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Two inbred strains, Lewis (LEW) and Spontaneously Hypertensive Rats (SHR), are well-known for their contrasting behavior related to anxiety/emotionality. Studies with these two strains led to the discovery of the Quantitative Trait Loci (QTL) on chromosome 4 (Anxrr16). To better understand the influences of this genomic region, the congenic rat strain SLA16 (SHR.LEW-Anxrr16) was developed. SLA16 rats present higher hyperactivity/impulsivity, deficits in learning and memory, and lower basal blood pressure than the SHR strain, even though genetic differences between them are only in chromosome 4. Thus, the present study proposed the alpha-synuclein and the dopaminergic system as candidates to explain the differential behavior of SHR and SLA16 strains. To accomplish this, beyond the behavioral analysis, we performed (I) the Snca gene expression and (II) quantification of the alpha-synuclein protein in the hippocampus (HPC), prefrontal cortex (PFC), and striatum (STR) of SHR and SLA16 strains; (III) sequencing of the 3'UTR of the Snca gene; and (IV) evaluation of miRNA binding in the 3'UTR site. A Single Nucleotide Polymorphism (SNP) was identified in the 3'UTR of the Snca gene, which exhibited upregulation in the HPC of SHR compared to SLA16 females. Alpha-synuclein protein was higher in the HPC of SHR males compared to SLA16 males. The results of this work suggested that differences in alpha-synuclein HPC content could be influenced by miRNA regulation and associated with behavioral differences between SHR and SLA16 animals., Competing Interests: Declarations of interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Methylphenidate (MPH) is a central nervous system stimulant that is mainly used for Attention-Deficit/Hyperactivity Disorder (ADHD). It is well known that there is a high rate of ADHD misdiagnosis, leading to a great number of neurotypical children chronically exposed to MPH in early periods of life. This increase raises concern about possible long-lasting effects of this exposure. We aimed to evaluate whether exposure to MPH during childhood might impact adult behavioral pattern. For this purpose, we used zebrafish as a translational model considering its robustness as experimental model and fast life cycle. Fish were exposed during juvenile period (from 30 to 60 post-natal day) at MPH therapeutic concentration (2 mg L -1 ), and behavioral tests were performed at fish adulthood (120 post-natal day). MPH provoked slight anxiolytic-like effects and hyperlocomotion, and no differences on sociability and cortisol levels were observed. Moreover, sex did not affect any of the parameters evaluated. These results demonstrate that early chronic exposure to MPH leads to neurobehavioral adaptations that persist into adulthood in zebrafish regardless of sex, suggesting that the misuse of MPH during childhood and adolescence can alter neurobehavioral plasticity and these alterations might persist until adulthood., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The significant number of deaths and infection caused by the new coronavirus SARS-CoV-2 has created an urgent demand for effective and readily available drugs for the treatment of COVID-19. However, the requirements for biosafety level 3 (NB-3) laboratories for experiments with the virus has made it very challenging for such research to meet this demand. It is known that angiotensin-converting enzyme 2 (ACE2), located on the surface of host cells, serves as the viral receptor for the spike (S) protein of SARS-CoV-2. This protein is a tetramer subdivided into S1 and S2 regions, with the former containing the receptor-binding domain (RBD). Therefore, drugs that interfere with the interaction between the spike and the receptor (as well as accessory proteins) or suppress their expression could inhibit the entry and spread of SARS-CoV-2 between cells. In this context, we standardized the use of recombinant SARS-CoV-2 S1 Protein with hFc (human Fc) for the analysis of binding in VERO E6 cells by flow cytometry, aiming to provide a new tool for identifying drugs and neutralizing antibodies, thus eliminating the need for NB-3 laboratories. Because minocycline (MCL), nimesulide (NMS), and berberine (BBR) have effects related to the ACE2 receptor, inhibit inflammation, and do not suppress the adaptive immune response (crucial for patient recovery), we investigated whether these drugs prevent the absorption of the spike protein into the host cell. For this purpose, we used VERO E6 cells under control conditions, pre-treated with these drugs and exposed to recombinant SARS-CoV-2 S1 Protein with hFC. We found that an exposure time of 30 min and a concentration of 10 μg/mL of spike S1 caused a strong signal detected by flow cytometry, using the secondary anti-hFc antibody conjugated with Alexa Fluor 647. Pre-treatment of cells with BBR for 30 min suppressed the signal from spike-positive cells, suggesting that this alkaloid interferes with spike adsorption on ACE2. The pre-incubation of spike protein with BBR did not alter its adsorption and internalization, indicating that BBR does not