RESUMO
Quercetin is a flavonol widely distributed in plants and has various described biological functions. Several studies have reported on its ability to restore neuronal function in a wide variety of disease models, including animal models of neurodegenerative disorders such as Parkinson's disease. Quercetin per se can act as a neuroprotector/neuromodulator, especially in diseases related to impaired dopaminergic neurotransmission. However, little is known about how quercetin interacts with the dopaminergic machinery. Here we employed the nematode Caenorhabditis elegans to study this putative interaction. After observing behavioral modulation, mutant analysis and gene expression in C. elegans upon exposure to quercetin at a concentration that does not protect against MPTP, we constructed a homology-based dopamine transporter protein model to conduct a docking study. This led to suggestive evidence on how quercetin may act as a dopaminergic modulator by interacting with C. elegans' dopamine transporter and alter the nematode's exploratory behavior. Consistent with this model, quercetin controls C. elegans behavior in a way dependent on the presence of both the dopamine transporter (dat-1), which is up-regulated upon quercetin exposure, and the dopamine receptor 2 (dop-2), which appears to be mandatory for dat-1 up-regulation. Our data propose an interaction with the dopaminergic machinery that may help to establish the effects of quercetin as a neuromodulator.
Assuntos
Dopamina , Quercetina , Transmissão Sináptica , Animais , Caenorhabditis elegans , Quercetina/farmacologia , Dopamina/metabolismo , Proteínas de Caenorhabditis elegans , Fármacos Neuroprotetores/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios/metabolismo , Estresse Oxidativo , Transmissão Sináptica/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-HidropiridinaRESUMO
Although it is known that regular physical activity is recommended as part of a healthy lifestyle, the number of data concerning efficacy of exercise and your relationship with a demand for iron during pregnancy is limited. The purpose of this study was to evaluate the relationship between iron supplementation and exercise during pregnancy on the behavior of rats. Molecular variables dopamine transporter (DAT) and dopamine receptor (D2) related to the locomotor behavior in response to the exercise and the iron supplemented diet were investigated. Sixty-day-old female Wistar rats were used. The pregnant rats were distributed into the following groups: standard diet (SD, n = 7), iron supplementation (IS, n = 9), exercise (EX, n = 10), and exercise + iron supplementation (EX + IS, n = 9). All rats in both the pregnant and non-pregnant groups were submitted to open-field tests. The iron supplementation diet was shown to reduce locomotor behaviors, with reduced central and peripheral ambulation, reduced rearing, and increased freezing. On the other hand, physical exercise caused an increase in central and peripheral ambulation, and in rearing. The expression of the D2 receptor protein and the dopamine transporter DAT did not show changes with the interventions over 21 days of pregnancy. In this context, the present study demonstrated that both iron supplementation and exercise exerted an influence during pregnancy on the behavior of rats, however, with different effects.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina , Ferro , Gravidez , Ratos , Feminino , Animais , Ratos Wistar , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Ferro/farmacologia , Ferro/metabolismo , Dieta , Suplementos Nutricionais , DopaminaRESUMO
The aim of the present research was to add to the growing literature on dopamine and gambling disorder (GD) by assessing whether GD is associated with dopamine transporter (DAT) density in the ventral striatum compared to healthy controls and whether DAT density was associated with key characteristics of GD (e.g., abstinence, craving). In a cross-sectional investigation using single-photon emission computed tomography with a technetium-99m-labeled tropane derivative as a radiotracer with SPECT imaging, fifteen participants with GD and 15 controls (non-gambling individuals, matched for age, gender, handedness, and smoking status) were measured. The GD group completed self-reported questionnaires regarding gambling. Striatal DAT density did not differ between the two groups. Conversely, striatal DAT density correlated significantly with various measures of recent gambling, but not with measures of chronic gambling. Multivariate analysis, adjusted for age and smoking status, showed that DAT density in the left striatum correlated positively with time spent gambling and gambling craving in the last month, whereas DAT density in the right striatum correlated negatively with abstinence self-efficacy. The results suggests that DAT density in the striatum is associated with recent gambling activity and gambling expectation.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina , Jogo de Azar , Humanos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Estudos Transversais , Jogo de Azar/psicologia , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , NeuroimagemRESUMO
ABSTRACT: The presynaptic dopamine transporter (DAT) modulates the uptake of dopamine by regulating its concentration in the central nervous system. We aimed to evaluate the DAT binding potential (DAT-BP) in a sample of healthy Brazilians through technetium-99 metastable TRODAT-1 single-photon emission computed tomography imaging.We selected 126 healthy individuals comprising 72 men and 54 women, aged 18 to 80âyears. We conducted semi-quantitative evaluation in transaxial slices, following which we identified the regions of interest in the striatal region using the occipital lobe as a region of non-specific DAT-BP.We found a decrease in DAT-BP in healthy individuals aged over 30âyears, culminating in a 42% mean reduction after 80âyears. There was no difference in the decrease by age group between the right (linear regression test [R2] linearâ=â0.466) and left striatum (R2 linearâ=â0.510). Women presented a higher DAT-BP than men (women: R2 linearâ=â0.431; men: R2 linearâ=â0.457); nonetheless, their decrease by age group was equal to that in men.Our study sheds light on important DAT-BP findings in healthy Brazilian subjects. Our results will facilitate understanding of brain illnesses that involve the dopamine system, such as neuropsychiatric disorders.
