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1.
Pediatrics ; 145(2)2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32015180

RESUMO

Phenotypic and biological characterization of rare monogenic disorders represents 1 of the most important avenues toward understanding the mechanisms of human disease. Among patients with SH3 and multiple ankyrin repeat domains 3 (SHANK3) mutations, a subset will manifest neurologic regression, psychosis, and mood disorders. However, which patients will be affected, when, and why are important unresolved questions. Authors of recent studies suggest neuronal SHANK3 expression is modulated by both inflammatory and hormonal stimuli. In this case series, we describe 4 independent clinical observations of an immunotherapy responsive phenotype of peripubertal-onset neuropsychiatric regression in 4 girls with pathogenic SHANK3 mutations. Each child exhibited a history of stable, mild-to-moderate lifelong developmental disability until 12 to 14 years of age, at which time each manifested a similar, subacute-onset neurobehavioral syndrome. Symptoms included mutism, hallucinations, insomnia, inconsolable crying, obsessive-compulsive behaviors, loss of self-care, and urinary retention and/or incontinence. Symptoms were relatively refractory to antipsychotic medication but improved after immunomodulatory treatment. All 4 patients exhibited chronic relapsing courses during a period of treatment and follow-up ranging from 3 to 6 years. Two of the 4 girls recovered their premorbid level of functioning. We briefly review the scientific literature to offer a conceptual and molecular framework for understanding these clinical observations. Future clinical and translational investigations in this realm may offer insights into mechanisms and therapies bridging immune function and human behavior.


Assuntos
Transtorno do Espectro Autista/genética , Deficiências do Desenvolvimento/genética , Mutação da Fase de Leitura , Imunoterapia/métodos , Proteínas do Tecido Nervoso/genética , Comportamento Estereotipado , Adolescente , Agressão/efeitos dos fármacos , Antipsicóticos/uso terapêutico , Ansiedade , Catatonia/tratamento farmacológico , Criança , Comportamento Compulsivo/tratamento farmacológico , Choro , Feminino , Alucinações/tratamento farmacológico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Humor Irritável/efeitos dos fármacos , Metilprednisolona/uso terapêutico , Mutismo/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Recidiva , Autocuidado , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Comportamento Estereotipado/efeitos dos fármacos , Síndrome , Incontinência Urinária , Retenção Urinária
2.
Psychopharmacology (Berl) ; 237(1): 199-208, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31595334

RESUMO

RATIONALE: Autism spectrum disorder (ASD), the fastest growing neurodevelopmental disorder, is characterized by social deficits, repetitive/stereotypic activity, and impaired verbal and nonverbal communication and is commonly diagnosed at early stages of life. Based on the excitatory-inhibitory imbalance theory of autism, some recent animal experiments have reported amelioration in autistic-like phenotypes in adult animals following acute treatment of NMDA antagonists. However, we suggested the neonatal period as a critical period for NMDA antagonist intervention. OBJECTIVES: This experiment was designed to determine the role of postnatal MK-801, an NMDA receptor blocker, in the prenatal valproic acid (VPA) rat model of ASD. METHODS: The model of autism was induced by subcutaneous administration of valproic acid (600 mg/kg) to pregnant rats at gestational day 12.5. The effects of MK-801 (0.03 mg/kg, from postnatal day 6-10) in correcting ASD-associated behaviors in male offspring were assessed by open-field, three-chambered social interaction tests. Moreover, the nociceptive threshold was measured by tail flick and hot plate. Behavioral tests were performed on PND 55-60. Nissl staining was performed to confirm the safety of 0.03 mg/kg MK-801 for the brain. RESULTS: We reported that MK-801 rescued social deficits, repetitive behaviors (self-grooming), anxiety-related behavior, and the low nociceptive threshold in the VPA-treated rats. Further, histological examination showed that there were no significant differences among all the groups in terms of the neuronal survival rate. CONCLUSIONS: Our results showed that postnatal low-dose MK-801 improved ASD-associated behaviors in the VPA-treated rats and that early exposure to NMDA antagonist resulted in permanent changes in adult behavior.


Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Maleato de Dizocilpina/uso terapêutico , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Comportamento Social , Comportamento Estereotipado/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Feminino , Masculino , Neurônios/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Ratos , Ácido Valproico
3.
Int J Dev Neurosci ; 79: 49-53, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31678549

RESUMO

Early childhood schizophrenia (COS) is a rare condition and has no established animal model to test new treatments. Previous studies have shown that repeated doses of 25 mg/kg ketamine produce schizophrenia-like changes in adult male Wistar rats, but adequate doses of ketamine in animal COS studies are not yet known. Male and female Wistar rats, 23 days old, received an injection of ketamine or intraperitoneal saline (i.p.) for 8 days. The animals underwent different behavioral tests: open field, social interaction, pre-pulse startle inhibition (PPI). Female rats showed behavioral changes at all ketamine doses (5, 15, 25 and 50 mg/kg), in contrast to males that only at 50 mg/kg dose had interrupted PPI and higher stereotypy in the open field test. The present study demonstrated that ketamine at a dose of 50 mg/kg once daily from 23 to 31 days postnatal reproduced changes similar to schizophrenia in pre-pubertal male and female Wistar rats and could be used, with other interventions, in future studies with animals in COS.