directly interact with spike protein. The ACE2 inactivation with a specific antibody inhibited spike protein adsorption and internalization. Furthermore, the pharmacological treatments did not alter the expression of ACE2. Exposure to spike protein increased IFNγ levels and the treatments with MCL and NMS were effective in inhibiting this increase. Taken together, we standardized a technique for analyzing the adsorption of SARS-CoV-2 and studying molecules that inhibit this process. Additionally, we demonstrated that BBR blocks spike entry bypre-binding to the host cell,and that the ACE2 receptor inactivation prevents Spike protein adsorption and penetration into cells., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background: The effects of tobacco smoke on the central nervous system are usually studied with isolated nicotine, ignoring other compounds present in cigarette smoke. The few studies that use in vivo whole-body cigarette smoke exposure are usually performed in expensive commercial apparatus., New Method: We presented a feasible, safe, and low-cost apparatus for cigarette smoke exposure in rodents., Results: Rats exposed to cigarette smoke in this apparatus showed cotinine levels similar to human active smokers. Additional results showed that cigarette smoke exposure increased glutamate and aspartic acid levels and decreased leucine, isoleucine, ornithine, phenylalanine, and tryptophan levels in the cerebrospinal fluid of rats., Comparison With Existing Method(s): Our apparatus is feasible, safe, and costs 67-fold less than a commercial automatized smoking machine. Beyond the low cost, it does not require specialized knowledge for building or maintenance., Conclusions: We concluded that our low-cost apparatus is reliable and reproduces cigarette smoke use in humans., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Central sensitization (CS) is characteristic of difficult to treat painful conditions, such as fibromyalgia and neuropathies and have sexual dimorphism involved. The calcium influx in nociceptive neurons is a key trigger for CS and the role of Cav2.1 and Cav2.2 voltage gated calcium channels (VGCC) in this role were evidenced with the use of ω-agatoxin IVA and ω-agatoxin MVIIA blockers, respectively. However, the participation of the α1 subunit of the voltage-gated channel Cav2.3, which conducts R-type currents, in CS is unknown. Furthermore, the role of sexual differences in painful conditions is still poorly understood. Thus, we investigated the role of Cav2.3 in capsaicin-induced secondary hyperalgesia in mice, which serve as a CS model predictive of the efficacy of novel analgesic drugs. Capsaicin injection in C57BL/6 mice caused secondary hyperalgesia from one to five hours after injection, and the effects were similar in male and female mice. In female but not male mice, intrathecal treatment with the Cav2.3 inhibitor SNX-482 partially and briefly reversed secondary hyperalgesia at a dose (300 pmol/site) that did not cause adverse effects. Moreover, Cav2.3 expression in the dorsal root ganglia (DRG) and spinal cord was reduced by intrathecal treatment with an antisense oligonucleotide (ASO) targeting Cav2.3 in female and male mice. However, ASO treatment was able to provide a robust and durable prevention of secondary hyperalgesia caused by capsaicin in female mice, but not in male mice. Thus, our results demonstrate that Cav2.3 inhibition, especially in female mice, has a relevant impact on a model of CS. Our results provide a proof of concept for Cav2.3 as a molecular target. In addition, the result associated to the role of differences in painful conditions linked to sex opens a range of possibilities to be explored and needs more attention. Thus, the relevance of testing Cav2.3 inhibition or knockdown in clinically relevant pain models is needed., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Degeneration of striatal neurons and cortical atrophy are pathological characteristics of glutaric acidemia type I (GA-I), a disease characterized by accumulation of glutaric acid (GA). The mechanisms that lead to neuronal loss and cognitive impairment are still unclear. The purpose of this study was to verify if acute exposure to GA during the neonatal period is sufficient to trigger apoptotic processes and lead to learning delay in early and late period. Besides, whether N-acetylcysteine (NAC) would protect against impairment induced by GA. Pups mice received a dose of GA (2.5 μmol/ g) or saline, 12 hs after birth, and were treated with NAC (250 mg/kg) or saline, up to 21th day of life. Although GA exhibited deficits in the procedural and working memories in 21 and 40-day-old mice, NAC protected against cognitive impairment. In striatum and cortex, NAC prevented glial cells activation (GFAP and Iba-1), decreased NGF, Bcl-2 and NeuN, the increase of lipid peroxidation and PARP induced by GA in both ages. NAC protected against increased p75 NTR induced by GA, but not in cortex of 21-day-old mice. Thus, we showed that the integrity of striatal and cortical pathways has an important role for learning and suggested that sustained glial reactivity in