RESUMO
Inflammation is a mediator of a number of chronic pathologies. We synthesized the diethyl (9Z,12Z)-octadeca-9,12-dien-1-ylphosphonate, called NKS3, which decreased lipopolysaccharide (LPS)-induced mRNA upregulation of proinflammatory cytokines (IL-1ß, IL-6 and TNF-α) not only in primary intraperitoneal and lung alveolar macrophages, but also in freshly isolated mice lung slices. The in-silico studies suggested that NKS3, being CD36 agonist, will bind to GPR120. Co-immunoprecipitation and proximity ligation assays demonstrated that NKS3 induced protein-protein interaction of CD36 with GPR120in RAW 264.7 macrophage cell line. Furthermore, NKS3, via GPR120, decreased LPS-induced activation of TAB1/TAK1/JNK pathway and the LPS-induced mRNA expression of inflammatory markers in RAW 264.7 cells. In the acute lung injury model, NKS3 decreased lung fibrosis and inflammatory cytokines (IL-1ß, IL-6 and TNF-α) and nitric oxide (NO) production in broncho-alveolar lavage fluid. NKS3 exerted a protective effect on LPS-induced remodeling of kidney and liver, and reduced circulating IL-1ß, IL-6 and TNF-α concentrations. In a septic shock model, NKS3 gavage decreased significantly the LPS-induced mortality in mice. In the last, NKS3 decreased neuroinflammation in diet-induced obese mice. Altogether, these results suggest that NKS3 is a novel anti-inflammatory agent that could be used, in the future, for the treatment of inflammation-associated pathologies.
Assuntos
Endotoxemia , Animais , Camundongos , Endotoxemia/induzido quimicamente , Interleucina-6/genética , Lipopolissacarídeos/toxicidade , Fator de Necrose Tumoral alfa , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Inflamação , Antígenos CD36/genética , Citocinas/genética , Interleucina-1beta/genética , RNA Mensageiro , Ácidos GraxosRESUMO
Repeated anodal transcranial direct current stimulation (RA-tDCS) is a neuromodulatory technique consisting of stimulating the cerebral cortex with a weak electric anodal current in a non-invasive manner. RA-tDCS over the dorsolateral prefrontal cortex has antidepressant-like properties and improves memory both in humans and laboratory animals. However, the mechanisms of action of RA-tDCS remain poorly understood. Since adult hippocampal neurogenesis is thought to be involved in the pathophysiology of depression and memory functioning, the purpose of this work was to evaluate the impact of RA-tDCS on hippocampal neurogenesis levels in mice. RA-tDCS was applied for 20 min per day for five consecutive days over the left frontal cortex of young adult (2-month-old, high basal level of neurogenesis) and middle-aged (10-month-old, low basal level of neurogenesis) female mice. Mice received three intraperitoneal injections of bromodeoxyuridine (BrdU) on the final day of RA-tDCS. The brains were collected either 1 day or 3 weeks after the BrdU injections to quantify cell proliferation and cell survival, respectively. RA-tDCS increased hippocampal cell proliferation in young adult female mice, preferentially (but not exclusively) in the dorsal part of the dentate gyrus. However, the number of cells that survived after 3 weeks was the same in both the Sham and the tDCS groups. This was due to a lower survival rate in the tDCS group, which suppressed the beneficial effects of tDCS on cell proliferation. No modulation of cell proliferation or survival was observed in middle-aged animals. Our RA-tDCS protocol may, therefore, influence the behavior of naïve female mice, as we previously described, but its effect on the hippocampus is only transient in young adult animals. Future studies using animal models for depression in male and female mice should provide further insights into RA-tDCS detailed age- and sex-dependent effects on hippocampal neurogenesis.
