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1.
Artigo em Inglês | MEDLINE | ID: mdl-32605096

RESUMO

The available arable land is unable to fulfill the food production need of rapidly the exponentially growing human population in the world. Pesticides are one of those different measures taken to meet this demand. As a plant growth regulator to block gibberellin, paclobutrazol (PBZ) is used excessively throughout the world to promote early fruit setting, and to increase seed setting which might be harmful because PBZ is a very stable compound; therefore, it can bioaccumulate into the food chain of an ecosystem. In the present study, we discovered unexpected effects of PBZ on zebrafish larvae and adult behaviors by challenging them with low dose exposure. Zebrafish larvae aged 4 days post-fertilization (dpf) were exposed for 24 h at 10 µg/L (0.01 ppm) and 100 µg/L (0.1 ppm) of PBZ, respectively, and adults were incubated at 100 µg/L (0.1 ppm) and 1000 µg/L (1 ppm) concentrations of PBZ, respectively, for fourteen days. After incubation, the locomotor activity, burst, and rotation movement for the larvae; and multiple behavioral tests such as novel tank exploration, mirror biting, shoaling, predator avoidance, and social interaction for adult zebrafish were evaluated. Brain tissues of the adult fish were dissected and subjected to biochemical analyses of the antioxidant response, oxidative stress, superoxide dismutase (SOD), and neurotransmitter levels. Zebrafish larvae exposed to PBZ exhibited locomotion hyperactivity with a high burst movement and swimming pattern. In adult zebrafish, PBZ resulted in anxiolytic exploratory behavior, while no significant results were found in social interaction, shoal making, and predator avoidance behaviors. Interestingly, high dose PBZ exposure significantly compromised the innate aggressive behavior of the adult fish. Biochemical assays for oxidative stress, antioxidant response, and superoxide dismutase (SOD) showed significant reductions in their relative contents. In conclusion, for the first time, our behavior assays revealed that chronic PBZ exposure induced behavioral alterations in both larvae and the adult zebrafish. Because PBZ is a widely-used plant growth regulator, we suggest that it is necessary to conduct more thorough tests for its biosafety and bioaccumulation.


Assuntos
Ansiolíticos , Comportamento Exploratório/efeitos dos fármacos , Peixe-Zebra , Animais , Ansiolíticos/toxicidade , Comportamento Animal , Ecossistema , Larva/efeitos dos fármacos , Locomoção , Atividade Motora , Triazóis
2.
Psychopharmacology (Berl) ; 237(8): 2435-2449, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32506234

RESUMO

RATIONALE: Νeurosteroids, like dehydroepiandrosterone (DHEA), play an important role in neurodegeneration and neural protection, but they are metabolized in androgens, estrogens, or other active metabolites. A newly developed synthetic DHEA analog, BNN27 ((20R)-3ß,21-dihydroxy-17R,20-epoxy-5-pregnene), exerts neurotrophic and neuroprotective actions without estrogenic or androgenic effects. OBJECTIVES: This study aimed to investigate potential anxiolytic or antidepressant properties of BNN27. METHODS: Male and female adult Wistar rats were treated with BNN27 (10, 30, or 90 mg/kg, i.p.) and subjected to behavioral tests measuring locomotion, exploration, and "depressive-like" behavior (open field, light/dark box, hole-board, and forced swim tests). The hippocampus and prefrontal cortex were collected for glutamate and GABA measurements, and trunk blood was collected for gonadal hormone analysis. RESULTS: Acute high-dose BNN27 reduced locomotion and exploratory behavior in both sexes. Intermediate acute doses (30 mg/kg) of BNN27 reduced exploration and testosterone levels only in males, and enhanced progesterone levels in both sexes. Notably, with the present design, BNN27 had neither anxiolytic nor antidepressant effects and did not affect estrogen levels. Interestingly, acute administration of a low BNN27 dose (10 mg/kg) increased glutamate turnover, GABA, and glutamine levels in the hippocampus. The same dose also enhanced glutamate levels in the prefrontal cortex of males only. Sex differences were apparent in the basal levels of behavioral, hormonal, and neurochemical parameters, as expected. CONCLUSIONS: BNN27 affects locomotion, progesterone, and testosterone levels, as well as the glutamatergic and GABAergic systems of the hippocampus and prefrontal cortex in a sex-dependent way.


Assuntos
Desidroepiandrosterona/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Neuroesteroides/farmacologia , Caracteres Sexuais , Animais , Desidroepiandrosterona/química , Comportamento Exploratório/fisiologia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Locomoção/fisiologia , Masculino , Neuroesteroides/química , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Wistar
3.
J Neurosci ; 40(24): 4739-4749, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32393533

