RESUMO
Major Depressive Disorder (MDD) is a disabling and particularly persistent mental disorder that is considered to be a priority public health problem. The active human dopamine transporter (DAT), which is encoded by the SLC6A3 gene, regulates the dopamine concentration in the synaptic cleft. In this sense, this neurotransmitter is primordial in modulating human emotions. This systematic review aims to verify the SLC6A3 (DAT1) 3'UTR VNTR (rs28363170) gene variant's SS (9R/9R) genotype and S (9R) allele frequency fluctuation and its influence on the modulation of pharmacotherapy in MDD. For this purpose, we searched different databases, and after applying the eligibility criteria, six articles were selected. Studies have shown an association between the SS (9R/9R) genotypic and S (9R) allelic presence with the risk of developing MDD, in addition to influencing the decrease in response to antidepressant therapy. However, despite the findings, disagreements were observed between other studies. For this reason, further studies with the SLC6A3 3'UTR VNTR (rs28363170) variant in different populations are necessary to understand this polymorphism's role in the onset of this disease.
RESUMO
Despite progress in understanding the role of the dorsal hippocampus in the acquisition, consolidation and retrieval of episodic-like memory, plastic changes within the intra- and extrahippocampal circuits for aversive memory formation and anxiety-like behaviours must still be identified since both processes contribute to multiple aspects of flexible decision-making. Here, we investigated the effect of reversible inactivation induced by a muscimol microinfusion into the dorsal CA1 subfield (dCA1) either prior to acquisition or to retrieval testing of a discriminative avoidance task performed in a plus-maze apparatus (PM-DAT). Differential cAMP-response-element-binding protein 1 (CREB-1) expression in the dorsal and ventral CA1 and CA3 of the hippocampus (dCA1, dCA3, vCA1, and vCA3), dorsal dentate gyrus (dDG), and infralimbic (IL) and prelimbic (PrL) regions of the medial prefrontal cortex was also assessed to investigate the molecular changes associated with the consolidation or retrieval of episodic-like memory and anxiety. Adult male Wistar rats were assigned to two control groups, learning (no surgery/no microinfusion, n = 7) and sham-operated (sham surgery/no microinfusion, n = 6) groups, or four experimental groups, in which the vehicle (0.5 µl per side, n = 8/per group) or a GABAA receptor agonist (0.5 µg/0.5 µl muscimol/per side) was bilaterally microinfused in the dCA1 30 min prior to training (n = 9) or prior to testing sessions (n = 6) with a 24 h intertrial interval. Memory was evaluated using the percentage of time spent in the nonaversive enclosed arms, whereas anxiety was measured by calculating the percentages of time spent and entries into open arms and the percentage of time spent self-grooming. Our findings corroborated previous data showing that the dCA1 is required for discriminative avoidance consolidation. Furthermore, additional information indicated that impaired long-term memory was associated with downregulated CREB-1 expression in the dDG and vCA3. Moreover, memory retrieval was not impaired by dCA1 inactivation prior to the testing session, which was associated with the upregulation of CREB-1 in the dCA3 and vCA1 and downregulation in the dCA1 and vCA3. Differential expression of CREB was not identified in the IL or PrL areas. These results improve our understanding of how the hippocampal circuitry mediates the acquisition and retrieval of aversive memory and anxiety.
Assuntos
Hipocampo , Memória , Ratos , Animais , Masculino , Ratos Wistar , Muscimol/farmacologia , AprendizagemRESUMO
Dopamine is an important neurotransmitter that regulates numerous essential functions, including cognition and voluntary movement. As such, it serves as an important scaffold for synthesis of novel analogues as part of drug development effort to obtain drugs for treatment of neurodegenerative diseases, such as Parkinson's disease. To that end, similarity search of the ZINC database based on two known dopamine-1 receptor (D1R) agonists, dihydrexidine (DHX) and SKF 38393, respectively, was used to predict novel chemical entities with potential binding to D1R. Three compounds that showed the highest similarity index were selected for synthesis and bioactivity profiling. All main synthesis products as well as the isolated intermediates, were properly characterized. The physico-chemical analyses were performed using HRESIMS, GC/MS, LC/MS with UV-Vis detection, and FTIR, 1H NMR and 13C NMR spectroscopy. Binding to D1 and D2 receptors and inhibition of dopamine reuptake via dopamine transporter were measured for the synthesized analogues of DHX and SKF 38393.