Assuntos
Estimulação Transcraniana por Corrente Contínua , Humanos , Adulto Jovem , Masculino , Feminino , Camundongos , Animais , Lactente , Estimulação Transcraniana por Corrente Contínua/métodos , Córtex Pré-Frontal , Bromodesoxiuridina , Lobo Frontal , Proliferação de Células , HipocampoRESUMO
Transcranial direct current stimulation (tDCS) is a non-invasive method to modulate cortical excitability. This technique is a promising emerging tool to treat several neuropathologies, including addiction. We have previously shown in mice that repeated tDCS normalizes pathological behaviors associated with chronic nicotine exposure. Here, we evaluated, in adult female mice, the impact of tDCS on cocaine-induced behavior and gene regulation in corticostriatal circuits implicated in psychostimulant addiction. Anodal tDCS was applied transcranially over the frontal cortex. Three weeks after repeated tDCS, we investigated the induction of a gene expression marker (Zif268) by cocaine (25 mg/kg) in 26 cortical and 23 striatal regions using in situ hybridization histochemistry. We also assessed place preference conditioning by cocaine (5, 10 and 25 mg/kg). tDCS pretreatment increased basal expression and attenuated cocaine (25 mg/kg)-induced expression of Zif268 in specific corticostriatal circuits. Cocaine-induced locomotor activation (25 mg/kg) and place preference conditioning (5 and 25 mg/kg) were also reduced. These results demonstrate that tDCS can attenuate molecular and behavioral responses to cocaine for several weeks. Together, our findings provide pre-clinical evidence that such electrical brain stimulation may be useful to modify the psychostimulant addiction risk.
Assuntos
Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Expressão Gênica/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Neostriado/efeitos dos fármacos , Estimulação Transcraniana por Corrente Contínua , Animais , Córtex Cerebral/metabolismo , Condicionamento Clássico , Proteína 1 de Resposta de Crescimento Precoce/efeitos dos fármacos , Feminino , Lobo Frontal , Expressão Gênica/genética , Camundongos , Neostriado/metabolismo , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismoRESUMO
There is a growing use of psychostimulants, such as methylphenidate (Ritalin; dopamine re-uptake inhibitor), for medical treatments and as cognitive enhancers in the healthy. Methylphenidate is known to produce some addiction-related gene regulation. Recent findings in animal models show that selective serotonin re-uptake inhibitors (SSRIs), including fluoxetine, can potentiate acute induction of gene expression by methylphenidate, thus indicating an acute facilitatory role for serotonin in dopamine-induced gene regulation. We investigated whether repeated exposure to fluoxetine, in conjunction with methylphenidate, in adolescent rats facilitated a gene regulation effect well established for repeated exposure to illicit psychostimulants such as cocaine-blunting (repression) of gene inducibility. We measured, by in situ hybridization histochemistry, the effects of a 5-day repeated treatment with methylphenidate (5 mg/kg), fluoxetine (5 mg/kg) or a combination on the inducibility (by cocaine) of neuroplasticity-related genes (Zif268, Homer1a) in the striatum. Repeated methylphenidate treatment alone produced minimal gene blunting, while fluoxetine alone had no effect. In contrast, fluoxetine added to methylphenidate robustly potentiated methylphenidate-induced blunting for both genes. This potentiation was widespread throughout the striatum, but was most robust in the lateral, sensorimotor striatum, thus mimicking cocaine effects. For illicit psychostimulants, blunting of gene expression is considered part of the molecular basis of addiction. Our results thus suggest that SSRIs, such as fluoxetine, may increase the addiction liability of methylphenidate.
Assuntos
Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Fluoxetina/farmacologia , Metilfenidato/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Corpo Estriado/metabolismo , Combinação de Medicamentos , Sinergismo Farmacológico , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Proteínas de Arcabouço Homer , Masculino , Ratos Sprague-DawleyRESUMO
We investigated whether linoleic acid (LA) supplementation could modulate emotional behavior and microglia-related neuroinflammation. For that, male mice of C57BL/6J genetic background fed either a high-fat diet (HFD) or a standard diet (STD) for 12 weeks, were treated with a vehicle or LA solution for 5 weeks before being evaluated for emotional behavior using a battery of behavioral tests. The animals were subsequently sacrificed and their brains collected and processed for immunofluorescence staining, targeting microglia-specific calcium-binding proteins (IBA-1). Neuroinflammation severity was assessed in multiple hypothalamic, cortical and subcortical brain regions. We show an anxio-depressive-like effect of sustained HFD feeding that was neither alleviated nor worsened with LA supplementation. However, increased IBA-1 expression and microgliosis in the HFD group were largely attenuated by LA supplementation. These observations demonstrate that the anti-neuroinflammatory properties of LA are not restricted to hypothalamic areas but are also evident at the cortical and subcortical levels. This study discloses that neuroinflammation plays a role in the genesis of neuropsychiatric disorders in the context of obesity, and that LA supplementation is a useful dietary strategy to alleviate the impact of obesity-related neuroinflammation.
