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Schizophrenia pathophysiology is associated with hypofunction of glutamate NMDA receptors (NMDAR) in GABAergic interneurons and dopaminergic hyperactivation in subcortical brain areas. The administration of NMDAR antagonists is used as an animal model that replicates behavioral phenotypes relevant to the positive, negative, and cognitive symptoms of schizophrenia. Such models overwhelmingly rely on rodents, which may lead to species-specific biases and poor translatability. Zebrafish, however, is increasingly used as a model organism to study evolutionarily conserved aspects of behavior. We thus aimed to review and integrate the major findings reported in the zebrafish literature regarding the behavioral effects of NMDAR antagonists with relevance to schizophrenia. We identified 44 research articles that met our inclusion criteria from 590 studies retrieved from MEDLINE (PubMed) and Web of Science databases. Dizocilpine (MK-801) and ketamine were employed in 29 and 10 studies, respectively. The use of other NMDAR antagonists, such as phencyclidine (PCP), APV, memantine, and tiletamine, was described in 6 studies. Frequently reported findings are the social interaction and memory deficits induced by MK-801 and circling behavior induced by ketamine. However, mixed results were described for several locomotor and exploratory parameters in the novel tank and open tank tests. The present review integrates the most relevant results while discussing variation in experimental design and methodological procedures. We conclude that zebrafish is a suitable model organism to study drug-induced behavioral phenotypes relevant to schizophrenia. However, more studies are necessary to further characterize the major differences in behavior as compared to mammals.

Schizophrenia pathophysiology has been associated with dopaminergic hyperactivity, NMDA receptor hypofunction, and redox dysregulation. Most behavioral assays and animal models to study this condition were developed in rodents, leaving room for species-specific biases that could be avoided by cross-species approaches. As MK-801 and amphetamine are largely used in mice and rats to mimic schizophrenia features, this study aimed to compare the effects of these drugs in several zebrafish (Danio rerio) behavioral assays. Male and female adult zebrafish were exposed to MK-801 (1, 5, and 10 μM) or amphetamine (0.625, 2.5, and 10 mg/L) and observed in paradigms of locomotor activity and social behavior. Oxidative parameters were quantified in brain tissue. Our results demonstrate that MK-801 disrupted social interaction, an effect that resembles the negative symptoms of schizophrenia. It also altered locomotion in a context-dependent manner, with hyperactivity when fish were tested in the presence of social cues and hypoactivity when tested alone. On the other hand, exposure to amphetamine was devoid of effects on locomotion and social behavior, while it increased lipid peroxidation in the brain. Key outcomes induced by MK-801 in rodents, such as social interaction deficit and locomotor alterations, were replicated in zebrafish, corroborating previous studies and reinforcing the use of zebrafish to study schizophrenia-related endophenotypes. More studies are necessary to assess the predictive validity of preclinical paradigms with this species and ultimately optimize the screening of potential novel treatments.

Most preclinical behavioral assays use rodents as model animals, leaving room for species-specific biases that could be avoided by an expanded cross-species approach. In this context, zebrafish emerges as an alternative model organism to study neurobiological mechanisms of anxiety, preference, learning, and memory, as well as other phenotypes with relevance to neuropsychiatric disorders. In recent years, several zebrafish studies using different types of mazes have been published. However, the protocols and apparatuses' shapes and dimensions vary widely in the literature. This variation may puzzle researchers attempting to implement maze behavioral assays and challenges the reproducibility across institutions. This review aims to provide an overview of the behavioral paradigms assessed in different types of mazes in zebrafish reported in the last couple of decades. Also, this review aims to contribute to a better characterization of multi-behavioral assessment in zebrafish.

Epilepsy affects around 50 million people worldwide, and an important number of patients (30%) fail to respond to any available antiepileptic drug. Previous studies have shown that luteolin presents a promising potential as an anticonvulsant. On the other hand, different studies showed that luteolin does not promote anticonvulsant effects. Therefore, there is a lack of consensus about the use of luteolin for seizure control. Luteolin low bioavailability could be a limiting factor to obtain better results. Attractively, micronization technology has been applied to improve flavonoids bioavailability. Thus, the present study aimed to investigate the effects of luteolin on its raw form and micronized luteolin in a PTZ-induced seizure model in adult zebrafish (Danio rerio). Our results demonstrate that luteolin and micronized luteolin did not block PTZ-induced seizures in adult zebrafish. Also, luteolin and micronized luteolin did not provoke behavioral changes. Finally, our results show that 24 h after seizure occurrence, no changes were detected for p70S6Kb, interleukin 1β, and caspase-3 transcript levels. Altogether, we failed to observe an anticonvulsant potential of luteolin in adult zebrafish, even in its micronized form. However, we recommend new studies to investigate luteolin benefits in epilepsy.

2,4-Dichlorophenoxyacetic acid (2,4-D) is one of the most commonly used herbicides worldwide. While the effects of 2,4-D in target organisms are well known, its consequences in nontarget organisms are not fully explained. Therefore, the purpose of this study was to investigate the effects of the herbicide on mitochondrial energy metabolism, oxidative status, and exploratory behavior in adult zebrafish. Animal exposure to 2,4-D increased cytochrome c oxidase and catalase activities and reduced SOD/CAT ratio, moreover, increased the total distance traveled and the number of crossings. Finally, animals exposed to 2,4-D spent more time in the upper zone of the tank and traveled a long distance in the upper zone. Overall, our results indicate the 2,4-D can provoke disabling effects in nontarget organisms. The obtained data showed that exposure to 2,4-D at environmentally relevant concentrations alters mitochondrial metabolism and antioxidant status and disturbs the zebrafish innate behavior.

Zebrafish larvae have been widely used in neuroscience and drug research and development. In the larval stage, zebrafish present a broad behavioral repertoire and physiological responses similar to adults. Curcumin (CUR), a major component of Curcuma longa L. (Zingiberaceae), has demonstrated the ability to modulate several neurobiological processes relevant to mental disorders in animal models. However, the low bioavailability of this compound can compromise its in vivo biological potential. Interestingly, it has been shown that micronization can increase the biological effects of several compounds. Thus, in this study, we compared the effects of acute exposure for 30 minutes to the following solutions: water (control), 0.1% DMSO (vehicle), 1 μM CUR, or 1 μM micronized curcumin (MC) in zebrafish larvae 7 days post-fertilization (dpf). We analyzed locomotor activity (open tank test), anxiety (light/dark test), and avoidance behavior (aversive stimulus test). Moreover, we evaluated parameters of oxidative status (thiobarbituric acid reactive substances and non-protein thiols levels). MC increased the total distance traveled and absolute turn angle in the open tank test. There were no significant differences in the other behavioral or neurochemical outcomes. The increase in locomotion induced by MC may be associated with a stimulant effect on the central nervous system, which was evidenced by the micronization process.