Assuntos
Comportamento Animal/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ketamina/farmacologia , Inibição Pré-Pulso/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , Esquizofrenia , Comportamento Estereotipado/efeitos dos fármacos
4.
Pharmacol Biochem Behav ; 181: 110-116, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31054946

RESUMO

Repetitive behaviors are diagnostic for autism spectrum disorder (ASD) and commonly observed in other neurodevelopmental disorders. Currently, there are no effective pharmacological treatments for repetitive behavior in these clinical conditions. This is due to the lack of information about the specific neural circuitry that mediates the development and expression of repetitive behavior. Our previous work in mouse models has linked repetitive behavior to decreased activation of the subthalamic nucleus, a brain region in the indirect and hyperdirect pathways in the basal ganglia circuitry. The present experiments were designed to further test our hypothesis that pharmacological activation of the indirect pathway would reduce repetitive behavior. We used a combination of adenosine A1 and A2A receptor agonists that have been shown to alter the firing frequency of dorsal striatal neurons within the indirect pathway of the basal ganglia. This drug combination markedly and selectively reduced repetitive behavior in both male and female C58 mice over a six-hour period, an effect that required both A1 and A2A agonists as neither alone reduced repetitive behavior. The adenosine A1 and A2A receptor agonist combination also significantly increased the number of Fos transcripts and Fos positive cells in dorsal striatum. Fos induction was found in both direct and indirect pathway neurons suggesting that the drug combination restored the balance of activation across these complementary basal ganglia pathways. The adenosine A1 and A2A receptor agonist combination also maintained its effectiveness in reducing repetitive behavior over a 7-day period. These findings point to novel potential therapeutic targets for development of drug therapies for repetitive behavior in clinical disorders.


Assuntos
Agonistas do Receptor A1 de Adenosina/uso terapêutico , Agonistas do Receptor A2 de Adenosina/uso terapêutico , Adenosina/análogos & derivados , Comportamento Compulsivo/tratamento farmacológico , Fenetilaminas/uso terapêutico , Comportamento Estereotipado/efeitos dos fármacos , Adenosina/administração & dosagem , Adenosina/química , Adenosina/uso terapêutico , Agonistas do Receptor A1 de Adenosina/administração & dosagem , Agonistas do Receptor A1 de Adenosina/química , Agonistas do Receptor A2 de Adenosina/administração & dosagem , Agonistas do Receptor A2 de Adenosina/química , Análise de Variância , Animais , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/metabolismo , Comportamento Animal/efeitos dos fármacos , Corpo Estriado/citologia , Quimioterapia Combinada , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Neurônios/metabolismo , Óleo de Amendoim/química , Óleo de Amendoim/farmacologia , Fenetilaminas/administração & dosagem , Fenetilaminas/química , Fenótipo , Proteínas Proto-Oncogênicas c-fos/metabolismo
5.
Toxicology ; 418: 70-80, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30836164

RESUMO

Polybrominated diphenyl ethers (PBDEs) and lead (Pb) are common pollutants that co-exist in the environment. These chemicals may be associated with autism spectrum disorder (ASD), yet direct evidence is lacking. More importantly, how co-exposure of these chemicals might affect ASD has never been explored. For assessing the relationship between PBDE/Pb exposure and ASD, pregnant C57BL/6 J female mice were exposed to BDE209 (0.12 ng/day), Pb (1.2 ng/day), or a BDE209/Pb mixture from gestational day (GD) 9.5 to postnatal day (PND) 21 using ALZET osmotic pumps. Polyinosinic-polycytidylic acid (poly I:C) was included as a positive control, as its single dose injection (20 mg/kg.bw; i.p.) at mid-pregnancy (GD 12.5) produces ASD-like behaviors in mouse offspring. These ASD-like phenotypes include decreased preference for social novelty, increased marble burying behavior, and learning impairment. Similar to the poly I:C control, perinatal exposure to Pb or BDE209/Pb mixture elicited increased marble burying and learning impairment, but it had no effect on sociability. Consistent with these behavioral anomalies, Pb and BDE209/Pb co-exposure as well as poly I:C exposure increased the production of pro-inflammation cytokines interleukin 4 (IL-4), interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor α (TNFα), interferon γ (IFNγ), and interleukin 17 A (IL-17 A) in the serum, and decreased neuronal cells in the CA1 and CA3 subregions of the hippocampus. The majority of these changes in the BDE209/Pb mixture group were due to the effect of Pb rather than BDE209. However, BDE209/Pb co-exposure elicited a synergistic increase in the production of IL-4, IL-6, TNFα, IFNγ, and IL-17A in the serum. BDE209 exposure alone also significantly affected spatial learning and increased the production of IL-10, TNFα, and IL-17 A in the serum of male offspring. Our work demonstrates that perinatal exposure to a low dose of Pb or the BDE209/Pb mixture, although it did not induce typical ASD-like symptoms, elicited restricted, repetitive patterns of behavior and affected learning in male offspring. In addition, the synergistic increase in the systemic inflammatory response in the BDE209/Pb co-exposure group underscores the importance of evaluating chemical mixtures in disease onset.


