline and during the 4th and 12th week of antiviral therapy., Statistical Analysis: generalized estimating equations and pairwise comparisons with Bonferroni adjustment., Results: In our sample the prevalence of the Genotype 1 was 42%, and the pegylated interferon alpha plus ribavirin was the most prevalent treatment used for hepatitis C (86%). We found increased risk of depression in the 4th week (34%) but not in the 12th week (24%) compared with baseline values (20%) (P=0.040). In addition, we found differences between depression prevalence and hepatitis C genotypes, with higher odds in the 4th week compared to the baseline and 12th week [OR: 2.1(1.15-2.9); P=0.040]. Patients with the Genotype 2/3 had significantly lower odds of presenting depression compared to the Genotype 1 [OR: 0.3 (0.1-0.9); P=0.030]., Conclusion: This study provides evidence for an association between hepatitis C genotype and major depression, showing that besides immune activation, the Genotype 1 is associated with increased risk for psychiatric symptoms during the follow-up., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Cecropia species are widely used in traditional medicine by its anti-diabetic, anti-hypertensive and anti-inflammatory properties. In the present study, we investigated the neuroprotective and antioxidant effects of the crude aqueous extract from Cecropia pachystachya leaves in a rat model of mania induced by ketamine. The results indicated that ketamine treatment (25 mg/kg i.p., for 8 days) induced hyperlocomotion in the open-field test and oxidative damage in prefrontal cortex and hippocampus, evaluated by increased lipid peroxidation, carbonyl protein formation and decreased total thiol content. Moreover, ketamine treatment reduced the activity of the antioxidant enzymes superoxide dismutase and catalase in hippocampus. Pretreatment of rats with C. pachystachya aqueous extract (200 and 400 mg/kg p.o., for 14 days) or with lithium chloride (45 mg/kg p.o., for 14 days, used as a positive control) prevented both behavioral and pro-oxidant effects of ketamine. These findings suggest that C. pachystachya might be a useful tool for preventive intervention in bipolar disorder, reducing the episode relapse and the oxidative damage associated with the manic phase of this disorder .

The consumption of caffeine (an adenosine receptor antagonist) correlates inversely with depression and memory deterioration, and adenosine A2A receptor (A2AR) antagonists emerge as candidate therapeutic targets because they control aberrant synaptic plasticity and afford neuroprotection. Therefore we tested the ability of A2AR to control the behavioral, electrophysiological, and neurochemical modifications caused by chronic unpredictable stress (CUS), which alters hippocampal circuits, dampens mood and memory performance, and enhances susceptibility to depression. CUS for 3 wk in adult mice induced anxiogenic and helpless-like behavior and decreased memory performance. These behavioral changes were accompanied by synaptic alterations, typified by a decrease in synaptic plasticity and a reduced density of synaptic proteins (synaptosomal-associated protein 25, syntaxin, and vesicular glutamate transporter type 1), together with an increased density of A2AR in glutamatergic terminals in the hippocampus. Except for anxiety, for which results were mixed, CUS-induced behavioral and synaptic alterations were prevented by (i) caffeine (1 g/L in the drinking water, starting 3 wk before and continued throughout CUS); (ii) the selective A2AR antagonist KW6002 (3 mg/kg, p.o.); (iii) global A2AR deletion; and (iv) selective A2AR deletion in forebrain neurons. Notably, A2AR blockade was not only prophylactic but also therapeutically efficacious, because a 3-wk treatment with the A2AR antagonist SCH58261 (0.1 mg/kg, i.p.) reversed the mood and synaptic dysfunction caused by CUS. These results herald a key role for synaptic A2AR in the control of chronic stress-induced modifications and suggest A2AR as candidate targets to alleviate the consequences of chronic stress on brain function.