Assuntos
Ácido Linoleico , Microglia , Camundongos , Masculino , Animais , Ácido Linoleico/farmacologia , Doenças Neuroinflamatórias , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Dieta Hiperlipídica/efeitos adversos , Suplementos NutricionaisRESUMO
Apathy is commonly defined as a loss of motivation leading to a reduction in goal-directed behaviors. This multidimensional syndrome, which includes cognitive, emotional and behavioral components, is one of the most prevalent neuropsychiatric features of Parkinson's disease (PD). It has been established that the prevalence of apathy increases as PD progresses. However, the pathophysiology and anatomic substrate of this syndrome remain unclear. Apathy seems to be underpinned by impaired anatomical structures that link the prefrontal cortex with the limbic system. It can be encountered in the prodromal stage of the disease and in fluctuating PD patients receiving bilateral chronic subthalamic nucleus stimulation. In these stages, apathy may be considered as a disorder of motivation that embodies amotivational behavioral syndrome, is underpinned by combined dopaminergic and serotonergic denervation and is dopa-responsive. In contrast, in advanced PD patients, apathy may be considered as cognitive apathy that announces cognitive decline and PD dementia, is underpinned by diffuse neurotransmitter system dysfunction and Lewy pathology spreading and is no longer dopa-responsive. In this review, we discuss the clinical patterns of apathy and their treatment, the neurobiological basis of apathy, the potential role of the anatomical structures involved and the pathways in motivational and cognitive apathy.
Assuntos
Apatia , Doença de Parkinson , Humanos , Apatia/fisiologia , Doença de Parkinson/metabolismo , Depressão , Sistema Límbico , Síndrome , Di-HidroxifenilalaninaRESUMO
Concomitant therapies combining psychostimulants such as methylphenidate and selective serotonin reuptake inhibitors (SSRIs) are used to treat several mental disorders, including attention-deficit hyperactivity disorder/depression comorbidity. The neurobiological consequences of these drug combinations are poorly understood. Methylphenidate alone induces gene regulation that mimics partly effects of cocaine, consistent with some addiction liability. We previously showed that the SSRI fluoxetine potentiates methylphenidate-induced gene regulation in the striatum. The present study investigated which striatal output pathways are affected by the methylphenidate + fluoxetine combination, by assessing effects on pathway-specific neuropeptide markers. Results demonstrate that fluoxetine (5 mg/kg) potentiates methylphenidate (5 mg/kg)-induced expression of substance P and dynorphin, markers for direct pathway neurons. In contrast, no drug effects on the indirect pathway marker enkephalin were found. Because methylphenidate alone has minimal effects on dynorphin, the potentiation of dynorphin induction represents a more cocaine-like effect for the drug combination. On the other hand, the lack of an effect on enkephalin suggests a greater selectivity for the direct pathway compared with psychostimulants such as cocaine. Overall, the fluoxetine potentiation of gene regulation by methylphenidate occurs preferentially in sensorimotor striatal circuits, similar to other addictive psychostimulants. These results suggest that SSRIs may enhance the addiction liability of methylphenidate.