Assuntos
Transtorno do Espectro Autista/induzido quimicamente , Comportamento Animal/efeitos dos fármacos , Éteres Difenil Halogenados/toxicidade , Hipocampo/efeitos dos fármacos , Chumbo/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Animais , Transtorno do Espectro Autista/sangue , Transtorno do Espectro Autista/fisiopatologia , Transtorno do Espectro Autista/psicologia , Morte Celular/efeitos dos fármacos , Citocinas/sangue , Feminino , Idade Gestacional , Asseio Animal/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Mediadores da Inflamação/sangue , Masculino , Exposição Materna/efeitos adversos , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Gravidez , Comportamento Estereotipado/efeitos dos fármacos
6.
eNeuro ; 6(1)2019.
Artigo em Inglês | MEDLINE | ID: mdl-30834304

RESUMO

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder characterized by the repeated rise of concerns (obsessions) and repetitive unwanted behavior (compulsions). Although selective serotonin reuptake inhibitors (SSRIs) is the first-choice drug, response rates to SSRI treatment vary between symptom dimensions. In this study, to find a therapeutic target for SSRI-resilient OCD symptoms, we evaluated treatment responses of quinpirole (QNP) sensitization-induced OCD-related behaviors in mice. SSRI administration rescued the cognitive inflexibility, as well as hyperactivity in the lateral orbitofrontal cortex (lOFC), while no improvement was observed for the repetitive behavior. D2 receptor signaling in the central striatum (CS) was involved in SSRI-resistant repetitive behavior. An adenosine A2A antagonist, istradefylline, which rescued abnormal excitatory synaptic function in the CS indirect pathway medium spiny neurons (MSNs) of sensitized mice, alleviated both of the QNP-induced abnormal behaviors with only short-term administration. These results provide a new insight into therapeutic strategies for SSRI-resistant OCD symptoms and indicate the potential of A2A antagonists as a rapid-acting anti-OCD drug.


Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Transtornos Psicóticos/tratamento farmacológico , Purinas/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Resistência a Medicamentos , Masculino , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Transtorno Obsessivo-Compulsivo/metabolismo , Transtornos Psicóticos/metabolismo , Quimpirol , Receptores de Dopamina D2/metabolismo , Inibidores de Captação de Serotonina/farmacologia , Comportamento Estereotipado/efeitos dos fármacos , Comportamento Estereotipado/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Técnicas de Cultura de Tecidos
7.
Neuropharmacology ; 149: 27-34, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30731137

RESUMO

Ketogenic diets (KDs) are high fat, low carbohydrate formulations traditionally used to treat epilepsy; more recently, KDs have shown promise for a wide range of other neurological disorders. Drug addiction studies suggest that repeated exposure to drugs of abuse, including cocaine, results in a suite of neurobiological changes that includes neuroinflammation, decreased glucose metabolism, and disordered neurotransmission. Given that KDs positively regulate these factors, we addressed whether administration of a KD has potential as a novel therapy for drug addiction. In this study, male and female Sprague-Dawley rats were placed on a KD or a control diet (CD), beginning at five weeks of age and continuing through the end of behavioral testing. Three weeks after initiation of dietary treatments, rats received daily i.p. injections of cocaine (15 mg/kg) or saline vehicle for one week, were drug free for a subsequent week, and then all animals received a final challenge injection of 15 mg/kg cocaine. In the absence of cocaine injections, stereotyped locomotor responses were minimal and were unaffected by dietary treatment. In contrast, both males and females fed a KD exhibited decreased cocaine-induced stereotyped responses as compared to CD-fed rats. The sensitization of ambulatory responses was also disrupted in KD-fed rats. These results suggest that KDs directly impact dopamine-mediated behaviors, and hence may hold potential as a therapy for drug addiction.


Assuntos
Cocaína/farmacologia , Dietoterapia/métodos , Dieta Cetogênica/psicologia , Atividade Motora/efeitos dos fármacos , Comportamento Estereotipado/efeitos dos fármacos , Ácido 3-Hidroxibutírico/sangue , Animais , Comportamento Animal , Peso Corporal , Dopamina , Feminino , Masculino , Metabolismo , Modelos Animais , Ratos , Ratos Sprague-Dawley
8.
Epilepsy Res ; 151: 1-6, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30669043

RESUMO

Lycopene (LCP) is a carotenoid that protects against many diseases by alleviating oxidative stress. However, the effect of LCP on epileptic seizures has not been examined well in previous studies. In the current work, we employed kainic acid (KA) to induce experimental epileptic seizures in mice, and investigated the function of LCP during this process. We found that the onset and extent of KA-induced seizures were alleviated in LCP-pretreated mice. Nissl staining of hippocampus showed that the granule cell dispersion lesion induced by KA was improved by the LCP treatment. Additionally, we analyzed the oxidative stress levels in mice and found that LCP elevated SOD activity and suppressed MDA level in KA-induced seizures. Moreover, the expression of GABA receptors was influenced by LCP treatment. LCP suppressed the upregulation of gabrb2 and gabrb3 induced by KA, whereas it enhanced the expression of gabrb1. Results suggested that LCP plays a protective function in KA-induced seizures. Hence, it may be a potential functional food alternative for controlling and treating epileptic seizures.


