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1.
Acta Neurol Scand ; 142(3): 275-280, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32415851

RESUMO

OBJECTIVES: The involvement of epigenetics mechanisms in the transcriptional regulation of key genes has been investigated in the initiation and progression of neurodegenerative disorders, including Parkinson's disease (PD). Among others, we, here, focused the attention on the dopamine transporter (DAT) gene playing a critical role in maintaining the integrity of dopaminergic neurons. MATERIALS AND METHODS: We performed bisulfite pyrosequencing to examine DNA methylation levels of six CpG sites in the 5'-UTR of DAT1 gene in human peripheral blood mononuclear cells (PBMCs) obtained from 101 sporadic PD patients and 59 healthy controls. RESULTS: We selectively report for CpG5 an increase in DNA methylation levels in PD subjects respect to controls, that almost reaches statistical significance (30.06 ± 12.4 vs 26.58 ± 7.6, P = .052). Of interest, a significantly higher methylation at specific CpG sites (ANOVA: P = .029) was observed in PD subjects with advanced stage of illness. Namely, a multivariate regression analysis showed that a higher methylation level at specific CpG sites in the group of PD patients was associated with increased methylation at CpG2, CpG3, and with H&Y stage but not with age and gender. This regression model explains the 38% of the variance of methylation at CpG5. CONCLUSION: Our results do seem to suggest that the methylation level of CpG5 is different between PD patients and controls. Moreover, this methylation level for CpG5 may be associated also with the stage of disease.


Assuntos
Regiões 5' não Traduzidas/genética , Metilação de DNA , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Doença de Parkinson/genética , Fatores Etários , Idoso , Ilhas de CpG/genética , Neurônios Dopaminérgicos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/química , Doença de Parkinson/patologia , Fatores Sexuais
2.
Psychiatr Danub ; 32(1): 84-91, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32303037

RESUMO

BACKGROUND: Symptomatic remission is an achievable goal in the treatment of schizophrenia. The type of antipsychotic medication and particular genetic variants of the dopaminergic system might be associated with remission. Potential pharmacogenetic markers of the treatment response to antipsychotic medication are missing. This study assessed the possible association between dopamine receptor type 2 (DRD2 rs1800497) and dopamine transporter (DAT1 rs28363170) gene variants with symptomatic remission in schizophrenia. SUBJECTS AND METHODS: Olanzapine (5-20 mg/d) monotherapy was administered for 6 months to 150 male Caucasian subjects with schizophrenia. Remission was evaluated according to "Remission in Schizophrenia Working Group" criteria. Genotyping was performed by PCR-RFLP. RESULTS: Symptomatic remission was found in 31% of patients. DRD2 rs1800497 and DAT1 rs28363170 gene variants were not significantly associated with symptomatic remission. The limitations are a relatively small sample size of patients with schizophrenia (N=150), especially of group with symptomatic remission (N=45). However, the study had moderate but adequate sample sizes for most of the comparisons. Only two dopaminergic polymorphisms were analyzed, and plasma concentration of olanzapine was not determined. CONCLUSION: These results revealed a lack of association between DRD2 rs1800497 and DAT1 rs28363170 genetic variants and symptomatic remission in male patients treated with olanzapine, suggesting that these genetic variants could not be used to predict symptomatic remission to olanzapine monotherapy. Negative results should be further confirmed or rejected in the larger samples, including haplotype analyses, to detect clinically useful and easy obtainable pharmacogenetic markers that might predict therapeutic response or remission in schizophrenia.


Assuntos
Antipsicóticos/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Mutação , Olanzapina/administração & dosagem , Olanzapina/uso terapêutico , Receptores de Dopamina D2/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Adulto , Antipsicóticos/administração & dosagem , Grupo com Ancestrais do Continente Europeu/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento
3.
J Neurosci ; 40(22): 4309-4322, 2020 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-32317389

