RESUMO
BACKGROUND: Treatment of refractory bipolar disorder (BD) is extremely challenging. Deep brain stimulation (DBS) holds promise as an effective treatment intervention. However, we still understand very little about the mechanisms of DBS and its application on BD. AIM: The present study aimed to investigate the behavioural and neurochemical effects of ventral tegmental area (VTA) DBS in an animal model of mania induced by methamphetamine (m-amph). METHODS: Wistar rats were given 14 days of m-amph injections, and on the last day, animals were submitted to 20 min of VTA DBS in two different patterns: intermittent low-frequency stimulation (LFS) or continuous high-frequency stimulation (HFS). Immediately after DBS, manic-like behaviour and nucleus accumbens (NAc) phasic dopamine (DA) release were evaluated in different groups of animals through open-field tests and fast-scan cyclic voltammetry. Levels of NAc dopaminergic markers were evaluated by immunohistochemistry. RESULTS: M-amph induced hyperlocomotion in the animals and both DBS parameters reversed this alteration. M-amph increased DA reuptake time post-sham compared to baseline levels, and both LFS and HFS were able to block this alteration. LFS was also able to reduce phasic DA release when compared to baseline. LFS was able to increase dopamine transporter (DAT) expression in the NAc. CONCLUSION: These results demonstrate that both VTA LFS and HFS DBS exert anti-manic effects and modulation of DA dynamics in the NAc. More specifically the increase in DA reuptake driven by increased DAT expression may serve as a potential mechanism by which VTA DBS exerts its anti-manic effects.
Assuntos
Estimulação Encefálica Profunda , Modelos Animais de Doenças , Mania , Metanfetamina , Ratos Wistar , Área Tegmentar Ventral , Animais , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismo , Metanfetamina/farmacologia , Masculino , Ratos , Mania/terapia , Mania/induzido quimicamente , Estimulantes do Sistema Nervoso Central/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Transtorno Bipolar/terapia , Transtorno Bipolar/induzido quimicamenteRESUMO
It is known that bipolar disorder has a multifactorial aetiology where the interaction between genetic and environmental factors is responsible for its development. Because of this, epigenetics has been largely studied in psychiatric disorders. The present study aims to evaluate the effects of histone deacetylase inhibitors on epigenetic enzyme alterations in rats or mice submitted to animal models of mania induced by dextro-amphetamine or sleep deprivation, respectively. Adult male Wistar rats were subjected to 14 days of dextro-amphetamine administration, and from the eighth to the fourteenth day, the animals were treated with valproate and sodium butyrate in addition to dextro-amphetamine injections. Adult C57BL/6 mice received 7 days of valproate or sodium butyrate administration, being sleep deprived at the last 36 hr of the protocol. Locomotor and exploratory activities of rats and mice were evaluated in the open-field test, and histone deacetylase, DNA methyltransferase, and histone acetyltransferase activities were assessed in the frontal cortex, hippocampus, and striatum. Dextro-amphetamine and sleep deprivation induced hyperactivity and increased histone deacetylase and DNA methyltransferase activities in the animal's brain. Valproate and sodium butyrate were able to reverse hyperlocomotion induced by both animal models, as well as the alterations on histone deacetylase and DNA methyltransferase activities. There was a positive correlation between enzyme activities and number of crossings for both models. Histone deacetylase and DNA methyltransferase activities also presented a positive correlation between theirselves. These results suggest that epigenetics can play an important role in BD pathophysiology as well as in its treatment.