RESUMO

High trait anxiety is associated with altered activity across emotion regulation circuitry and a higher risk of developing anxiety disorders and depression. This circuitry is extensively modulated by serotonin. Here, to understand why some people may be more vulnerable to developing affective disorders, we investigated whether serotonin-related gene expression across the brain's emotion regulation circuitry may underlie individual differences in trait anxiety using the common marmoset (Callithrix jacchus, mixed sexes) as a model. First, we assessed the association of region-specific expression of the serotonin transporter (SLC6A4) and serotonin receptor (HTR1A, HTR2A, HTR2C) genes with anxiety-like behavior; and second, we investigated their causal role in two key features of the high trait anxious phenotype: high responsivity to anxiety-provoking stimuli and an exaggerated conditioned threat response. While the expression of the serotonin receptors did not show a significant relationship with anxiety-like behavior in any of the targeted brain regions, serotonin transporter expression, specifically within the right ventrolateral prefrontal cortex (vlPFC) and most strongly in the right amygdala, was associated positively with anxiety-like behavior. The causal relationship between amygdala serotonin levels and an animal's sensitivity to threat was confirmed via direct amygdala infusions of a selective serotonin reuptake inhibitor (SSRI), citalopram. Both anxiety-like behaviors, and conditioned threat-induced responses were reduced by the blockade of serotonin reuptake in the amygdala. Together, these findings provide evidence that high amygdala serotonin transporter expression contributes to the high trait anxious phenotype and suggest that reduction of threat reactivity by SSRIs may be mediated by their actions in the amygdala.SIGNIFICANCE STATEMENT Findings here contribute to our understanding of how the serotonin system underlies an individual's expression of threat-elicited negative emotions such as anxiety and fear within nonhuman primates. Exploration of serotonergic gene expression across brain regions implicated in emotion regulation revealed that serotonin transporter gene expression in the ventrolateral prefrontal cortex (vlPFC) and most strongly in the amygdala, but none of the serotonin receptor genes, were predictive of interindividual differences in anxiety-like behavior. Targeting of amygdala serotonin reuptake with selective serotonin reuptake inhibitors (SSRIs) confirmed the causal relationship between amygdala serotonin transporter and an animal's sensitivity to threat by reversing expression of two key features of the high trait-like anxiety phenotype: high responsivity to anxiety-provoking uncertain threat and responsivity to certain conditioned threat.


Assuntos
Tonsila do Cerebelo/metabolismo , Ansiedade/metabolismo , Emoções/fisiologia , Comportamento Exploratório/fisiologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Ansiedade/genética , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Callithrix , Citalopram/farmacologia , Emoções/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Medo/efeitos dos fármacos , Medo/fisiologia , Feminino , Humanos , Masculino , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Inibidores de Captação de Serotonina/farmacologia
4.
Psychopharmacology (Berl) ; 237(7): 2043-2053, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32419116

RESUMO

RATIONALE: In rodents, acute haloperidol treatment induces psychomotor impairments known as catalepsy, which models akinesia in humans and is characterized as an animal model of acute Parkinsonism, whereas sub-chronic haloperidol reduces exploratory behavior, which resembles bradykinesia. Haloperidol-induced catalepsy in rats can be ameliorated by playback of 50-kHz ultrasonic vocalizations (USV), an emotionally and motivationally relevant appetitive auditory stimulus, representing an animal model of paradoxical kinesia. In a condition like PD where patients suffer from chronic motor impairments, it is paramount to assess the long-term symptom relief in an animal model of Parkinsonism. OBJECTIVES: We investigated whether 50-kHz USV playback ameliorates psychomotor deficits induced by haloperidol in a sub-chronic dosing regimen. METHODS: In phase 1, distance traveled and number of rearing behavior were assessed in an activity chamber in order to investigate whether sub-chronic haloperidol treatment induced psychomotor impairments. In phase 2, we investigated whether 50-kHz USV playback could overcome these impairments by assessing exploratory behaviors and approach behavior towards the sound source in the 50-kHz USV radial maze playback paradigm. RESULTS: Sub-chronic haloperidol treatment led to psychomotor deficits since the distance traveled and number of rearing behavior were reduced as compared to saline control group or baseline. These psychomotor impairments were ameliorated during playback of 50-kHz USV, with haloperidol treated rats showing a clear social approach behavior towards the sound source exclusively during playback. CONCLUSIONS: This study provides evidence that 50-kHz USV playback induces paradoxical kinesia in rats exhibiting motor deficits after sub-chronic haloperidol, as we previously showed after acute haloperidol treatment.


Assuntos
Estimulação Acústica/métodos , Haloperidol/toxicidade , Transtornos Psicomotores/induzido quimicamente , Transtornos Psicomotores/terapia , Terapia por Ultrassom/métodos , Vocalização Animal/fisiologia , Animais , Modelos Animais de Doenças , Antagonistas de Dopamina/toxicidade , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Masculino , Transtornos Psicomotores/psicologia , Ratos , Ratos Wistar
5.
PLoS One ; 15(4): e0228357, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32275662

RESUMO

Increasingly, studies are revealing that endocrine disrupting chemicals (EDCs) can alter animal behavior. Early life exposure to EDCs may permanently alter phenotypes through to adulthood. In addition, the effects of EDCs may not be isolated to a single generation - offspring may indirectly be impacted, via non-genetic processes. Here, we analyzed the effects of paternal atrazine exposure on behavioral traits (distance moved, exploration, bottom-dwelling time, latency to enter the top zone, and interaction with a mirror) and whole-brain mRNA of genes involved in the serotonergic system regulation (slc6a4a, slc6a4b, htr1Aa, htr1B, htr2B) of zebrafish (Danio rerio). F0 male zebraFIsh were exposed to atrazine at 0.3, 3 or 30 part per billion (ppb) during early juvenile development, the behavior of F1 progeny was tested at adulthood, and the effect of 0.3 ppb atrazine treatment on mRNA transcription was quantified. Paternal exposure to atrazine significantly reduced interactions with a mirror (a proxy for aggression) and altered the latency to enter the top zone of a tank in unexposed F1 offspring. Bottom-dwelling time (a proxy for anxiety) also appeared to be somewhat affected, and activity (distance moved) was reduced in the context of aggression. slc6a4a and htr1Aa mRNA transcript levels were found to correlate positively with anxiety levels in controls, but we found that this relationship was disrupted in the 0.3 ppb atrazine treatment group. Overall, paternal atrazine exposure resulted in alterations across a variety of behavioral traits and showed signs of serotonergic system dysregulation, demonstrating intergenerational effects. Further research is needed to explore transgenerational effects on behavior and possible mechanisms underpinning behavioral effects.