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Compostos de Organotecnécio , Compostos Radiofarmacêuticos , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Tropanos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Adulto JovemRESUMO
BACKGROUND Studies on the routine clinical use of dopamine transporter (DAT) imaging have largely been conducted in Europe and the United States. In this real-world study, we investigated the use of cerebral 99mTc-TRODAT-1 SPECT imaging of DAT in patients with Parkinson disease (PD) at a tertiary hospital in Brazil. MATERIAL AND METHODS We included 119 patients with suspected PD or clinically unclear parkinsonism who underwent brain scintigraphy with 99mTc-TRODAT-1 during a 3-year period. Additionally, a brief interview was conducted with the physician who requested the scan to determine the usefulness of the method in clinical decision-making. RESULTS Regarding the scan requests, most were intended to evaluate or confirm dopaminergic denervation (69%), distinguish PD from essential tremor (10%), or distinguish degenerative parkinsonism from drug-induced parkinsonism (6%). Data analysis showed that scintigraphy with 99mTc-TRODAT-1 was useful in 85% of cases, changing the management of 75% of the patients who underwent a scan. The majority of physicians who requested the scan were neurologists, and 54% were self-reported movement disorder specialists. An inappropriate use of DAT imaging was seen in 5% of cases. CONCLUSIONS This study demonstrated that brain scintigraphy with the DAT ligand 99mTc-TRODAT-1 may influence diagnostic or therapeutic interventions, meaning that Brazilian physicians who requested the exam have taken in vivo DAT results into account at the time of clinical decision-making.
Assuntos
Encéfalo/diagnóstico por imagem , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Compostos de Organotecnécio/química , Doença de Parkinson/diagnóstico por imagem , Centros de Atenção Terciária , Tomografia Computadorizada de Emissão de Fóton Único , Tropanos/química , Idoso , Encéfalo/patologia , Brasil , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , CintilografiaRESUMO
Cocaine (COC) is a psychostimulant that acts by increasing catecholaminergic neurotransmission mainly due to its effects on the dopamine transporter (DAT). However, other neurotransmitter systems may also be regulated by COC, including the GABAergic system. Since the effect of COC in modulating gamma-aminobutyric acid (GABA) reuptake is not defined, we investigated the molecular mechanisms related to the increase in GABA uptake induced by acute COC exposure and its effects on locomotor activity in adolescent mice. Behavioral experiments showed that COC increased locomotor activity and decreased immobilization time in mice. A single COC exposure reduced both GABA uptake and GAT-1 protein levels. On the other hand, cyclic adenosine monophosphate (cAMP) levels increased after a COC challenge. The major changes induced by acute COC on behavioral and neurochemical assays were avoided by previous treatment with the selective D1 receptor antagonist SCH-23390 (0.5 mg/kg). Our findings suggest that GABA uptake naturally decreases during mice development from preadolescence until adulthood and that dopamine (DA) D1-like receptors are key players in the regulation of GABA uptake levels following a single COC exposure in adolescent mice.