Ochratoxin A (OTA) is a mycotoxin produced by species of filamentous fungi widely found as a contaminant in food and with high toxic potential. Studies have shown that this toxin cause kidney and liver damage, however, data on the effects of exposure to OTA on the central nervous system are still scarce. Zebrafish (Danio rerio) is a teleost often used in translational research due to its physiological, genetic, and behavioral homology with mammals, in addition to being useful as an environmental bioindicator. Thus, this study aimed to investigate the effects of exposure to OTA on behavioral and neurochemical parameters in adult zebrafish. The animals were treated with different doses of OTA (1.38, 2.77, and 5.53 mg/kg) and submitted to behavioral evaluations in the open tank and social interaction tests. Subsequently, they were euthanized, and the brains were used to assess markers associated with oxidative status. In the open tank test OTA induced changes in distance, absolute turn angle, mean speed, and time-freezing. However, no significant effects were observed in the social interaction test. Moreover, OTA also induced alterations in neurochemical parameters with changes in non-protein thiols (NPSH), glutathione peroxidase (GPx), glutathione-S-transferase (GST), and glutathione reductase (GR). This study showed that OTA can affect neurobiological aspects in zebrafish even at low doses.

Curcumin, a polyphenol extracted from the rhizome of Curcuma longa L. (Zingiberaceae), presents neuroprotective properties and can modulate neuronal pathways related to mental disorders. However, curcumin has low bioavailability, which can compromise its use. The micronization process can reduce the mean particle diameter and improve this compound’s bioavailability and therapeutic potential. In this study, we compared the behavioral (in the open tank test, OTT) and neurochemical (thiobarbituric acid reactive substances (TBARS) and non-protein thiols (NPSH) levels) effects of non-micronized curcumin (CUR, 10 mg/kg, i.p.) and micronized curcumin (MC, 10 mg/kg, i.p.) in adult zebrafish subjected to 90-minute acute restraint stress (ARS). ARS increased the time spent in the central area and the number of crossings and decreased the immobility time of the animals. These results suggest an increase in locomotor activity and a decrease in thigmotaxis behavior in the OTT. Furthermore, ARS also induced oxidative damage by increasing TBARS and decreasing NPSH levels. ARS-induced behavioral and biochemical effects were not blocked by any curcumin preparation. Therefore, we suppose that curcumin does not have anti-stress effects on the ARS in zebrafish.

Anxiety disorders are highly prevalent and a leading cause of disability worldwide. Their etiology is related to stress, an adaptive response of the organism to restore homeostasis, in which oxidative stress and glutamatergic hyperactivity are involved. N-Acetylcysteine (NAC) is a multitarget approved drug proved to be beneficial in the treatment of various mental disorders. Nevertheless, NAC has low membrane permeability and poor bioavailability and its limited delivery to the brain may explain inconsistencies in the literature. N-Acetylcysteine amide (AD4) is a synthetic derivative of NAC in which the carboxyl group was modified to an amide. The amidation of AD4 improved lipophilicity and blood-brain barrier permeability and enhanced its antioxidant properties. The purpose of this study was to investigate the effects of AD4 on behavioral and biochemical parameters in zebrafish anxiety models. Neither AD4 nor NAC induced effects on locomotion and anxiety-related parameters in the novel tank test. However, in the light/dark test, AD4 (0.001 mg/L) increased the time spent in the lit side in a concentration 100 times lower than NAC (0.1 mg/L). In the acute restraint stress protocol, NAC and AD4 (0.001 mg/L) showed anxiolytic properties without meaningful effects on oxidative status. The study suggests that AD4 has anxiolytic effects in zebrafish with higher potency than the parent compound. Additional studies are warranted to characterize the anxiolytic profile of AD4 and its potential in the management of anxiety disorders.

Objective: Anxiety disorders are highly prevalent and the efficacy of the available anxiolytic drugs is less than desired. Adverse effects also compromise patient quality of life and adherence to treatment. Accumulating evidence shows that the pathophysiology of anxiety and related disorders is multifactorial, involving oxidative stress, neuroinflammation, and glutamatergic dysfunction. The aim of this review was to evaluate data from animal studies and clinical trials showing the anxiolytic effects of agents whose mechanisms of action target these multiple domains. Methods: The PubMed database was searched for multitarget agents that had been evaluated in animal models of anxiety, as well as randomized double-blind placebo-controlled clinical trials of anxiety and/or anxiety related disorders. Results: The main multitarget agents that have shown consistent anxiolytic effects in various animal models of anxiety, as well in clinical trials, are agomelatine, N-acetylcysteine (NAC), and omega-3 fatty acids. Data from clinical trials are preliminary at best, but reveal good safety profiles and tolerance to adverse effects. Conclusion: Agomelatine, NAC and omega-3 fatty acids show beneficial effects in clinical conditions where mainstream treatments are ineffective. These three multitarget agents are considered promising candidates for innovative, effective, and better-tolerated anxiolytics.

Curcumin, a polyphenol extracted from the rhizome ofCurcuma longaL. (Zingiberaceae), is shown to have antioxidant, anti-inflammatory, neuroprotective, anxiolytic, and antidepressant properties in both preclinical and clinical studies. However, its low bioavailability is a limitation for its potential adoption as a therapeutic agent. The process of micronization can overcome this barrier by reducing the particle size and increasing the dissolution rate, potentially improving the bioavailability of the compounds of interest. In this study, we compared thein vitroantioxidant effects of curcumin (CUR) and micronized curcumin (MC) and studied their effects on behavioral and neurochemical parameters in zebrafish submitted to unpredictable chronic stress (UCS). MC (1 g/L) presented higher antioxidant activityin vitroas compared to CUR, as measured by iron-reducing antioxidant power (FRAP), 1,1-diphenyl-2-2-picyryl-hydrazyl radical removal (DPPH), and deoxyribose tests. UCS increased total distance traveled in the social interaction test (SI), while decreased crossings, time, and entries to the top area in the novel tank test (NTT). No effects of UCS were observed in the open tank test (OTT). The behavioral effects induced by UCS were not blocked by any curcumin preparation. UCS also decreased non-protein thiols (NPSH) levels, while increased glutathione reductase (GR) activity and thiobarbituric acid reactive substances (TBARS) levels on zebrafish brain. MC presented superior antioxidant properties than CURin vivo, blocking the stress-induced neurochemical effects. Although this study did not measure the concentration of curcumin on the zebrafish brain, our results suggest that micronization increases the bioavailability of curcumin, potentiating its antioxidant activity bothin vitroandin vivo. Our study also demonstrates that counteracting the oxidative imbalance induced by UCS is not sufficient to block its behavioral effects.