RESUMO

Classical studies suggest that growth hormone (GH) secretion is controlled by negative-feedback loops mediated by GH-releasing hormone (GHRH)- or somatostatin-expressing neurons. Catecholamines are known to alter GH secretion and neurons expressing TH are located in several brain areas containing GH-responsive cells. However, whether TH-expressing neurons are required to regulate GH secretion via negative-feedback mechanisms is unknown. In the present study, we showed that between 50% and 90% of TH-expressing neurons in the periventricular, paraventricular, and arcuate hypothalamic nuclei and locus ceruleus of mice exhibited STAT5 phosphorylation (pSTAT5) after an acute GH injection. Ablation of GH receptor (GHR) from TH cells or in the entire brain markedly increased GH pulse secretion and body growth in both male and female mice. In contrast, GHR ablation in cells that express the dopamine transporter (DAT) or dopamine ß-hydroxylase (DBH; marker of noradrenergic/adrenergic cells) did not affect body growth. Nevertheless, less than 50% of TH-expressing neurons in the hypothalamus were found to express DAT. Ablation of GHR in TH cells increased the hypothalamic expression of Ghrh mRNA, although very few GHRH neurons were found to coexpress TH- and GH-induced pSTAT5. In summary, TH neurons that do not express DAT or DBH are required for the autoregulation of GH secretion via a negative-feedback loop. Our findings revealed a critical and previously unidentified group of catecholaminergic interneurons that are apt to sense changes in GH levels and regulate the somatotropic axis in mice.SIGNIFICANCE STATEMENT Textbooks indicate until now that the pulsatile pattern of growth hormone (GH) secretion is primarily controlled by GH-releasing hormone and somatostatin neurons. The regulation of GH secretion relies on the ability of these cells to sense changes in circulating GH levels to adjust pituitary GH secretion within a narrow physiological range. However, our study identifies a specific population of tyrosine hydroxylase-expressing neurons that is critical to autoregulate GH secretion via a negative-feedback loop. The lack of this mechanism in transgenic mice results in aberrant GH secretion and body growth. Since GH plays a key role in cell proliferation, body growth, and metabolism, our findings provide a major advance to understand how the brain regulates the somatotropic axis.


Assuntos
Exocitose , Retroalimentação Fisiológica , Hormônio do Crescimento/metabolismo , Neurônios/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Animais , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Dopamina beta-Hidroxilase/genética , Dopamina beta-Hidroxilase/metabolismo , Feminino , Hormônio Liberador de Hormônio do Crescimento/genética , Hormônio Liberador de Hormônio do Crescimento/metabolismo , Hipotálamo/metabolismo , Locus Cerúleo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores da Somatotropina/metabolismo , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Tirosina 3-Mono-Oxigenase/genética
4.
J Photochem Photobiol B ; 204: 111742, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31982670

RESUMO

Human dental pulp stem cells (hDPSCs) are able to differentiate into dopaminergic neurons and help the maintenance of partially degenerated neurons, which makes them as an alternative cell source for treatment of Parkinsons' disease (PD) patients. Here, the effect of photobiomodulation with polychromatic light source in the near infrared (NIR) range (600-1200 nm) or low level 660 nm diode laser light on hDPSCs during dopaminergic induction was investigated. Real time RT-qPCR analysis indicated that expressions of brain derived neurotrophic factor (BDNF), glial cell line derived neurotropic factor (GNDF), matrix associated protein 2 (MAP2), nuclear receptor related 1 protein (NURR1) and dopamine transporter (DAT) were increased, especially in the first 7 days of dopaminergic induction when 660 nm laser light was applied with a total energy density of 1.6 J/cm2. The activity of polychromatic light on hDPSCs depended on the differentiation media and protein type. BDNF, GDNF, NURR-1 and MAP2 expressions were increased in the presence of pre-induction factors, and decreased when the post-induction factors were added into the culture medium. In contrast with all these promising results, the dopaminergically induced hDPSCs did not show any functional characteristics of dopaminergic neurons and died after they were transferred to a new laminin coated culture plates. In conclusion, the expression of dopaminergic neuron protective protein mRNAs in hDPSCs was increased by photobiomodulation in defined conditions. However, the cells were not able to differentiate into functional dopaminergic neurons either in control or in photobiomodulated groups that are prone to cell death and exhibit immature dopaminergic neuron characteristics.


Assuntos
Raios Infravermelhos , Lasers Semicondutores , Transcriptoma/efeitos da radiação , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Sobrevivência Celular/efeitos da radiação , Células Cultivadas , Polpa Dentária/citologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Humanos , Imunofenotipagem , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/efeitos da radiação , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Espécies Reativas de Oxigênio/metabolismo
5.
J Biomed Sci ; 27(1): 16, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900153