Assuntos
Corpo Estriado/citologia , Fluoxetina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neuropeptídeos/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Animais , Autorradiografia , Estimulantes do Sistema Nervoso Central/farmacologia , Corpo Estriado/efeitos dos fármacos , Sinergismo Farmacológico , Dinorfinas/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Encefalinas/metabolismo , Masculino , Metilfenidato/farmacologia , Vias Neurais/fisiologia , Neuropeptídeos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Substância P , Substância Negra/citologia , Substância Negra/fisiologiaRESUMO
Transcranial direct current stimulation (tDCS) is an emerging noninvasive brain neuromodulation technique aimed at relieving symptoms associated with psychiatric disorders, including addiction. The goal of the present study was to better identify which phase of alcohol-related behavior (hedonic effect, behavioral sensitization, self-administration, or motivation to obtain the drug) might be modulated by repeated anodal tDCS over the frontal cortex (0.2 mA, 20 min, twice a day for 5 consecutive days), using female mice as a model. Our data showed that tDCS did not modulate the hedonic effects of ethanol as assessed by a conditioned place preference test (CPP) or the expression of ethanol-induced behavioral sensitization. Interestingly, tDCS robustly reduced reacquisition of ethanol consumption (50% decrease) following extinction of self-administration in an operant paradigm. Furthermore, tDCS significantly decreased motivation to drink ethanol on a progressive ratio schedule (30% decrease). Taken together, our results show a dissociation between the effects of tDCS on "liking" (hedonic aspect; no effect in the CPP) and "wanting" (motivation; decreased consumption on a progressive ratio schedule). Our tDCS procedure in rodents will allow us to better understand its mechanisms of action in order to accelerate its use as a complementary and innovative tool to help alcohol-dependent patients maintain abstinence or reduce ethanol intake.
Assuntos
Consumo de Bebidas Alcoólicas/prevenção & controle , Comportamento Animal , Comportamento de Procura de Droga , Etanol/administração & dosagem , Motivação , Estimulação Transcraniana por Corrente Contínua , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/psicologia , Animais , Condicionamento Operante , Etanol/toxicidade , Extinção Psicológica , Feminino , Camundongos , Modelos Animais , AutoadministraçãoRESUMO
BACKGROUND: Trauma-based psychotherapy is a first line treatment for post-traumatic stress disorder (PTSD) but not all patients achieve long-term remission. Transcranial direct current stimulation (tDCS) received considerable attention as a neuromodulation method that may improve trauma-based psychotherapy. OBJECTIVE: We explored the effects of repeated anodal tDCS over the prefrontal cortex (PFC) on fear extinction in mice as a preclinical model for trauma-based psychotherapy. METHODS: We performed auditory fear conditioning with moderate or high shock intensity on C57BL6/J mice. Next, mice received anodal tDCS (0.2 mA, 20 min) or sham stimulation over the PFC twice daily for five consecutive days. Extinction training was performed by repeatedly exposing mice to the auditory cue the day after the last stimulation session. Early and late retention of extinction were evaluated one day and three weeks after extinction training respectively. RESULTS: We observed no significant effect of tDCS on the acquisition or retention of fear extinction in mice subjected to fear conditioning with moderate intensity. However, when the intensity of fear conditioning was high, tDCS significantly lowered freezing during the acquisition of extinction, regardless of the extinction protocol. Moreover, when tDCS was combined with a strong extinction protocol, we also observed a significant improvement of early extinction recall. Finally, we found that tDCS reduced generalized fear induced by contextual cues when the intensity of conditioning is high and extinction training limited. CONCLUSIONS: Our data provide a rationale to further explore anodal tDCS over the PFC as potential support for trauma-based psychotherapy for PTSD.
Assuntos
Estimulação Transcraniana por Corrente Contínua , Animais , Extinção Psicológica , Medo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-FrontalRESUMO
The psychostimulant methylphenidate (Ritalin) is used in conjunction with selective serotonin reuptake inhibitors (SSRIs) in the treatment of medical conditions such as attention-deficit hyperactivity disorder with anxiety/depression comorbidity and major depression. Co-exposure also occurs in patients on SSRIs who use psychostimulant 'cognitive enhancers'. Methylphenidate is a dopamine/norepinephrine reuptake inhibitor that produces altered gene expression in the forebrain; these effects partly mimic gene regulation by cocaine (dopamine/norepinephrine/serotonin reuptake inhibitor). We investigated whether the addition of SSRIs (fluoxetine or citalopram; 5 mg/kg) modified gene regulation by methylphenidate (2-5 mg/kg) in the striatum and cortex of adolescent rats. Our results show that SSRIs potentiate methylphenidate-induced expression of the transcription factor genes zif268 and c-fos in the striatum, rendering these molecular changes more cocaine-like. Present throughout most of the striatum, this potentiation was most robust in its sensorimotor parts. The methylphenidate + SSRI combination also enhanced behavioral stereotypies, consistent with dysfunction in sensorimotor striatal circuits. In so far as such gene regulation is implicated in psychostimulant addiction, our findings suggest that SSRIs may enhance the addiction potential of methylphenidate.