The benefits of creatine supplementation have been reported in a broad range of central nervous systems diseases, including depression. A previous study from our group demonstrated that creatine produces an antidepressant-like effect in the tail suspension test (TST), a predictive model of antidepressant activity. Since depression is associated with a dysfunction of the adenosinergic system, we investigated the involvement of adenosine A1 and A2A receptors in the antidepressant-like effect of creatine in the TST. The anti-immobility effect of creatine (1 mg/kg, po) or ketamine (a fast-acting antidepressant, 1 mg/kg, ip) in the TST was prevented by pretreatment of mice with caffeine (3 mg/kg, ip, nonselective adenosine receptor antagonist), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (2 mg/kg, ip, selective adenosine A1 receptor antagonist), and 4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo-{2,3-a}{1,3,5}triazin-5-yl-amino]ethyl)-phenol (ZM241385) (1 mg/kg, ip, selective adenosine A2A receptor antagonist). In addition, the combined administration of subeffective doses of creatine and adenosine (0.1 mg/kg, ip, nonselective adenosine receptor agonist) or inosine (0.1 mg/kg, ip, nucleoside formed by the breakdown of adenosine) reduced immobility time in the TST. Moreover, the administration of subeffective doses of creatine or ketamine combined with N-6-cyclohexyladenosine (CHA) (0.05 mg/kg, ip, selective adenosine A1 receptor agonist), N-6-[2-(3,5-dimethoxyphenyl)-2-(methylphenyl)ethyl]adenosine (DPMA) (0.1 mg/kg, ip, selective adenosine A2A receptor agonist), or dipyridamole (0.1 μg/mouse, icv, adenosine transporter inhibitor) produced a synergistic antidepressant-like effect in the TST. These results indicate that creatine, similarly to ketamine, exhibits antidepressant-like effect in the TST probably mediated by the activation of both adenosine A1 and A2A receptors, further reinforcing the potential of targeting the purinergic system to the management of mood disorders.

Objective: The present study investigated whether peripheral leptin levels are associated with current depressive episodes in a cross-sectional study nested within a population-based study., Methods: The Mini-International Neuropsychiatric Interview (MINI) 5.0 was used to assess the presence of current depressive episodes. The sample was composed of 206 subjects (103 controls and 103 subjects with a current depressive episode) paired by gender, BMI and age. Medication use and lifestyle characteristics were self-reported., Results: Serum leptin levels were lower in currently depressive subjects (10.9 ± 12.0 ng/ml) than in the control group (20.3 ± 24.0 ng/ml; p = 0.023). According to the clinical diagnosis, individuals with bipolar depression present lower leptin levels (8.4 ± 8.1 ng/ml) than those with unipolar depression (12.0 ± 13.4 ng/ml) and the control group (20.3 ± 24.0 ng/ml; p = 0.031). In addition, ANCOVA showed that leptin is an independent factor associated with current depressive episodes (p = 0.018)., Conclusion: A decreased leptin level might be a useful peripheral marker associated with depressive episodes in the context of bipolar disorder., (© 2015 S. Karger AG, Basel.)

