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1.
Adv Exp Med Biol ; 1191: 197-218, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32002931

RESUMO

The present chapter is an overview of possible biomarkers which distinguish anxiety disorders as classified by the DSM-5. Structural or activity changes in the brain regions; changes in N-acetylaspartate/creatine, dopamine, serotonin, and oxytocin; hearth rate variability; hypothalamic-pituitary-adrenal axis activity; error-related negativity; respiratory regulation; and genetic variants are proposed. However, their clinical utility is questionable due to low specificity and sensitivity: the majority does not distinguish subjects with different anxiety disorders, and they might be influenced by stress, comorbidity, physical activity, and psychotropic medications. In this framework, the staging model, a clinimetric tool which allows to define the degree of progression of a disease at a point in time and where the patient is located on the continuum of the course of the disease, is proposed since several DSM anxiety disorders take place at different stages of the same syndrome according to the staging model. Thus, a stage-specific biomarker model for anxiety disorders is hypothesized and illustrated.


Assuntos
Transtornos de Ansiedade/classificação , Transtornos de Ansiedade/diagnóstico , Biomarcadores/análise , Manual Diagnóstico e Estatístico de Transtornos Mentais , Dopamina/metabolismo , Humanos , Sistema Hipotálamo-Hipofisário , Ocitocina/metabolismo , Sistema Hipófise-Suprarrenal , Serotonina/metabolismo
2.
Ecotoxicol Environ Saf ; 188: 109909, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31740235

RESUMO

Mn3O4 nanoparticles (NPs) are used increasingly in various fields due to their excellent physiochemical properties. Previous studies have documented that Mn-based nanomaterials resulted in excess reactive oxygen species (ROS) generation and dopamine (DA) reduction both in vivo and in vitro experiments. However, little is known about the mechanism of ROS production and DA decrease induced by Mn-based nanomaterials. The present study was carried out to elucidate the mechanism of the co-incubation model of dopaminergic neuron PC12 cells and the synthesized Mn3O4 NPs. The results demonstrated that exposure to Mn3O4 NPs reduced cell viability, increased level of lactate dehydrogenase (LDH), triggered oxidative stress and induced apoptosis. Notably, the level of ROS was remarkably increased (>10-fold) with Mn3O4 NPs exposure. We also found that mitochondrial calcium Ca2+ uniporter (MCU) was up-regulated and the mitochondrial Ca2+ concentration ([Ca2+]mito) increased induced by Mn3O4 NPs in PC12 cells. Furthermore, the MCU inhibitor RuR significantly attenuated Mn3O4 NPs-induced [Ca2+]mito, ROS production and apoptosis. In PC12 cells, the decrease of DA content was mainly due to the downregulation of DOPA decarboxylase (DDC) expression caused by Mn3O4 NPs treatment. The expression of proteins related to DA storage system was not significantly affected by treatment.


Assuntos
Apoptose/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Óxidos/toxicidade , Animais , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Sobrevivência Celular , Dopa Descarboxilase/genética , Dopa Descarboxilase/metabolismo , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Compostos de Manganês/química , Nanopartículas Metálicas/química , Estresse Oxidativo/efeitos dos fármacos , Óxidos/química , Células PC12 , Ratos , Espécies Reativas de Oxigênio/metabolismo
3.
Immunity ; 51(6): 1102-1118.e7, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31757673

RESUMO

Young children are more susceptible to developing allergic asthma than adults. As neural innervation of the peripheral tissue continues to develop after birth, neurons may modulate tissue inflammation in an age-related manner. Here we showed that sympathetic nerves underwent a dopaminergic-to-adrenergic transition during post-natal development of the lung in mice and humans. Dopamine signaled through a specific dopamine receptor (DRD4) to promote T helper 2 (Th2) cell differentiation. The dopamine-DRD4 pathway acted synergistically with the cytokine IL-4 by upregulating IL-2-STAT5 signaling and reducing inhibitory histone trimethylation at Th2 gene loci. In murine models of allergen exposure, the dopamine-DRD4 pathway augmented Th2 inflammation in the lungs of young mice. However, this pathway operated marginally after sympathetic nerves became adrenergic in the adult lung. Taken together, the communication between dopaminergic nerves and CD4+ T cells provides an age-related mechanism underlying the susceptibility to allergic inflammation in the early lung.