Assuntos
Antimaníacos , Privação do Sono , Anfetamina , Animais , Antimaníacos/farmacologia , Antimaníacos/uso terapêutico , Modelos Animais de Doenças , Epigênese Genética , Masculino , Mania , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Wistar , Sono REMRESUMO
Evaluate the efficacy of folic acid (FA) as a therapeutic adjunct to lithium (Li) on the manic-like behaviors as well as parameters of oxidative stress and inflammation in an animal model of mania induced by m-amphetamine (m-AMPH). Wistar rats first received m-AMPH or saline (NaCl 0.9%, Sal) for 14 days. Between the 8th and 14th day, rats were treated with water, Li, FA or a combination of thereof drugs (Li + FA). Manic-like behaviors were assessed in the open-field test. Oxidative stress and inflammation parameters were assessed in the frontal cortex, striatum, and hippocampus. Administration of m-AMPH in rats significantly enhanced the exploratory and locomotor behaviors, as well as the risk-taking and stereotypic behaviors. Li + FA reversed these behavioral alterations elicited by m-AMPH. Administration of this psychostimulant also increased oxidative damage to lipids and proteins, whereas Li + FA reversed these oxidative damages. m-AMPH also induced an increase in the glutathione peroxidase (GPx) activity and a decrease in the glutathione reductase (GR) activity. Li + FA reversed the alteration in GR activity, but not in GPx activity. In addition, m-AMPH increased the IL-1ß and TNF-α levels in the rat brain; Li + FA combined therapy reversed the alterations on these inflammatory parameters. FA administration per se reduced the increased TNF-α content induced by m-AMPH. Present study provides evidence that FA is effective as an adjunct to Li standard therapy on manic-like behaviors, oxidative stress and inflammatory parameters in a model of mania induced by m-AMPH.
Assuntos
Antimaníacos/administração & dosagem , Ácido Fólico/administração & dosagem , Mediadores da Inflamação/antagonistas & inibidores , Lítio/administração & dosagem , Mania/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Anfetamina/toxicidade , Animais , Estimulantes do Sistema Nervoso Central/toxicidade , Modelos Animais de Doenças , Quimioterapia Combinada , Mediadores da Inflamação/metabolismo , Masculino , Mania/induzido quimicamente , Mania/metabolismo , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar , Resultado do TratamentoRESUMO
Background: The intracerebroventricular injection of ouabain, a specific inhibitor of the Na+/K+-adenosine-triphosphatase (Na+/K+-ATPase) enzyme, induces hyperactivity in rats in a putative animal model of mania. Several evidences have suggested that the protein kinase C signaling pathway is involved in bipolar disorder. In addition, it is known that protein kinase C inhibitors, such as lithium and tamoxifen, are effective in treating acute mania. Methods: In the present study, we investigated the effects of lithium and tamoxifen on the protein kinase C signaling pathway in the frontal cortex and hippocampus of rats submitted to the animal model of mania induced by ouabain. We showed that ouabain induced hyperlocomotion in the rats. Results: Ouabain increased the protein kinase C activity and the protein kinase C and MARCKS phosphorylation in frontal cortex and hippocampus of rats. Lithium and tamoxifen reversed the behavioral and protein kinase C pathway changes induced by ouabain. These findings indicate that the Na+/K+-ATPase inhibition can lead to protein kinase C alteration. Conclusions: The present study showed that lithium and tamoxifen modulate changes in the behavior and protein kinase C signalling pathway alterations induced by ouabain, underlining the need for more studies of protein kinase C as a possible target for treatment of bipolar disorder.
Assuntos
Antidepressivos/uso terapêutico , Transtorno Bipolar/induzido quimicamente , Inibidores Enzimáticos/toxicidade , Lítio/uso terapêutico , Ouabaína/toxicidade , Proteína Quinase C/metabolismo , Tamoxifeno/uso terapêutico , Análise de Variância , Animais , Transtorno Bipolar/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Modelos Animais de Doenças , Vias de Administração de Medicamentos , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Ratos , Ratos WistarRESUMO
OBJECTIVES: The goal of the present study was to investigate the effects of lithium administration on behavior, oxidative stress parameters and cytokine levels in the periphery and brain of mice subjected to an animal model of mania induced by paradoxical sleep deprivation (PSD). METHODS: Male C57 mice were treated with saline or lithium for 7 days. The sleep deprivation protocol started on the 5th day during for the last 36 hours of the treatment period. Immediately after the sleep deprivation protocol, animals locomotor activity was evaluated and serum and brain samples was extracted to evaluation of corticosterone and adrenocorticotropic hormone circulating levels, oxidative stress parameters and citokynes levels. RESULTS: The results showed that PSD induced hyperactivity in mice, which is considered a mania-like behavior. PSD increased lipid peroxidation and oxidative damage to DNA, as well as causing alterations to antioxidant enzymes in the frontal cortex, hippocampus and serum of mice. In addition, PSD increased the levels of cytokines in the brains of mice. Treatment with lithium prevented the mania-like behavior, oxidative damage and cytokine alterations induced by PSD. CONCLUSIONS: Improving our understanding of oxidative damage in biomolecules, antioxidant mechanisms and the inflammatory system - alterations presented in the animal models of mania - is important in helping us to improve our knowledge concerning the pathophysiology of BD, and the mechanisms of action employed by mood stabilizers.