RESUMO

BACKGROUND: Over-stimulation of dopamine signaling is thought to underlie the pathophysiology of a list of mental disorders, such as psychosis, mania and attention-deficit/hyperactivity disorder. These disorders are frequently associated with cognitive deficits in attention or learning and memory, suggesting that persistent activation of dopamine signaling may change neural plasticity to induce cognitive or emotional malfunction. METHODS: Dopamine transporter knockdown (DAT-KD) mice were used to mimic a hyper-dopamine state. Novel object recognition (NOR) task was performed to assess the recognition memory. To test the role of dopamine D3 receptor (D3R) on NOR, DAT-KD mice were treated with either a D3R antagonist, FAUC365 or by deletion of D3R. Total or phospho-GSK3 and -ERK1/2 signals in various brain regions were measured by Western blot analyses. To examine the impact of GSK3 signal on NOR, wild-type mice were systemically treated with GSK3 inhibitor SB216763 or, micro-injected with lentiviral shRNA of GSK3ß or GSK3α in the medial prefrontal cortex (mPFC). RESULTS: We confirmed our previous findings that DAT-KD mice displayed a deficit in NOR memory, which could be prevented by deletion of D3R or exposure to FAUC365. In WT mice, p-GSK3α and p-GSK3ß were significantly decreased in the mPFC after exposure to novel objects; however, the DAT-KD mice exhibited no such change in mPFC p-GSK3α/ß levels. DAT-KD mice treated with FAUC365 or with D3R deletion exhibited restored novelty-induced GSK3 dephosphorylation in the mPFC. Moreover, inhibition of GSK3 in WT mice diminished NOR performance and impaired recognition memory. Lentiviral shRNA knockdown of GSK3ß, but not GSK3α, in the mPFC of WT mice also impaired NOR. CONCLUSION: These findings suggest that D3R acts via GSK3ß signaling in the mPFC to play a functional role in NOR memory. In addition, treatment with D3R antagonists may be a reasonable approach for ameliorating cognitive impairments or episodic memory deficits in bipolar disorder patients.


Assuntos
Transtorno Bipolar/genética , Disfunção Cognitiva/genética , Glicogênio Sintase Quinase 3 beta/genética , Quinase 3 da Glicogênio Sintase/genética , Receptores de Dopamina D3/genética , Animais , Transtorno Bipolar/patologia , Disfunção Cognitiva/patologia , Dopamina/genética , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Técnicas de Silenciamento de Genes , Humanos , Sistema de Sinalização das MAP Quinases/genética , Memória Episódica , Camundongos , Córtex Pré-Frontal/metabolismo
6.
Nat Neurosci ; 22(11): 1820-1833, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31611706

RESUMO

Basal amygdala (BA) neurons guide associative learning via acquisition of responses to stimuli that predict salient appetitive or aversive outcomes. We examined the learning- and state-dependent dynamics of BA neurons and ventral tegmental area (VTA) dopamine (DA) axons that innervate BA (VTADA→BA) using two-photon imaging and photometry in behaving mice. BA neurons did not respond to arbitrary visual stimuli, but acquired responses to stimuli that predicted either rewards or punishments. Most VTADA→BA axons were activated by both rewards and punishments, and they acquired responses to cues predicting these outcomes during learning. Responses to cues predicting food rewards in VTADA→BA axons and BA neurons in hungry mice were strongly attenuated following satiation, while responses to cues predicting unavoidable punishments persisted or increased. Therefore, VTADA→BA axons may provide a reinforcement signal of motivational salience that invigorates adaptive behaviors by promoting learned responses to appetitive or aversive cues in distinct, intermingled sets of BA excitatory neurons.


Assuntos
Tonsila do Cerebelo/fisiologia , Neurônios Dopaminérgicos/fisiologia , Filtro Sensorial/fisiologia , Área Tegmentar Ventral/fisiologia , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Sinais (Psicologia) , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Vias Neurais/fisiologia , Estimulação Luminosa , Punição , Recompensa , Percepção Visual/fisiologia
7.
eNeuro ; 6(5)2019.
Artigo em Inglês | MEDLINE | ID: mdl-31481399

RESUMO

Transgenic mouse lines are instrumental in our attempt to understand brain function. Promoters driving transgenic expression of the gene encoding Cre recombinase are crucial to ensure selectivity in Cre-mediated targeting of floxed alleles using the Cre-Lox system. For the study of dopamine (DA) neurons, promoter sequences driving expression of the Dopamine transporter (Dat) gene are often implemented and several DAT-Cre transgenic mouse lines have been found to faithfully direct Cre activity to DA neurons. While evaluating an established DAT-Cre mouse line, reporter gene expression was unexpectedly identified in cell somas within the amygdala. To indiscriminately explore Cre activity in DAT-Cre transgenic lines, systematic whole-brain analysis of two DAT-Cre mouse lines was performed upon recombination with different types of floxed reporter alleles. Results were compared with data available from the Allen Institute for Brain Science. The results identified restricted DAT-Cre-driven reporter gene expression in cell clusters within several limbic areas, including amygdaloid and mammillary subnuclei, septum and habenula, areas classically associated with glutamatergic and GABAergic neurotransmission. While no Dat gene expression was detected, ample co-localization between DAT-Cre-driven reporter and markers for glutamatergic and GABAergic neurons was found. Upon viral injection of a fluorescent reporter into the amygdala and habenula, distinct projections from non-dopaminergic DAT-Cre neurons could be distinguished. The study demonstrates that DAT-Cre transgenic mice, beyond their usefulness in recombination of floxed alleles in DA neurons, could be implemented as tools to achieve selective targeting in restricted excitatory and inhibitory neuronal populations within the limbic neurocircuitry.