Assuntos
Comportamento Animal/efeitos dos fármacos , Herbicidas/toxicidade , Exposição Paterna , Serotonina/metabolismo , Peixe-Zebra/fisiologia , Animais , Atrazina/toxicidade , Cruzamentos Genéticos , Comportamento Exploratório/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento
6.
PLoS One ; 15(3): e0230743, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214350

RESUMO

Social experience, particularly aggression, is considered a major determinant of consistent inter-individual behavioural differences between animals of the same species and sex. We investigated the influence of pre-adult aggressive experience on future behaviour in male, last instar nymphs of the cricket Gryllus bimaculatus. We found that aggressive interactions between male nymphs are far less fierce than for adults in terms of duration and escalation. This appears to reflect immaturity of the sensory apparatus for releasing aggression, rather than the motor system controlling it. First, a comparison of the behavioural responses of nymphs and adults to mechanical antennal stimulation using freshly excised, untreated and hexane-washed antennae taken from nymphs and adults, indicate that nymphs neither respond to nor produce sex-specific cuticular semiochemicals important for releasing aggressive behaviour in adults. Second, treatment with the octopamine agonist chlordimeform could at least partially compensate for this deficit. In further contrast to adults, which become hyper-aggressive after victory, but submissive after defeat, such winner and loser effects are not apparent in nymphs. Aggressive competition between nymphs thus appears to have no consequence for future behaviour in crickets. Male nymphs are often attacked by adult males, but not by adult females. Furthermore, observations of nymphs raised in the presence, or absence of adult males, revealed that social subjugation by adult males leads to reduced aggressiveness and depressed exploratory behaviour when the nymphs become adult. We conclude that social subjugation by adults during pre-adult development of nymphs is a major determinant of consistent inter-individual behavioural differences in adult crickets.


Assuntos
Agressão , Comportamento Animal , Gryllidae , Agressão/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Clorfenamidina/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Gryllidae/efeitos dos fármacos , Relações Interpessoais , Masculino , Octopamina/farmacologia
7.
Int J Mol Sci ; 21(3)2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32041135

RESUMO

To promote efficient explorative behaviors, subjects adaptively select spatial navigational strategies based on landmarks or a cognitive map. The hippocampus works alone or in conjunction with the dorsal striatum, both representing the neuronal underpinnings of the navigational strategies organized on the basis of different systems of spatial coordinate integration. The high expression of cannabinoid type 1 (CB1) receptors in structures related to spatial learning-such as the hippocampus, dorsal striatum and amygdala-renders the endocannabinoid system a critical target to study the balance between landmark- and cognitive map-based navigational strategies. In the present study, mice treated with the CB1-inverse agonist/antagonist AM251 or vehicle were trained on a Circular Hole Board, a task that could be solved through either navigational strategy. At the end of the behavioral testing, c-Fos immunoreactivity was evaluated in specific nuclei of the hippocampus, dorsal striatum and amygdala. AM251 treatment impaired spatial learning and modified the pattern of the performed navigational strategies as well as the c-Fos immunoreactivity in the hippocampus, dorsal striatum and amygdala. The present findings shed light on the involvement of CB1 receptors as part of the selection system of the navigational strategies implemented to efficiently solve the spatial problem.


Assuntos
Piperidinas/administração & dosagem , Proteínas Proto-Oncogênicas c-fos/metabolismo , Pirazóis/administração & dosagem , Receptor CB1 de Canabinoide/metabolismo , Aprendizagem Espacial/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Corpo Estriado/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores
8.
J Neurosci ; 40(11): 2282-2295, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32024781

RESUMO

Oxytocin (OT) is critical for the expression of social behavior across a wide array of species; however, the role of this system in the encoding of socially relevant information is not well understood. In the present study, we show that chemogenetic activation of OT neurons within the paraventricular nucleus of the hypothalamus (PVH) of male mice (OT-Ires-Cre) enhanced social investigation during a social choice test, while chemogenetic inhibition of these neurons abolished typical social preferences. These data suggest that activation of the OT system is necessary to direct behavior preferentially toward social stimuli. To determine whether the presence of a social stimulus is sufficient to induce activation of PVH-OT neurons, we performed the first definitive recording of OT neurons in awake mice using two-photon calcium imaging. These recordings demonstrate that social stimuli activate PVH-OT neurons and that these neurons differentially encode social and nonsocial stimuli, suggesting that PVH-OT neurons may act to convey social salience of environmental stimuli. Finally, an attenuation of social salience is associated with social disorders, such as autism. We therefore also examined possible OT system dysfunction in a mouse model of autism, Shank3b knock-out (KO) mice. Male Shank3b KO mice showed a marked reduction in PVH-OT neuron number and administration of an OT receptor agonist improved social deficits. Overall, these data suggest that the presence of a social stimulus induces activation of the PVH-OT neurons to promote adaptive social behavior responses.SIGNIFICANCE STATEMENT Although the oxytocin (OT) system is well known to regulate a diverse array of social behaviors, the mechanism in which OT acts to promote the appropriate social response is poorly understood. One hypothesis is that the presence of social conspecifics activates the OT system to generate an adaptive social response. Here, we selectively recorded from OT neurons in the paraventricular hypothalamic nucleus (PVH) to show that social stimulus exposure indeed induces activation of the OT system. We also show that activation of the OT system is necessary to promote social behavior and that mice with abnormal social behavior have reduced numbers of PVH-OT neurons. Finally, aberrant social behavior in these mice was rescued by administration of an OT receptor agonist.