Assuntos
Transtorno Bipolar , Encéfalo/metabolismo , Citocinas/sangue , Compostos de Lítio/farmacologia , Estresse Oxidativo , Privação do Sono/complicações , Hormônio Adrenocorticotrópico/sangue , Animais , Antimaníacos/farmacologia , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/etiologia , Transtorno Bipolar/metabolismo , Corticosterona/sangue , Modelos Animais de Doenças , Hipercinese/metabolismo , Hipercinese/prevenção & controle , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Esforço Físico/efeitos dos fármacos , Resultado do TratamentoRESUMO
OBJECTIVES: Several recent studies have suggested that the physiopathology of bipolar disorder (BD) is related to immune system alterations and inflammation. Lithium (Li) is a mood stabilizer that is considered the first-line treatment for this mood disorder. The goal of the present study was to investigate the effects of Li administration on behavior and cytokine levels [interleukin (IL)-1ß, IL-4, IL-6, IL-10, and tumor necrosis factor-alpha (TNF-α)] in the periphery and brains of rats subjected to an animal model of mania induced by amphetamine (d-AMPH). METHODS: Male Wistar rats were treated with d-AMPH or saline (Sal) for 14 days; on Day 8 of treatment, the rats were administered Li or Sal for the final seven days. Cytokine (IL-1ß, IL-4, IL-6, IL-10, and TNF-α) levels were evaluated in the cerebrospinal fluid (CSF), serum, frontal cortex, striatum, and hippocampus. RESULTS: The present study showed that d-AMPH induced hyperactivity in rats (p < 0.001), and Li treatment reversed this behavioral alteration (p < 0.001). In addition, d-AMPH increased the levels of IL-4, IL-6, IL-10, and TNF-α in the frontal cortex (p < 0.001), striatum (p < 0.001), and serum (p < 0.001), and treatment with Li reversed these cytokine alterations (p < 0.001). CONCLUSIONS: Li modulates peripheral and cerebral cytokine production in an animal model of mania induced by d-AMPH, suggesting that its action on the inflammatory system may contribute to its therapeutic efficacy.
Assuntos
Antimaníacos/farmacologia , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/imunologia , Encéfalo/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Compostos de Lítio/farmacologia , Atividade Motora/efeitos dos fármacos , Animais , Antimaníacos/uso terapêutico , Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/tratamento farmacológico , Encéfalo/imunologia , Estimulantes do Sistema Nervoso Central/toxicidade , Citocinas/líquido cefalorraquidiano , Citocinas/imunologia , Dextroanfetamina/toxicidade , Modelos Animais de Doenças , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/imunologia , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Hipercinese/induzido quimicamente , Hipercinese/tratamento farmacológico , Hipercinese/imunologia , Interleucina-10/líquido cefalorraquidiano , Interleucina-10/imunologia , Interleucina-1beta/líquido cefalorraquidiano , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/imunologia , Interleucina-4/líquido cefalorraquidiano , Interleucina-4/imunologia , Interleucina-6/líquido cefalorraquidiano , Interleucina-6/imunologia , Compostos de Lítio/uso terapêutico , Masculino , Atividade Motora/imunologia , Neostriado/efeitos dos fármacos , Neostriado/imunologia , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/líquido cefalorraquidiano , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/imunologiaRESUMO
The consumption of palatable high-fat and high-sugar foods have increased dramatically over the past years. Overconsumption of calorically dense food contributes to increasing rates of overweight and obesity that are associated with psychiatry disorders, in particular mood and anxiety disorders. This study evaluated the impact of palatable cafeteria diet (CAF) intake on cognitive and noncognitive behaviors, as well as identified factors related to these behaviors through an evaluation of brain neurotrophic factor (BDNF, NGF, and GDNF) levels in hippocampus of mice. Male Swiss mice received two different diets during 13 weeks: standard chow (STA) and highly CAF. Posteriorly, forced swimming test (FST), tail suspension test (TST), plus-maze test (PMT), open-field tests (OFT), and object recognition task (ORT) were utilized as behavioral tests. In addition, brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and nerve growth factor (NGF) neurotrophins' levels were evaluated in hippocampus of mice. The results demonstrated that mice from the CAF group showed a decrease in the immobility time in the FST and TST. Besides, mice in the CAF group spent more time in the open arms of the PMT. No significant differences were observed in the cognitive behaviors, which were evaluated in the OFT and ORT. In addition, the CAF group showed that BDNF and NGF protein levels increased in the hippocampus of mice. In conclusion, our data suggest that the consumption of palatable high-fat and high-sugar foods induces antidepressant- and anxiolytic-like behaviors, which can be related with BDNF and NGF expression increases in hippocampus of mice in the CAF group.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/biossíntese , Encéfalo/metabolismo , Cognição/fisiologia , Dieta Hiperlipídica , Sacarose Alimentar/administração & dosagem , Fator de Crescimento Neural/biossíntese , Animais , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Ingestão de Energia/fisiologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/biossíntese , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Fatores de Crescimento Neural/biossínteseRESUMO
Fenproporex (Fen) is an amphetamine-based anorectic; amphetamine use causes a broad range of severe cognitive deficits and anxiogenic-like effects. In this study we evaluated pharmacological effects of the chronic administration of Fen on cognitive and non-cognitive behaviors. Male adult Wistar rats received intraperitoneal administration of vehicle (control group) or Fen (6.25, 12.5 or 25 mg/kg) for 14 days; the animals were then subjected to habituation and object recognition tasks in open-field apparatus, and elevated plus-maze task. The administration of Fen (12.5 and 25 mg/kg) impaired habituation during the second exposure to the habituation task. In addition, the same doses of Fen also impaired the performance in object recognition task. In elevated plus-maze task, the administration of Fen (in all doses tested) induced anxiogenic-like effects in rats. Our results suggest that chronic Fen administration alters memory and induces anxiogenic-like effects in rats.
Assuntos
Anfetaminas/farmacologia , Depressores do Apetite/farmacologia , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Animais , Ansiedade/induzido quimicamente , Ansiedade/psicologia , Relação Dose-Resposta a Droga , Habituação Psicofisiológica/efeitos dos fármacos , Injeções Intraperitoneais , Masculino , Memória/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/psicologia , Ratos , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacosRESUMO
Studies have consistently reported the participation of oxidative stress in bipolar disorder (BD). Evidences indicate that omega-3 (ω3) fatty acids play several important roles in brain development and functioning. Moreover, preclinical and clinical evidence suggests roles for ω3 fatty acids in BD. Considering these evidences, the present study aimed to investigate the effects of ω3 fatty acids on locomotor behavior and oxidative stress parameters (TBARS and protein carbonyl content) in brain of rats subjected to an animal model of mania induced by fenproporex. The fenproporex treatment increased locomotor behavior in saline-treated rats under reversion and prevention model, and ω3 fatty acids prevented fenproporex-related hyperactivity. Moreover, fenproporex increased protein carbonyls in the prefrontal cortex and cerebral cortex, and the administration of ω3 fatty acids reversed this effect. Lipid peroxidation products also are increased in prefrontal cortex, striatum, hippocampus and cerebral after fenproporex administration, but ω3 fatty acids reversed this damage only in the hippocampus. On the other hand, in the prevention model, fenproporex increased carbonyl content only in the cerebral cortex, and administration of ω3 fatty acids prevented this damage. Additionally, the administration of fenproporex resulted in a marked increased of TBARS in the prefrontal cortex, hippocampus, striatum and cerebral cortex, and prevent this damage in the prefrontal cortex, hippocampus and striatum. In conclusion, we are able to demonstrate that fenproporex-induced hyperlocomotion and damage through oxidative stress were prevented by ω3 fatty acids. Thus, the ω3 fatty acids may be important adjuvant therapy of bipolar disorder.