Assuntos
Sistema Límbico/fisiologia , Camundongos Transgênicos , Neurônios/fisiologia , Animais , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Integrases/genética , Integrases/metabolismo , Masculino , Camundongos
8.
Molecules ; 24(17)2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31480324

RESUMO

There is behavioral evidence for the interaction between crude khat extract and the endocannabinoid system, whereby the endocannabinoid system alters khat extract-mediated behavioral effects through modulation of the monoaminergic system. The objective of this study was to investigate the role of the endocannabinoid system on the neurobehavioral effect of khat extract in mice following concomitant administration of khat extract and the CB2R agonist, JWH133. Locomotor activity test, immunohistochemistry, and reverse transcriptase polymerase chain reaction technique were utilized to assess locomotor activity, tyrosine hydroxylase immunoreactivity, and expression of dopamine transporter mRNA gene. The results show sub-acute administration of khat extract alone increased locomotor activity in mice and co-administration of the CB2R agonist, JWH133, reduced khat extract induced hyperlocomotor activity. The data revealed that cell type specific deletion of CB2Rs on dopaminergic neurons increased the hyperlocomotor behavior of khat extract. Furthermore, the results revealed that khat extract attenuated MPTP induced motor deficits, which is enhanced by JWH133. Khat extract also increased expression of tyrosine hydroxylase positive cells and expression of dopamine transporter mRNA gene in wild type mice. Nevertheless, JWH133 did not alter the effect of khat extract on tyrosine hydroxylase immunoreactivity and dopamine transporter mRNA expression when given together with khat extract. Taken together, the results suggest that the CB2Rs selectively interact with khat extract-mediated locomotor effects and could be utilized as therapeutic target in central nervous system movement disorders associated with dopamine dysregulation.


Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/fisiologia , Catha/química , Extratos Vegetais/farmacologia , Receptor CB2 de Canabinoide/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Encéfalo/efeitos dos fármacos , Canabinoides/administração & dosagem , Canabinoides/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/fisiologia , Deleção de Genes , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor CB2 de Canabinoide/agonistas , Tirosina 3-Mono-Oxigenase/metabolismo
9.
Brain Behav ; 9(9): e01340, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31392839

RESUMO

INTRODUCTION: Ginseng polysaccharide (GPS, same as Panax polysaccharide) is a kind of polysaccharide extracted from ginseng. It has been reported that GPS has the ability to activate innate immunity, regulates blood sugar balance, and improves antioxidant capacity, but the effect on feeding behavior and its mechanism remains unclear. METHOD: To investigate the possible effect of GPS on feeding behavior of animals, mice were supplied with GPS in water, and food intake, hedonic feeding behavior, anxiety-like behavior, expression of appetite-regulation peptides in the central nervous system and glucose-related hormone levels in the serum of mice were measured. RESULTS: Ginseng polysaccharide significantly increased the average daily food intake in mice and promoted hedonic eating behavior. Meanwhile, the levels of serum glucose and glucagon were significantly reduced by GPS, and GPS promoted hypothalamic neuropeptide Y expression, inhibited proopiomelanocortin (POMC) expression, and reduced dopamine D1 receptor (DRD1) levels in the midbrain. We also found that the anxiety level of mice was significantly lower after GPS intake. In conclusion, oral supplementation with GPS promoted food intake in mice, most likely through the regulation of circulating glucose levels.


Assuntos
Comportamento Alimentar/efeitos dos fármacos , Panax , Polissacarídeos/farmacologia , Animais , Ansiedade , Comportamento Animal/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Suplementos Nutricionais , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Ingestão de Alimentos/efeitos dos fármacos , Glucagon/efeitos dos fármacos , Glucagon/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Insulina/metabolismo , Masculino , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Camundongos , Neuropeptídeo Y/efeitos dos fármacos , Neuropeptídeo Y/metabolismo , Pró-Opiomelanocortina/efeitos dos fármacos , Pró-Opiomelanocortina/metabolismo , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/genética
10.
Psychiatr Danub ; 31(2): 235-240, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31291231