Assuntos
Neurônios/fisiologia , Ocitocina/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Comportamento Social , Potenciais de Ação/efeitos dos fármacos , Animais , Comportamento Apetitivo/efeitos dos fármacos , Comportamento Apetitivo/fisiologia , Transtorno Autístico/fisiopatologia , Benzodiazepinas/farmacologia , Sinalização do Cálcio , Clozapina/farmacologia , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Genes Reporter , Masculino , Camundongos , Camundongos Knockout , Neurônios/efeitos dos fármacos , Ocitocina/análise , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Técnicas de Patch-Clamp , Pirazóis/farmacologia , Receptores de Ocitocina/agonistas , Receptores de Ocitocina/antagonistas & inibidores , Receptores de Ocitocina/fisiologia , Vigília
9.
J Neurochem ; 153(4): 495-509, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32031241

RESUMO

Current theories on the role of serotonin (5-HT) in vertebrate defensive behavior suggest that this monoamine increases anxiety but decreases fear, by acting at different levels of the neuroaxis. This paradoxical, dual role of 5-HT suggests that a serotonergic tone inhibits fear responses, while an acute increase in 5-HT would produce anxiety-like behavior. However, so far no evidence for a serotonergic tone has been found. Using zebrafish alarm responses, we investigate the participation of phasic and tonic 5-HT levels in fear-like behavior, as well as in behavior after stimulation. Conspecific alarm substance (CAS) increased bottom-dwelling and erratic swimming, and animals transferred to a novel environment after CAS exposure (post-exposure behavior) showed increased bottom-dwelling and freezing. Clonazepam blocked CAS effects during and after exposure. Acute fluoxetine dose-dependently decreased fear-like behavior, but increased post-exposure freezing. Metergoline had no effect on fear-like behavior, but blocked the effects of CAS on post-exposure behavior; similar effects were observed with para-chlorophenylalanine. Finally, CAS was shown to decrease the activity of monoamine oxidase in the zebrafish brain after exposure. These results suggest that phasic and tonic serotonin encode an aversive expectation value, switching behavior toward cautious exploration/risk assessment/anxiety when the aversive stimulus is no longer present.


Assuntos
Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Medo/efeitos dos fármacos , Medo/fisiologia , Inibidores de Captação de Serotonina/farmacologia , Serotonina/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Relação Dose-Resposta a Droga , Medo/psicologia , Feminino , Masculino , Natação/fisiologia , Peixe-Zebra
10.
Psychopharmacology (Berl) ; 237(6): 1577-1593, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32076746

RESUMO

RATIONALE: Schizophrenia is a mental illness which is characterised by positive and negative symptoms and by cognitive impairments. While the major prevailing hypothesis is that altered dopaminergic and/or glutamatergic transmission contributes to this disease, there is evidence that the noradrenergic system also plays a role in its major symptoms. OBJECTIVES: In the present paper, we investigated the pro-cognitive effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) an endogenous neuroprotective compound, on ketamine-modelled schizophrenia in rats. METHODS: We used an antagonist of NMDA receptors (ketamine) to model memory deficit symptoms in rats. Using the novel object recognition (NOR) test, we investigated the pro-cognitive effect of 1MeTIQ. Additionally, olanzapine, an atypical antipsychotic drug, was used as a standard to compare the pro-cognitive effects of the substances. In vivo microdialysis studies allowed us to verify the changes in the release of monoamines and their metabolites in the rat striatum. RESULTS: Our study demonstrated that 1MeTIQ, similarly to olanzapine, exhibits a pro-cognitive effect in NOR test and enhances memory disturbed by ketamine treatment. Additionally, in vivo microdialysis studies have shown that ketamine powerfully increased noradrenaline release in the rat striatum, while 1MeTIQ and olanzapine completely antagonised this neurochemical effect. CONCLUSIONS: 1MeTIQ, as a possible pro-cognitive drug, in contrast to olanzapine, expresses beneficial neuroprotective activity in the brain, increasing concentration of the extraneuronal dopamine metabolite, 3-methoxytyramine (3-MT), which plays an important physiological role in the brain as an inhibitory regulator of catecholaminergic activity. Moreover, we first demonstrated the essential role of noradrenaline release in memory disturbances observed in the ketamine-model of schizophrenia, and its possible participation in negative symptoms of the schizophrenia.