Stress-related disorders are extremely harmful and cause significant impacts on the individual and society. Despite the limited evidence regarding glucagon-like peptide-1 receptor (GLP-1R) and mental disorders, a few clinical and preclinical studies suggest that modulating this system could improve symptoms of stress-related disorders. This study aimed to investigate the effects of liraglutide, a GLP-1R agonist, on neurobehavioral phenotypes and brain oxidative status in adult zebrafish. Acute liraglutide promoted anxiolytic-like effects in the light/dark test, while chronic treatment blocked the impact of unpredictable chronic stress on behavioral and physiological parameters. Taken together, our study demonstrates that liraglutide is active on zebrafish brain and may counteract some of the effects induced by stress. More studies are warranted to further elucidate the potential of GLP-1R agonists for the management of brain disorders.

Background and PurposeSchizophrenia pathophysiology has been associated with dopaminergic hyperactivity, loss of parvalbumin-positive GABAergic interneurons, NMDA receptor hypofunction, and redox dysregulation. Most behavioral assays and animal models to study this condition were developed in rodents, leaving room for species-specific biases that could be avoided by cross-species approaches. As MK-801 and amphetamine are largely used in mice and rats to mimic schizophrenia features, this study aimed to investigate the effects of these drugs in zebrafish.Experimental ApproachAdult zebrafish were exposed to MK-801 (1, 5, and 10 μM) or amphetamine (0.625, 2.5, and 10 mg·L-1) and observed in paradigms of locomotor activity and social behavior. Oxidative parameters relevant to schizophrenia were quantified in brain tissue.Key ResultsMK-801 disrupted social interaction, an effect that resembles the negative symptoms of schizophrenia. It also altered locomotion in a context-dependent manner, with hyperactivity when fish were tested in the presence of social cues and hypoactivity when tested alone. On the other hand, exposure to amphetamine was devoid of effects on locomotion and social behavior, while increased lipid peroxidation in the brain.Conclusion and ImplicationsKey outcomes induced by MK-801 in rodents were replicated in zebrafish, which suggests this species is suitable as an alternative model animal to study psychotic disorders. More studies are necessary to further develop preclinical paradigms with this species and ultimately optimize the screening of potential novel treatments.

The N-Acetylcysteine (NAC) is a thiol compound with a strong antioxidant effect and demonstrated preventive action as protector in chronic kidney disease, cancer, pulmonary insufficiency, in the treatment of AIDS and other systemic diseases. Experimental phase equilibrium data provide fundamental information for the micronization supercritical fluid SEDS technique, which is characterized by the reduction of the average particle size leads to changes in physical structure of the compounds processed. There are numerous advantages in particle size reduction and make narrower particle size distribution, the main one being the resulting increased bioavailability. Therefore, the aim of this work was to study the high pressure phase behavior of the ternary system {carbon dioxide (1) + dichloromethane (2) + acetone (3)} and for the quaternary system {carbon dioxide (1) + dichloromethane (2) + acetone (3) + NAC (4)} in order to assist the micronization process in supercritical media. The experiments were performed using a variable volume cell over the temperature range from 308 to 328 K, pressure from 4.7 to 9.87 MPa, and mass ratio dichlorometane/acetone of 1.5:1 for the ternary system. For the quaternary system, the same mass ratio of dichlorometane/acetone was adopted and an amount of 0.001 and 0.004 g cm−3 of NAC was added to solution. Phase transitions of vapor-liquid type (bubble or dew points), in the presence or absence of solid phase were observed. The experimental results of the ternary system were modeled using the Peng-Robinson (PR) equation of state with the Wong-Sandler (PR-WS) mixing rule, providing a good representation of the experimental phase equilibrium data.

O objetivo desse estudo foi conhecer a dinâmica do consumo de substâncias psicoativas entre acadêmicos de diferentes cursos numa universidade do sul do Brasil. Trata-se de um estudo quantitativo, realizado com acadêmicos dos cursos de medicina, direito e engenharia civil, por meio de um questionário estruturado. Dentre os acadêmicos, 39,3% já usaram, ao menos uma vez na vida, substâncias psicoativas. As substâncias mais utilizadas foram os tranquilizantes e ansiolíticos (20%). Não se obteve uma evidencia estatística quanto o aumento do consumo de substâncias psicoativas ao longo dos anos dos cursos. Conhecer a dinâmica do uso de substâncias psicoativas entre universitários é importante para o planejamento de políticas preventivas que estabeleçam estratégias para a redução e controle dessa realidade no âmbito das universidades brasileiras. The aim of this study was to examine the dynamics of consumption of psychoactive substances among students of different courses at a university in southern Brazil. This is a quantitative study was conducted with academic courses in medicine, law and engineering through a structured questionnaire. Among academics, 39.3% had used at least once in their life. The most commonly used substances are tranquilizers and anxiolytics (20%). No statistical evidence was obtained as increased consumption of psychoactive substances over the years of the courses. Knowing the dynamics of psychoactive substance use among college students is important for planning policies that establish preventive strategies to reduce and control this reality within the universities.

The micronization process is characterized by the reduction of particle size towards obtaining changes in physical structure and increase the dissolution rate, which leads to increased solubility of the compound and consequently greater bioavailability. Trans-resveratrol is a nutraceutical compound with many biological properties; however, its use in the food, pharmaceutical and chemical industry is limited because of its low solubility in aqueous medium and hence low bioavailability. Due to the large potential of resveratrol, this work aims to investigate the properties of dissolution rate, solubility and in vitro antioxidant activity of micronized resveratrol by SEDS technique. The micronized compound increased by around 2.8 times its solubility in water while there was an increase in the dissolution rate of about 1.8 times. Results obtained in this work are promising as it enables the use of resveratrol in the food, pharmaceutical and chemical industry since the micronization process led to improved properties of the compound.

The micronization techniques by supercritical fluid have been gaining more prominence especially in the pharmaceutical area. N-acetylcysteine (NAC) is a mucolytic which has emerged as a promising molecule for the treatment of neuropsychiatric disorders. This work aims to study the micronization process of NAC by the anti-solvent SEDS technique, and to evaluate both in vitro and in vivo improvements in the properties of this compound. Herein we demonstrate that the micronization process led to a 245-fold reduction in particle size. In vitro tests showed an increase in dissolution rate, in antioxidant activity and beyond modification of the crystalline structure. In the in vivo tests, it was observed that the micronization process decreased the minimum effective concentration of NAC that induced anxiolytic-like effects in zebrafish. Micronization may thus increase bioavailability and potentiate the therapeutic effect of drugs, opening new horizons in the area of supercritical fluid micronization in the pharmaceutical industry.

The glucocorticoid cortisol, the end product of hypothalamus-pituitary-interrenal axis in zebrafish (Danio rerio), is synthesized via steroidogenesis and promotes important physiological regulations in response to a stressor. The failure of this axis leads to inability to cope with environmental challenges preventing adaptive processes in order to restore homeostasis. Pesticides and agrichemicals are widely used, and may constitute an important class of environmental pollutants when reach aquatic ecosystems and nontarget species. These chemical compounds may disrupt hypothalamus-pituitary-interrenal axis by altering synthesis, structure or function of its constituents. We present evidence that organophosphorus exposure disrupts stress response by altering the expression of key genes of the neural steroidogenesis, causing downregulation of star, hsp70, and pomc genes. This appears to be mediated via muscarinic receptors, since the muscarinic antagonist scopolamine blocked these effects.