RESUMO

BACKGROUND: Previous research showed inconsistent results concerning a possible association between solute carrier family 6 member 3 (SLC6A3) gene polymorphisms and dopamine symptoms of posttraumatic stress disorder (PTSD). Several studies also indicate that the myelin basic protein (MBP) gene is of importance in the etiology of several psychiatric disorders. The aim of this study was to investigate the relation of distinct SLC6A3 and MBP gene polymorphisms with PTSD and whether SLC6A3 and MBP genotypes contribute to PTSD symptom severity. SUBJECTS AND METHODS: The study included 719 individuals who had experienced war trauma in the South Eastern Europe (SEE). Genotypes of variable number tandem repeat (VNTR) polymorphism within the SLC6A3 gene were assessed in 696 participants, and the single nucleotide polymorphism (SNP) rs12458282 located within the MBP gene region was genotyped in a total of 703 subjects. The Mini International Neuropsychiatric Interview, the Clinical Administrated PTSD Scale (CAPS) and Brief Symptom Inventory (BSI), were used for data collection. RESULTS: No significant differences concerning the investigated SLC6A3 and MBP polymorphisms was identifiable between PTSD and non PTSD participants. Also we could not detect significant influence of these distinct SLC6A3 and MBP alleles on the severity of PTSD symptoms (CAPS) or BSI scores. However, the results of MBP rs12458282 within the patients with lifetime PTSD may point to a possible correlation of the major allele (T) with elevated CAPS scores. CONCLUSIONS: Our results do not support an association of the analysed SLC6A3 and MBP gene polymorphisms with PTSD in war traumatized individuals. We found that there is a possibility for a correlation of the T allele rs12458282 within the MBP gene with higher CAPS scores in lifetime PTSD patients which would need to be tested in a sample providing more statistical power.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteína Básica da Mielina/genética , Polimorfismo de Nucleotídeo Único , Transtornos de Estresse Pós-Traumáticos/genética , Alelos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
11.
Neuron ; 103(6): 1056-1072.e6, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31324539

RESUMO

Motor and cognitive functions depend on the coordinated interactions between dopamine (DA) and acetylcholine (ACh) at striatal synapses. Increased ACh availability was assumed to accompany DA deficiency based on the outcome of pharmacological treatments and measurements in animals that were critically depleted of DA. Using Slc6a3DTR/+ diphtheria-toxin-sensitive mice, we demonstrate that a progressive and L-dopa-responsive DA deficiency reduces ACh availability and the transcription of hyperpolarization-activated cation (HCN) channels that encode the spike timing of ACh-releasing tonically active striatal interneurons (ChIs). Although the production and release of ACh and DA are reduced, the preponderance of ACh over DA contributes to the motor deficit. The increase in striatal ACh relative to DA is heightened via D1-type DA receptors that activate ChIs in response to DA release from residual axons. These results suggest that stabilizing the expression of HCN channels may improve ACh-DA reciprocity and motor function in Parkinson's disease (PD). VIDEO ABSTRACT.


Assuntos
Acetilcolina/metabolismo , Neurônios Colinérgicos/metabolismo , Dopamina/deficiência , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Interneurônios/metabolismo , Neostriado/metabolismo , Doença de Parkinson/metabolismo , Anfetamina/farmacologia , Animais , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Dopaminérgicos/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Interneurônios/efeitos dos fármacos , Interneurônios/fisiologia , Camundongos , Neostriado/citologia , Neostriado/efeitos dos fármacos , Neostriado/fisiopatologia , Doença de Parkinson/fisiopatologia , Técnicas de Patch-Clamp , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Transcrição Genética
12.
Mol Biol Rep ; 46(5): 5155-5162, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31325142

RESUMO

The dopamine transporter (DAT) is involved in dopamine signaling and distribution, controlling dopamine concentrations and contributing to several central nervous system disorders. The purpose of this study was to determine the association between two functional polymorphisms in DAT1 gene, the 40-base pair Variable Number of Tandem Repeats (VNTR) and the Single Nucleotide Polymorphism (SNP) -839C/T and obsessive-compulsive disorder (OCD) and/or its clinical features. To do so, 199 OCD patients and 201 healthy controls were genotyped using Polymerase Chain Reaction (PCR). Genotype distribution of both polymorphisms was in Hardy-Weinberg equilibrium. Although OCD and controls did not differ in terms of polymorphisms distribution, we observed that the presence of 10R-allele protected men of having OCD (P = 0.03). We also observed a significant association between the presence of 10R and checking in women (P = 0.02; OR = 3.14; 95%CI 1.08-9.11), and between the 9/9 genotype and neutralization in men (P = 0.04; OR = 3.38; 95%CI 1.03-11.11). Finally, the T-allele of -839C/T was significantly associated with the "obsession" score (P = 0.02; OR = 2.66; 95%CI 1.15-6.13). Our results demonstrate an important influence of dopaminergic pathways, particularly DAT1 polymorphisms, in OCD.