Assuntos
Cocaína/farmacologia , Dopamina/metabolismo , Lobo Frontal/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Ácido gama-Aminobutírico/efeitos dos fármacos , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Cocaína/administração & dosagem , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Lobo Frontal/metabolismo , Camundongos , Atividade Motora/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismoRESUMO
Psychostimulant drugs addiction is a chronic public health problem and individuals remain susceptible to relapses increasing public expenses even after withdrawal and treatment. Our research group has focused on finding new therapies to be employed in drug addiction treatment, suggesting the physical exercise as a promising tool. This way, it is necessary to know the mechanisms involved in the beneficial influences of physical exercise observing the pathway that could be explored in drug addiction treatment. Male Wistar rats were conditioned with amphetamine (AMPH) following the conditioned place preference (CPP) protocol and subsequently submitted to swimming for 5 weeks (1 h per day, 5 days per week). Half of the animals were injected with Naloxone (0.3 mg/mL/kg body weight, i.p.) 5 min prior each physical exercise day. After AMPH-CPP re-exposure, our outcomes showed that physical exercise, in addition to minimizing the relapse behavior in the CPP, it increased D1R, D2R and DAT in the Ventral Tegmental Area (VTA), but not in the Nucleus accumbens (NAc). Interestingly, while naloxone inhibited the partial beneficial influence of the exercise on drug-relapse behavior, exercise-induced changes in the dopaminergic system were not observed in the group administered with naloxone as well. Based on these evidences, besides reinforcing the beneficial influence of the physical exercise on AMPH-induced drug addiction, we propose the involvement of endogenous opioid system activation, not as a single one, but as a possible mechanism of action resulting from the physical activity practice, thus characterizing an important therapeutic approach, which may contribute to drug withdrawal consequently preventing relapse.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/terapia , Anfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Condicionamento Físico Animal/métodos , Animais , Condicionamento Clássico/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Núcleo Accumbens/metabolismo , Ratos , Ratos Wistar , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Natação , Área Tegmentar Ventral/metabolismoRESUMO
Despite recent advances, current antidepressants have considerable limitations: late onset of action and the high profile of refractoriness. Biomedical research with natural products has gained growing interest in the last years, and had provide useful candidates for new antidepressants. Riparins are a group of natural alkamides obtained from Aniba riparia, which had marked neuroactive effects, mainly as antidepressant and antinociceptive agents. We made modifications of the basic structure of riparins, originating a synthetic alkamide, also known as riparin IV (RipIV). RipIV demonstrated a superior analgesic effect than its congeners and a marked antidepressant-like effect. However, the basic mechanism for the central effects of RipIV remains unknown. Here, we aimed to investigate the participation of monoaminergic neurotransmission targets in the antidepressant-like effects of RipIV. To do this, we applied a combined approach of experimental (classical pharmacology and neurochemistry) and computer-aided techniques. Our results demonstrated that RipIV presented antidepressant- and anxiolytic-like effects without modifying locomotion and motor coordination of mice. Also, RipIV increased brain monoamines and their metabolite levels. At the higher dose (100â¯mg/kg), RipIV increased serotonin concentrations in all studied brain areas, while at the lower one (50â¯mg/kg), it increased mainly dopamine and noradrenaline levels. When tested with selective receptor antagonists, RipIV antidepressant effect showed dependence of the activation of multiple targets, including D1 and D2 dopamine receptors, 5-HT2A/2, 5-HT3 receptors and α2 adrenergic receptors. Molecular docking demonstrated favorable binding conformation and affinity of RipIV to monoamine oxidase B (MAO-B), serotonin transporter (SERT), α1 receptor, D2 receptor, dopamine transporter (DAT) and at some extent GABA-A receptor. RipIV also presented a computationally predicted favorable pharmacokinetic profile. Therefore, this study demonstrated the involvement of monoaminergic targets in the mechanism of RipIV antidepressant-like action, and provide evidence of it as a promising new antidepressant.
Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Monoaminoxidase/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , Tiramina/análogos & derivados , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Bupropiona/farmacologia , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Fluoxetina/farmacologia , Imipramina/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Monoaminoxidase/metabolismo , Norepinefrina/metabolismo , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores de Dopamina D1 , Receptores de Dopamina D2 , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Receptores de Serotonina/metabolismo , Receptores 5-HT2 de Serotonina/efeitos dos fármacos , Receptores 5-HT2 de Serotonina/metabolismo , Receptores 5-HT3 de Serotonina/efeitos dos fármacos , Receptores 5-HT3 de Serotonina/metabolismo , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Tiramina/farmacologiaRESUMO
PURPOSE: Dopamine transporters (DAT) modulate pre-synaptic dopamine and physiological functions such as movement and reward. DAT also mirrors disease state in neurological disorders, rendering it an essential diagnostic target. [18F]PR04.MZ is a new PET imaging agent for DAT with an improved affinity and selectivity profile, for which we here describe the complete pharmacokinetic evaluation in healthy controls. METHODS: Thirty-two healthy subjects underwent T1-weighted MRI and dynamic PET scans for 180 min with arterial blood sampling (n = 5) or 90 min without blood sampling (n = 25) after injection of 197.6 ± 12.2 MBq [18F]PR04.MZ. Blood and plasma metabolite analysis were performed. MRI-based normalization of brain images, delineation of VOIs, and kinetic modeling was conducted to determine distribution volumes (Vt) and binding potentials (BPnd). The impact of scan duration was evaluated and repeated PET scans were performed to assess test-retest variability (n = 5). A static imaging protocol has been validated for clinical applications. RESULTS: [18F]PR04.MZ showed rapid metabolization in circulation, very high uptake in striatum and midbrain, and very low non-specific binding. The two-tissue compartment model 2TCM provided best fits for measured time-activity-curves and calculated Vts in putamen, caudate, substantia nigra pars compacta (SNpc), and cerebellar cortex were 11.83, 9.73, 2.12, and 0.57, respectively. All non-invasive models correlated well with BPnd values derived from 2TCM but underestimated DAT availability by about 28-33%. Of those, simplified reference tissue model (SRTM) provided the best fits, lowest Akaike Information Criteria values, and BPnd values of 14.82, 11.95, and 2.63 in putamen, caudate, and SNpc, respectively. BPnd estimates for striatal regions and SNpc were stable between 90 and 130 min post-injection. Test-retest results were excellent, showing low variability in all and excellent reliability in most relevant regions. Static imaging from 60 to 90-min post-injection is a viable alternative for quantification. CONCLUSIONS: [18F]PR04.MZ is a PET tracer with very high affinity, selectivity, and specific uptake in striatum and midbrain. 2TCM and SRTM provide good fits, high and stable Vts or BPnds, and good test-retest reliability for precise quantification of DAT in human subjects.
Assuntos
Dopamina , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Humanos , Tomografia por Emissão de Pósitrons , Reprodutibilidade dos TestesRESUMO
Exposure to environmental contaminants represents an important etiological factor in sporadic Parkinson's disease (PD). It has been reported that PD could arise from events that occur early in development and that lead to delayed adverse consequences in the nigrostriatal dopaminergic system at adult life. We investigated the occurrence of late nigrostriatal dopaminergic neurotoxicity induced by exposures to the pesticides paraquat (PQ) and maneb (MB) during the early postnatal period in mice, as well as whether the exposure to pesticides during development could enhance mice vulnerability to subsequent challenges. Male Swiss mice were exposed to a combination of 0.3 mg/kg PQ and 1.0 mg/kg MB (PQ + MB) from postnatal (PN) day 5 to 19. PN exposure to pesticides neither induced mortally nor modified motor-related parameters. However, PN pesticides exposure decreased the number of tyrosine hydroxylase (TH)- and dopamine transporter (DAT)-positive neurons in the substantia nigra pars compacta (SNpc), as well as reduced TH and DAT immunoreactivity in the striatum. A parallel group of animals developmentally exposed to the pesticides was re-challenged at 3 months of age with 10 mg/kg PQ plus 30 mg/kg MB (twice a week, 6 weeks). Mice exposed to pesticides at both periods (PN + adulthood) presented motor deficits and reductions in the number of TH- and DAT-positive neurons in the SNpc. These findings indicate that the exposure to PQ + MB during the early PN period can cause neurotoxicity in the mouse nigrostriatal dopaminergic system, rendering it more susceptible to a subsequent adult re-challenge with the same pesticides.