Background Applying cross-species approaches in animal preclinical studies of psychiatric disorders can minimize the overinterpretations often generated using specific strains or species in animal models of human conditions. Zebrafish is a model organism widely used in neuroscience research as an alternative to rodents, but protocols relevant to the symptoms and neurobiology of schizophrenia have not been fully established and validated in this species. MK-801, an NMDA receptor antagonist, is frequently used to recapitulate schizophrenia symptoms in rodent models. We thus aimed to evaluate the effects of a concentration curve of MK-801 on locomotor activity, social interaction, and neurochemical parameters related to oxidative stress in adult zebrafish. Methods Wild-type male and female zebrafish (50:50 ratio) were randomly allocated to 4 groups: control; 1 µM MK-801; 5 µM MK-801 or 10 µM MK-801 (n = 12). In the locomotor activity test animals were individually and sequentially placed in (1) a beaker with 200 mL of water for 20 min, (2) test aquarium for 30 min to assess basal locomotor activity, (3) beaker with water or MK-801 at the different concentrations for 20 min, and (4) test aquarium for 60 min. Locomotor and exploratory parameters (total distance traveled and upper zone time) were automatically analyzed using ANY-Maze software. In the social interaction test animals were individually exposed to water or MK-801 for 20 min and then placed for 7 min in a tank flanked by two identical tanks either empty or containing 10 zebrafish serving as social stimuli. Distance traveled was automatically tracked while social interaction time was manually and blindly scored using Boris software; only the last 5 minutes were analyzed. Oxidative damage in the brain was assessed by the levels of thiobarbituric acid reactive substances (TBARS). Data were analyzed by ANOVA followed by Tukey post hoc test. Results Exposure to 5 µM MK-801 decreased the total distance traveled in the locomotor activity test. In the social interaction test, exposure to 5 and 10 µM MK-801 significantly increased the total distance traveled while reduced the time of social interaction with the stimulus animals. No differences in TBARS levels were found between the groups. Discussion Unlike what is observed in rodents after MK-801 administration, zebrafish did not show hyperlocomotion at the concentrations tested. Other studies point to the context-dependent effect of this drug, as an increase in locomotor activity is only observed when animals are tested in a novel environment. In the social interaction test, on the other hand, animals were tested in a novel context with social stimulus and zebrafish exhibited hyperlocomotion and decreased social interaction, similar to what is observed in rodents. In contrast to chronic animal models and patients with schizophrenia, there were no differences in TBARS levels after acute exposure to MK-801. These preliminary results reinforce that zebrafish is an alternative model organism useful to the study of psychotic disorders. More behavioral and biochemical tests are needed to achieve reproducible tests and models to study multiple schizophrenia domains in zebrafish.

Background Cognitive and negative symptoms are the core reason for the functional deficits experienced by patients with schizophrenia. Drugs that can modulate these symptoms are especially needed since no progress has been achieved in the last few decades with currently available antipsychotics. Taurine is an amino acid not used for protein synthesis but widely distributed in mammalian tissues. In the central nervous system, it has been shown to act as an inhibitory neuromodulator and possess neuroprotective, antioxidant and immunomodulatory properties. Decreased plasma and brain levels of taurine have been reported in patients as well as in animal models of schizophrenia. Furthermore, taurine improved symptoms and was well tolerated in a clinical trial of patients with first-episode psychosis. We investigated whether taurine counteracts social deficits in a zebrafish model of social interaction following acute exposure to MK-801 (dizocilpine), an NDMA antagonist commonly used in schizophrenia animal models. Methods Ninety-six 3-month-old wild-type zebrafish (Danio rerio, 50:50 male:female ratio) were used. For the social interaction test, animals were individually placed in a beaker with 200 mL of tank water (control) or taurine solution (42, 150 and 400 mg/L) for 20 minutes, and then exposed to water or MK-801 (5 µM) for another 20 minutes (n = 12 animals per group). Immediately after the treatments, zebrafish were transferred to the social interaction apparatus, a tank virtually divided in 3 vertical zones and sided by an empty tank and a tank containing 10 zebrafish. Behavior was recorded for 7 minutes and the last 5 were analyzed by automated tracking with the software ANY-Maze. The time spent in the stimulus zone was measured as a proxy for social interaction; total distance traveled was also computed. Data were analyzed by two-way ANOVA. Results MK-801 increased the total distance traveled (F1,88 = 4.935, p = 0.0289) and reduced the time spent in the tank zone next to the conspecifics (F1,88 = 23.14, p < 0.0001). No main effects of taurine or interaction effects were observed on locomotor or social interaction parameters. Discussion Although taurine has been shown to increase social interaction in rats and modulate shoaling behavior in ethanol-exposed zebrafish, it had not been tested against social deficits induced by NMDA antagonists. We observed that taurine did not counteract the hyperlocomotion and social deficit induced by acute exposure to MK-801 in zebrafish. As schizophrenia etiology has been linked to cortical and hippocampal disruption in GABAergic signaling, taurine may be effective as a preventive treatment in early neurodevelopmental stages. Further testing using animal models that more closely resemble the course of schizophrenia are thus needed to investigate the potential of this molecule.

Acute and chronic stressors are common triggers of human mental illnesses. Experimental animal models and their cross-species translation to humans are critical for understanding of the pathogenesis of stress-related psychiatric disorders. Mounting evidence suggests that both pharmacological and non-pharmacological approaches can be efficient in treating these disorders. Here, we analyze human, rodent and zebrafish (Danio rerio) data to compare the impact of non-pharmacological and pharmacological therapies of stress-related psychopathologies. Emphasizing the likely synergism and interplay between pharmacological and environmental factors in mitigating daily stress both clinically and in experimental models, we argue that environmental enrichment emerges as a promising complementary therapy for stress-induced disorders across taxa. We also call for a broader use of novel model organisms, such as zebrafish, to study such treatments and their potential interplay.

Pesticide commercial mixtures, including the insecticide fipronil and the fungicides pyraclostrobin and methyl-thiophanate, have been used in concomitant pest control, facilitating agricultural management. Their widespread use can lead to soil and water contamination and potentially induce damages in the ecosystem, producing toxic effects in non-target organisms. Despite their toxicological potential, their effects on behavioral and biochemical parameters are not well understood. Here we investigated the effects of the mixture of fipronil and fungicides (MFF) pyraclostrobin and methyl- thiophanate on behavioral and biochemical parameters of oxidative stress in adult zebrafish. Animals exposed to the highest MFF tested concentration showed a decrease in the total distance traveled and in the number of crossings in the different zones of the tank. Furthermore, animals exposed to highest MFF tested concentration spent more time in water surface. In addition, our data showed that the exposure to this preparation promoted a decrease in non-protein thiol content as well as in catalase activity. Finally, pesticide exposure induced an increase in the superoxide dismutase/catalase ratio. Our results indicate that alterations in behavioral and oxidative parameters are involved in MFF toxicity in zebrafish. The antioxidant mechanisms analyzed were altered in concentrations that did not affect zebrafish behavior. Therefore, the assessment of oxidative stress parameters in zebrafish brains could be very useful to detect the early effects of environmental exposure to the MFF.