Objective: The aim of the present study was to investigate the relationship between peripheral levels of corticotropin-releasing hormone (CRH) and interleukin-1β (IL-1β) in individuals with bipolar disorder (BD) with and without suicide risk (SR), and controls., Methods: A total of 120 young adults (40 controls, 40 subjects with BD without SR, and 40 subjects with BD with SR) were enrolled from a population-based study carried out in the city of Pelotas, Brazil. BD and SR were assessed through the Mini International Neuropsychiatric Interview (MINI 5.0), and peripheral markers were evaluated by enzyme-linked immunosorbent assay (ELISA)., Results: Levels of CRH were significantly lower both in subjects with BD without SR (p = 0.04) and subjects with BD with SR (p = 0.02) when compared to controls. However, levels of IL-1β were increased in subjects with BD with SR (p = 0.05) when compared to controls. Sociodemographic and clinical variables, current mood episode, and use of psychiatric medications were not associated with changes in these markers. No correlation was found between peripheral levels of CRH and IL-1β (p = 0.60) in the population or in the BD with SR group (p = 0.88)., Conclusions: These results suggest that peripheral mechanisms linking stress hormones and the immune system might be critical patterns involved in suicidal behavior associated with BD., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Chronic stressful stimuli influence disease susceptibility to depression, cardiovascular, metabolic and neurodegenerative disorders. The present work investigated antidepressant and antioxidant properties of the aqueous extract from Cecropia pachystachya in a mouse model of chronic unpredictable stress (CUS). Our results indicated that acute administration of the aqueous extract (AE) from C. pachystachya (200 and 400mg/kg, p.o.) produced an antidepressant-like effect in the forced swimming test (FST). The chronic treatment with C. pachystachya extract (200mg/kg, p.o., for 14 days) prevented the depressant-like effect but not the anxiogenic effect induced by CUS. In addition to the behavioral modifications, the 14 days of CUS increased lipid peroxidation in the hippocampus (HP) and prefrontal cortex (PFC), decreased total thiol content and glutathione peroxidase activity in the HP. C. pachystachya AE administration during CUS protocol was able to prevent the oxidative damage induced by stress. However, no changes were observed in the activity of the antioxidant enzymes superoxide dismutase and catalase in the above cited brain areas after the stress protocol and treatment. Our results suggest that C. pachystachya prevented both depressive behavior and oxidative damage induced by CUS, supporting its neuroprotective potential against behavioral and biochemical dysfunctions induced by chronic stress., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Bipolar disorder (BD) is a chronic and debilitating illness characterized by recurrent manic and depressive episodes. Our research investigates the protective effects of curcumin, the main curcuminoid of the Indian spice turmeric, in a model of mania induced by ketamine administration in rats. Our results indicated that ketamine treatment (25 mg/kg, for 8 days) induced hyperlocomotion in the open-field test and oxidative damage in prefrontal cortex (PFC) and hippocampus (HP), evaluated by increased lipid peroxidation and decreased total thiol content. Moreover, ketamine treatment reduced the activity of the antioxidant enzymes superoxide dismutase and catalase in the HP. Pretreatment of rats with curcumin (20 and 50 mg/kg, for 14 days) or with lithium chloride (45 mg/kg, positive control) prevented behavioral and pro-oxidant effects induced by ketamine. These findings suggest that curcumin might be a good compound for preventive intervention in BD, reducing the episode relapse and the oxidative damage associated with the manic phase of this disorder., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The present study aimed to determine whether any gender-related difference exists concerning oxidative stress parameters in a population of 231 subjects, and if these changes might be related to gender-associated differences in major depressive disorder (MDD) or bipolar disorder (BD) vulnerability. This is a case-control nested in a population-based study. The initial psychopathology screen was performed with the Mini-International Neuropsychiatric Interview and the diagnostic was further confirmed with the Structured Clinical Interview for DSM-IV. Blood samples were obtained after the interview and the oxidative stress parameters such as uric acid, advanced oxidation protein product (PCC) and lipid hydroperoxides (TBARS) were determined. Our results indicated a higher prevalence of MDD and BD in women when compared to men. In addition, significant gender differences were found in the levels of PCC (0.27±0.27 vs. 0.40±0.31nmol CO/mg protein, men vs. women, respectively; P=0.02) and uric acid (4.88±1.39mg/dL vs. 3.53±1.02mg/dL, men vs. women, respectively; P=0.0001), but not in TBARS (0.013±0.01nmol/mg of protein vs. 0.017±0.02nmol/mg of protein, men vs. women respectively; P=0.243). After sample stratification by gender, no association was found between oxidative stress parameters and clinical diagnosis of MDD and BD for women (P=0.516 for PCC; P=0.620 for TBARS P=0.727 for uric acid) and men (P=0.367 for PCC; P=0.372 for TBARS P=0.664 for uric acid). In this study, women seem more susceptible to oxidative stress than male. However, these gender-based differences do not seem to provide a biochemical basis for the epidemiologic differences in mood disorders susceptibility between sexes., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)