neonatal period can be an initial trigger for delay of cognitive development. Furthermore, NAC protected against cognitive impairment induced by GA. This work shows that early identification of the alterations induced by GA is important to avoid future clinical complications and suggest that NAC could be an adjuvant treatment for this acidemia., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Early life is a critical period for the development of the central nervous system (CNS) when the brain undergoes functional organization, neuronal proliferation and migration. This study aimed to evaluate influences and possible interactions of the neonatal handling (NH) on morphologic, biochemical and molecular markers in the hippocampus, as well as on Mu opioid receptors (MOR) immunoreactivity when adolescent rats were exposed to morphine. On postnatal day (PND) 1, male pups were assigned to two experimental groups: unhandled (UH) or neonatal handling (NH), whose procedure was applied from PND2 to PND9. On PND 50, animals were submitted to memory behavioral test, anesthesia and euthanasia for blood collection and hippocampus removal. Animals exposed to NH showed: i) increased levels of proBDNF and brain-derived neurotrophic factor (BDNF); ii) increased memory performance; iii) decreased lipid peroxidation (LP) in plasma and hippocampus; iv) increased antioxidant defenses; v) increased glucocorticoids receptor (GR) levels. Interestingly, our data showed a positive correlation between BDNF and working memory after NH procedure (r 2  = 0.73; P = 0.006). Animals submitted to NH showed an increased per se of MOR immunoreactivity regardless of morphine exposure, while this increasing was also observed in the UH group after morphine exposure, even in a small extent. NH beneficial influence during early stage of life can be reflected during the development of the puppies, enhancing memory performance, preventing oxidative events and improving molecular targets in hippocampus. Further experimental studies in addition to clinical ones are needed to validate NH protocol as a therapeutic tool., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Interactions on neurotransmitter systems in the reward pathways may explain the high frequency of combined use of alcohol and cigarettes in humans. In this study, we evaluated some behavioral and neurochemical changes promoted by chronic exposure to alcohol and cigarette smoke in rats. Adult rats were administered with 2 g/kg alcohol (v.o.) or/and inhaled the smoke from 6 cigarettes, twice/day, for 30 days. Behavioral tests were performed 3 h after the alcohol administration and 1 h after the last exposure to cigarette smoke in the morning. Cerebrospinal fluid was collected for glutamate determination and the hippocampus was dissected for GABA A and NMDA receptor subunits mRNA expression determination. Results showed that the combined use of alcohol and cigarette smoke (ALTB) in rats increased the locomotor activity and all interventions decreased anxiety-like behaviors. Despite being on a short-term withdrawal, the cigarette smoke exposure decreased the percentage of open arm entries in the elevated plus maze test, which was prevented by combined use with alcohol. Even though GABA A and glutamate receptor subunits expression did not change in the hippocampus, glutamate levels were significantly higher in the cerebrospinal fluid from ALTB rats. Therefore, we showed that the combined use of alcohol and cigarette maintained a psychostimulant effect after a short-term withdrawal that was associated with the elevated glutamatergic activity. The combined use also prevented anxiety-like signs in cigarette smoke exposure rats, decreasing an adverse effect caused by nicotine withdrawal. These results could explain, in part, the elevated frequency of combined use of these two drugs of abuse in humans., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Prolonged activation of the hypothalamic-pituitary-adrenal (HPA) axis and sustained increase of glucocorticoids have been evidenced in major depression and are related to changes involving neurotrophins and markers of oxidative stress in response to inflammation. This study aimed to evaluate central measures of brain-derived neurotrophic factor (BDNF), oxidative damage and total antioxidant capacity in rats submitted to chronic unpredictable mild stress (CUMS), as well as to investigate the relationship between BDNF levels and differentially processes. For this purpose, male Wistar rats were submitted to CUMS for six weeks. Based on a sucrose preference test (SPT), the animals were divided into anhedonic or non-anhedonic clusters. Afterwards, forced swim test (FST) and open field test (OFT) were performed, and the animals were euthanized. Brain tissue was collected, followed by quantification of oxidative damage, total antioxidant capacity and BDNF levels. Anhedonic behavior was evidenced in stress-susceptible animals through decreased sucrose preference. No differences were found in FST or OFT results. We observed increased BDNF levels in the hippocampus (HPC) of animals exposed to the CUMS protocol, accompanied by decreased