Preclinical evidence on the role of glucagon-like peptide-1 receptor (GLP-1r) agonists in the brain led to an increased interest in repurposing these compounds as a therapy for central nervous system (CNS) disorders and associated comorbidities. We aimed to investigate the neuroprotective effects of acute treatment with exendin (EX)-4, a GLP-1r agonist, in an animal model of inflammation. We evaluated the effect of different doses of EX-4 on inflammatory, neurotrophic, and oxidative stress parameters in the hippocampus and serum of lipopolysaccharide (LPS)-injected animals. Male Wistar rats were injected with LPS (0.25 mg/kg i.p.) and treated with different doses of EX-4 (0.1, 0.3, or 0.5 μg/kg i.p.). Sickness behavior was assessed by locomotor activity and body weight, and depressive-like behavior was also evaluated using forced swim test (FST). Brain-derived neurotrophic factor (BDNF), thiobarbituric acid reactive species (TBARS), and interleukin (IL)-6 were quantified in the serum and hippocampus. Glycemia was also analyzed pre- and post-EX-4 treatment. LPS groups exhibited decreased frequency of crossing and reduced body weight (p 0.001), while alterations on FST were not observed. The higher dose of EX-4 reduced IL-6 in the hippocampus of LPS-injected animals (p = 0.018), and EX-4 per se reduced TBARS serum levels with a modest antioxidant effect in the LPS groups (p ≤ 0.005). BDNF hippocampal levels seemed to be increased in the LPS+EX-4 0.5 group compared with LPS+Saline (p 0.05). Our study provides evidence on acute anti-inflammatory effects of EX-4 in the hippocampus of rats injected with LPS, contributing to future studies on repurposing compounds with potential neuroprotective properties.

The use of pesticides has been growing along with the demand for agricultural products. These compounds, however, are not restricted to the field, spreading easily through the soil, contaminating groundwater and reaching urban centers. Propiconazole is a triazole fungicide that has been increasingly used in agriculture. However, there are few data about its effects on non-target organisms. This study aimed to evaluate the effects of propiconazole in zebrafish. The animals were exposed for 96 h to different concentrations of propiconazole (425, 850, 1700, 8500 ng/L), then submitted to the novel tank test for behavioral analyses. The brains were collected for evaluation of oxidative stress parameters. Exposure to propiconazole (1700 and 8500 ng/L) decreased the number of crossings, entries, and time spent in the top, and increased the time spent in the bottom area of the tank. We also observed an increase in the activities of superoxide dismutase and catalase in zebrafish brain exposed to propiconazole at 425, 850, and 1700 ng/L. We conclude that propiconazole alters normal fish behavior and disrupts oxidative status. More studies are necessary to elucidate the exact mechanism underlying the effects of propiconazole on non-target-organisms.

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.

Trans-resveratrol is a polyphenol found in a variety of foods, especially in blackberries, grape seeds, grape skin and in red wine. This compound presents countless human health benefits, including antioxidant, antiplaquetary, antifungal, anti-inflammatory and cardioprotective activities, among others. The aim of this work was to investigate the application of SEDS (Solution Enhanced Dispersion by Supercritical Fluids) technique in the micronization of trans-resveratrol using a 23 Central Composite Design (CCD) with 3 central points so as to assess the influence of compound concentration (4, 12 and 20 mg mL−1), temperature (308, 313 and 318 K) and pressure (8, 10 and 12 MPa) on the particle size (Dp) produced. It was noted that the mean particle size obtained at 20 mg mL−1 resveratrol concentration, 8 MPa and 308 K was 0.22 μm, a significant reduction compared with the original value of 36.65 μm. In the majority/in most of the experiments spherical particles were obtained. At 95% confidence level temperature showed a positive effect while operating pressure and the interaction pressure × temperature showed a significant, negative effect, on the particle size. Analysis of micronized material proved that it is in compliance with pharmaceutical human consumption standards.

Several model organisms have been employed to study the impacts of stress on biological systems. Different models of unpredictable chronic stress (UCS) have been established in rodents; however, these protocols are expensive, long-lasting, and require a large physical structure. Our group has recently reported an UCS protocol in zebrafish with several advantages compared to rodent models. We observed that UCS induced behavioral, biochemical, and molecular changes similar to those observed in depressed patients, supporting the translational relevance of the protocol. Considering that a pharmacological assessment is lacking in this zebrafish model, our aim was to evaluate the effects of anxiolytic (bromazepam) and antidepressant drugs (fluoxetine and nortriptyline) on behavioral (novel tank test), biochemical (whole-body cortisol), and molecular parameters (cox-2, tnf-α, il-6, and il-10 gene expression) in zebrafish subjected to UCS. We replicated previous data showing that UCS induces behavioral and neuroendocrine alterations in zebrafish, and we show for the first time that anxiolytic and antidepressant drugs are able to prevent such effects. Furthermore, we extended the molecular characterization of the model, revealing that UCS increases expression of the pro-inflammatory markers cox-2 and il-6, which was also prevented by the drugs tested. This study reinforces the use of zebrafish as a model organism to study the behavioral and physiological effects of stress. The UCS protocol may also serve as a screening tool for evaluating new drugs that can be used to treat psychiatric disorders with stress-related etiologies.

Alcohol abuse is a highly prevalent condition that substantially contributes to global morbidity and mortality. Most available pharmacological treatments offer little efficacy as relapse rates are high, due in part to the symptoms experienced during abstinence. The roles of oxidative stress and glutamatergic transmission in alcohol withdrawal have been demonstrated in several studies, suggesting that restoration of oxidative status and glutamatergic function may represent a new pharmacological target to prevent the behavioral and biochemical alterations observed during withdrawal. A well-known antioxidant and glutamatergic modulator, N-acetylcysteine (NAC), has shown promise in treating a variety of psychiatric conditions, including substance use disorders, and is a promising molecule in the management of alcohol withdrawal syndrome. Thus, the aim of this study was to investigate whether NAC is able to prevent the expression of behavioral and biochemical alterations induced by ethanol withdrawal in chronically exposed zebrafish. Animals were exposed to ethanol (1% v/v, 20 min) or control water, followed by treatment with NAC (1 mg/L, 10 min) or control water daily for 8 days; 24 h later, experimental animals were submitted to the novel tank test (NTT). Ethanol withdrawal decreased the distance traveled and increased the number of immobile episodes, indicating locomotor deficits; moreover, withdrawal decreased the number of entries and time spent in the top area, while increasing time spent in the bottom area, indicating anxiety-like behavior. Alcohol withdrawal also increased lipid peroxidation (TBARS) and decreased non-protein reduced sulfhydryl (NPSH) and superoxide dismutase (SOD) and catalase (CAT) activities. NAC attenuated these locomotor deficits and prevented the manifestation of anxiety-like behavior as well as the oxidative damage observed following ethanol withdrawal. Given its favorable safety profile, additional clinical and preclinical studies are warranted to unravel the long-term effects of NAC in the context of alcohol abuse and the exact mechanisms involved. Nevertheless, our study adds to the existing body of evidence supporting the clinical evaluation of NAC in substance abuse disorders.