Assuntos
Antioxidantes/administração & dosagem , Licopeno/administração & dosagem , Convulsões/prevenção & controle , Animais , Piscadela/efeitos dos fármacos , Modelos Animais de Doenças , Esquema de Medicação , Agonistas de Aminoácidos Excitatórios/toxicidade , Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Ácido Caínico/toxicidade , Malondialdeído , Camundongos , RNA Mensageiro/metabolismo , Receptores de GABA/genética , Receptores de GABA/metabolismo , Convulsões/induzido quimicamente , Convulsões/patologia , Comportamento Estereotipado/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Fatores de Tempo
9.
Behav Brain Res ; 360: 354-364, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30562568

RESUMO

The glutamate N-methyl-D-aspartate receptor (NMDAR) non-selective antagonist, ketamine, has been recently repurposed as a rapidly acting antidepressant, catalyzing the vigorous investigation of glutamate-signaling modulators as novel therapeutic agents for depressive disorders. Beneficial effects of this drug in the quick-acting treatment of depression are recognized. The long-term effects of ketamine have not been known, including the cognitive sphere. It is well acknowledged that prolonged exposure to stress induces depression and cognitive impairment. It seemed reasonable to ask how the long-term ketamine administration would affect stressed animals in the aspect of cognitive functions. In the current study we tested whether it is possible for ketamine, used in prolonged-regimen in rats, to alleviate stress-evoked memory deficits? Stressed (restraint 2 h daily for 21 days) and non-stressed rats (6-weeks-old) were treated with ketamine for 21 days and next subjected to a battery of behavioral tests: for the assessment of working and reference spatial memory (Morris water maze (MWM) and Barnes maze (BM)), stereotypy (stereotypy test - ST), locomotor functions (Open field - OF) and anxiety behavior (Elevated plus maze - EPM). Ketamine administration resulted in a significant stereotype behaviour in rats tested in ST. Stressed rats displayed a significant decline in the spatial working and reference memory. The effect of chronic ketamine administration depended on the type of test and differed between control rats and animals simultaneously exposed to chronic stress. However, in the MWM the impact was quite unequivocal, as we observed an improvement in spatial memory in stressed animals and a deterioration in non-stressed animals after ketamine administration. In the BM, the effect of ketamine changed in successive attempts, from favorable in the initial period to negative at the end of the test in the group of stressed animals and without a significant impact on control animals. We found no significant effects of ketamine on locomotor performance and on the level of anxiety. Taken together, these findings demonstrate that ketamine potently abolishes or prevents some kinds of stress-induced memory impairments and cognitive decline in rats, although in some circumstances, it could even increase damage to memory, especially in unstressed animals. It seems that the prolonged use of ketamine in the prevention of stress-induced memory declines can fulfill its role.


Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Ketamina/farmacologia , Estresse Fisiológico/fisiologia , Análise de Variância , Animais , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Wistar , Memória Espacial/efeitos dos fármacos , Comportamento Estereotipado/efeitos dos fármacos , Comportamento Estereotipado/fisiologia , Estresse Fisiológico/efeitos dos fármacos
10.
Artigo em Inglês | MEDLINE | ID: mdl-30261217

RESUMO

Autism is a neurodevelopmental disorder that affects social cognitive abilities resulting in communication or sensory deficits, and stereotyped behaviors in millions of people worldwide. Oxidant-antioxidant imbalance contributes significantly to the neurobehavioral dysregulations and severity of symptoms in patients with autism, however it has not been explored earlier whether it affects autism-like behavior directly. Therefore, we investigated oxidant-antioxidant balance in peripheral immune cells (neutrophils and CD3+ T cells) and cerebellum of BTBR T + tf/J (BTBR) mice which show autism-like behavior and the social C57BL/6 J (C57) mice. Further, we utilized buthionine sulfoximine (BSO), a glutathione depleting agent to assess the impact of oxidant-antioxidant dysregulation on autism-like behavior. Our study shows that BTBR mice have increased lipid/protein oxidation products in cerebellum and neutrophils/CD3+ T cells along with increased NADPH oxidase (NOX2) and inducible nitric oxide synthase (iNOS) expression. This was concurrent with lower levels of glutathione and enzymatic antioxidants such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the cerebellum and peripheral immune cells. BSO administration led to further lowering of glutathione with a concurrent upregulation of iNOS, and NOX2 in cerebellum and peripheral immune cells. However, there was deficiency of an adaptive antioxidant response which was associated with exaggerated repetitive behaviors in BTBR mice. On the other hand, C57 mice also had increased oxidative stress after BSO treatment, however there was an enzymatic antioxidant response both in cerebellum and periphery. Overall, this study suggests that BTBR mice have increased oxidative stress with a deficient enzymatic antioxidant response that is associated with autism-like repetitive behaviors.


Assuntos
Transtorno Autístico/metabolismo , Cerebelo/metabolismo , Neutrófilos/metabolismo , Estresse Oxidativo/fisiologia , Comportamento Estereotipado/fisiologia , Linfócitos T/metabolismo , Animais , Antimetabólitos/farmacologia , Butionina Sulfoximina/farmacologia , Complexo CD3/metabolismo , Cerebelo/efeitos dos fármacos , Glutationa/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Comportamento Social , Especificidade da Espécie , Comportamento Estereotipado/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos
11.
Mol Neurobiol ; 56(6): 4492-4517, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30338483

RESUMO

We utilized a cell-level approach to examine glycolytic pathways in the DLPFC of subjects with schizophrenia (n = 16) and control (n = 16) and found decreased mRNA expression of glycolytic enzymes in pyramidal neurons, but not astrocytes. To replicate these novel bioenergetic findings, we probed independent datasets for bioenergetic targets and found similar abnormalities. Next, we used a novel strategy to build a schizophrenia bioenergetic profile by a tailored application of the Library of Integrated Network-Based Cellular Signatures data portal (iLINCS) and investigated connected cellular pathways, kinases, and transcription factors using Enrichr. Finally, with the goal of identifying drugs capable of "reversing" the bioenergetic schizophrenia signature, we performed a connectivity analysis with iLINCS and identified peroxisome proliferator-activated receptor (PPAR) agonists as promising therapeutic targets. We administered a PPAR agonist to the GluN1 knockdown model of schizophrenia and found it improved long-term memory. Taken together, our findings suggest that tailored bioinformatics approaches, coupled with the LINCS library of transcriptional signatures of chemical and genetic perturbagens, may be employed to identify novel treatment strategies for schizophrenia and related diseases.