Assuntos
Ketamina/toxicidade , Atividade Motora/efeitos dos fármacos , Nootrópicos/uso terapêutico , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Animais , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Corpo Estriado/efeitos dos fármacos , Dopamina/análogos & derivados , Dopamina/metabolismo , Antagonistas de Aminoácidos Excitatórios/toxicidade , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Masculino , Microdiálise , Atividade Motora/fisiologia , Nootrópicos/farmacologia , Norepinefrina/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Tetra-Hidroisoquinolinas/farmacologia , Resultado do Tratamento
11.
Psychopharmacology (Berl) ; 237(6): 1595-1606, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32088835

RESUMO

INTRODUCTION: Depression is characterized by behavioral, cognitive and physiological changes, imposing a major burden on the overall wellbeing of the patient. Some evidence indicates that social stress, changes in growth factors (e.g., brain-derived neurotrophic factor (BDNF)), and neuroinflammation are involved in the development and progression of the disease. The monoamine oxidase A inhibitor drug harmine was suggested to have both antidepressant and anti-inflammatory properties and may, therefore, be a potential candidate for treatment of depression. AIM: The goal of this study was to assess the effects of harmine on behavior, brain BDNF levels, and microglia activation in control rats and a rat model of social stress. MATERIAL AND METHODS: Rats were submitted to 5 consecutive days of repeated social defeat (RSD) or control conditions. Animals were treated daily with harmine (15 mg/kg) or vehicle from day 3 until the end of the experiment. To assess the effects of harmine treatment on behavior, the sucrose preference test (SPT) was performed on days 1, 6, and 15, the open field test (OFT) on days 6 and 14, and the novel object recognition test (NOR) on day 16. Brain microgliosis was assessed using [11C]PBR-28 PET on day 17. Animals were terminated on day 17, and BDNF protein concentrations in the hippocampus and frontal cortex were analyzed using ELISA. RESULTS: RSD significantly decreased bodyweight and increased anxiety and anhedonia-related parameters in the OFT and SPT on day 6, but these behavioral effects were not observed anymore on day 14/15. Harmine treatment caused a significant reduction in bodyweight gain in both groups, induced anhedonia in the SPT on day 6, and significantly reduced the mobility and exploratory behavior of the animals in the OFT mainly on day 14. PET imaging and the NOR test did not show any significant effects on microglia activation and memory, respectively. BDNF protein concentrations in the hippocampus and frontal cortex were not significantly affected by either RSD or harmine treatment. DISCUSSION: Harmine was not able to reverse the acute effects of RSD on anxiety and anhedonia and even aggravated the effect of RSD on bodyweight loss. Moreover, harmine treatment caused unexpected side effects on general locomotion, both in RSD and control animals, but did not influence glial activation status and BDNF concentrations in the brain. In this model, RSD-induced stress was not strong enough to induce long-term effects on the behavior, neuroinflammation, or BDNF protein concentration. Thus, the efficacy of harmine treatment on these delayed parameters needs to be further evaluated in more severe models of chronic stress.


Assuntos
Depressão/tratamento farmacológico , Depressão/metabolismo , Harmina/administração & dosagem , Inibidores da Monoaminoxidase/administração & dosagem , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Animais , Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/psicologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Ratos , Ratos Wistar , Estresse Psicológico/psicologia , Resultado do Tratamento
12.
J Vet Med Sci ; 82(3): 350-359, 2020 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-31983702

RESUMO

Dinotefuran (DIN) belongs to the neonicotinoids (NNs), a class of globally applied pesticides originally developed to exhibit selective toxicity in insects. However, several reports have suggested that NNs also exert neurotoxic effects in mammals. We previously demonstrated neurobehavioral effects of DIN on mice under non-stressful conditions. For further toxicity assessments in the present study, we investigated the effects of DIN on mice exposed to stressful conditions. After subacutely administering a no-observed-effect-level (NOEL) dose of DIN and/or chronic unpredictable mild stress (CUMS) to mice, we conducted three behavioral tests (i.e., open field test [OFT], tail suspension test [TST] and forced swimming test [FST]). In addition, serotonin (5-HT) and tryptophan hydroxylase 2 (TPH2) of the dorsal raphe nuclei (DRN) and median raphe nuclei (MRN) and tyrosine hydroxylase (TH) of the ventral tegmental area and substantia nigra (SN) were evaluated immunohistochemically. A NOEL dose of DIN or CUMS alone increased of the total distance in OFT, decreased or increased the immobility time in TST or FST, respectively, and increased the positive intensity of 5-HT and TPH2 in the DRN/MRN, and TH in the SN. These changes were suppressed under the conditions of combined exposure to DIN and CUMS, though the blood corticosterone level was increased depending on the blood DIN values and the presence of CUMS. The present study suggests the multifaceted toxicity of the neurotoxin DIN.


Assuntos
Encéfalo/metabolismo , Guanidinas/toxicidade , Neonicotinoides/toxicidade , Nitrocompostos/toxicidade , Estresse Psicológico , Animais , Comportamento Animal/efeitos dos fármacos , Corticosterona/sangue , Emoções/fisiologia , Comportamento Exploratório/efeitos dos fármacos , Guanidinas/sangue , Elevação dos Membros Posteriores , Inseticidas/toxicidade , Masculino , Camundongos Endogâmicos C57BL , Neonicotinoides/sangue , Nitrocompostos/sangue , Serotonina/metabolismo , Natação , Triptofano Hidroxilase/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
13.
Int J Mol Sci ; 21(2)2020 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-31963761

RESUMO

The demyelinating diseases of the central nervous system involve myelin abnormalities, oligodendrocyte damage, and consequent glia activation. Neurotoxicant cuprizone (CPZ) was used to establish a mouse model of demyelination. However, the effects of CPZ on microRNA (miRNA) expression and behavior have not been clearly reported. We analyzed the behavior of mice administered a diet containing 0.2% CPZ for 6 weeks, followed by 6 weeks of recovery. Rotarod analysis demonstrated that the treated group had poorer motor coordination than control animals. This effect was reversed after 6 weeks of CPZ withdrawal. Open-field tests showed that CPZ-treated mice exhibited significantly increased anxiety and decreased exploratory behavior. CPZ-induced demyelination was observed to be alleviated after 4 weeks of CPZ treatment, according to luxol fast blue (LFB) staining and myelin basic protein (MBP) expression. miRNA expression profiling showed that the expression of 240 miRNAs was significantly changed in CPZ-fed mice compared with controls. Furthermore, miR-155-5p and miR-20a-5p upregulations enhanced NgR induction through Smad 2 and Smad 4 suppression in demyelination. Taken together, our results demonstrate that CPZ-mediated demyelination induces behavioral deficits with apparent alterations in miRNA expression, suggesting that differences in miRNA expression in vivo may be new potential therapeutic targets for remyelination.