Here we show that the novel object recognition test can discriminate between high (HRN, neophobic) and low (LRN, neophilic) novelty responders in zebrafish populations. Especially when we observe the latency to the first entry in the novel object zone, zebrafish did not maintain these behavioral phenotypes in sequential tests and only the HRN group returned to their initial responsive behavior when exposed to fluoxetine. Our results have important implications for behavioral data analysis since such behavioral differences can potentially increase individual response variability and interfere with the outcomes obtained from various behavioral tasks. Our data reinforce the validity of personality determination in zebrafish since we show clear differences in behavior in response to fluoxetine.

Made available in DSpace on 2018-11-26T17:54:45Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-08-03 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Here we show that the feeding regimen modulates zebrafish (panic) rerio) behavior. With regard to the time elapsed between feeding and behavioral evaluation, fish fed 3 h before behavioral evaluation in the novel tank test (NTT) showed decreased activity and a trend toward an an)dolytic reaction (increased use of the upper section of the aquarium) in comparison to fish fed 0.5, 6, 12, 24 or 48 h before. testing, although fferences were not statistically,significant for all comparisons.Activity and use of the upper section of the aquarium did not differ significantly among the other treatments. Regarding feeding frequency, fish fed once a day showed higher anxiety-like behavior (decreased use of the upper section of the aquarium) in comparison to fish fed twice a day but feeding four or six times Per day or only every second day did not result in differences from feeding twice a day. Feeding frequency had no effect on activity level. Metabolically, fish fed once a day presented decreased levels of glucose and glycogen and increased lactate when compared to the regular feeding (fish fed twice a day),suggesting that feeding regimen may modulate carbohydrate metabolism. Mechanistically we suggest that the metabolic changes caused by the feeding regimen may induce behavioral changes. Our results suggest that the high variability of the results among different laboratories might be related to different feeding protocols. Therefore, if issues pertaining to the feeding regimen are not considered during experiments with zebrafish, erroneous interpretations of atasets may occur. Univ Passo Fundo, Programa Posgrad Bioexpt, Passo Fundo, RS, Brazil Univ Fed Santa Maria, Programa Posgrad Farmacol, Santa Maria, RS, Brazil Univ Passo Fundo, Fac Agron & Med Vet, Passo Fundo, Brazil UniSociesc, Curso Med Vet, Blumenau, Brazil Univ Passo Fundo, Programa Posgrad Ciencias Ambientais, Passo Fundo, RS, Brazil Unilasalle, Programa Posgrad Avaliacao Impactos Ambientais Mi, Canoas, Brazil UNESP, CAUNESP, Dept Fisiol, Inst Biociencias, Botucatu, SP, Brazil Univ Fed Rio Grande do Sul, Programa Posgrad Farmacol & Terapeut, Porto Alegre, RS, Brazil UNESP, CAUNESP, Dept Fisiol, Inst Biociencias, Botucatu, SP, Brazil CNPq: 301992/2014-2

BackgroundParkinson’s disease (PD) is the second most common neurodegenerative disorder. In addition to its highly debilitating motor symptoms, non-motor symptoms may precede their motor counterparts by many years, which may characterize a prodromal phase of PD. A potential pharmacological strategy is to introduce neuroprotective agents at an earlier stage in order to prevent further neuronal death.N-acetylcysteine (NAC) has been used against paracetamol overdose hepatotoxicity by restoring hepatic concentrations of glutathione (GSH), and as a mucolytic in chronic obstructive pulmonary disease by reducing disulfide bonds in mucoproteins. It has been shown to be safe for humans at high doses. More recently, several studies have evidenced that NAC has a multifaceted mechanism of action, presenting indirect antioxidant effect by acting as a GSH precursor, besides its anti-inflammatory and neurotrophic effects. Moreover, NAC modulates glutamate release through activation of the cystine-glutamate antiporter in extra-synaptic astrocytes. Its therapeutic benefits have been demonstrated in clinical trials for several neuropsychiatric conditions but has not been tested in PD models yet.MethodsIn this study, we evaluated the potential of NAC to prevent the damage induced by 6-hydroxydopamine (6-OHDA) on motor, optomotor and morphological parameters in a PD model in larval zebrafish.ResultsNAC was able to prevent the motor deficits (total distance, mean speed, maximum acceleration, absolute turn angle and immobility time), optomotor response impairment and morphological alterations (total length and head length) caused by exposure to 6-OHDA, which reinforce and broaden the relevance of its neuroprotective effects.DiscussionNAC acts in different targets relevant to PD pathophysiology. Further studies and clinical trials are needed to assess this agent as a candidate for prevention and adjunctive treatment of PD.

Fish production ponds and natural water body areas located in close proximity to agricultural fields receive water with variable amounts of agrochemicals, and consequently, compounds that produce adverse effects may reach nontarget organisms. The aim of this study was to investigate whether waterborne methyl-parathion-based insecticide (MPBI) affected gene expression patterns of brain glucocorticoid receptor (GR), steroidogenic acute regulatory protein (StAR), and heat shock protein 70 (hsp70) in adult zebrafish (Danio rerio) exposed to this chemical for 96 h. Treated fish exposed to MPBI-contaminated water showed an inhibition of brain StAR and hsp70 gene expression. Data demonstrated that MPBI produced a decrease brain StAR and hsp70 gene expression.

Despite the recent advances in understanding the pathophysiology of anxiety disorders, the pharmacological treatments currently available are limited in efficacy and induce serious side effects. A possible strategy to achieve clinical benefits is drug repurposing, i.e., discovery of novel applications for old drugs, bringing new treatment options to the market and to the patients who need them. N-acetylcysteine (NAC), a commonly used mucolytic and paracetamol antidote, has emerged as a promising molecule for the treatment of several neuropsychiatric disorders. The mechanism of action of this drug is complex, and involves modulation of antioxidant, inflammatory, neurotrophic and glutamate pathways. Here we evaluated the effects of NAC on behavioral parameters relevant to anxiety in zebrafish. NAC did not alter behavioral parameters in the novel tank test, prevented the anxiety-like behaviors induced by an acute stressor (net chasing), and increased the time zebrafish spent in the lit side in the light/dark test. These data may indicate that NAC presents an anti-stress effect, with the potential to prevent stress-induced psychiatric disorders such as anxiety and depression. The considerable homology between mammalian and zebrafish genomes invests the current data with translational validity for the further clinical trials needed to substantiate the use of NAC in anxiety disorders.