Assuntos
Metabolismo Energético , Redes Reguladoras de Genes , Esquizofrenia/metabolismo , Esquizofrenia/terapia , Animais , Análise por Conglomerados , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Descoberta de Drogas , Metabolismo Energético/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Microdissecção e Captura a Laser , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Pioglitazona/farmacologia , Inibição Pré-Pulso/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Reflexo de Sobressalto/efeitos dos fármacos , Reprodutibilidade dos Testes , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Comportamento Estereotipado/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
12.
Nat Neurosci ; 21(12): 1689-1703, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30397325

RESUMO

Genetic analyses have linked microRNA-137 (MIR137) to neuropsychiatric disorders, including schizophrenia and autism spectrum disorder. miR-137 plays important roles in neurogenesis and neuronal maturation, but the impact of miR-137 loss-of-function in vivo remains unclear. Here we show the complete loss of miR-137 in the mouse germline knockout or nervous system knockout (cKO) leads to postnatal lethality, while heterozygous germline knockout and cKO mice remain viable. Partial loss of miR-137 in heterozygous cKO mice results in dysregulated synaptic plasticity, repetitive behavior, and impaired learning and social behavior. Transcriptomic and proteomic analyses revealed that the miR-137 mRNA target, phosphodiesterase 10a (Pde10a), is elevated in heterozygous knockout mice. Treatment with the Pde10a inhibitor papaverine or knockdown of Pde10a ameliorates the deficits observed in the heterozygous cKO mice. Collectively, our results suggest that MIR137 plays essential roles in postnatal neurodevelopment and that dysregulation of miR-137 potentially contributes to neuropsychiatric disorders in humans.


Assuntos
Comportamento Animal/fisiologia , MicroRNAs/genética , Diester Fosfórico Hidrolases/metabolismo , Comportamento Social , Comportamento Estereotipado/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Camundongos , Camundongos Knockout , MicroRNAs/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/genética , Papaverina/farmacologia , Comportamento Estereotipado/efeitos dos fármacos
13.
Brain Res Bull ; 142: 328-337, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30172736

RESUMO

Autism spectrum disorder (ASD) is an extremely predominant neurodevelopmental disorder expressed as impairment in reciprocal social interaction along with repetitive, restricted, and stereotyped behaviors. The protein tyrosine kinase inhibitor, tyrphostin AG126 (AG126), regulates the expression of several genes that play an important role in the development of neuroinflammatory disorders. Here, we investigate the possible effects of AG126 (5 mg/kg daily through intraperitoneal injection) on self-grooming, marble burying, and hot plate test results in BTBR T + Itpr3tf/J mice (BTBR is a model of autism). We also explore the effects of AG126 administration on IL-17 A, RORγt, T-bet, and IFN-γ production in CD4+ T cells and on CCR6+ chemokine receptors in splenic cells. We further investigated the effect of AG126 administration on the mRNA and protein expression of IL-17 A, RORγt, T-bet, IFN-γ, and NF-κB in the brain tissue. Our results demonstrate that treatment of BTBR mice with AG126 reduced repetitive self-grooming scores and lowered hot plate sensitivity potentials. Furthermore, AG126 administration also caused a substantial reduction of IL-17 A, RORγt, T-bet, and IFN-γ production in CD4+ T cells and on CCR6+ chemokine receptors in splenic cells. BTBR mice treated with AG126 also show decreased mRNA and protein expression levels of IL-17 A, RORγt, T-bet, IFN-γ, and NF-κB activation in brain tissue. Our results indicate that treating BTBR mice with AG126 leads to protection against neuroimmune dysfunction/dysregulation through the inhibition of cytokines and transcription factor signaling. This mechanism may be useful in the development of future therapies for neuroimmune disorders.


Assuntos
Transtorno Autístico/tratamento farmacológico , Transtorno Autístico/metabolismo , Fármacos Neuroprotetores/farmacologia , Psicotrópicos/farmacologia , Tirfostinas/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Modelos Animais de Doenças , Interferon gama/metabolismo , Interleucina-17/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NF-kappa B/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Receptores CCR6/metabolismo , Transdução de Sinais/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/metabolismo , Comportamento Estereotipado/efeitos dos fármacos , Comportamento Estereotipado/fisiologia , Proteínas com Domínio T/metabolismo
14.
J Neuroinflammation ; 15(1): 249, 2018 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-30170624