Assuntos
Cuprizona/efeitos adversos , Doenças Desmielinizantes/psicologia , Comportamento Exploratório/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Animais , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/genética , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/efeitos dos fármacos , MicroRNAs/genética , Teste de Desempenho do Rota-Rod
14.
Braz J Med Biol Res ; 52(11): e8441, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31721904

RESUMO

The heptapeptide Bj-PRO-7a, isolated and identified from Bothrops jararaca (Bj) venom, produces antihypertensive and other cardiovascular effects that are independent on angiotensin converting enzyme inhibition, possibly relying on cholinergic muscarinic receptors subtype 1 (M1R). However, whether Bj-PRO-7a acts upon the central nervous system and modifies behavior is yet to be determined. Therefore, the aims of this study were: i) to assess the effects of acute administration of Bj-PRO-7a upon behavior; ii) to reveal mechanisms involved in the effects of Bj-PRO-7a upon locomotion/exploration, anxiety, and depression-like behaviors. For this purpose, adult male Wistar (WT, wild type) and spontaneous hypertensive rats (SHR) received intraperitoneal injections of vehicle (0.9% NaCl), diazepam (2 mg/kg), imipramine (15 mg/kg), Bj-PRO-7a (71, 213 or 426 nmol/kg), pirenzepine (852 nmol/kg), α-methyl-DL-tyrosine (200 mg/kg), or chlorpromazine (2 mg/kg), and underwent elevated plus maze, open field, and forced swimming tests. The heptapeptide promoted anxiolytic and antidepressant-like effects and increased locomotion/exploration. These effects of Bj-PRO-7a seem to be dependent on M1R activation and dopaminergic receptors and rely on catecholaminergic pathways.


Assuntos
Ansiedade , Comportamento Animal/efeitos dos fármacos , Venenos de Crotalídeos/química , Depressão , Comportamento Exploratório/efeitos dos fármacos , Oligopeptídeos/farmacologia , Prolina/farmacologia , Animais , Comportamento Animal/fisiologia , Masculino , Oligopeptídeos/isolamento & purificação , Prolina/isolamento & purificação , Ratos , Ratos Wistar
15.
Int J Mol Sci ; 20(22)2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31752171

RESUMO

There is an imperative need to develop efficient whole-animal-based testing assays to determine the potential toxicity of engineered nanomaterials. While previous studies have demonstrated toxicity in lung and skin cells after C70 nanoparticles (NPs) exposure, the potential detrimental role of C70 NPs in neurobehavior is largely unaddressed. Here, we evaluated the chronic effects of C70 NPs exposure on behavior and alterations in biochemical responses in adult zebrafish. Two different exposure doses were used for this experiment: low dose (0.5 ppm) and high dose (1.5 ppm). Behavioral tests were performed after two weeks of exposure of C70 NPs. We found decreased locomotion, exploration, mirror biting, social interaction, and shoaling activities, as well as anxiety elevation and circadian rhythm locomotor activity impairment after ~2 weeks in the C70 NP-exposed fish. The results of biochemical assays reveal that following exposure of zebrafish to 1.5 ppm of C70 NPs, the activity of superoxide dismutase (SOD) in the brain and muscle tissues increased significantly. In addition, the concentration of reactive oxygen species (ROS) also increased from 2.95 ± 0.12 U/ug to 8.46 ± 0.25 U/ug and from 0.90 ± 0.03 U/ug to 3.53 ± 0.64 U/ug in the muscle and brain tissues, respectively. Furthermore, an increased level of cortisol was also observed in muscle and brain tissues, ranging from 17.95 ± 0.90 pg/ug to 23.95 ± 0.66 pg/ug and from 3.47 ± 0.13 pg/ug to 4.91 ± 0.51 pg/ug, respectively. Increment of Hif1-α level was also observed in both tissues. The elevation was ranging from 11.65 ± 0.54 pg/ug to 18.45 ± 1.00 pg/ug in the muscle tissue and from 4.26 ± 0.11 pg/ug to 6.86 ± 0.37 pg/ug in the brain tissue. Moreover, the content of DNA damage and inflammatory markers such as ssDNA, TNF-α, and IL-1ß were also increased substantially in the brain tissues. Significant changes in several biomarker levels, including catalase and malondialdehyde (MDA), were also observed in the gill tissues. Finally, we used a neurophenomic approach with a particular focus on environmental influences, which can also be easily adapted for other aquatic fish species, to assess the toxicity of metal and carbon-based nanoparticles. In summary, this is the first study to illustrate the adult zebrafish toxicity and the alterations in several neurobehavior parameters after zebrafish exposure to environmentally relevant amounts of C70 NPs.