Assuntos
Catecolaminas , Receptores de Dopamina D1 , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Fenantridinas/farmacologia , Receptores de Dopamina D1/metabolismoRESUMO
Iron restriction during pregnancy can lead to iron deficiency and changes in the dopaminergic system in the adulthood of offspring, and restless legs syndrome (RLS) is closely related to these changes. Objectives: Analyze whether iron restriction during pregnancy would cause changes in the behavior, sleep, and dopaminergic system of the male offspring. In addition, we aimed to assess whether exercise would be able to modulate these variables. The pregnant rats (Wistar) were divided into four groups with different concentrations of iron in the diet: standard (St), supplementation (Su), restriction since weaning (R1), and restriction only during pregnancy (R2). After birth, the offspring were assigned to their respective groups according to the dams diet (St, Su, R1, and R2) and distributed into sedentary (SD) and exercised (EX) (for 8 weeks of training), reaching eight groups of offspring (O): OSt SD, OSt EX, OSu SD, OSu EX, OR1 SD, OR1 EX, OR2 SD, and OR2 EX. Sleep, behavior, and analysis of key genes of dopaminergic system (D2, DAT) were performed after 8 weeks. The results for trained offspring that the mother received supplementation diet were the most expressive, with increased freezing and the OR1 SD group showed an increase in DAT protein content. These changes may have been due to the association between the dams diet during pregnancy and the practice of exercise by the offspring. The different concentrations of iron during pregnancy caused changes in the offspring, however, they were not associated with fetal programming in the context of RLS.
Assuntos
Deficiências de Ferro , Síndrome das Pernas Inquietas , Animais , Feminino , Ferro , Masculino , Gravidez , Ratos , Ratos Wistar , SonoRESUMO
Amphetamine derivatives have been used in a wide variety of pathologies because of their pharmacological properties as psychostimulants, entactogens, anorectics, and antidepressants. However, adverse cardiovascular effects (sympathomimetics) and substance abuse problems (psychotropic and hallucinogenic effects) have limited their use. 4-Methylthioamphetamine (MTA) is an amphetamine derivative that has shown to inhibit monoamine uptake and monoamine oxidase. However, the pharmacological characterization (neurochemical, behavioral, and safety) of its derivatives 4-ethylthioamphetamine (ETA) and 4-methylthio-phenil-2-butanamine (MT-But) have not been studied. In the current experiments, we show that ETA and MT-But do not increase locomotor activity and conditioned place preference with respect to MTA. At the neurochemical level, ETA and MT-But do not increase in vivo DA release in striatum, but ETA and MT-But affect the nucleus accumbens bioaccumulation of DA and DOPAC. Regarding cardiovascular effects, the administration of MTA and ETA increased the mean arterial pressure and only ETA significantly increases the heart rate. Our results show that the pharmacological and safety profiles of MTA are modulated by changing the methyl-thio group or the methyl group of the aminoethyl chain.
Assuntos
Ácido 3,4-Di-Hidroxifenilacético/farmacologia , Anfetamina/farmacologia , Anfetaminas/farmacologia , Corpo Estriado/efeitos dos fármacos , Dopamina/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Anfetaminas/química , Animais , Comportamento Animal , Temperatura Corporal , Ligantes , Locomoção/efeitos dos fármacos , Masculino , Simulação de Acoplamento Molecular , Oxigênio/química , Ratos , Ratos Sprague-Dawley , Proteínas da Membrana Plasmática de Transporte de Serotonina/químicaRESUMO
The performance of distinct serological tests (rK39-ICT, IFAT, DAT-LPC, FC-Simplex IgG1) was assessed and a laboratorial algorithm was proposed for accurate diagnosis of VL. DAT-LPC and FC-Simplex IgG1 showed outstanding accuracy (AUC = 0.93) to identify VL patients. The use of a sequential serological algorithm (rK39-ICT screening followed by DAT-LPC or FC-Simplex IgG1) improved the global accuracy for VL (97.2%) diagnosis. An alternative approach for diagnosis of VL has been also assessed for interchangeable use of serum/whole blood lysate samples in DAT-LPC and FC-Simplex IgG1. Our data showed an outstanding agreement for the results obtained with whole blood lysate samples as compared to serum samples (DAT-LPC =100%; FC-Simplex IgG1 = 99%). Together, these findings provide insights to improve the current overall accuracy of VL diagnosis and present innovative laboratorial tests and alternative samples from use in public health services.