Assuntos
Neurônios Adrenérgicos/citologia , Asma/patologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/citologia , Pulmão/patologia , Células Th2/imunologia , Adolescente , Adulto , Fatores Etários , Idoso , Animais , Asma/imunologia , Células Cultivadas , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Interleucina-2/metabolismo , Interleucina-4/imunologia , Pulmão/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Neurogênese/fisiologia , Receptores de Dopamina D4/metabolismo , Fator de Transcrição STAT5/metabolismo , Sistema Nervoso Simpático/citologia
4.
Expert Opin Ther Pat ; 29(12): 979-985, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31694421

RESUMO

Introduction: Parkinson's disease (PD), is a disorder debilitant characterized by the reduction of nigrostriatal dopaminergic neurons within the midbrain, specifically in the substantia nigra pars compacta, which results for the dopamine (DA) depletion in the striatum. Dopamine replacement therapies with the 3,4-dihydroxy-L-phenylalanine (Levodopa or L-DOPA) represent the most common strategy to treat PD. However, chronic administration of L-DOPA results in abnormal involuntary movement (AIMs). Thus, the present study aimed to prospect patents of alternative treatment strategies for L-DOPA-induced dyskinesias.Areas covered: This review covers the therapeutic patents published over the 2001-2019 period in the WIPO, INPI, and ESPACENET, which report treatment strategies for L-DOPA induced dyskinesias (LIDs).Expert opinion: In recent years, several pharmaceutical companies, as well as universities and researchers have tested effective compounds for LIDs treatment, showing substances that act on central pathways as antagonists and agonists of the serotonergic system, which may result in the key to onset of LIDs in animal models of PD. Future works aiming to elucidate the L-DOPA, Flibanserin, Eltoprazine, and Pridopidina mechanisms of action on the receptors of the serotonergic system and D2 receptors of the indirect pathway, will allow the development of effective therapies for LIDs.


Assuntos
Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/tratamento farmacológico , Levodopa/efeitos adversos , Animais , Antiparkinsonianos/administração & dosagem , Modelos Animais de Doenças , Dopamina/metabolismo , Humanos , Levodopa/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Patentes como Assunto
5.
Expert Opin Investig Drugs ; 28(12): 1081-1094, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31714807

RESUMO

Introduction: Binge eating disorder (BED) is the most common eating disorder and is frequently associated with psychiatric and medical comorbidities and functional impairment. Although psychological treatments have been the cornerstones of BED treatment, pharmacologic interventions also play an important part of the multimodal management of this condition.Areas covered: This review examines investigational, approved and other pharmacological agents for the treatment of BED. We searched PubMed and clinicaltrials.gov to identify pharmacological interventions for the management of this condition.Expert opinion: BED pharmacological studies have incorporated new drug targets based on our enhanced understanding of the pathophysiology of BED. Neurobiological dysregulation in the reward center and impulse control circuitry and related disturbances in dopamine neurotransmission are among the neurobiological explanations that have been suggested for BED. These mechanisms serve as a pharmacodynamic foundation for the development of new compounds such as lisdexamfetamine (LDX) and dasotraline. Despite these advances, pharmacological trials in BED have numerous challenges that must be overcome. For most compounds studied, larger and more definitive trials is a high priority.


Assuntos
Transtorno da Compulsão Alimentar/tratamento farmacológico , Desenvolvimento de Medicamentos , Drogas em Investigação/administração & dosagem , Animais , Transtorno da Compulsão Alimentar/fisiopatologia , Transtorno da Compulsão Alimentar/psicologia , Dopamina/metabolismo , Drogas em Investigação/farmacologia , Humanos , Recompensa
7.
Nat Neurosci ; 22(12): 1975-1985, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31611707