RESUMO

BACKGROUND: The deficiency in 1α, 25-dihydroxyvitamin D3 (VD3) seems to increase the risk for neurodegenerative pathologies, including Parkinson's disease (PD). The majority of its actions are mediated by the transcription factor, VD3 receptor (VD3R). METHODS: The neuroprotective effects of VD3 were investigated on a PD model. Male Wistar rats were divided into the following groups: sham-operated (SO), 6-OHDA-lesioned (non-treated), and 6-OHDA-lesioned and treated with VD3 (7 days before the lesion, pre-treatment or for 14 days after the 6-OHDA striatal lesion, post-treatment). Afterwards, the animals were subjected to behavioral tests and euthanized for striatal neurochemical and immunohistochemical assays. The data were analyzed by ANOVA and the Tukey test and considered significant for p < 0.05. RESULTS: We showed that pre- or post-treatments with VD3 reversed behavioral changes and improved the decreased DA contents of the 6-OHDA group. In addition, VD3 reduced the oxidative stress, increased (TH and DAT), and reduced (TNF-alpha) immunostainings in the lesioned striata. While significant decreases in VD3R immunoreactivity were observed after the 6-OHDA lesion, these changes were blocked after VD3 pre- or post-treatments. We showed that VD3 offers neuroprotection, decreasing behavioral changes, DA depletion, and oxidative stress. In addition, it reverses partially or completely TH, DAT, TNF-alpha, and VD3R decreases of immunoreactivities in the non-treated 6-OHDA group. CONCLUSIONS: Taken together, VD3 effects could result from its anti-inflammatory and antioxidant actions and from its actions on VD3R. These findings should stimulate translational research towards the VD3 potential for prevention or treatment of neurodegenerative diseases, as PD.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Encefalite/etiologia , Encefalite/patologia , Estresse Oxidativo/efeitos dos fármacos , Transtornos Parkinsonianos/complicações , Vitamina D/farmacologia , Animais , Apomorfina/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Oxidopamina/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Ratos , Ratos Wistar , Comportamento Estereotipado/efeitos dos fármacos , Natação/fisiologia , Simpatolíticos/toxicidade , Tirosina 3-Mono-Oxigenase/metabolismo
15.
Sci Rep ; 8(1): 13077, 2018 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-30166610

RESUMO

Autistic spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in social communication and restricted/repetitive behavior patterns or interests. Antagonists targeting histamine H3 receptor (H3R) are considered potential therapeutic agents for the therapeutic management of different brain disorders, e.g., cognitive impairments. Therefore, the effects of subchronic treatment with the potent and selective H3R antagonist DL77 (5, 10, or 15 mg/kg, i.p.) on sociability, social novelty, anxiety, and aggressive/repetitive behavior in male Tuck-Ordinary (TO) mice with ASD-like behaviors induced by prenatal exposure to valproic acid (VPA, 500 mg/kg, i.p.) were evaluated using the three-chamber test (TCT), marble burying test (MBT), nestlet shredding test (NST), and elevated plus maze (EPM) test. The results showed that VPA-exposed mice exhibited significantly lower sociability and social novelty preference compared to VPA-exposed mice that were pretreated with DL77 (10 or 15 mg/kg, i.p.). VPA-exposed mice presented a significantly higher percentage of buried marbles in MBT and shredded nestlet significantly more in NST compared to the control groups. However, VPA-exposed animals pretreated with DL77 (10 or 15 mg/kg, i.p.) buried a reduced percentage of marbles in MBT and presented a significantly lower percentage of shredding behavior in NST. On the other hand, pretreatment with DL77 (5, 10, or 15 mg/kg, i.p.) failed to restore the disturbed anxiety levels and hyperactivity observed in VPA-exposed animals in EPM, whereas the reference drug donepezil (DOZ, 1 mg/kg, i.p.) significantly palliated the anxiety and reduced the hyperactivity measures of VPA-exposed mice. Furthermore, pretreatment with DL77 (10 or 15 mg/kg, i.p.) modulated oxidative stress status by increasing GSH and decreasing MDA, and it attenuated the proinflammatory cytokines IL-1ß, IL-6 and TNF-α exacerbated by lipopolysaccharide (LPS) challenge, in VPA-exposed mouse brain tissue. Taken together, these results provide evidence that modulation of brain histaminergic neurotransmission, such as by subchronic administration of the H3R antagonist DL77, may serve as an effective pharmacological therapeutic target to rescue ASD-like behaviors in VPA-exposed animals, although further investigations are necessary to corroborate and expand these initial data.


Assuntos
Transtorno Autístico/induzido quimicamente , Transtorno Autístico/tratamento farmacológico , Comportamento Animal , Antagonistas dos Receptores Histamínicos H3/uso terapêutico , Éteres Fenílicos/uso terapêutico , Piperidinas/uso terapêutico , Receptores Histamínicos H3/metabolismo , Ácido Valproico/efeitos adversos , Animais , Ansiedade/complicações , Ansiedade/fisiopatologia , Transtorno Autístico/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Comportamento de Escolha/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Donepezila/farmacologia , Donepezila/uso terapêutico , Comportamento Exploratório/efeitos dos fármacos , Feminino , Antagonistas dos Receptores Histamínicos H3/farmacologia , Mediadores da Inflamação/metabolismo , Malondialdeído/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Atividade Motora/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Éteres Fenílicos/farmacologia , Piperidinas/farmacologia , Comportamento Social , Comportamento Estereotipado/efeitos dos fármacos
16.
J Comp Neurol ; 526(13): 2133-2146, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30007046