BackgroundThe enriched environment (EE) is a laboratory housing model that emerged from efforts to minimize the impact of environmental conditions on laboratory animals. Recently, we showed that EE promoted positive effects on behavior and cortisol levels in zebrafish submitted to the unpredictable chronic stress (UCS) protocol. Here, we expanded the characterization of the effects of UCS protocol by assessing parameters of oxidative status in the zebrafish brain and reveal that EE protects against the oxidative stress induced by chronic stress.MethodsZebrafish were exposed to EE (21 or 28 days) or standard housing conditions and subjected to the UCS protocol for seven days. Oxidative stress parameters (lipid peroxidation (TBARS), reactive oxygen species (ROS) levels, non-protein thiol (NPSH) and total thiol (SH) levels, superoxide dismutase (SOD) and catalase (CAT) activities were measured in brain homogenate.ResultsOur results revealed that UCS increased lipid peroxidation and ROS levels, while decreased NPSH levels and SOD activity, suggesting oxidative damage. EE for 28 days prevented all changes induced by the UCS protocol, and EE for 21 days prevented the alterations on NPSH levels, lipid peroxidation and ROS levels. Both EE for 21 or 28 days increased CAT activity.DiscussionOur findings reinforce the idea that EE exerts neuromodulatory effects in the zebrafish brain. EE promoted positive effects as it helped maintain the redox homeostasis, which may reduce the susceptibility to stress and its oxidative impact.

Studies have suggested that oxidative stress may contribute to the pathogenesis of mental disorders. In this context, molecules with antioxidant activity may be promising agents in the treatment of these deleterious conditions. Acetyl-L-carnitine (ALC) is a multi-target molecule that modulates the uptake of acetyl-CoA into the mitochondria during fatty acid oxidation, acetylcholine production, protein, and membrane phospholipid synthesis, capable of promoting neurogenesis in case of neuronal death. Moreover, neurochemical effects of ALC include modulation of brain energy and synaptic transmission of multiple neurotransmitters, including expression of type 2 metabotropic glutamate (mGlu2) receptors. The aim of this study was to investigate the effects of ALC in zebrafish by examining behavioral and biochemical parameters relevant to anxiety and mood disorders in zebrafish. ALC presented anxiolytic effects in both novel tank and light/dark tests and prevented the anxiety-like behavior induced by an acute stressor (net chasing). Furthermore, ALC was able to prevent the lipid peroxidation induced by acute stress in the zebrafish brain. The data presented here warrant further investigation of ALC as a potential agent in the treatment of neuropsychiatric disorders. Its good tolerability also subsidizes the additional studies necessary to assess its therapeutic potential in clinical settings.

Several studies have shown that manipulations to the housing environment modulate the susceptibility to stress in laboratory animals, mainly in rodents. Environmental enrichment (EE) is one such manipulation that promotes neuroprotection and neurogenesis, besides affecting behaviors such as drug self-administration. Zebrafish are a popular and useful animal model for behavioral neuroscience studies; however, studies evaluating the impact of housing conditions in this species are scarce. In this study, we verified the effects of EE on behavioral (novel tank test) and biochemical (cortisol and reactive oxygen species (ROS)) parameters in zebrafish submitted to unpredictable chronic stress (UCS). Consistent with our previous findings, UCS increased anxiety-like behavior, cortisol and ROS levels in zebrafish. EE for 21 or 28 days attenuated the effects induced by UCS on behavior and cortisol, and prevented the effects on ROS levels. Our findings reinforce the idea that EE exerts neuromodulatory effects across species, reducing vulnerability to stress and its biochemical impact. Also, these results indicate that zebrafish is a suitable model animal to study the behavioral effects and neurobiological mechanisms related to EE.

Here, we show that individually housed zebrafish presented a reduced cortisol response to an acute stressor (persecution with a pen net for 120 s) compared to zebrafish housed in groups of 10. We hypothesized that the cortisol response to stress was reduced in individually housed zebrafish because they depend solely on their own perceptions of the stressor, whereas among grouped zebrafish, the stress response might be augmented by chemical and/or behavioral cues from the other members of the shoal. This hypothesis was based on previous described chemical communication of stress in fish as well on individual variation in stressor perception and potential individual differences in fish personality.

Alcohol hangover refers to unpleasant symptoms experienced as a direct consequence of a binge drinking episode. The effects observed in this condition are related to the increase in alcohol metabolites and imbalance in oxidative status. N-acetylcysteine (NAC) is a mucolytic agent and an antidote for paracetamol overdose. Preclinical and clinical studies have shown that NAC is a multi-target drug acting through neuroprotective, antioxidant and neurotrophic mechanisms as well as a glutamate modulator. The aim of this study was to investigate the effects of NAC in zebrafish acutely exposed to ethanol (EtOH). Animals pretreated or not with NAC (1 mg/L, 10 min) were exposed for 60 min to standard tank water (EtOH-) or to 1% EtOH (EtOH+) to evaluate anxiety-like behavior and locomotion in the novel tank test and oxidative damage in the brain. Zebrafish (Danio rerio) exposed to EtOH displayed a decrease in the distance traveled, crossings, entries and time spent in the top area in the novel tank test. Exposure to EtOH also caused oxidative damage, shown by increased lipid peroxidation, decreased non-protein thiols and increased production of reactive oxygen species (DCF assay). NAC prevented both the behavioral alterations and the oxidative stress observed in EtOH+ animals. Given the effects of NAC in preventing the acute behavioral and biochemical effects of EtOH, additional studies are warranted to further investigate the basis of its anecdotal use to prevent hangover.

We examined whether lithium carbonate (Li2CO3, 100mg/L) is able to prevent memory impairment induced by scopolamine. Moreover, we evaluated the effects of lithium on anxiety-like behavior and acetylcholinesterase activity in adult zebrafish. We demonstrated that lithium prevents the memory impairment induced by scopolamine, decreases exploration and increases the activity of acetylcholinesterase in zebrafish. Collectively, this contributes to a better understanding of the pharmacology of lithium, its interaction with cholinergic neurotransmission, and its possible application to therapeutic treatments aimed at improving cognition.

Stressful experiences are related to the triggering of anxiety and mood disorders. Tryptophan (amino acid precursor of serotonin synthesis) emerges as important treatment of these disorders. Here, we evaluate the effects of pre-treatment with tryptophan (300 mg/L) and fluoxetine (50 μg/L) in response to acute stress in zebrafish. Overall, acute stress decreased the distance traveled, entries and time in top of tank, as well as increased the cortisol levels, demonstrating an anxiogenic behavior. Tryptophan and fluoxetine prevented anxiogenic effects. This study showed the importance of tryptophan and fluoxetine in the regulation of stress and anxiety-like behavior in adult zebrafish. Collectively, our data support tryptophan effects on stress responses in zebrafish and reinforce the growing utility of this aquatic model to screen CNS therapies.