Assuntos
Transtorno da Personalidade Compulsiva/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Repetições Minissatélites , Transtorno Obsessivo-Compulsivo/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Brasil , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Caracteres Sexuais , Adulto Jovem
13.
Neurochem Int ; 129: 104507, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31325476

RESUMO

Heightened activity of glycogen synthase kinase-3ß (GSK-3ß) is linked to the degeneration of dopaminergic neurons in Parkinson's disease (PD). Phytic acid (PA), a naturally occurring compound with potent antioxidant property, has been shown to confer neuroprotection on dopaminergic neurons in PD. However, the underlying mechanism remains unclear. In the present study, MPTP and MPP+ treatments were used to model PD in mice and SH-SY5Y cells, respectively. We observed reduced tissue dopamine, disrupted synaptic vesicle recycling, and defective neurotransmitter exocytosis. Furthermore, expression of GSK-3ß was upregulated while that of ß-catenin was downregulated, concentration of cytosolic calcium was increased, and expressions of two dopamine carriers, dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) were decreased. PA treatment attenuated the MPTP-induced upregulation of GSK-3ß, increase in cytosolic calcium concentration, decreases in the levels of DAT, VMAT2, tissue dopamine, and synaptic vesicle recycling. Importantly, disturbances in synaptic vesicle recycling are thought to be early events in PD pathology. These findings suggest that PA is a promising therapeutic agent to treat early events in PD.


Assuntos
Antiparkinsonianos/uso terapêutico , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Intoxicação por MPTP/tratamento farmacológico , Ácido Fítico/uso terapêutico , Vesículas Sinápticas/efeitos dos fármacos , Animais , Antiparkinsonianos/farmacologia , Cálcio/metabolismo , Linhagem Celular Tumoral , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/biossíntese , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Indução Enzimática/efeitos dos fármacos , Exocitose/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/biossíntese , Glicogênio Sintase Quinase 3 beta/genética , Humanos , Intoxicação por MPTP/metabolismo , Camundongos Endogâmicos C57BL , Neuroblastoma/patologia , Ácido Fítico/farmacologia , Teste de Desempenho do Rota-Rod , Vesículas Sinápticas/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/biossíntese , Proteínas Vesiculares de Transporte de Monoamina/genética , Via de Sinalização Wnt/efeitos dos fármacos
14.
Artigo em Inglês | MEDLINE | ID: mdl-31323798

RESUMO

Parental psychopathological risk is considered as one of the most crucial features associated with epigenetic modifications in offspring, which in turn are thought to be related to their emotional/behavioral profiles. The dopamine active transporter (DAT) gene is suggested to play a significant role in affective/behavioral regulation. On the basis of the previous literature, we aimed at verifying whether children's DAT1 polymorphisms moderated the relationship between parents' psychological profiles, children's emotional/behavioral functioning, and DAT1 methylation in a normative sample of 79 families with school-age children (Ntot = 237). Children's biological samples were collected through buccal swabs, while Symptom Check-List-90 item Revised, Adult Self Report, and Child Behavior Check-List/6-18 was administered to assess parental and children's psychological functioning. We found that higher maternal externalizing problems predicted the following: higher levels of children's DAT1 methylation at M1, but only among children with 10/10 genotype; higher levels of methylation at M2 among children with 10/10 genotype; while lower levels for children with a 9-repeat allele. There was also a positive relationship between fathers' externalizing problems and children's externalizing problems, only for children with a 9-repeat allele. Our findings support emerging evidence of the complex interplay between genetic and environmental factors in shaping children' emotional/behavioral functioning, contributing to the knowledge of risk variables for a child's development and psychological well-being.


Assuntos
Comportamento Infantil , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Emoções , Pai/psicologia , Mães/psicologia , Adulto , Criança , Metilação de DNA , Depressão , Feminino , Humanos , Masculino , Metilação , Pais , Estresse Psicológico
15.
Res Dev Disabil ; 92: 103430, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31306870

RESUMO

Dopamine active transporter gene (DAT1) is a candidate gene associated with attention-deficit/hyperactivity disorder (ADHD). The DAT1 variable number tandem repeat (VNTR)-3' polymorphism is functional and 9R carriers have been shown to produce more DAT than 10R homozygotes. We used functional magnetic resonance imaging (fMRI) to investigate the effects of this polymorphism on the neural substrates of working memory (WM) in a small but selected population of children with ADHD, naïve of any psychotropic treatment and without comorbidity. MRI and genotype data were obtained for 36 children (mean age: 10,36 +/- 1,49 years) with combined-type ADHD (9R n = 15) and 25 typically developing children (TDC) (mean age: 9,55 +/- 1,25 years) (9R n = 12). WM performance was similar between conditions. We found a cross-over interaction effect between gene (9R vs. 10R) and diagnosis (TDC vs. ADHD) in the orbito-frontal gyrus, cerebellum and inferior temporal lobe. In these areas, WM-related activity was higher for 9R carriers in ADHD subjects and lower in TDC. In ADHD children only, 10R homozygotes exhibited higher WM-related activity than 9R carriers in a network encompassing the parietal and the temporal lobes, the ventral visual cortex, the orbito-frontal gyrus and the head of the caudate nucleus. There was no significant results in TDC group. Our preliminary findings suggest that DAT1 VNTR polymorphism can modulate WM-related brain activity ADHD children.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Encéfalo , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Memória de Curto Prazo/fisiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Criança , Correlação de Dados , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Repetições Minissatélites/genética , Polimorfismo Genético
16.
Metab Brain Dis ; 34(5): 1421-1430, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31313126