Assuntos
Comportamento Animal/efeitos dos fármacos , Fulerenos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Peixe-Zebra/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Exposição Ambiental/efeitos adversos , Comportamento Exploratório/efeitos dos fármacos , Feminino , Brânquias/efeitos dos fármacos , Brânquias/metabolismo , Hidrocortisona/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Nanopartículas Metálicas , Músculos/efeitos dos fármacos , Músculos/metabolismo , Testes de Toxicidade Crônica , Peixe-Zebra/metabolismo
16.
Braz J Med Biol Res ; 52(11): e8899, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31664307

RESUMO

Few behavioral tests allow measuring several characteristics and most require training, complex analyses, and/or are time-consuming. We present an apparatus based on rat exploratory behavior. Composed of three different environments, it allows the assessment of more than one behavioral characteristic in a short 3-min session. Factorial analyses have defined three behavioral dimensions, which we named Exploration, Impulsivity, and Self-protection. Behaviors composing the Exploration factor were increased by chlordiazepoxide and apomorphine and decreased by pentylenetetrazole. Behaviors composing the Impulsivity factor were increased by chlordiazepoxide, apomorphine, and both acute and chronic imipramine treatments. Behaviors composing the Self-protection factor were decreased by apomorphine. We submitted Wistar rats to the open-field test, the elevated-plus maze, and to the apparatus we are proposing. Measures related to exploratory behavior in all three tests were correlated. Measures composing the factors Impulsivity and Self-protection did not correlate with any measures from the two standard tests. Also, compared with existing impulsivity tests, the one we proposed did not require previous learning, training, or sophisticated analysis. Exploration measures from our test are as easy to obtain as the ones from other standard tests. Thus, we have proposed an apparatus that measured three different behavioral characteristics, was simple and fast, did not require subjects to be submitted to previous learning or training, was sensitive to drug treatments, and did not require sophisticated data analyses.


Assuntos
Ansiedade/psicologia , Comportamento Animal/fisiologia , Pesquisa Comportamental/instrumentação , Comportamento Exploratório/fisiologia , Medo/fisiologia , Comportamento Impulsivo/fisiologia , Animais , Ansiolíticos/farmacologia , Antidepressivos Tricíclicos/farmacologia , Apomorfina/farmacologia , Comportamento Animal/efeitos dos fármacos , Clordiazepóxido/farmacologia , Agonistas de Dopamina/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Medo/efeitos dos fármacos , Antagonistas GABAérgicos/farmacologia , Comportamento Impulsivo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Modelos Animais , Pentilenotetrazol/farmacologia , Ratos Wistar , Fatores de Tempo
17.
Transl Psychiatry ; 9(1): 222, 2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501410

RESUMO

BTB/POZ domain-containing 3 (BTBD3) was identified as a potential risk gene in the first genome-wide association study of obsessive-compulsive disorder (OCD). BTBD3 is a putative transcription factor implicated in dendritic pruning in developing primary sensory cortices. We assessed whether BTBD3 also regulates neural circuit formation within limbic cortico-striato-thalamo-cortical circuits and behaviors related to OCD in mice. Behavioral phenotypes associated with OCD that are measurable in animals include compulsive-like behaviors and reduced exploration. We tested Btbd3 wild-type, heterozygous, and knockout mice for compulsive-like behaviors including cage-mate barbering, excessive wheel-running, repetitive locomotor patterns, and reduced goal-directed behavior in the probabilistic learning task (PLT), and for exploratory behavior in the open field, digging, and marble-burying tests. Btbd3 heterozygous and knockout mice showed excessive barbering, wheel-running, impaired goal-directed behavior in the PLT, and reduced exploration. Further, chronic treatment with fluoxetine, but not desipramine, reduced barbering in Btbd3 wild-type and heterozygous, but not knockout mice. In contrast, Btbd3 expression did not alter anxiety-like, depression-like, or sensorimotor behaviors. We also quantified dendritic morphology within anterior cingulate cortex, mediodorsal thalamus, and hippocampus, regions of high Btbd3 expression. Surprisingly, Btbd3 knockout mice only showed modest increases in spine density in the anterior cingulate, while dendritic morphology was unaltered elsewhere. Finally, we virally knocked down Btbd3 expression in whole, or just dorsal, hippocampus during neonatal development and assessed behavior during adulthood. Whole, but not dorsal, hippocampal Btbd3 knockdown recapitulated Btbd3 knockout phenotypes. Our findings reveal that hippocampal Btbd3 expression selectively modulates compulsive-like and exploratory behavior.


Assuntos
Encéfalo/metabolismo , Comportamento Compulsivo/metabolismo , Comportamento Exploratório/fisiologia , Rede Nervosa/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Comportamento Compulsivo/tratamento farmacológico , Comportamento Compulsivo/genética , Desipramina/farmacologia , Desipramina/uso terapêutico , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Camundongos , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Proteínas do Tecido Nervoso/genética , Transtorno Obsessivo-Compulsivo/genética , Transtorno Obsessivo-Compulsivo/metabolismo
18.
Pharmacol Biochem Behav ; 186: 172790, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31499145

RESUMO

Binge drinking is characterized by excessive alcohol consumption in a short period of time and is associated with a poor quality of life. Zebrafish are commonly used to investigate neurochemical, behavioral, and genetic parameters associated with ethanol (EtOH) exposure. However, few studies have used zebrafish as a model to investigate binge EtOH exposure. In order to elucidate the potential neurobehavioral impairments evoked by binge EtOH exposure in zebrafish, animals were immersed in 1.4% EtOH for 30 min three consecutive times with intervals of one week. Neurobehavioral parameters were analyzed immediately following the third exposure, as well as 2 and 9 days later. Brain choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities were reduced 9 days after the treatment. Thiobarbituric acid-reactive species and dichlorodihydrofluorescein levels were increased immediately after the treatment, but both returned to normal levels 2 days after the treatment. Catalase and glutathione reductase were impaired 2 and 9 days after the treatment. No alteration was observed in superoxide dismutase and glutathione peroxidase activities. EtOH treatment did not alter brain expression of inflammatory genes such as il-1ß, il-10, and tnf-α. Zebrafish displayed anxiolytic-like behavior immediately after the last exposure, though there was no behavioral alteration observed 9 days after the treatment. Therefore, binge EtOH exposure in zebrafish leads to long lasting brain cholinergic alteration, probably related to oxidative stress immediately after the exposure, which is independent of classical inflammatory markers.