RESUMO

Dopamine (DA) neurons derived from human embryonic stem cells (hESCs) are a promising unlimited source of cells for cell replacement therapy in Parkinson's disease (PD). A number of studies have demonstrated functionality of DA neurons originating from hESCs when grafted to the striatum of rodent and non-human primate models of PD. However, several questions remain in regard to their axonal outgrowth potential and capacity to integrate into host circuitry. Here, ventral midbrain (VM) patterned hESC-derived progenitors were grafted into the midbrain of 6-hydroxydopamine-lesioned rats, and analyzed at 6, 18, and 24 weeks for a time-course evaluation of specificity and extent of graft-derived fiber outgrowth as well as potential for functional recovery. To investigate synaptic integration of the transplanted cells, we used rabies-based monosynaptic tracing to reveal the origin and extent of host presynaptic inputs to grafts at 6 weeks. The results reveal the capacity of grafted neurons to extend axonal projections toward appropriate forebrain target structures progressively over 24 weeks. The timing and extent of graft-derived dopaminergic fibers innervating the dorsolateral striatum matched reduction in amphetamine-induced rotational asymmetry in the animals where recovery could be observed. Monosynaptic tracing demonstrated that grafted cells integrate with host circuitry 6 weeks after transplantation, in a manner that is comparable with endogenous midbrain connectivity. Thus, we demonstrate that VM patterned hESC-derived progenitors grafted to midbrain have the capacity to extensively innervate appropriate forebrain targets, integrate into the host circuitry and that functional recovery can be achieved when grafting fetal or hESC-derived DA neurons to the midbrain.


Assuntos
Neurônios Dopaminérgicos/fisiologia , Neurônios Dopaminérgicos/transplante , Mesencéfalo/cirurgia , Vias Neurais/fisiologia , Células-Tronco Neurais/fisiologia , Células-Tronco Neurais/transplante , Transtornos Parkinsonianos/cirurgia , Prosencéfalo/fisiologia , Sinapses/fisiologia , Anfetamina/farmacologia , Animais , Inibidores da Captação de Dopamina/farmacologia , Feminino , Humanos , Hidroxidopaminas , Camundongos , Fibras Nervosas/fisiologia , Transtornos Parkinsonianos/induzido quimicamente , Ratos Nus , Transplante de Células-Tronco , Comportamento Estereotipado/efeitos dos fármacos
17.
Int J Dev Neurosci ; 69: 68-79, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30004004

RESUMO

BACKGROUND: Previous studies have indicated an association between maternal metabolic conditions and general developmental disturbances of the offspring. OBJECTIVE: We aimed to investigate the influence of long-term maternal fructose intake during gestation and lactation on neurobehavioral development of rat offspring. METHODS: Twelve female Sprague Dawley rats were received either 30% fructose enriched water (n = 6) or regular tap water (control, n = 6) for 12 weeks. Then, control and fructose-received females were caged with a fertile male, and received 30% fructose and regular chow throughout pregnancy, delivery and until offspring's weaning. On P21, forty littermates (10 male control, 10 female control, 10 male fructose and 10 female fructose) were separated and housed with ad libitum access to standard food and tap water. Following behavioral evaluations at P50, brain levels of TNF-α, neuregulin 1 (NRG1), glutamic acid decarboxylase 67 (GAD67), nerve growth factor (NGF), insulin-like growth factor 1 (IGF-1), and 5-hydroxyindoleacetic acid (5-HIAA) were measured. Histologically, hippocampal neuronal density and GFAP expression were assessed. RESULTS: Analysis of the behavioral tests (three-chamber social test, open field test, passive avoidance learning test and stereotypy test) revealed significant differences among the groups. Histologically, hippocampal CA1 and CA3 regions displayed significant alterations such as gliosis and neuronal cell death in fructose-exposed groups compare to controls. Biochemical measurements of the brain levels of TNF-α and neurodevelopmental markers showed significant differences between controls and fructose-exposed groups. CONCLUSION: These results suggest a possible link between the chronic maternal metabolic stress, such as long-term fructose intake, and neurodevelopmental disturbances in the offspring.


Assuntos
Comportamento Animal/efeitos dos fármacos , Frutose/farmacologia , Sistema Nervoso/efeitos dos fármacos , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Feminino , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Lactação , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Neurônios/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/psicologia , Ratos , Ratos Sprague-Dawley , Comportamento Social , Comportamento Estereotipado/efeitos dos fármacos
18.
Acta Neuropathol ; 136(4): 621-639, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30046897

RESUMO

Parkinson's disease (PD), the most common neurodegenerative movement disorder, is characterized by the progressive loss of nigral dopamine neurons. The deposition of fibrillary aggregated α-synuclein in Lewy bodies (LB), that is considered to play a causative role in the disease, constitutes another key neuropathological hallmark of PD. We have recently described that synapsin III (Syn III), a synaptic phosphoprotein that regulates dopamine release in cooperation with α-synuclein, is present in the α-synuclein insoluble fibrils composing the LB of patients affected by PD. Moreover, we observed that silencing of Syn III gene could prevent α-synuclein fibrillary aggregation in vitro. This evidence suggests that Syn III might be crucially involved in α-synuclein pathological deposition. To test this hypothesis, we studied whether mice knock-out (ko) for Syn III might be protected from α-synuclein aggregation and nigrostriatal neuron degeneration resulting from the unilateral injection of adeno-associated viral vectors (AAV)-mediating human wild-type (wt) α-synuclein overexpression (AAV-hαsyn). We found that Syn III ko mice injected with AAV-hαsyn did not develop fibrillary insoluble α-synuclein aggregates, showed reduced amount of α-synuclein oligomers detected by in situ proximity ligation assay (PLA) and lower levels of Ser129-phosphorylated α-synuclein. Moreover, the nigrostriatal neurons of Syn III ko mice were protected from both synaptic damage and degeneration triggered by the AAV-hαsyn injection. Our observations indicate that Syn III constitutes a crucial mediator of α-synuclein aggregation and toxicity and identify Syn III as a novel therapeutic target for PD.