RESUMO

The increased legal availability of cannabis has led to a common misconception that it is a safe natural remedy for, among others, pregnancy-related ailments such as morning sickness. Emerging clinical evidence, however, indicates that prenatal cannabis exposure (PCE) predisposes offspring to various neuropsychiatric disorders linked to aberrant dopaminergic function. Yet, our knowledge of how cannabis exposure affects the maturation of this neuromodulatory system remains limited. Here, we show that male, but not female, offspring of Δ9-tetrahydrocannabinol (THC)-exposed dams, a rat PCE model, exhibit extensive molecular and synaptic changes in dopaminergic neurons of the ventral tegmental area, including altered excitatory-to-inhibitory balance and switched polarity of long-term synaptic plasticity. The resulting hyperdopaminergic state leads to increased behavioral sensitivity to acute THC exposure during pre-adolescence. The neurosteroid pregnenolone, a US Food and Drug Administration (FDA) approved drug, rescues synaptic defects and normalizes dopaminergic activity and behavior in PCE offspring, thus suggesting a therapeutic approach for offspring exposed to cannabis during pregnancy.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Dronabinol/efeitos adversos , Dronabinol/farmacologia , Pregnenolona/farmacologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Dopamina/metabolismo , Neurônios Dopaminérgicos/fisiologia , Dronabinol/antagonistas & inibidores , Endofenótipos , Feminino , Aprendizagem em Labirinto/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Atividade Motora/efeitos dos fármacos , Inibição Neural/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Gravidez , Inibição Pré-Pulso/efeitos dos fármacos , Inibição Pré-Pulso/fisiologia , Ratos , Assunção de Riscos , Filtro Sensorial/efeitos dos fármacos , Filtro Sensorial/fisiologia , Caracteres Sexuais , Área Tegmentar Ventral/metabolismo
8.
Br J Anaesth ; 123(6): 853-864, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31558312

RESUMO

Chronic post-surgical pain (CPSP) is a debilitating condition affecting 10-50% of surgical patients. The current treatment strategy for CPSP is not optimal, and the identification of genetic variation in surgical patients might help to improve prediction and treatment of CPSP. The neurotransmitter dopamine (DA) has been associated with several chronic pain disorders. This narrative review focuses on DA neurotransmission as a potential target in the treatment of CPSP. The current knowledge on genetic variation within DA neurotransmission and its role in CPSP susceptibility are reviewed. Three genes involved in DA neurotransmission (COMT, GCH1, and DRD2) have been associated with variability in pain sensitivity, development of CPSP, and analgesic requirement. The direction of the effect of the association is sometimes inconclusive because of contradictory results, but ample evidence suggests a modulatory role of DA. Because of this modulatory role, DA is an excellent pharmacological target in the treatment of pain. Pharmacotherapy focused on DA neurotransmission has potential in both prevention (via D1-like receptors) and treatment (via D2-like receptors and DA reuptake inhibitors) of CPSP. The development of prediction models including genetic risk factors is necessary to better identify patients at risk.


Assuntos
Dopamina/metabolismo , Variação Genética/genética , Dor Pós-Operatória/genética , Dor Pós-Operatória/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Dor Crônica/genética , Dor Crônica/metabolismo , Dopamina/genética , Humanos , Transmissão Sináptica/genética
9.
Nat Commun ; 10(1): 4263, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31537790

RESUMO

Mesostriatal dopaminergic neurons possess extensively branched axonal arbours. Whether action potentials are converted to dopamine output in the striatum will be influenced dynamically and critically by axonal properties and mechanisms that are poorly understood. Here, we address the roles for mechanisms governing release probability and axonal activity in determining short-term plasticity of dopamine release, using fast-scan cyclic voltammetry in the ex vivo mouse striatum. We show that brief short-term facilitation and longer short term depression are only weakly dependent on the level of initial release, i.e. are release insensitive. Rather, short-term plasticity is strongly determined by mechanisms which govern axonal activation, including K+-gated excitability and the dopamine transporter, particularly in the dorsal striatum. We identify the dopamine transporter as a master regulator of dopamine short-term plasticity, governing the balance between release-dependent and independent mechanisms that also show region-specific gating.


Assuntos
Axônios/metabolismo , Corpo Estriado/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Animais , Transporte Biológico , Inibidores da Captação de Dopamina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasticidade Neuronal/fisiologia
10.
Arch Insect Biochem Physiol ; 102(4): e21619, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31532855

RESUMO

In natural populations, insects regularly face an adverse impact of different natures: harsh weather swings, lack of food resources, the insecticidal treatment. We studied the effect of repeated episodes of mild heat stress of different frequencies on stress resistance of Drosophila melanogaster females. We found out that the mild heat stress (38°Ð¡, 1 hr) repeated daily within 2 weeks resulted in (a) an increased activity of the dopamine (DA) metabolism enzymes, DA-dependent arylalkylamine N-acetyltransferase and alkaline phosphatase, which suggested a decrease in DA level, and (b) an increased survival rate under acute heat stress (38°Ð¡, 4 hr). The same mild heat stress repeated weekly had no effect on these parameters.