Assuntos
Anfetaminas/toxicidade , Antioxidantes/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/tratamento farmacológico , Ácidos Graxos Ômega-3/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/psicologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Ácidos Graxos Ômega-3/farmacologia , Hipercinese/induzido quimicamente , Hipercinese/tratamento farmacológico , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Terminações Pré-Sinápticas/efeitos dos fármacos , Carbonilação Proteica/efeitos dos fármacos , Ratos , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/análiseRESUMO
There is increasing interest in the possibility that mitochondrial impairment may play an important role in bipolar disorder (BD). The Krebs cycle is the central point of oxidative metabolism, providing carbon for biosynthesis and reducing agents for generation of ATP. Recently, studies have suggested that histone deacetylase (HDAC) inhibitors may have antimanic effects. The present study aims to investigate the effects of sodium butyrate (SB), a HDAC inhibitor, on Krebs cycle enzymes activity in the brain of rats subjected to an animal model of mania induced by D-amphetamine (D-AMPH). Wistar rats were first given D-AMPH or saline (Sal) for 14 days, and then, between days 8 and 14, rats were treated with SB or Sal. The citrate synthase (CS), succinate dehydrogenase (SDH), and malate dehydrogenase (MDH) were evaluated in the prefrontal cortex, hippocampus, and striatum of rats. The D-AMPH administration inhibited Krebs cycle enzymes activity in all analyzed brain structures and SB reversed D-AMPH-induced dysfunction analyzed in all brain regions. These findings suggest that Krebs cycle enzymes' inhibition can be an important link for the mitochondrial dysfunction seen in BD and SB exerts protective effects against the D-AMPH-induced Krebs cycle enzymes' dysfunction.
Assuntos
Encéfalo/efeitos dos fármacos , Ácido Butírico/farmacologia , Citrato (si)-Sintase/metabolismo , Antagonistas dos Receptores Histamínicos/farmacologia , Malato Desidrogenase/metabolismo , Succinato Desidrogenase/metabolismo , Anfetamina/farmacologia , Análise de Variância , Animais , Encéfalo/enzimologia , Estimulantes do Sistema Nervoso Central/farmacologia , Ciclo do Ácido Cítrico/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Masculino , Ratos , Ratos WistarRESUMO
Bipolar disorder is a severe mood disorder with high morbidity and mortality. Despite adequate treatment, patients continue to have recurrent mood episodes, residual symptoms, and functional impairment. Some preclinical studies have shown that histone deacetylase inhibitors may act on depressive-like and manic-like behaviors. Therefore, the aim of the present study was to evaluate the effects of sodium butyrate (SB) on behavioral changes in animal models of depression and mania. The animals were submitted to protocols of chronic mild stress or maternal deprivation for induction of depressive-like behaviors and subjected to amphetamine, or ouabain administration for induction of manic-like behaviors. SB reversed the depressive-like and manic-like behaviors evaluated in the animal models. From these results we can suggest that SB may be a potential mood stabilizer.
Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Ácido Butírico/farmacologia , Afeto/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/fisiopatologia , Modelos Animais de Doenças , Masculino , Ratos , Ratos WistarRESUMO
This study aimed to evaluate Haloperidol's (Hal) effects on the behavioral, neurotrophic factors, and epigenetic parameters in an animal model of schizophrenia (SCZ) induced by ketamine (Ket). Injections of Ket or saline were administered intraperitoneal (once a day) between the 1st and 14th days of the experiment. Water or Hal was administered via gavage between the 8th and 14th experimental days. Thirty minutes after the last injection, the animals were subjected to behavioral analysis. The activity of DNA methyltransferase (DNMT), histone deacetylase (HDAC), and histone acetyltransferase and levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and glial-derived neurotrophic factor (GDNF) were evaluated in the frontal cortex, hippocampus, and striatum. Ket increased the covered distance and time spent in the central area of the open field, and Hal did not reverse these behavioral alterations. Significant increases in the DNMT and HDAC activities were detected in the frontal cortex and striatum from rats that received Ket, Hal, or a combination thereof. Besides, Hal per se increased the activity of DNMT and HDAC in the hippocampus of rats. Hal per se or the association of Ket plus Hal decreased BDNF, NGF, NT-3, and GDNF, depending on the brain region and treatment regimen. The administration of Hal can alter the levels of neurotrophic factors and the activity of epigenetic enzymes, which can be a factor in the development of effect collateral in SCZ patients. However, the precise mechanisms involved in these alterations are still unclear.