Assuntos
Citalopram/farmacologia , Corpo Estriado/efeitos dos fármacos , Fluoxetina/farmacologia , Expressão Gênica/efeitos dos fármacos , Metilfenidato/farmacologia , Análise de Variância , Animais , Autorradiografia , Corpo Estriado/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Hibridização In Situ , Masculino , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
Non-invasive neuromodulatory techniques, including transcranial direct current stimulation (tDCS), have been shown to modulate neuronal function and are used both in cognitive neuroscience and to treat neuropsychiatric conditions. In this context, animal models provide a powerful tool to identify the neurobiological mechanisms of action of tDCS. However, finding a current generator that is easily usable and which allows a wide range of stimulation parameters can be difficult and/or expensive. Here, we introduce the Open-tES device, a project under a Creative Commons License (CC BY, SA 4.0) shared on the collaborative platform Git-Hub. This current generator allows tDCS (and other kinds of stimulations) to be realized, is suitable for rodents, is easy to use, and is low-cost. Characterization has been performed to measure the precision and accuracy of the current delivered. We also aimed to compare its effects with a commercial stimulator used in clinical trials (DC-Stimulator Plus, NeuroConn, Germany). To achieve this, a behavioral study was conducted to evaluate its efficacy for decreasing depression related-behavior in mice. The stimulator precision and accuracy were better than 250 nA and 25 nA, respectively. The behavioral evaluation performed in mice in the present study did not reveal any significant differences between the commercial stimulator used in clinical trials and the Open-tES device. Accuracy and precision of the stimulator ensure high repeatability of the stimulations. This current generator constitutes a reliable and inexpensive tool that is useful for preclinical studies in the field of non-invasive electrical brain stimulation.
Assuntos
Pesquisa/instrumentação , Software , Estimulação Transcraniana por Corrente Contínua/instrumentação , Animais , Feminino , Camundongos , Tempo de ReaçãoRESUMO
BACKGROUND: Although it is generally believed that chronic ethanol consumption impairs learning and memory, results obtained in experimental animals are not univocal, and there are conditions in which ethanol paradoxically improves cognitive functions. In the present work, we investigated the effects of prenatal stress and of chronic ethanol exposure during adulthood on spatial memory in rats. METHODS: Rats were subjected to a prenatal stress delivered as 3 daily 45-minute sections of restraint stress to the mothers during the last 10 days of pregnancy (PRS rats). After 7 months of ethanol exposure (ethanol 10%, oral intake), memory performances were evaluated in a spatial discrimination test in control and PRS male rats. Then, the oxidative damages and the expression of metabotropic glutamate (mGlu) receptors were assessed in their hippocampus. RESULTS: Chronic ethanol exposure resulted in a reduced performance in a spatial recognition task in control animals. Unexpectedly, however, the same treatment attenuated spatial memory deficits in rats that had been subjected to prenatal stress. This paradigm of ethanol administration did not produce detectable signs of oxidative damage in the hippocampus in either unstressed or PRS rats. Interestingly, ethanol intake resulted in differential effects in the expression of mGlu receptor subtypes implicated in mechanisms of learning and memory. In control rats, ethanol intake reduced mGlu2/3 and mGlu5 receptor levels in the hippocampus; in PRS rats, which exhibited a constitutive reduction in the levels of these mGlu receptor subtypes, ethanol increased the expression of mGlu1a receptors but did not change the expression of mGlu2/3 or mGlu5 receptors. CONCLUSION: Our findings support the idea that stress-related events occurring before birth have long-lasting effects on brain function and behavior, and suggest that the impact of ethanol on cognition is not only dose- and duration-dependent, but also critically influenced by early life experiences.