Assuntos
Drosophila melanogaster/fisiologia , Resposta ao Choque Térmico , Adaptação Fisiológica , Fosfatase Alcalina/metabolismo , Animais , Arilalquilamina N-Acetiltransferase/metabolismo , Dopamina/metabolismo , Drosophila melanogaster/enzimologia , Feminino , Temperatura Alta/efeitos adversos
11.
Aquat Toxicol ; 216: 105312, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31563086

RESUMO

Many coastal systems have been experiencing the effects of non-chemical and chemical anthropological stressors through respective increases in surface water temperatures and rainstorm-derived runoff events of pyrethroid pesticide movement into waterways such as the San Francisco Bay-Delta. Salmonid populations in the Bay-Delta have been dramatically declining in recent decades. Therefore, the aim of this study was to investigate the interactive effects of bifenthrin, a pyrethroid insecticide, and increasing water temperatures on targeted neuroendocrine and behavioral responses in Chinook salmon (Oncorhynchus tshawytscha) parr (10- month post-hatch). Parr were reared at 11 °C, 16.4 °C, or 19 °C for 14 days and, in the final 96 h of rearing, exposed to nominal concentrations of 0, 0.15, or 1.5 µg/L bifenthrin. A predatory avoidance Y-Maze behavioral assay was conducted immediately following exposures. Parr were presented a choice of clean or odorant zones, and locomotive behavior was recorded. Thyroid hormones (T3 and T4), estradiol, and testosterone were quantified within plasma using ELISAs, and the expression of brain hormone and dopamine receptor genes were also evaluated by qPCR. Brain dopamine levels were analyzed by LC/MS. No significant changes were observed in brain transcripts or plasma hormone concentrations with bifenthrin or increasing temperature. However, temperature did significantly lower brain dopamine levels in fish reared at 19 °C compared to 11 °C controls, but was unaltered by bifenthrin treatment. In contrast, parr reared at 11 °C and exposed to 1.5 µg/L bifenthrin spent significantly less time avoiding a predatory odorant compared to vehicle controls reared at 11 °C. The 16.4 °C and 1.5 µg/L-treated fish spent significantly more time in the neutral arm compared to the odorant and clean arms, as well as spending significantly less time in the clean arm compared to the 11 °C control fish. These results suggest that the interaction of temperature and bifenthrin may be adversely impacting predator-avoidance behavior, which may not be related to dopaminergic responses.


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Predatório/efeitos dos fármacos , Piretrinas/toxicidade , Salmão/fisiologia , Temperatura Ambiente , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Dopamina/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônios/metabolismo , Poluentes Químicos da Água/toxicidade
12.
Eur J Med Chem ; 183: 111674, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31518969

RESUMO

Polypharmacology approaches may help the discovery of pharmacological tools for the study or the potential treatment of complex and multifactorial diseases as well as for addictions and also smoke cessation. In this frame, following our interest in the development of molecules able to modulate either the endocannabinoid or the dopaminergic system, and given the multiple and reciprocal interconnections between them, we decided to merge the pharmacophoric elements of some of our early leads for identifying new molecules as tools able to modulate both systems. We herein describe the synthesis and biological characterization of compounds 5a-j inspired by the structure of our potent and selective fatty acid amide hydrolase (FAAH) inhibitors (3a-c) and ligands of dopamine D2 or D3 receptor subtypes (4a,b). Notably, the majority of the new molecules showed a nanomolar potency of interaction with the targets of interest. The drug-likeliness of the developed compounds (5a-j) was investigated in silico while hERG affinity, selectivity profile (for some proteins of the endocannabinoid system), cytotoxicity profiles (on fibroblast and astrocytes), and mutagenicity (Ames test) were experimentally determined. Metabolic studies also served to complement the preliminary drug-likeliness profiling for compounds 3a and 5c. Interestingly, after assessing the lack of toxicity for the neuroblastoma cell line (IMR 32), we demonstrated a potential anti-inflammatory profile for 3a and 5c in the same cell line.