total antioxidant capacity, despite the absence of oxidative damage to lipids and proteins. Moreover, we used a bioinformatics approach to identify proteins involved in oxidative stress and inflammation pathways, which were differentially expressed in anhedonic animals from other studies with similar experimental protocol. expressed proteins (DEP) involved in oxidative stress and inflammatory biological Anhedonic behavior was associated with peroxiredoxin-1 (PRDX-1) up-regulation and down-regulation of proteins involved with apoptotic and inflammation signaling (RELA, ASK-1 and TAK-1) in the HPC. Taken together, these data suggest that BDNF and PRDX-1 might be involved in initial stress response, playing a compensatory role by preventing oxidative damage to lipids and proteins through the modulation of antioxidant defense after CUMS in anhedonic animals., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Haloperidol (Hal) is an antipsychotic related to movement disorders. Magnesium (Mg) showed benefits on orofacial dyskinesia (OD), suggesting its involvement with N-methyl-D-aspartate receptors (NMDAR) since it acts blocking calcium channels. Comparisons between nifedipine (NIF; a calcium channel blocker) and Mg were performed to establish the Mg mechanism. Male rats concomitantly received Hal and Mg or NIF for 28 days, and OD behaviors were weekly assessed. Both Mg and NIF decreased Hal-induced OD. Hal increased Ca 2+ -ATPase activity in the striatum, and Mg reversed it. In the cortex, both Mg and NIF decreased such activity. Dopaminergic and glutamatergic immunoreactivity were modified by Hal and treatments: i) in the cortex: Hal reduced D1R and D2R, increasing NMDAR immunoreactivity. Mg and NIF reversed this Hal influence on D1R and NMDAR, while only Mg reversed Hal effects on D2R levels; ii) in the striatum: Hal decreased D2R and increased NMDAR while Mg and NIF decreased D1R and reversed the Hal-induced decreasing D2R levels. Only Mg reversed the Hal-induced increasing NMDAR levels; iii) in the substantia nigra (SN): while Hal increased D1R, D2R, and NMDAR, both Mg and NIF reversed this influence on D2R, but only Mg reversed the Hal-influence on D1R levels. Only NIF reversed the Hal effects on NMDAR immunoreactivity. These findings allow us to propose that Mg may be useful to minimize Hal-induced movement disturbances. Mg molecular mechanism seems to be involved with a calcium channel blocker because the NIF group showed less expressive effects than the Mg group., (Copyright © 2019. Published by Elsevier B.V.)

The Spontaneously Hypertensive Rat (SHR) has been proposed as a good model to study the pathways related to neurodegenerative diseases and glucose intolerance. Our research group developed the SLA16 (SHR.LEW-Anxrr16) congenic strain, which is genetically identical to the SHR strain, except for a locus on chromosome 4 (DGR). We applied in silico analysis on DGR to evaluate the association of their genes with neurobiological and metabolic pathways. After, we characterized cholesterol, triglycerides, metabolism of glucose and the behavioral performance of young (2 months old) and adult (8 months old) SHR and SLA16 rats in the open field, object location and water maze tasks. Finally, naïve young rats were repeatedly treated with metformin (200 mg/kg; v.o.) and evaluated in the same tests. Bioinformatics analysis showed that DGR presents genes related to glucose metabolism, oxidative damage and neurodegenerative diseases. Young SLA16 presented higher cholesterol, triglycerides, glucose and locomotion in the open field than SHR rats. In adulthood, SLA16 rats presented high triglycerides and locomotion in the open field and impairment on spatial learning and memory. Finally, the treatment with metformin decreased the glucose tolerance curve and also improved long-term memory in SLA16 rats. These results indicate that DGR presents genes associated with metabolic pathways and neurobiological processes that may produce alterations in glucose metabolism and spatial learning/memory. Therefore, we suggest that SHR and SLA16 strains could be important for the study of genes and subsequent mechanisms that produce metabolic glucose alterations and age-related cognitive deficits., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Maltreatments in childhood may have implications for neurodevelopment that could remain throughout life. Childhood trauma seems to be associated with the onset of bipolar disorder (BD), and its occurrence might accentuate the overall disease impairments related to cognitive deficits in BD. We aimed to evaluate the effects of a history of childhood trauma to estimated intellectual functioning (IQ) of individuals with BD. We included 72 subjects with BD during euthymia. Participants underwent a clinical interview and were assessed through the Childhood Trauma Questionnaire (CTQ) and Wechsler Abbreviated Scale of Intelligence (WASI). Most prevalent trauma subtypes were emotional abuse and neglect (54.1%). A linear regression model that included perceived childhood trauma, family history of severe mental disorders, age at diagnosis and psychotic symptoms during the first episode as main factors showed that only childhood trauma had a significant effect in predicting estimated IQ. Therefore, the history of childhood trauma in individuals with BD may play a role in intellectual development, suggesting that adversities during development result in decreased general cognitive abilities. These results reinforce the need to promote early interventions to protect childhood and to promote the well-being of children, contributing to the growth of healthy adults., (Copyright © 2019 Elsevier B.V. All rights reserved.)