Assuntos
Etanol/administração & dosagem , Hipocampo/metabolismo , Transtornos da Memória/prevenção & controle , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Receptores de Glutamato Metabotrópico/biossíntese , Estresse Psicológico/metabolismo , Animais , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Hipocampo/efeitos dos fármacos , Masculino , Transtornos da Memória/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley , Comportamento Espacial/efeitos dos fármacos , Comportamento Espacial/fisiologia , Regulação para Cima/efeitos dos fármacosRESUMO
Objectives: Vortioxetine has already shown its efficacy in the acute and long-term treatment of major depressive disorder (MDD) and its potential interest in the prevention of relapse. The aim of this study was to review the current status of knowledge regarding its cognitive effects. Methods: We conducted a review of key data obtained from preclinical behavioral models and clinical trials in MDD focusing on vortioxetine-induced cognitive changes. Results: In animals, acute and chronic administration of vortioxetine improves performance on objective measures that cover a broad range of cognitive domains. In human, vortioxetine appears to be a useful treatment option in MDD patients with cognitive dysfunction. Conclusion: Vortioxetine constitutes a promising treatment for treatment of cognitive impairment in MDD, but its place in the therapeutic armamentarium still needs to be determined.
RESUMO
Prenatal restraint stress (PRS) in rats is associated with hippocampal dysfunctions and several behavioural and endocrine disorders related to this brain area. Recently, we have reported that the PRS modifies the hypothalamic-pituitary-adrenal (HPA) response to an ethanol challenge in adolescent animals. Since hippocampus is particularly sensitive to the deleterious effects of ethanol during adolescence, we investigated in this study the combined effects of PRS and ethanol administration on the oxidative status in the hippocampus of 28-day-old male rats. Thirty minutes after an intraperitoneal (i.p.) injection of ethanol (1.5 g/kg), the activities of several antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase) but also non-enzymatic antioxidant (reduced glutathione) were assayed. Thiobarbituric acid reactive substances (TBARS) levels were also measured as a marker of lipid peroxidation. Ethanol enhanced superoxide dismutase activity in control rats but not in PRS rats. At basal level, catalase activity was lower in PRS rats than in control rats, indicating a potentially higher sensitivity to oxidative damages after this early stress. However, the hippocampal TBARS levels were not significantly affected by the ethanol administration, showing that an acute ethanol exposure does not induce oxidative damage in adolescent male rats. In conclusion, our data suggest that PRS affects both basal antioxidant status in the hippocampus and antioxidant response after an acute ethanol exposure. These findings extend previous works showing that PRS leads to hippocampal dysfunctions and raise the question of the potential increase of the hippocampal oxidative damage in PRS rats after repeated exposure to ethanol.
Assuntos
Intoxicação Alcoólica/enzimologia , Hipocampo/enzimologia , Estresse Oxidativo/efeitos dos fármacos , Oxirredutases/metabolismo , Efeitos Tardios da Exposição Pré-Natal/enzimologia , Estresse Psicológico/enzimologia , Fatores Etários , Intoxicação Alcoólica/complicações , Animais , Antioxidantes/metabolismo , Catalase/efeitos dos fármacos , Catalase/metabolismo , Modelos Animais de Doenças , Etanol/farmacologia , Feminino , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Peroxidase/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/crescimento & desenvolvimento , Masculino , Oxirredutases/efeitos dos fármacos , Gravidez , Ratos , Restrição Física , Estresse Psicológico/complicações , Superóxido Dismutase/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive method increasingly popular for the treatment of several brain disorders, such as major depression. Despite great enthusiasm and promising results, some studies report discrepant findings and no consensus exists for the clinical use of tDCS. OBJECTIVE: The present study aims to (i) determine the most effective stimulation parameters to optimize antidepressant-like effect of tDCS in the forced-swim test in mice and (ii) identify brain regions recruited by tDCS and possibly involved in its behavioral effect using Fos immunohistochemistry. RESULTS: We reported that tDCS induced long-lasting antidepressant-like effect, which varied as a function of stimulation settings including number, duration, intensity and polarity of stimulation. Interestingly, the present study also demonstrated that tDCS reduced depressive-like behaviors induced by chronic corticosterone exposure. Furthermore, behavioral outcomes induced by a single stimulation were associated with neuronal activation in the prefrontal cortex, dorsal hippocampus, ventral tegmental area and nucleus accumbens, whereas no overexpression of c-fos was associated with 10 stimulations. CONCLUSION: The strongest behavioral response was observed with an anodal stimulation of 200 µA during 20min. The repetition of this stimulation was necessary to induce long-lasting behavioral effects that are probably associated with plastic changes in the neuronal response.