Assuntos
Amidoidrolases/antagonistas & inibidores , Dopamina/metabolismo , Endocanabinoides/metabolismo , Amidoidrolases/metabolismo , Ligação Competitiva , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Ligantes , Piperazinas/química , Piperazinas/farmacologia , Pirróis/química , Pirróis/farmacologia
13.
Nanoscale ; 11(33): 15576-15588, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31403155

RESUMO

Drug delivery systems are based on reversible interactions between carriers and drugs. Spacers are often introduced to tailor the type of interaction and to keep drugs intact. Here, we model a drug delivery system based on a functionalized curved TiO2 nanoparticle of realistic size (700 atoms - 2.2 nm) by the neurotransmitter dopamine to carry the anticancer chemotherapeutic agent doxorubicin (DOX). The multiscale quantum chemical study aims at unraveling the nature and mechanism of the interactions between the components and the electronic properties of the composite system. We simulate the temperature effect through molecular dynamics runs of thermal annealing. Dopamine binds preferentially to low coordinated Ti sites on the nanoparticle through dissociated bidentate and chelate modes involving the diol groups. DOX is tethered by H-bonds, π-π stacking, dipole-dipole interactions and dispersion forces. Comparing different coverage densities of the spacer on the nanoparticle surface, we assess the best conditions for an effective drug transport and release: only at full coverage, DOX does not slip among the dopamine molecules to reach the nanoparticle surface, which is crucial to avoid the formation of stable coordinative bonds with under-coordinated Ti atoms. Finally, given the strong absorption properties and fluorescence of DOX and of the TiO2 photocatalyst, we model the effect of light irradiation through excited state calculations to localize excitons and to follow the charge carrier's life path. This fundamental study on the nature and mechanism of drug/carrier interaction provides a solid ground for the rational design of new experimental protocols for a more efficient drug transport and release and its combination with photodynamic therapy.


Assuntos
Portadores de Fármacos/química , Nanopartículas Metálicas/química , Teoria Quântica , Antineoplásicos/química , Antineoplásicos/metabolismo , Catálise , Dopamina/química , Dopamina/metabolismo , Doxorrubicina/química , Doxorrubicina/metabolismo , Humanos , Luz , Simulação de Dinâmica Molecular , Fotoquimioterapia , Temperatura Ambiente , Titânio/química
14.
Biophys Chem ; 253: 106241, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31398633

RESUMO

Micro graphitic - diamond - multi electrode arrays (µG-D-MEAs) are suitable for measuring multisite quantal dopamine (DA) release from PC12 cells. Following cell stimulation with high extracellular KCl and electrode polarization at +650 mV, amperometric spikes are detected with a mean frequency of 0.60 ±â€¯0.16 Hz. In each recording, simultaneous detection of secretory events is occurred in approximately 50% of the electrodes. Kinetic spike parameters and background noise are preserved among the different electrodes. Comparing the amperometric spikes recorder under control conditions with those recorders from PC12 cells previously incubated for 30 min with the dopamine precursor Levodopa (L-DOPA, 20 µM) it appears that the quantal size of amperometric spikes is increased by 250% and the half-time width (t1/2) by over 120%. On the contrary, L-DOPA has no effect on the frequency of secretory events. Overall, these data demonstrate that the µG-D-MEAs represent a reliable bio-sensor to simultaneously monitor quantal exocytotic events from different cells and in perspective can be exploited as a drug-screening tool.


Assuntos
Técnicas Biossensoriais , Diamante/química , Dopamina/metabolismo , Grafite/química , Animais , Células Cultivadas , Diamante/metabolismo , Dopamina/química , Eletrodos , Grafite/metabolismo , Células PC12 , Tamanho da Partícula , Ratos , Propriedades de Superfície
15.
PLoS Genet ; 15(8): e1008331, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31412019