Assuntos
Algoritmos , Anticorpos Antiprotozoários/sangue , Antígenos de Protozoários/imunologia , Imunoglobulina G/sangue , Leishmania donovani/imunologia , Leishmaniose Visceral/diagnóstico , Kit de Reagentes para Diagnóstico , Testes Sorológicos , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Brasil , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Interações Hospedeiro-Parasita , Humanos , Lactente , Leishmaniose Visceral/sangue , Leishmaniose Visceral/imunologia , Leishmaniose Visceral/parasitologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Adulto JovemRESUMO
Addiction is a devastating worldwide disorder that requires effective and innovative therapies. Physical exercise could be useful in addiction treatment because it shares a common neural circuit with addictive drugs. Based on this, molecular adaptations consequent to time of exercise in opioid exposed animals were evaluated. Rats were designed as sedentary (SED) or exercised (EXE). This last group was separated to perform three different periods of swimming: short-term (S-EXE), medium-term (M-EXE) and long-term (L-EXE) for 14, 28 and 42 days, respectively. On the last exercising week, one-half of the animals from SED and all animals from S-, M- and l-EXE were concomitantly exposed to morphine-conditioned place preference (CPP) paradigm and y-maze task for behavioral assessments followed by molecular assays in both Nucleus accumbens (NAc) and hippocampus. Between SED groups, morphine conditioning showed drug-CPP and increased dopamine transporter (DAT), dopamine receptor type-1 (D1R), type-2 (D2R) and glucocorticoid receptor (GR) in both brain areas in relation to saline group. Besides the small morphine-CPP in relation to SED group, all periods decreased DAT, D1R, and GR immunoreactivity in NAc, DAT and D1R in hippocampus, while D2R in both brain areas and GR in hippocampus were primarily decreased by L-EXE. Our findings show that even a short-term exercise modifies behaviors related to drug withdrawal, changing DA targets and GR, which are closely linked to addiction. Therefore, our outcomes involving physical exercise are interesting to perform a possible clinical trial, thus expanding the knowledge about drug addiction.
Assuntos
Condicionamento Psicológico/fisiologia , Transtornos Relacionados ao Uso de Opioides/metabolismo , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Condicionamento Físico Animal/fisiologia , Comportamento Sedentário , Animais , Condicionamento Psicológico/efeitos dos fármacos , Masculino , Morfina/administração & dosagem , Condicionamento Físico Animal/psicologia , Condicionamento Físico Animal/tendências , Ratos , Ratos Wistar , Natação/fisiologia , Natação/psicologia , Natação/tendências , Fatores de TempoRESUMO
Resumo Ao longo do tempo, os caninos impactados sempre se apresentaram como um grande desafio para os ortodontistas. Sendo assim diferentes técnicas cirúrgicas são citadas na literatura, variando desde as mais invasivas até as mais conservadoras. O diagnóstico, planejamento cirúrgico e técnica de tracionamento fazem parte dos três principais pilares para se obter um bom prognóstico, quando se trata de tracionamento de caninos impactados. Dentre os procedimentos cirúrgicos encontrados na literatura, pode-se destacar a técnica VISTA, que apresenta uma característica menos invasiva dentre as técnicas de tracionamento de caninos impactos. (AU)
Abstract Over time, impacted canines have always been a great challenge for orthodontists. Therefore, different surgical techniques are mentioned in the literature, and these vary from the most invasive to the most conservative ones. The diagnosis, surgical planning and traction techniques are part of the three main pillars to obtain a good prognosis, when it comes to traction of impacted canines. Among the surgical procedures found in the literature, we can highlight the VISTA technique, which has a less invasive characteristic among the techniques of impacted canine traction. (AU)
Assuntos
Ortodontia , Implantes Dentários , Dente CaninoRESUMO