Assuntos
Etanol/administração & dosagem , Comportamento Exploratório/efeitos dos fármacos , Peixe-Zebra/fisiologia , Acetilcolinesterase/metabolismo , Animais , Comportamento Animal , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Colina O-Acetiltransferase/metabolismo , Etanol/farmacologia
19.
Neuropsychobiology ; 78(4): 218-228, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31514182

RESUMO

BACKGROUND: Gamma-aminobutyric acid (GABA)ergic and opioid systems play a crucial role in the neural modulation of innate fear organised by the inferior colliculus (IC). In addition, the IC is rich in GABAergic fibres and opioid neurons, which are also connected to other mesencephalic structures, such as the superior colliculus and the substantia nigra. However, the contribution of distinct opioid receptors (ORs) in the IC during the elaboration and expression of innate fear and panic-like responses is unclear. The purpose of the present work was to investigate a possible integrated action exerted by ORs and the GABAA receptor-mediated system in the IC on panic-like responses. METHODS: The effect of the blockade of either µ1- or κ-ORs in the IC was evaluated in the unconditioned fear-induced responses elicited by GABAA antagonism with bicuculline. Microinjections of naloxonazine, a µ1-OR antagonist, or nor-binaltorphimine (nor-BNI), a κ-OR antagonist, were made into the IC, followed by intramesencephalic administration of the GABAA-receptor antagonist bicuculline. The defensive behaviours elicited by the treatments in the IC were quantitatively analysed, recording the number of escapes expressed as running (crossing), jumps, and rotations, over a 30-min period in a circular arena. The exploratory behaviour of rearing was also recorded. RESULTS: GABAA-receptor blockade with bicuculline in the IC increased defensive behaviours. However, pretreatment of the IC with higher doses (5 µg) of naloxonazine or nor-BNI followed by bicuculline resulted in a significant decrease in unconditioned fear-induced responses. CONCLUSIONS: These findings suggest a role played by µ1- and κ-OR-containing connexions and GABAA receptor-mediated neurotransmission on the organisation of panic attack-related responses elaborated by the IC neurons.


Assuntos
Comportamento Animal/efeitos dos fármacos , Colículos Inferiores/efeitos dos fármacos , Mesencéfalo/efeitos dos fármacos , Antagonistas de Entorpecentes/farmacologia , Pânico/efeitos dos fármacos , Receptores Opioides kappa/antagonistas & inibidores , Receptores Opioides mu/antagonistas & inibidores , Animais , Bicuculina/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Antagonistas de Receptores de GABA-A/farmacologia , Masculino , Naloxona/análogos & derivados , Naloxona/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Neurônios/efeitos dos fármacos , Ratos , Ratos Wistar
20.
Neurosci Res ; 147: 39-47, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31446906

RESUMO

Perinatal virus infection is an environmental risk factor for neurodevelopmental disorders such as schizophrenia. We previously demonstrated that neonatal treatment with a viral mimetic, polyriboinosinic-polyribocytidilic acid (polyI:C), in mice leads to emotional and cognitive deficits in adolescence. Here, we investigated the effects of antipsychotics on polyI:C-induced behavioral abnormalities. We also performed a proteomic analysis in the hippocampus of polyI:C-treated adult mice using two-dimensional electrophoresis to understand the changes in protein expression following neonatal immune activation. Neonatal mice were subcutaneously injected with polyI:C for 5 days (postnatal day 2-6). At 10 weeks, sensorimotor gating, emotional and cognitive function were analyzed in behavioral tests. Clozapine improved PPI deficit and emotional and cognitive dysfunction in polyI:C-treated mice. However, haloperidol improved only PPI deficit. Proteomic analysis revealed that two candidate proteins were obtained in the hippocampus of polyI:C-treated mice, including aldehyde dehydrogenase family 1 member L1 (ALDH1L1) and collapsin response mediator protein 5 (CRMP5). These data suggest that the neonatal polyI:C-treated mouse model may be useful for evaluating antipsychotic activity of compounds. Moreover, changes in the protein expression of ALDH1L1 and CRMP5 support our previous findings that astrocyte-neuron interaction plays a role in the pathophysiology of neurodevelopmental disorders induced by neonatal immune activation.


Assuntos
Antipsicóticos/farmacologia , Poli I-C/farmacologia , Proteômica , Esquizofrenia/induzido quimicamente , Aldeído Desidrogenase 1/metabolismo , Animais , Animais Recém-Nascidos , Clozapina/farmacologia , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Feminino , Haloperidol/farmacologia , Hipocampo/efeitos dos fármacos , Hidrolases/metabolismo , Relações Interpessoais , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas do Tecido Nervoso , Gravidez , Inibição Pré-Pulso , Reconhecimento Psicológico , Filtro Sensorial/efeitos dos fármacos
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