Assuntos
Transtorno Depressivo Maior/terapia , Estimulação Transcraniana por Corrente Contínua , Animais , Transtorno Depressivo Maior/fisiopatologia , Feminino , Hipocampo/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/fisiopatologia , NataçãoRESUMO
The lateral hypothalamic area (LHA) has two major roles: arousal/waking and food intake controls. Here, it is shown that a premammillary part of the LHA is neurochemically and cytoarchitectonically distinct from the tuberal LHA in male rats. This part contains nuclear masses, namely the parasubthalamic nucleus and the calbindin nucleus, involved in pathways that predict its participation in the control of food intake. Analyzing c-Fos expression in experiments related to feeding behavior, this region responded specifically to the ingestion of palatable nutriments.
Assuntos
Condicionamento Clássico/fisiologia , Comportamento Alimentar/fisiologia , Região Hipotalâmica Lateral/citologia , Região Hipotalâmica Lateral/metabolismo , Animais , Nível de Alerta , Calbindinas/metabolismo , Núcleo Central da Amígdala/citologia , Córtex Cerebral/citologia , Ingestão de Alimentos , Glutamato Descarboxilase/metabolismo , Hormônios Hipotalâmicos/metabolismo , Masculino , Melaninas/metabolismo , Vias Neurais/citologia , Vias Neurais/metabolismo , Orexinas/metabolismo , Parvalbuminas/metabolismo , Hormônios Hipofisários/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Substância P/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Drug combinations that include the psychostimulant methylphenidate plus a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine are increasingly used in children and adolescents. For example, this combination is indicated in the treatment of attention-deficit/hyperactivity disorder and depression comorbidity and other mental disorders. Such co-exposure also occurs in patients on SSRIs who use methylphenidate as a cognitive enhancer. The neurobiological consequences of these drug combinations are poorly understood. Methylphenidate alone can produce gene regulation effects that mimic addiction-related gene regulation by cocaine, consistent with its moderate addiction liability. We have previously shown that combining SSRIs with methylphenidate potentiates methylphenidate-induced gene regulation in the striatum. The present study investigated which striatal output pathways are affected by the methylphenidate + fluoxetine combination, by assessing effects on pathway-specific neuropeptide markers, and which serotonin receptor subtypes may mediate these effects. Our results demonstrate that a 5-day repeated treatment with fluoxetine (5 mg/kg) potentiates methylphenidate (5 mg/kg)-induced expression of both dynorphin (direct pathway marker) and enkephalin (indirect pathway). These changes were accompanied by correlated increases in the expression of the 5-HT1B, but not 5-HT2C, serotonin receptor in the same striatal regions. A further study showed that the 5-HT1B receptor agonist CP94253 (3-10 mg/kg) mimics the fluoxetine potentiation of methylphenidate-induced gene regulation. These findings suggest a role for the 5-HT1B receptor in the fluoxetine effects on striatal gene regulation. Given that 5-HT1B receptors are known to facilitate addiction-related gene regulation and behavior, our results suggest that SSRIs may enhance the addiction liability of methylphenidate by increasing 5-HT1B receptor signaling.