This study evaluated the in vivo anticonvulsant effect of a spray-dried powder for reconstitution containing phenytoin-loaded lipid-core nanocapsules. The effect of chitosan coating on redispersibility, gastrointestinal stability, and drug release from nanoparticles was evaluated during the development of the powders. Maltodextrin was used as adjuvant in the spray-drying process. Chitosan coating played an important role in redispersibility, and large particles (>100 μm) were obtained using the highest concentration of solids in the feed. However, after aqueous redispersion, volume-based particle size was reduced to about 1 µm. The release of nanoparticles from the surface of the spherical microagglomerates (roundness index = 0.75) was confirmed by SEM analysis. Powders reconstituted in water recovered partially the nanometric properties of the original suspensions and were stable for 24 h. Phenytoin-loaded chitosan-coated nanocapsules and their redispersed powders have good gastrointestinal stability, and are able to control drug release in simulated gastric and intestinal fluids. Besides that, the reconstituted powder containing chitosan-coated nanocapsules exhibited improved anticonvulsant activity against seizures induced by pilocarpine in mice, compared to the non-encapsulated drug, representing an important approach in anticonvulsant treatments for children and adults., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Studies with zebrafish use acclimatizing periods of at least one week immediately before the experiments. During this time, animals can be housed in sexually segregated conditions (only females or males in the tank) or in mixed-sex conditions (both sexes in the tank). The influence of sex and housing conditions regarding the presence of one or two sexes is largely unknown in zebrafish. Our aim was to evaluate the influence that sex and housing regarding the sex of animals had in the open tank task, in the inhibitory avoidance memory test, in cortisol levels and weight in zebrafish. Four groups of animals were used: 1) segregated housed females (only females were kept in the tank); 2) segregated housed males (only males were kept in the tank); 3) mixed-sex housed females (only females were analyzed from a tank containing 50% ratio of each sex); 4) mixed-sex housed males (only males were analyzed from a tank containing 50% ratio of each sex). Males showed higher total distance travelled and mean speed when compared to females. In the inhibitory avoidance memory, sexually segregated animals had higher latencies than their mixed-sex counterparts in the 1day test and sexually segregated females presented a memory that persisted longer and was able to be reinstated. Whole-body cortisol levels were higher in mixed-sex animals while weight was lower in these fish. To the best of our knowledge, this is the first time that effects of sex and housing regarding sex were investigated in behavior and physiology of zebrafish., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Preventing damage caused by nerve degeneration is a great challenge. There is a growing body of evidence implicating extracellular nucleotides and their P2 receptors in many pathophysiological mechanisms. In this work we aimed to investigate the effects of the administration of Brilliant Blue G (BBG) and Pyridoxalphosphate-6-azophenyl-2', 4'- disulphonic acid (PPADS), P2X7 and P2 non-selective receptor antagonists, respectively, on sciatic nerve regeneration. Four groups of mice that underwent nerve crush lesion were used: two control groups treated with vehicle (saline), a group treated with BBG and a group treated with PPADS during 28days. Gastrocnemius muscle weight was evaluated. For functional evaluation we used the Sciatic Functional Index (SFI) and the horizontal ladder walking test. Nerves, dorsal root ganglia and spinal cords were processed for light and electron microscopy. Antinoceptive effects of BBG and PPADS were evaluated through von Frey E, and the levels of IL-1β and TNF-α were analyzed by ELISA. BBG promoted an increase in the number of myelinated fibers and on axon, fiber and myelin areas. BBG and PPADS led to an increase of TNF-α and IL-1β in the nerve on day 1 and PPADS caused a decrease of IL-1β on day 7. Mechanical allodynia was reversed on day 7 in the groups treated with BBG and PPADS. We concluded that BBG promoted a better morphological regeneration after ischiatic crush injury, but this was not followed by anticipation of functional improvement. In addition, both PPADS and BBG presented anti-inflammatory as well as antinociceptive