Assuntos
Ketamina , Esquizofrenia , Humanos , Ratos , Animais , Haloperidol/farmacologia , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Ketamina/toxicidade , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial , Fator de Crescimento Neural/genética , Modelos Animais de Doenças , Epigênese GenéticaRESUMO
In this study methamphetamine (m-AMPH) and dextroamphetamine (d-AMPH) were compared to determine the potency of the two drugs on behavior and oxidative damage in brain of rats. Male adult Wistar rats were given single (acute administration) or repeated (chronic administration, 14 days) intraperitoneal injections of saline (0.9% NaCl), d-AMPH (2 mg/kg) or m-AMPH (0.25, 0.5, 1 or 2 mg/kg). Locomotor activity was evaluated in open-field apparatus 2 h after the last drug injection. Additionally, thiobarbituric acid reactive substances (TBARS) and protein carbonyl formation were measured in the prefrontal cortex, amygdala, hippocampus and striatum. In both experiments, d-AMPH and m-AMPH (all doses administered) increased the locomotor activity of animals, meantime, no significant difference between d-AMPH and m-AMPH was observed. d-AMPH and m-AMPH increased lipid and protein damage, but m-AMPH was more potent than d-AMPH, however, this effect varies depending on the brain region and the experimental protocol. The results of this study show that d-AMPH and m-AMPH have similar behavioral effects, which previous studies had already reported. On the other hand, this study demonstrated that the m-AMPH induces oxidative damage greater than d-AMPH, showing neurochemical differences previously unknown.
Assuntos
Encéfalo/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/toxicidade , Dextroanfetamina/toxicidade , Comportamento Exploratório/efeitos dos fármacos , Metanfetamina/toxicidade , Atividade Motora/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Carbonilação Proteica , Ratos , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Fatores de TempoRESUMO
Susceptibility to psychiatric disorders seems to be influenced by environmental disturbances throughout all stages of life. Epigenetics is described as a key "bridge" between gene and environment, shaping gene expression and phenotype in response to environmental influences. For a long time, it was believed the epigenetic information could not be transmitted from one generation to the next, however, recent evidence has demonstrated that these acquired changes can be transmitted across generations in different species, with implications also for humans. The emerging evidence of epigenetic inheritance mechanisms is changing the concept of how and what information can be transferred across generations, rising as a promising theory to explain how psychiatric-related information can be inherited. In this review, we will discuss the main theory about epigenetic inheritance, present clinical evidence of its potential role in major psychiatric disorders, and how studies with patients and animal models have helped describe the epigenetic mechanisms and possible targets underlying this process in schizophrenia, bipolar disorder, depression, post-traumatic stress disorder, anxiety, substance use disorder and autism.
Assuntos
Padrões de Herança , Transtornos Mentais , Animais , Metilação de DNA , Epigênese Genética/genética , Epigenômica , Humanos , Transtornos Mentais/genética , FenótipoRESUMO
The present study investigated the effect of the histone deacetylase inhibitor, sodium butyrate (SB), on locomotor behavior and on mitochondrial respiratory-chain complexes activity in the brain of rats subjected to an animal model of mania induced by d-amphetamine (d-AMPH). In the reversal treatment, Wistar rats were first treated with d-AMPH or saline (Sal) for 14 days. Thereafter, between days 8 and 14, rats were administered SB or Sal. In the prevention treatment, rats were treated with SB or Sal for 14 days and received d-AMPH or Sal between days 8 and 14. The d-AMPH treatment increased locomotor behavior in Sal-treated rats under reversion and prevention treatment, and SB reversed and prevented d-AMPH-related hyperactivity. Moreover, d-AMPH decreased the activity of mitochondrial respiratory-chain complexes in Sal-treated rats in the prefrontal cortex, hippocampus, striatum, and amygdala in both experiments, and SB was able to reverse and prevent this impairment. The present study suggests that the mechanism of action of SB involves induction of mitochondrial function in parallel with behavioral changes, reinforcing the need for more studies on histone deacetylase inhibitors as a possible target for new medications for bipolar disorder treatment.