Assuntos
Corpo Estriado/fisiologia , Fluoxetina/administração & dosagem , Metilfenidato/administração & dosagem , Receptor 5-HT1B de Serotonina/fisiologia , Animais , Corpo Estriado/efeitos dos fármacos , Sinergismo Farmacológico , Regulação da Expressão Gênica , Masculino , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Ratos , Ratos Sprague-Dawley , Agonistas do Receptor 5-HT1 de Serotonina/farmacologiaRESUMO
Successful available treatments to quit smoking remain scarce. Recently, the potential of transcranial direct current stimulation (tDCS) as a tool to reduce craving for nicotine has gained interest. However, there is no documented animal model to assess the neurobiological mechanisms of tDCS on addiction-related behaviors. To address this topic, we have developed a model of repeated tDCS in mice and used it to validate its effectiveness in relieving nicotine addiction. Anodal repeated tDCS was applied over the frontal cortex of Swiss female mice. The stimulation electrode (anode) was fixed directly onto the cranium, and the reference electrode was placed onto the ventral thorax. A 2 × 20 min/day stimulation paradigm for five consecutive days was used (0.2 mA). In the first study, we screened for behaviors altered by the stimulation. Second, we tested whether tDCS could alleviate abnormal behaviors associated with abstinence from nicotine consumption. In naive animals, repeated tDCS had antidepressant-like properties 3 weeks after the last stimulation, improved working memory, and decreased conditioned place preference for nicotine without affecting locomotor activity and anxiety-related behavior. Importantly, abnormal behaviors associated with chronic nicotine exposure (ie, depression-like behavior, increase in nicotine-induced place preference) were normalized by repeated tDCS. Our data show for the first time in an animal model that repeated tDCS is a promising, non-expensive clinical tool that could be used to reduce smoking craving and facilitate smoking cessation. Our animal model will be useful to investigate the mechanisms underlying the effects of tDCS on addiction and other psychiatric disorders.
Assuntos
Transtornos Mentais/induzido quimicamente , Transtornos Mentais/prevenção & controle , Nicotina/efeitos adversos , Agonistas Nicotínicos/efeitos adversos , Síndrome de Abstinência a Substâncias , Estimulação Magnética Transcraniana/métodos , Fatores Etários , Animais , Peso Corporal/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Modelos Animais de Doenças , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Aprendizagem em Labirinto/efeitos da radiação , Memória/efeitos dos fármacos , Camundongos , Atividade Motora/efeitos dos fármacos , Atividade Motora/efeitos da radiação , Nicotina/metabolismo , Agonistas Nicotínicos/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/efeitos da radiação , NataçãoRESUMO
Use of psychostimulants such as methylphenidate (Ritalin) in medical treatments and as cognitive enhancers in the healthy is increasing. Methylphenidate produces some addiction-related gene regulation in animal models. Recent findings show that combining selective serotonin reuptake inhibitor (SSRI) antidepressants such as fluoxetine with methylphenidate potentiates methylphenidate-induced gene regulation. We investigated the endurance of such abnormal gene regulation by assessing an established marker for altered gene regulation after drug treatments - blunting (repression) of immediate-early gene (IEG) inducibility - 14 days after repeated methylphenidate+fluoxetine treatment in adolescent rats. Thus, we measured the effects of a 6-day repeated treatment with methylphenidate (5 mg/kg), fluoxetine (5 mg/kg) or their combination on the inducibility (by cocaine) of neuroplasticity-related IEGs (Zif268, Homer1a) in the striatum, by in situ hybridization histochemistry. Repeated methylphenidate treatment alone produced modest gene blunting, while fluoxetine alone had no effect. In contrast, fluoxetine given in conjunction with methylphenidate produced pronounced potentiation of methylphenidate-induced blunting for both genes. This potentiation was seen in many functional domains of the striatum, but was most robust in the lateral, sensorimotor striatum. These enduring molecular changes were associated with potentiated induction of behavioral stereotypies in an open-field test. For illicit psychostimulants, blunting of gene expression is considered part of the molecular basis of addiction. Our results thus suggest that SSRIs such as fluoxetine may increase the addiction liability of methylphenidate. Key words: cognitive enhancer, dopamine, serotonin, gene expression, psychostimulant, SSRI antidepressant, striatum.
RESUMO
There is a growing demand for new brain-enhancing technologies to improve mental performance, both for patients with cognitive disorders and for healthy individuals. Transcranial direct current stimulation (tDCS) is a non-invasive, painless, and easy to use neuromodulatory technique that can improve performance on a variety of cognitive tasks in humans despite its exact mode of action remains unclear. We have conducted a mini-review of the literature to first briefly summarize the growing amount of data from clinical trials assessing the efficacy of tDCS, focusing exclusively on learning and memory performances in healthy human subjects and in patients with depression, schizophrenia, and other neurological disorders. We then discuss these findings in the context of the strikingly few studies resulting from animal research. Finally, we highlight future directions and limitations in this field and emphasize the need to develop translational studies to better understand how tDCS improves memory, a necessary condition before it can be used as a therapeutic tool.