Assuntos
Neostriado/patologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Substância Negra/patologia , Sinapses/patologia , Sinapsinas/deficiência , alfa-Sinucleína/metabolismo , Anfetamina/farmacologia , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Dependovirus/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Degeneração Neural/genética , Degeneração Neural/patologia , Neurônios/patologia , Comportamento Estereotipado/efeitos dos fármacos , Proteína 2 Associada à Membrana da Vesícula/metabolismo
19.
Pharmacol Rep ; 70(4): 650-657, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29902669

RESUMO

BACKGROUND: The endocannabinoid (eCB) system is strongly involved in the regulation of anxiety and feeding behavior. RVD-hemopressin(α) [RVD-hp(α)], a N-terminally extended form of hemopressin, is a negative allosteric modulator of the cannabinoid (CB) 1 receptor and a positive allosteric modulator of CB2 receptor which has been recently reported to exert anxiolytic/antidepressant and anorexigenic effects after peripheral administration in rats. Pharmacological evidences reported a possible link between brain hypocretin/orexin, monoamine and eCB systems, as regards appetite and emotional behavior control. Considering this, the aim of our work was to investigated the effects of RVD-hp(α) on anxiety like behavior and food intake after central administration and related it to monoamine levels and orexin-A gene expression, in the hypothalamus. METHODS: We have studied the effects of central RVD-hp(α) (10nmol) injection on anxiety-like behavior and feeding using different behavioral tests. Hypothalamic levels of norepinephrine (NE), dopamine (DA) and serotonin (5-hydroxytryptamine, 5-HT) and gene expression of orexin-A and proopiomelanocortin (POMC) were measured by high performance liquid chromatography (HPLC) and real-time reverse transcription polymerase chain reaction (RT-PCR) analysis, respectively. RESULTS: Central RVD-hp(α) administration decreased locomotion activity and stereotypies. Moreover, RVD-hp(α) treatment inhibited anxiogenic-like behavior and food intake, NE levels and orexin-A gene expression, in the hypothalamus. CONCLUSION: Concluding, in the present study we demonstrated that central RVD-hp(α) induced anxiolytic and anorexigenic effects possibly related to reduced NE and orexin-A and POMC signaling, in the hypothalamus. These findings further support the central role of the peptide in rat brain thus representing an innovative pharmacological approach for designing new anorexigenic drugs targeting eCB system.


Assuntos
Comportamento Exploratório/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Hemoglobinas/farmacologia , Hipotálamo/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Norepinefrina/metabolismo , Orexinas/biossíntese , Fragmentos de Peptídeos/farmacologia , Animais , Dopamina/metabolismo , Hemoglobinas/administração & dosagem , Hipotálamo/metabolismo , Injeções Intraventriculares , Masculino , Atividade Motora/efeitos dos fármacos , Fragmentos de Peptídeos/administração & dosagem , Pró-Opiomelanocortina/biossíntese , Ratos , Serotonina/metabolismo , Comportamento Estereotipado/efeitos dos fármacos
20.
Alcohol ; 71: 5-13, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29929089

RESUMO

Clinical studies have shown a positive correlation between novelty-seeking behavior and the susceptibility to consume drugs of abuse. Although several animal studies have demonstrated this correlation with psychostimulants or morphine, studies with alcohol have shown conflicting results. The aim of this work was to investigate alcohol-induced motor effects in Wistar rats with different responses to novelty. Animals were classified as Low- (LR) or High-Responders (HR) to novelty, depending on their horizontal activity in an automated open field. Motor activity was recorded in naïve, saline, and alcohol-administered rats at different doses (0.1, 0.25, 0.5, 1.0, or 2.5 g/kg). Horizontal movements, rearings, and stereotyped behaviors were evaluated. After the behavioral test, animals were sacrificed and blood alcohol concentrations (BACs) were measured. Low (0.1 and 0.25 g/kg) and high (2.5 g/kg) alcohol doses decreased horizontal movements in LR animals, whereas 1.0 g/kg increased this parameter in HR rats. Rearings were increased by alcohol 1.0 g/kg in LR animals. In HR rats, alcohol doses of 0.5 and 1.0 g/kg also increased this parameter. Stereotyped behaviors were decreased by an alcohol dose of 2.5 g/kg in LR animals, but were increased by an intermediate dose (1.0 g/kg) in HR rats. Differences in horizontal movements and rearings were found between LR and HR animals at certain ethanol doses. Horizontal movements (0.25 g/kg) and rearings (0.5 g/kg) were lower in LR than HR rats; however, rearings were lower in HR than LR rats at 1.0 g/kg. BACs were similar between LR and HR rats at all ethanol doses. These findings suggest that HR rats are more responsive to the stimulant effects of intermediate alcohol doses, whereas LR animals are sensitive to low/high doses of the drug. Sensitivity to alcohol motor effects may substantially depend on the initial animal's response to a novel environment. The stimulant effects of alcohol may constitute important behavioral traits significantly associated with the rewarding properties of the drug.


Assuntos
Etanol/farmacologia , Atividade Motora/efeitos dos fármacos , Animais , Concentração Alcoólica no Sangue , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Comportamento Estereotipado/efeitos dos fármacos
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