Assuntos
Antimaníacos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Ácido Butírico/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Atividade Motora/efeitos dos fármacos , Animais , Antimaníacos/farmacologia , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/metabolismo , Encéfalo/metabolismo , Ácido Butírico/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Dextroanfetamina/farmacologia , Modelos Animais de Doenças , Inibidores de Histona Desacetilases/farmacologia , Hipercinese/induzido quimicamente , Hipercinese/tratamento farmacológico , Hipercinese/metabolismo , Masculino , Ratos , Ratos WistarRESUMO
BACKGROUND: The present study aims to evaluate the effects of ouabain on memory and neurotrophic parameters in the brains of rats. METHODS: Wistar rats received an intracerebroventricular (ICV) injection of ouabain or artificial cerebrospinal fluid (aCSF). Seven and 14 days after ICV administration, the animals were subjected to the open-field and splash tests. Furthermore, the pro-BDNF, BDNF, TrkB, and CREB were assessed in the frontal cortex and hippocampus of the rats, in both seven and 14 days after ICV injection. The memory of the animals was tested by novel object recognition test (NOR) and inhibitory avoidance task (IA), only 14 days after ICV administration. RESULTS: Ouabain increased locomotion and exploration in the animals seven days after its administration; however, 14 days after ICV, these behavioral parameters return to the basal level. Seven days after ouabain administration increased grooming behavior in the splash test; on the other hand, seven days after ouabain injection decreased the grooming behavior, which is considered an anhedonic response. Besides, ouabain decreased recognition index in the NOR and decreased aversive memory in the IA, when compared to the control group. The levels of pro-BDNF and BDNF decreased in the frontal cortex seven days after ouabain; but its receptor (TrkB) and CREB decreased seven and 14 days after ouabain, in both cerebral structures evaluated. CONCLUSION: Ouabain-induced animal model of BD is an excellent model to assess memory alteration, observed in bipolar patients. Besides, the memory impairment induced by ouabain seems to be related to BDNF signaling pathway alterations.
Assuntos
Transtorno Bipolar , Ouabaína , Animais , Transtorno Bipolar/induzido quimicamente , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cognição , Modelos Animais de Doenças , Hipocampo/metabolismo , Humanos , Ouabaína/toxicidade , Ratos , Ratos Wistar , Transdução de SinaisRESUMO
BACKGROUND: The etiology of bipolar disorder (BD) is multifactorial, involving both environmental and genetic factors. Current pharmacological treatment is associated with several side effects, which are the main reason patients discontinue treatment. Epigenetic alterations have been studied for their role in the pathophysiology of BD, as they bridge the gap between gene and environment. OBJECTIVE: Evaluate the effects of histone deacetylase inhibitors on behavior and epigenetic enzymes activity in a rat model of mania induced by ouabain. METHODS: Adult male rats were subjected to a single intracerebroventricular injection of ouabain (10-3 M) followed by 7 days of valproate (200 mg/kg) or sodium butyrate (600 mg/kg) administration. Locomotor and exploratory activities were evaluated in the open-field test. Histone deacetylase, DNA methyltransferase, and histone acetyltransferase activity were assessed in the frontal cortex, hippocampus, and striatum. RESULTS: Ouabain induced hyperactivity in rats, which was reversed by valproate and sodium butyrate treatment. Ouabain did not alter the activity of any of the enzymes evaluated. However, valproate and sodium butyrate decreased the activity of histone deacetylase and DNA methyltransferase. Moreover, there was a positive correlation between these two enzymes. CONCLUSION: These results suggest that targeting epigenetic mechanisms may play an important role in mania-like behavior management.
Assuntos
Comportamento Animal/efeitos dos fármacos , Ácido Butírico/administração & dosagem , Inibidores de Histona Desacetilases/administração & dosagem , Mania/induzido quimicamente , Mania/tratamento farmacológico , Ouabaína/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Ácido Valproico/administração & dosagem , Animais , Transtorno Bipolar/tratamento farmacológico , Ácido Butírico/farmacologia , Corpo Estriado/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , Modelos Animais de Doenças , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Histona Acetiltransferases/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Resultado do Tratamento , Ácido Valproico/farmacologiaRESUMO
BACKGROUND: Bipolar Disorder (BD) is a chronic psychiatric disorder characterized by mood disturbances that include depressive, manic, and hypomanic episodes. Despite the severity of the symptoms, there is still a gap in the literature on the precise neurobiology and treatment of BD. The investigations of inflammatory changes in BD has increased in the last decade, evincing the importance of its role in the pathophysiology of the disorder. The present study aimed to investigate the inflammatory role in BD, through the evaluation of biomarkers and their relation to biological rhythms. METHODS: It was conducted a case-control study that included 36 BD and 46 healthy controls (HC). The Cyclooxygenase 2 (COX-2) enzyme, Arachidonic Acid (AA), interleukins (IL) IL-4, IL-5, IL-6, IL-10, IL-33, and Tumor Necrosis Factor Alpha (TNF-α) in the serum of individuals. It also was administered the Biological Rhythm Interview of Assessment in Neuropsychiatry (BRIAN) to the BD and healthy control groups. RESULTS: The results indicated that the individuals with BD showed increased COX-2, AA, IL-6, and TNF-α levels in comparison to the HC without psychiatric disorders, as well as significant commitments in all domains evaluated by BRIAN. LIMITATIONS: Uncontrolled pharmacotherapy used by the included bipolar participants, which had important effects on participants' inflammatory systems and the lack of cases with bipolar manic episodes. CONCLUSIONS: The results of the present study reaffirm that inflammation has an important role in BD, as well as the significant changes in biological rhythms. It is still necessary to better characterize the inflammatory pathway of AA.