effects., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Chronic use of typical antipsychotic haloperidolis related to movement disturbances such as parkinsonism, akathisia and tardive dyskinesia which have been related to excitotoxicity in extrapyramidal brain areas, requiring their prevention and treatment. In the current study we evaluated the influence of the magnesium on prevention (for 28days before-), reversion (for 12days after-) and concomitant supplementation on haloperidol-induced movement disorders in rats. Sub-chronic haloperidol was related to orofacial dyskinesia (OD) and catalepsy development, increased generation of reactive species (RS) and levels of protein carbonyl (PC) in cortex, striatum and substantia nigra (SN) in all experimental protocols. When provided preventatively, Mg reduced the increase of OD and catalepsy time 14 and 7days after haloperidol administration, respectively. When supplemented after haloperidol-induced OD establishment, Mg reversed this behavior after 12days, while catalepsy was reversed after 6days of Mg supplementation.When Mg was concomitantly supplemented with haloperidol administration, OD and catalepsy were prevented. Moreover, Mg supplementation was able to prevent the RS generation in both cortex and SN, reducing PC levels in all brain areas evaluated. When supplemented after haloperidol, Mg reversed RS generation in cortex and striatum, decreasing PC levels in SN and striatum.The co-administration of haloperidol and Mg supplementation prevented RS generation in cortex, striatum and SN, and PC levels in the SN.These outcomes indicate that Mg supplementation may be a useful alternative to prevent movement disturbances resulting of classic antipsychotic pharmacotherapy as haloperidol., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Olfaction plays a key role in modulating behavioral and physiological responses of various animal species, including fishes. Olfactory deficits can be induced in fish experimentally, and utilized to examine the role of olfaction in their normal and pathological behaviors. Here, we examine whether experimental anosmia, evoked by ZnSO 4 in adult zebrafish can be associated with behavioral and/or physiological responses. We show that experimental ZnSO 4 -induced anosmia caused acute, but not prolonged, anxiogenic-like effects on zebrafish behavior tested in the novel tank test. The procedure also elevated whole-body cortisol levels in zebrafish. Moreover, ZnSO4 treatment, but not sham, produced damage to olfactory epithelium, inducing overt basal cell vacuolization and intercellular edema. The loss of olfaction, assessed by the fish food preference behavior in the aquatic Y-maze, was present 1h, but not 24h, after the treatment. Collectively, this suggests that transient experimental anosmia by ZnSO 4 modulates zebrafish behavior and olfaction, which can be used to evoke and assess their stress-related anxiety-like states., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Anxiety disorders are highly prevalent and often result in poor quality of life. Available anxiolytics show significant adverse effects as well as partial efficacy in a sizable part of patients. Innovative treatments with more favorable risk-benefit ratio are sorely needed. A growing body of clinical data indicates the benefits of N-acetylcysteine (NAC) in psychiatric conditions. NAC modulates antioxidant, glutamatergic, inflammatory and neurotrophic pathways in the central nervous system, all of which are relevant to anxiety pathology. We evaluated the effects of NAC in mice models commonly used to characterize anxiolytic compounds. Male adult CF1 or BALB/c mice were treated (i.p.) acutely or subacutely (4 consecutive days) with NAC (60-150mg/kg) 60min before open field, light/dark, hole-board, social interaction, elevated T-maze or stress-induced hyperthermia tests. Diazepam (2mg/kg) was used as positive control. We found that NAC presents anxiolytic effects in all models, except for the elevated T-maze. Subacute treatments resulted in lower effective doses in comparison to acute treatment. The anxiolytic effects of NAC were comparable to diazepam. NAC is a safe and low cost medicine with suggested benefits in psychiatric conditions often presenting co-morbidity with anxiety. This study contributes evidence to support the validity of clinical trials with NAC in the context of anxiety disorders, especially considering the safety profile in comparison to the limitations of diazepam for long term treatment., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Chronic unpredictable mild stress (CUMS) elicits aspects of cognitive and behavioral alterations that can be used to model comparable aspects of depression in humans. The aim of the present study was to investigate the antidepressant-like potential of 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI), a novel isoquinoline compound, in CUMS, a model that meets face, construct and predictive criteria for validity. Swiss mice were subjected to different stress paradigms daily for a period of 35 days to induce the depressive-like behavior. The animals received concomitant FDPI (0.1 and 1mg/kg, intragastric) or paroxetine (8mg/kg, intraperitoneal) and CUMS. The behavioral tests (splash test, tail suspension test, modified forced swimming test and locomotor activity) were performed. The levels of cytokines, corticosterone and adrenocorticotropic (ACTH) hormones were determined in the mouse prefrontal cortex and serum. The synaptosomal [(3)H] serotonin (5-HT) uptake, nuclear factor (NF)-κB, tyrosine kinase receptor (TrkB) and pro-brain-derived neurotrophic factor (BDNF) levels were determined in the mouse prefrontal cortex. CUMS induced a depressive-like behavior in mice, which was demonstrated in the modified forced swimming, tail suspension and splash tests. FDPI at both doses prevented depressive-like behavior induced by CUMS, without altering the locomotor activity of mice. FDPI at the highest dose prevented the increase in the levels of NF-kB, pro-inflammatory cytokines, corticosterone and ACTH and modulated [(3)H]5-HT uptake and the proBDNF/TrkB signaling pathway altered by CUMS. The present findings demonstrated that FDPI elicited an antidepressant-like effect in a model of stress-induced depression., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Experimental animal studies have shown that early life periods are highly vulnerable to environmental factors, which may exert prolonged impact on HPA axis function and on subsequent neurochemical and behavioral responses in adulthood. Here we evaluated the influence of environmental stressful situations in two different early life stages on stress-related behaviors, and morphine-conditioned place preference (CPP), which is indicative of addiction. While in the gestational stress (Gest-S) dams were exposed to daily sessions of chronic mild stress (CMS) for 2 weeks, in the postnatal stress (post-NS) the offspring were exposed daily to neonatal isolation from postnatal day (PND) 2 to PND 9 for 60 min. Animals exposed to post-NS showed lesser anxiety in different behavioral paradigms (elevated plus maze-EPM and defensive burying test-DBT) as well as increased exploratory behavior (open-field task-OFT), and no preference for morphine in CPP. In contrast, animals exposed to Gest-S showed increased corticosterone plasma levels together with anxiety symptoms and greater preference for morphine following three days of drug withdrawal. Our findings indicate that the gestational period is critical for stress, whose effects may be manifest throughout life. On the other hand, post-NS can trigger neuroadaptations able to overcome emotional consequences of early life. We hypothesized that Gest-S is able to modify responses to opioids along adulthood, which may facilitate development of addiction to these drugs., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Drug residue contamination in aquatic ecosystems has been studied extensively, but the behavioral effects exerted by the presence of these drugs are not well known. Here, we investigated the effects of acute stress on anxiety, memory, social interaction, and aggressiveness in zebrafish exposed to fluoxetine and diazepam at concentrations that disrupt the hypothalamic-pituitary-interrenal (HPI) axis. Stress increased the locomotor activity and time spent in the bottom area of the tank (novel tank). Fluoxetine and diazepam prevented these behaviors. We also observed that stress and fluoxetine and diazepam exposures decreased social interaction. Stress also increased aggressive behavior, which was not reversed by fluoxetine or diazepam. These data suggest that the presence of these drugs in aquatic ecosystems causes significant behavioral alterations in fish., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Exercise has been reported to attenuate rewarding symptoms related to addictive drugs mainly by affecting the brain neuroplasticity and neurotransmission. In this study, we investigated the influence of physical exercise on the behavioral and enzymatic status related to drug relapse in rats. Animals were primarily treated with amphetamine (AMPH; 4.0 mg/kg, i.p.) or vehicle (C; NaCl 0.9% solution) in the conditioned place preference (CPP) paradigm for 14 days. Half of each experimental group was then submitted to swimming sessions (60 min/day, 5 days/week) for 5 weeks. Animals were re-exposed to AMPH- or vehicle-CPP paradigm for another 3 days, in order to observe drug relapse and anxiety-like symptoms, which were observed 24h after AMPH reconditioning in CPP, and elevated plus maze (EPM), respectively, and brain biochemical evaluations were carried out subsequently. While AMPH was related to place preference and anxiety, indicating drug addiction and abstinence symptoms, respectively, physical activity was able to prevent relapse symptoms after AMPH reconditioning, as observed through consecutive decreased CPP and anxiety-like symptoms. In addition, AMPH exposure increased reactive species (RS) generation and protein carbonyl (PC) levels together with decreased activity of catalase- and Na(+)K(+)-ATPase in hippocampus. On the other hand, while all AMPH-induced effects were prevented by physical activity, there was a negative correlation between PC levels (r=0.65; p<0.003) and CAT activity, and a positive correlation between RS generation and PC levels (r=0.54; r=0.52, p<0.05) with AMPH-CPP after exercise. These results indicate that exercise has a clear beneficial influence on the prevention of psychostimulant drug relapse., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In this study we evaluated the influence of neonatal tactile stimulation (TS) on behavioral and biochemical effects related to a low dose of diazepam (DZP) in adult rats. Male pups of Wistar rats were handled (TS) daily from PND1 to PND21 for 10 min, while unhandled (UH) rats were not touched. In adulthood, half the animals of each group received a single administration of diazepam (0.25mg/kg body weight i.p.) or vehicle and then were submitted to behavioral and biochemical evaluations. In the TS group, DZP administration reduced anxiety-like symptoms in different behavioral paradigms (elevated plus maze, EPM; staircase and open-field and defensive burying) and increased exploratory behavior. These findings show that neonatal TS increased DZP pharmacological responses in adulthood compared to neonatally UH animals, as observed by reduced anxiety-like symptoms and lower levels of plasma cortisol. TS also changed plasma levels of antioxidant defenses such as vitamin C and glutathione peroxidase, whose increase may be involved in lower oxidative damages to proteins in cortex, subthalamic region and hippocampus of these animals. Here we are showing for the first time that neonatal TS is able to change responsiveness to benzodiazepine drugs in adulthood and provides better pharmacological responses in novel situations of stress., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The influence of trans fatty acids (FA) on development of orofacial dyskinesia (OD) and locomotor activity was evaluated. Rats were fed with diets enriched with 20% soybean oil (SO; n-6 FA), lard (L; saturated FA) or hydrogenated vegetable fat (HVF; trans FA) for 60 weeks. In the last 12 weeks each group was subdivided into sedentary and exercised (swimming). Brains of HVF and L-fed rats incorporated 0.33% and 0.20% of trans FA, respectively, while SO-fed group showed no incorporation of trans FA. HVF increased OD, while exercise exacerbated this in L and HVF-fed rats. HVF and L reduced locomotor activity, and exercise did not modify. Striatal catalase activity was reduced by L and HVF, but exercise increased its activity in the HVF-fed group. Na(+)K(+)-ATPase activity was not modified by dietary FA, however it was increased by exercise in striatum of SO and L-fed rats. We hypothesized that movement disorders elicited by HVF and less by L could be related to increased dopamine levels in striatum, which have been related to chronic trans FA intake. Exercise increased OD possibly by increase of brain dopamine levels, which generates pro-oxidant metabolites. Thus, a long-term intake of trans FA caused a small but significant brain incorporation of trans FA, which favored development of movement disorders. Exercise worsened behavioral outcomes of HVF and L-fed rats and increased Na(+)K(+)-ATPase activity of L and SO-fed rats, indicating its benefits. HVF blunted beneficial effects of exercise, indicating a critical role of trans FA in brain neurochemistry., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Acute reserpine and subchronic haloperidol are animal models of extrapyramidal disorders often used to study parkinsonism, akinesia and tardive dyskinesia. In humans, these usually irreversible and disabling extrapyramidal disorders are developed by typical antipsychotic treatment, whose pathophysiology has been related to oxidative damages development. So far, there is no treatment to prevent these problems of the psychiatric clinic, and therefore further studies are needed. Here we used the animal models of extrapyramidal disorders cited above, which were performed in two distinct experiments: orofacial dyskinesia (OD)/catalepsy induced by acute reserpine and subchronic haloperidol after (experiment 1) and before (experiment 2) oral treatment with pecan shell aqueous extract (AE), a natural and promissory antioxidant. When administered previously (exp.1), the AE prevented OD and catalepsy induced by both reserpine and haloperidol. When reserpine and haloperidol were administered before the extract (exp.2), the animals developed OD and catalepsy all the same. However, the orofacial parameter (but not catalepsy) in both animal models was reversed after 7 and 14 days of AE treatment. These results indicate that, acute reserpine and subchronic haloperidol administrations induced similar motor disorders, although through different mechanisms, and therefore are important animal models to study the physiopathology of extrapyramidal disorders. Comparatively, the pecan shell AE was able to both prevent and reverse OD but only to prevent catalepsy. These results reinforce the role of oxidative stress and validate the two animal models used here. Our findings also favor the idea of prevention of extrapyramidal disorders, rather than their reversal., (Copyright © 2011 Elsevier B.V. All rights reserved.)