RESUMO

Holometabolous insects stop feeding at the final larval instar stage and then undergo metamorphosis; however, the mechanism is unclear. In the present study, using the serious lepidopteran agricultural pest Helicoverpa armigera as a model, we revealed that 20-hydroxyecdysone (20E) binds to the dopamine receptor (DopEcR), a G protein-coupled receptor, to stop larval feeding and promote pupation. DopEcR was expressed in various tissues and its level increased during metamorphic molting under 20E regulation. The 20E titer was low during larval feeding stages and high during wandering stages. By contrast, the dopamine (DA) titer was high during larval feeding stages and low during the wandering stages. Injection of 20E or blocking dopamine receptors using the inhibitor flupentixol decreased larval food consumption and body weight. Knockdown of DopEcR repressed larval feeding, growth, and pupation. 20E, via DopEcR, promoted apoptosis; and DA, via DopEcR, induced cell proliferation. 20E opposed DA function by repressing DA-induced cell proliferation and AKT phosphorylation. 20E, via DopEcR, induced gene expression and a rapid increase in intracellular calcium ions and cAMP. 20E induced the interaction of DopEcR with G proteins αs and αq. 20E, via DopEcR, induced protein phosphorylation and binding of the EcRB1-USP1 transcription complex to the ecdysone response element. DopEcR could bind 20E inside the cell membrane or after being isolated from the cell membrane. Mutation of DopEcR decreased 20E binding levels and related cellular responses. 20E competed with DA to bind to DopEcR. The results of the present study suggested that 20E, via binding to DopEcR, arrests larval feeding and promotes pupation.


Assuntos
Ecdisterona/metabolismo , Proteínas de Insetos/metabolismo , Mariposas/fisiologia , Receptores Dopaminérgicos/metabolismo , Animais , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Flupentixol/farmacologia , Técnicas de Silenciamento de Genes , Proteínas de Insetos/genética , Larva/efeitos dos fármacos , Larva/fisiologia , Muda/efeitos dos fármacos , Muda/fisiologia , Mariposas/efeitos dos fármacos , Interferência de RNA , Receptores Dopaminérgicos/genética , Células Sf9
16.
Anim Reprod Sci ; 208: 106102, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31405485

RESUMO

In the present study, there was testing of the hypothesis that a centrally administered dopamine (DA) derivative, salsolinol, could affect pulsatile luteinizing hormone (LH) secretion in seasonally anestrous sheep by affecting the neuronal components of the estradiol (E2) negative feedback. In two experiments performed during early spring (increasing day length - March/April), salsolinol or Ringer-Locke solution (control) were administered into the third brain ventricle (IIIv): 1) in several injections for three consecutive days; and 2) in several hour-long infusions. In addition to determining the LH concentration (in both experiments), the abundances of gonadotropin-releasing hormone (GnRH) and kisspeptin mRNA were examined in the hypothalamus and LHß subunit mRNA in the pituitary (Experiment 1). In Experiment 2, concentrations of DA and 3,4-dihydroxyphenylacetic acid (DOPAC) were determined in perfusates collected from the infundibular nucleus/median eminence (IN/ME) by the push-pull method. In both experiments, salsolinol increased both LH pulse frequency (P < 0.05) and plasma LH concentration (P < 0.001) compared to controls. The injected salsolinol also increased (P < 0.05) the abundance of GnRH mRNA in the mediobasal hypothalamus and kisspeptin mRNA in the arcuate nucleus. The two doses of infused salsolinol decreased DA to undetectable concentrations and DOPAC concentration by 60% in perfusates collected from the IN/ME. In conclusion, exogenous salsolinol functioning centrally stimulates pulsatile LH secretion in sheep during seasonal anestrus. It is suggested that salsolinol may have this effect by reducing the activity of the hypothalamic neuroendocrine dopaminergic system, which results in an increase in both kisspeptin and GnRH neurons activity.


Assuntos
Dopamina/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Isoquinolinas/farmacologia , Kisspeptinas/metabolismo , Hormônio Luteinizante/metabolismo , Ovinos/fisiologia , Anestro , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Hipotálamo , RNA Mensageiro , Estações do Ano
17.
Biomed Pharmacother ; 117: 109184, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31387167

RESUMO

With the elderly population rapidly growing, the prevalence of Parkinson's disease (PD) is quickly increasing because neurodegenerative disorders are usually late-onset. Herbal medicines and formula are adjuvant therapies of conventional PD agents, which result in serious side effects with long-term use. This study evaluated the neuroprotective effects of DA-9805, a standardized herbal formula that consists of an ethanolic extract of Moutan Cortex Radix, Angelica Dahuricae Radix, and Bupleuri Radix against 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in vitro and in vivo. In PC12 cells, DA-9805 at concentrations of 1 and 10 µg/mL ameliorated cell viability, which was reduced by 6-OHDA. In addition, DA-9805 activated the extracellular-regulated kinase-nuclear transcription factor-erythroid 2-related factor 2 pathway, subsequently stimulating antioxidative enzymes such as NAD(P)H:quinone oxidoreductase 1 and catalase and suppressing apoptosis. Furthermore, DA-9805 prevented 6-OHDA-induced movement impairment, as well as a decrease of dopaminergic neurons and dopamine transmission in rodents. Taken together, these results suggest that the mixed herbal formula DA-9805 may be a pharmaceutical agent for preventing or improving PD.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/tratamento farmacológico , Oxidopamina/farmacologia , Doença de Parkinson/tratamento farmacológico , Preparações de Plantas/farmacologia , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Dopamina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , NADP/metabolismo , Síndromes Neurotóxicas/metabolismo , Células PC12 , Extratos Vegetais/farmacologia , Ratos
18.
Dokl Biochem Biophys ; 486(1): 168-170, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31367813