RESUMO

The precise contributions of ventral tegmental area (VTA) dopaminergic (DAergic) neurons to reward-related behaviors are a longstanding hot topic of debate. Whether the activity of VTA DAergic neurons directly modulates rewarding behaviors remains uncertain. In the present study, we investigated the fundamental role of VTA DAergic neurons in reward-related movement and reinforcement by employing dopamine transporter (DAT)-Cre transgenic mice expressing hM3Dq, hM4Di or channelrhodopsin 2 (ChR2) in VTA DAergic neurons through Cre-inducible adeno-associated viral vector transfection. On the one hand, locomotion was tested in an open field to examine motor activity when VTA DAergic neurons were stimulated or inhibited by injection of the hM3Dq or hM4Di ligand clozapine-N-oxide (CNO), respectively. CNO injection to selectively activate or inhibit VTA DAergic neurons significantly increased or decreased locomotor activity, respectively, compared with vehicle injection, indicating that VTA DAergic neuron stimulation is directly involved in the regulation of motor activity. On the other hand, we used the optical intracranial self-stimulation (oICSS) model to investigate the causal link between reinforcement and VTA DAergic neurons. Active poking behavior but not inactive poking behavior was significantly escalated in a frequency- and pulse duration-dependent manner. In addition, microdialysis revealed that the concentration of dopamine (DA) in the nucleus accumbens (NAc) was enhanced by selective optogenetic activation of VTA DAergic neurons. Furthermore, systemic administration of a DA D1 receptor antagonist significantly decreased oICSS reinforcement. Our research profoundly demonstrates a direct regulatory role of VTA DAergic neurons in movement and reinforcement and provides meaningful guidance for the development of novel treatment strategies for neuropsychiatric diseases related to the malfunction of the reward system.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Atividade Motora/fisiologia , Área Tegmentar Ventral/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Clozapina/análogos & derivados , Clozapina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Optogenética , Recompensa , Autoestimulação , Área Tegmentar Ventral/efeitos dos fármacos
17.
Am J Pathol ; 189(7): 1375-1385, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31230667

RESUMO

Advances in antiretroviral therapy have resulted in significantly decreased HIV-related mortality. HIV-associated neurocognitive disorders, however, continue to be a major problem in infected patients. The neuropathology underlying HIV-associated neurocognitive disorders has not been well characterized, and evidence suggests different contributing mechanisms. One potential mechanism is the induction of oxidative stress. Using the HIV-1 transgenic (Tg) rat model of HIV, we found increased striatal NADPH oxidase-4 and neuronal nitric oxide synthase expression in the adult (7- to 9-month-old) Tg rat compared with control rats but not in the young (1-month-old) Tg rats. This was accompanied by increased 3-nitrotyrosine (3-NT) immunostaining in the adult Tg rats, which worsened significantly in the old Tg rats (18 to 20 months old). There was, however, no concurrent induction of the antioxidant systems because there was no change in the expression of the nuclear factor-erythroid 2-related factor 2 and its downstream targets (thioredoxin and glutathione antioxidant systems). Colocalization of 3-NT staining with neurofilament proteins and evidence of decreased tyrosine hydroxylase and dopamine transporter expression in the old rats support dopaminergic involvement. We conclude that the HIV-1 Tg rat brain shows evidence of nitrosative stress without appropriate oxidation-reduction adaptation, whereas 3-NT modification of striatal neurofilament proteins likely points to the ensuing dopaminergic neuronal loss and dysfunction in the aging HIV-1 Tg rat.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina , Dopamina , Infecções por HIV , HIV-1 , Transtornos Neurocognitivos , Estresse Oxidativo/genética , Animais , Dopamina/genética , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Infecções por HIV/genética , Infecções por HIV/metabolismo , Infecções por HIV/patologia , HIV-1/genética , HIV-1/metabolismo , Humanos , Transtornos Neurocognitivos/genética , Transtornos Neurocognitivos/metabolismo , Transtornos Neurocognitivos/patologia , Ratos , Ratos Transgênicos , Tirosina/análogos & derivados , Tirosina/genética , Tirosina/metabolismo
18.
Acta Neuropsychiatr ; 31(3): 159-166, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31182183