Living animals exploit information released from dead animals to conduct adaptive biological responses. For instance, a recently published study has shown that avoidance behavior is triggered by death-associated odors in zebrafish. Stress can clearly act as an adaptive response that allows an organism to deal with an imminent threat. However, it has not been demonstrated whether these chemical cues are stressful for fish. Here, we confirmed that dead zebrafish scents induce defensive behavior in live conspecifics. Additionally, we show for the first time in fish that these scents increase cortisol in conspecifics. To reach this conclusion, firstly, we exposed zebrafish to multi-sensorial cues (e.g., visual, tactile, chemical cues) from dead conspecifics that displayed defensive behaviors and increased cortisol. Also, when we limited zebrafish to chemical cues from dead conspecifics, similar responses arose. These responses coincide with the decaying destruction of epidermal cells, indicating that defensive and stress responses could take place as an effect of substances emanating from decaying flesh, as well as alarm substance released due to rupture of epidermal cells. Taken together, these results illustrate that living zebrafish utilize cues from dead conspecific to avoid or to cope with danger and ensure survival.

Background Alpinia zerumbet (Pers.) B.L. Burtt & R.M. Sm., Zingiberaceae, is traditionally used in Brazil to treat hypertension, inflammation, anxiety, and hysteria. However, investigations of antioxidant and central effects of A . zerumbet extract are lacking. Objective The aim of this study was to verify the effects of a hydroethanolic extract of A . zerumbet (HEA) on tail suspension and light/dark tests to screen for possible antidepressant- and anxiolytic-like activities, respectively. We also evaluated the in vitro antioxidant effects of HEA. Materials and methods Swiss male mice were orally treated with saline or HEA (200, 400 or 800 mg/kg) 60 min before testing. The in vitro antioxidant activity of HEA was determined using the ferric-reducing antioxidant property method and assays involving free radical and reactive oxygen species scavenging. Protections against glutathione oxidation and lipid peroxidation were also evaluated. Results HEA (200, 400 and 800 mg/kg) significantly reduced the period of immobility in the tail suspension test, similarly to imipramine. In the tail suspension test, HEA (400 and 800 mg/kg but not 200 mg/kg) and diazepam significantly increased time spent in the light side. The antioxidant activity of HEA was remarkable, as it showed significant ferric-reduction power, 1,1-diphenyl-2-picrylhydrazyl radical and hydrogen peroxide scavenging activity, and protection against lipid peroxidation. Conclusion This study showed the antioxidant, antidepressant- and anxiolytic-like effects of HEA in mice. More studies and the identification of active components of the extract are necessary to further assess the therapeutic potential of this species in the treatment of psychiatric diseases.

Animal models of disease are ultimately only as strong as the clinical phenotype(s) upon which they are based. Many obstacles impede our ability to design animal models of complex mental illnesses, such as depression. An animal model that attempts to re-create any disease strives to maximize construct, face, and predictive validities. Strategies to model depression in representative animals have largely focused on one or more symptoms of depression, which have left many knowledge gaps open. In approaching these knowledge gaps, there are three primary areas that we feel need to be focused on: development of translational animal models, identification of genetic determinants, and discovery of novel targets/biomarkers of depression. Here, we discuss how zebrafish may be utilized in the modeling and analysis of the mechanisms of depression. Furthermore, this chapter also provides a detailed description of the behavioral responses and makes recommendations for further development of these methods, and how they may be employed in forward genetic screening for mutations involved in depression-related phenotypes.

The ability to avoid and escape from predators are clearly relevant behaviors from the ecological perspective and directly interfere with the survival of organisms. Detected in the aquatic environment, risperidone can alter the behavior of exposed species. Considering the risk of exposure in the early stages of life, we exposed zebrafish embryos to risperidone during the first 5 days of life. Risperidone caused hyperactivity in exposed larvae, which in an environmental context, the animals may be more vulnerable to predation due to greater visibility or less perception of risk areas.

Chronic stress may cause physical, behavioral and neuropsychiatric changes, affecting the health condition of an individual. Aggression is a universal behavior with great relevance on human and animal social systems. Despite studies showing the influence of chronic stress on aggression, the effects of unpredictable chronic stress (UCS) on aggressive behavior in male and female zebrafish remain unknown. Thus, the aim of this study was to evaluate the effects of UCS on the aggressive behavior and cortisol levels in adult zebrafish of both sexes. Our results showed that UCS increased aggression in males, but not in females, which displayed more aggressive behavior at baseline than control males. Increased whole-body cortisol levels were observed in stressed males; however, no differences were found between female groups. In conclusion, we reported for the first time gender differences on behavioral parameters and cortisol levels in response to UCS in zebrafish. These results highlight the relevance of studying behavioral and physiological parameters in both sexes separately.

Here we provide, at least to our knowledge, the first evidence that aripiprazole (APPZ) in the water blunts the stress response of exposed fish in a concentration ten times lower than the concentration detected in the environment. Although the mechanism of APPZ in the neuroendocrine axis is not yet determined, our results highlight that the presence of APPZ residues in the environment may interfere with the stress responses in fish. Since an adequate stress response is crucial to restore fish homeostasis after stressors, fish with impaired stress response may have trouble to cope with natural and/or imposed stressors with consequences to their welfare and survival.

Cynara scolymus L., Asteraceae, are traditionally used to treat dyspepsia. This study evaluated the hypolipidemic and antiatherogenic effects of an aqueous extract prepared from the leaves of C. scolymus in rat's model. Hypercholesterolemic rats (1% cholesterol and 0.5% cholic acid for 15 days) were treated (0.5 ml/200 g) with extract of C. scolymus (150, 300, or 600 mg/kg p.o.; n = 6) or simvastatin (4 mg/kg p.o.; n = 6) once per day for 30 days along with hypercaloric diet. A control group (C) was given water (0.5 ml/200 g; n = 6). A high-cholesterol diet was maintained throughout the treatment period. Rats treated with extract of C. scolymus (150, 300, or 600 mg/kg) and simvastatin showed significant decreases in serum levels of total cholesterol (−46.9%, −51.9%, −44%, and −41.9%, respectively) and low-density lipoprotein-cholesterol (LDL-C; −52.1%, −54.8%, −51.9%, and −46.7%, respectively), compared with group C (p

With the recognition that high levels of sustained stress are associated with the natural course of countless illnesses, effective anti-stress agents have gained importance. Improved endurance to particularly stressful periods is one of the medicinal claims for Marapuama (Ptychopetalum olacoides Bentham, PO), a popular Amazonian herbal. The purpose of this study was to evaluate if PO possesses anti-stress properties. To this end, an extract from PO (POEE) was evaluated on anxiety and glucose levels in mice submitted to the unpredictable chronic mild stress (UCMS) paradigm. POEE did not present anxiolytic effects, but was able to prevent (p