Assuntos
Transtorno Bipolar , Biomarcadores , Estudos de Casos e Controles , Humanos , Periodicidade , Fator de Necrose Tumoral alfaRESUMO
Studies have suggested the involvement of oxidative stress in the physiopathology of bipolar disorder. Preclinical data have shown that PKC inhibitors may act as mood-stabilizing agents and protect the brain in animal models of mania. The present study aimed to evaluate the effects of Lithium (Li) or tamoxifen (TMX) on behavioral changes and oxidative stress parameters in an animal model of mania induced by ouabain (OUA). Wistar rats received a single intracerebroventricular (ICV) injection of OUA or artificial cerebrospinal fluid (ACSF). From the day following ICV injection, the rats were treated for seven days with intraperitoneal injections of saline, Li or TMX twice a day. On the 7th day after OUA injection, locomotor activity was measured using the open-field test, and the oxidative stress parameters were evaluated in the hippocampus and frontal cortex of rats. The results showed that OUA induced hyperactivity in rats, which is considered a manic-like behavior. Also, OUA increased lipid peroxidation and oxidative damage to proteins, as well as causing alterations to antioxidant enzymes in the frontal cortex and hippocampus of rats. The Li or TMX treatment reversed the manic-like behavior induced by OUA. Besides, Li, but not TMX, reversed the oxidative damage caused by OUA. These results suggest that the manic-like effects induced by OUA and the antimanic effects of TMX seem not to be related to the oxidative stress.
Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Estresse Oxidativo , Tamoxifeno/farmacologia , Animais , Transtorno Bipolar/fisiopatologia , Modelos Animais de Doenças , Masculino , Ouabaína/administração & dosagem , Ratos , Ratos Wistar , Moduladores Seletivos de Receptor Estrogênico/farmacologiaRESUMO
The present study evaluated the effects of AR-A014418 on behavioral and oxidative stress parameters of rats submitted to the animal model of mania induced by ouabain (OUA). Wistar rats were submitted to stereotaxic surgery and received a single intracerebroventricular (ICV) injection of artificial cerebrospinal fluid (aCSF), OUA, or AR-A014418. After 7 days, the animals were submitted to open-field test. After behavioral analysis, the brains were dissected in frontal cortex and hippocampus to the evaluation of oxidative stress. The OUA induced manic-like behavior in rats, which was reversed by AR-A014418 treatment. The ICV administration of OUA increases the levels of superoxide in submitochondrial particles, lipid hydroperoxide (LPH), 4-hydroxynonenal (4-HNE), 8-isoprostane, protein carbonyl, 3-nitrotyrosine, and activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) in both structures evaluated. In general, the treatment with AR-A014418 reversed these effects of OUA on the submitochondrial particles, LPH, 4-HNE, 8-isoprostane, protein carbonyl, 3-nitrotyrosine levels, and SOD activity. Furthermore, the injection of OUA decreased the catalase activity, and AR-A014418 promoted an increase in activity of this enzyme in the brain structures. These results suggest that GSK-3ß inhibition can modulate manic-like behaviors. Also, it can be suggested that inhibition of GSK-3ß can be effective against oxidative stress. However, more studies are needed to better elucidate these mechanisms. Graphical Abstract The effects of AR-A014418 on the behavioral and oxidative stress parameters in the animal model of mania induced by ouabain. Superoxide = superoxide production in submitochondrial particles; LPH = lipid hydroperoxide; 4-HNE = 4-hydroxynonenal; SOD = superoxide dismutase; GPx = glutathione peroxidase; GR = glutathione reductase.