Nicotinic acetylcholine receptors (nAChRs), serotonin transporters (SERT) and dopamine transporters (DAT) represent targets for the development of novel nicotinic derivatives acting as multiligands associated with different health conditions, such as depressive, anxiety and addiction disorders. In the present work, a series of functionalized esters structurally related to acetylcholine and nicotine were synthesized and pharmacologically assayed with respect to these targets. The synthesized compounds were studied in radioligand binding assays at α4ß2 nAChR, h-SERT and h-DAT. SERT experiments showed not radioligand [3H]-paroxetine displacement, but rather an increase in the radioligand binding percentage at the central binding site was observed. Compound 20 showed Ki values of 1.008 ± 0.230 µM for h-DAT and 0.031 ± 0.006 µM for α4ß2 nAChR, and [3H]-paroxetine binding of 191.50% in h-SERT displacement studies, being the only compound displaying triple affinity. Compound 21 displayed Ki values of 0.113 ± 0.037 µM for α4ß2 nAChR and 0.075 ± 0.009 µM for h-DAT acting as a dual ligand. Molecular docking studies on homology models of α4ß2 nAChR, h-DAT and h-SERT suggested potential interactions among the compounds and agonist binding site at the α4/ß2 subunit interfaces of α4ß2 nAChR, central binding site of h-DAT and allosteric modulator effect in h-SERT.
Assuntos
Acetilcolina/análogos & derivados , Proteínas da Membrana Plasmática de Transporte de Dopamina/química , Nicotina/análogos & derivados , Receptores Nicotínicos/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Acetilcolina/agonistas , Acetilcolina/síntese química , Acetilcolina/química , Regulação Alostérica , Sítios de Ligação , Dopamina/química , Agonistas de Dopamina/química , Proteínas da Membrana Plasmática de Transporte de Dopamina/agonistas , Ésteres/química , Células HEK293 , Humanos , Ligantes , Simulação de Acoplamento Molecular , Nicotina/agonistas , Nicotina/síntese química , Nicotina/química , Agonistas Nicotínicos/química , Pirrolidinas/química , Ensaio Radioligante , Proteínas da Membrana Plasmática de Transporte de Serotonina/agonistas , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Genetic polymorphisms of the dopamine transporter gene (DAT1) and perinatal complications associated with poor oxygenation are risk factors for attentional problems in childhood and may show interactive effects. METHODS: We created a novel expression-based polygenic risk score (ePRS) reflecting variations in the function of the DAT1 gene network (ePRS-DAT1) in the prefrontal cortex and explored the effects of its interaction with perinatal hypoxic-ischemic-associated conditions on cognitive flexibility and brain gray matter density in healthy children from two birth cohorts-MAVAN from Canada (n = 139 boys and girls) and GUSTO from Singapore (n = 312 boys and girls). RESULTS: A history of exposure to several perinatal hypoxic-ischemic-associated conditions was associated with impaired cognitive flexibility only in the high-ePRS group, suggesting that variation in the prefrontal cortex expression of genes involved in dopamine reuptake is associated with differences in this behavior. Interestingly, this result was observed in both ethnically distinct birth cohorts. Additionally, parallel independent component analysis (MAVAN cohort, n = 40 children) demonstrated relationships between single nucleotide polymorphism-based ePRS and gray matter density in areas involved in executive (cortical regions) and integrative (bilateral thalamus and putamen) functions, and these relationships differ in children from high and low exposure to hypoxic-ischemic-associated conditions. CONCLUSIONS: These findings reveal that the impact of conditions associated with hypoxia-ischemia on brain development and executive functions is moderated by genotypes associated with dopamine signaling in the prefrontal cortex. We discuss the potential impact of innovative genomic and environmental measures for the identification of children at high risk for impaired executive functions.