RESUMO

In the present study, we analyzed the uptake of radiolabeled dopamine by intact synaptosomes and purified synaptic vesicles isolated from the dorsal striatum of mice with constitutive inactivation of all three synuclein-coding genes and wild-type mice. Synuclein deficiency substantially compromised the uptake of this neurotransmitter by synaptic vesicles but had no effect on synaptosomal dopamine uptake.


Assuntos
Dopamina/metabolismo , Vesículas Sinápticas/metabolismo , Sinucleínas/deficiência , Animais , Transporte Biológico/genética , Inativação Gênica , Camundongos , Camundongos Endogâmicos C57BL , Sinucleínas/genética
19.
Psychopharmacology (Berl) ; 236(8): 2373-2388, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31367850

RESUMO

In the context of Pavlovian conditioning, two types of behaviour may emerge within the population (Flagel et al. Nature, 469(7328): 53-57, 2011). Animals may choose to engage either with the conditioned stimulus (CS), a behaviour known as sign-tracking (ST) which is sensitive to dopamine inhibition for its acquisition, or with the food cup in which the reward or unconditioned stimulus (US) will eventually be delivered, a behaviour known as goal-tracking (GT) which is dependent on dopamine for its expression only. Previous work by Lesaint et al. (PLoS Comput Biol, 10(2), 2014) offered a computational explanation for these phenomena and led to the prediction that varying the duration of the inter-trial interval (ITI) would change the relative ST-GT proportion in the population as well as phasic dopamine responses. A recent study verified this prediction, but also found a rich variance of ST and GT behaviours within the trial which goes beyond the original computational model. In this paper, we provide a computational perspective on these novel results.


Assuntos
Simulação por Computador , Condicionamento Clássico/fisiologia , Condicionamento Operante/fisiologia , Metas , Animais , Dopamina/metabolismo , Masculino , Motivação , Recompensa , Fatores de Tempo
20.
Chemosphere ; 237: 124378, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31376700

RESUMO

Benzo[a]pyrene (B[a]P) is a ubiquitous neurotoxic pollutant that widely distributes in the natural environment. However, the exact mechanism of B[a]P-induced neurotoxicity has not been well established. As one key synaptic protein, SNAP-25 plays an important role in the regulation of neurotransmitter release, including synaptic dopamine release. In this study, we demonstrated that, after intragastric administration of B[a]P in rats aged postnatal day 5 for 7 weeks, B[a]P significantly increased the level of dopamine and the expression of SNAP-25, dopamine receptor 1 (DRD1) and DRD 3. Moreover, treatment of B[a]P also caused the ultra-structural pathological changes in the cerebral cortex of rats. To further reveal the potential role of SNAP-25 in the regulation of DRDs, we treated the dopaminergic PC-12 cells with 20 µM B[a]P for 24 h. A significant cytotoxicity and apoptosis were observed, and more importantly, we found that SNAP-25, DRD 1 and DRD 3 co-localized in the cells, and down-regulation of SNAP-25 by CRISPR-Cas9 plasmid remarkably reduced the expression of DRD1 and DRD3. Together, our findings suggest that, synaptic dopamine release may be positively regulated by SNAP-25 via its receptors, and thus affecting the neurotoxicity induced by B[a]P.


Assuntos
Benzo(a)pireno/toxicidade , Dopamina/metabolismo , Proteína 25 Associada a Sinaptossoma/metabolismo , Animais , Animais Recém-Nascidos , Apoptose , Síndromes Neurotóxicas/etiologia , Células PC12 , Ratos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D3/metabolismo , Transmissão Sináptica
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