RESUMO

OBJECTIVE: Road traffic injuries are the leading cause of death among young people. Recognition of the contribution of impulsive behaviour may help novice drivers to behave more safely. Previously a brief intervention focusing on impulsive traffic behaviour conducted by psychologists in driving schools had been effective. The aim of this study was an independent re-evaluation of the effect of the intervention, as conducted by driving school teachers, and assessment of the potential associations with candidate genotypes. METHODS: Driving school students (mean age 22.5, SD=7.9) were divided into intervention (n=704) and control (n=737) groups. Driving school teachers were trained to administer the intervention which consisted of a lecture and group work (1.5 h in total) on impulsivity. Traffic offences and crashes were monitored during 3 years, using police and traffic insurance fund databases. Functional polymorphisms of the dopamine transporter (DAT) and serotonin transporter genes (DAT1 VNTR and 5-HTTLPR) were assessed. RESULTS: The intervention significantly lowered general traffic risk and prevalence of traffic accidents. DAT1 VNTR 9R carriers, particularly males, had higher general traffic risk in the whole sample. Female 5-HTTLPR s' allele carriers of the intervention group had the lowest general traffic risk. Intervention was most effective in female DAT1 VNTR 10R/10R homozygotes. CONCLUSIONS: Brief impulsivity-centred intervention appears as a promising strategy for preventing risk-taking behaviour in novice drivers and can be fully integrated to driving school curriculum.


Assuntos
Acidentes de Trânsito/prevenção & controle , Comportamento Impulsivo , Polimorfismo Genético , Comportamento de Redução do Risco , Acidentes de Trânsito/estatística & dados numéricos , Alelos , Condução de Veículo/educação , Bases de Dados Factuais , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Psicoterapia Breve/métodos , Psicoterapia de Grupo/métodos , Instituições Acadêmicas , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Fatores Sexuais , Estudantes/psicologia , Adulto Jovem
19.
Nat Commun ; 10(1): 2508, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175277

RESUMO

Midbrain dopamine (mDA) neurons play a central role in reward signaling and are widely implicated in psychiatric and neurodegenerative disorders. To understand how mDA neurons perform these functions, it is important to understand how mDA-specific genes are regulated. However, cellular heterogeneity in the mammalian brain presents a major challenge to obtaining this understanding. To this end, we developed a virus-based approach to label and capture mDA nuclei for transcriptome (RNA-Seq), and low-input chromatin accessibility (liDNase-Seq) profiling, followed by predictive modeling to identify putative transcriptional regulators of mDA neurons. Using this method, we identified Gmeb1, a transcription factor predicted to regulate expression of Th and Dat, genes critical for dopamine synthesis and reuptake, respectively. Gmeb1 knockdown in mDA neurons resulted in downregulation of Th and Dat, as well as in severe motor deficits. This study thus identifies Gmeb1 as a master regulator of mDA gene expression and function, and provides a general method for identifying cell type-specific transcriptional regulators.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Neurônios Dopaminérgicos/metabolismo , Parte Compacta da Substância Negra/metabolismo , Fatores de Transcrição/genética , Tirosina 3-Mono-Oxigenase/genética , Animais , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Mesencéfalo/citologia , Camundongos
20.
Int J Mol Sci ; 20(12)2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31197099

RESUMO

Glucocorticoids are produced by the adrenal cortex and regulate cell metabolism in a variety of organs. This occurs either directly, by acting on specific receptors in a variety of cells, or by stimulating catecholamine expression within neighbor cells of the adrenal medulla. In this way, the whole adrenal gland may support specific metabolic requirements to cope with stressful conditions from external environment or internal organs. In addition, glucocorticoid levels may increase significantly in the presence of inappropriate secretion from adrenal cortex or may be administered at high doses to treat inflammatory disorders. In these conditions, metabolic alterations and increased blood pressure may occur, although altered sleep-waking cycle, anxiety, and mood disorders are frequent. These latter symptoms remain unexplained at the molecular level, although they overlap remarkably with disorders affecting catecholamine nuclei of the brainstem reticular formation. In fact, the present study indicates that various doses of glucocorticoids alter the expression of genes and proteins, which are specific for reticular catecholamine neurons. In detail, corticosterone administration to organotypic mouse brainstem cultures significantly increases Tyrosine hydroxylase (TH) and Dopamine transporter (DAT), while Phenylethanolamine N-methyltransferase (PNMT) is not affected. On the other hand, Dopamine Beta-Hydroxylase (DBH) increases only after very high doses of corticosterone.


Assuntos
Tronco Encefálico/metabolismo , Catecolaminas/metabolismo , Corticosterona/farmacologia , Animais , Tronco Encefálico/citologia , Tronco Encefálico/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Dopamina beta-Hidroxilase/genética , Dopamina beta-Hidroxilase/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Cultura de Órgãos/métodos , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Regulação para Cima
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