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1.
Gene ; 763: 145115, 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-32891773

RESUMO

Dopamine (DA) is a crucial neuroendocrine-immune factor regulating the stress response of Litopenaeus vannamei. To understand the regulatory mechanisms of DA in L. vannamei, the eyestalks of L. vannamei with injection of DA (10-6 mol/shrimp) at 3 and 12 h were chosen to perform transcriptome analysis in this study. Furthermore, quantitative real-time PCR (RT-PCR) method was used to validate the accuracy of transcriptome data and analyze the expression pattern of candidate differentially expressed genes (DEGs) at different time points (0, 3, 6, and 12 h) after DA injection. The transcriptome data showed that 79,434 unigenes were generated. Therein 204 and 434 DEGs were obtained at 3 and 12 h respectively. Besides, the results of enriched pathways showed that the DEGs were involved in GnRH signaling pathway (ko04912) dopaminergic synapse (ko04728), glutamatergic synapse (ko04724), synapse (GO:0045202), synaptic vesicle transport (GO:0048489). Moreover, the Pearson's correlation coefficient (R) of 13 candidate DEGs between transcriptome sequencing and RT-PCR was 0.948, which confirmed the reliability and the accuracy of the transcriptome sequencing results. Furthermore, the results of interaction analysis uncovered 4 pairs of DEGs between eyestalks and hemocytes. Therefore, these results revealed that DA promoted the sensitivity of eyestalk to gonadal related hormones, induced the expression of neuroendocrine factor, enhanced the synaptic behavior and neural signal transduction, regulated immune systems and antioxidation, inhibited the visual function, and promoted the molting. These findings will benefit to foster the understanding on the effects of biogenic amines on neuroendocrine-immune (NEI) networks of crustacean, and supply a substantial material and foundation for further researching of the NEI response.


Assuntos
Dopamina/metabolismo , Hormônios/metabolismo , Penaeidae/genética , Transmissão Sináptica , Transcriptoma , Animais , Dopamina/farmacologia , Olho/metabolismo , Hemócitos/metabolismo , Penaeidae/efeitos dos fármacos , Penaeidae/metabolismo , Pró-Proteína Convertase 2/genética , Pró-Proteína Convertase 2/metabolismo , Estresse Fisiológico
2.
Nat Commun ; 11(1): 3460, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32651365

RESUMO

The learning of stimulus-outcome associations allows for predictions about the environment. Ventral striatum and dopaminergic midbrain neurons form a larger network for generating reward prediction signals from sensory cues. Yet, the network plasticity mechanisms to generate predictive signals in these distributed circuits have not been entirely clarified. Also, direct evidence of the underlying interregional assembly formation and information transfer is still missing. Here we show that phasic dopamine is sufficient to reinforce the distinctness of stimulus representations in the ventral striatum even in the absence of reward. Upon such reinforcement, striatal stimulus encoding gives rise to interregional assemblies that drive dopaminergic neurons during stimulus-outcome learning. These assemblies dynamically encode the predicted reward value of conditioned stimuli. Together, our data reveal that ventral striatal and midbrain reward networks form a reinforcing loop to generate reward prediction coding.


Assuntos
Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Tubérculo Olfatório/efeitos dos fármacos , Animais , Dopamina/farmacologia , Masculino , Mesencéfalo/citologia , Camundongos , Modelos Teóricos , Estriado Ventral/efeitos dos fármacos , Estriado Ventral/metabolismo
3.
PLoS Biol ; 18(6): e3000744, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32559190

RESUMO

Dopamine guides behavior and learning through pleasure, according to classic understanding. Dopaminergic neurons are traditionally thought to signal positive or negative prediction errors (PEs) when reward expectations are, respectively, exceeded or not matched. These signed PEs are quite different from the unsigned PEs, which report surprise during sensory processing. But mounting theoretical accounts from the predictive processing framework postulate that dopamine, as a neuromodulator, could potentially regulate the postsynaptic gain of sensory neurons, thereby scaling unsigned PEs according to their expected precision or confidence. Despite ample modeling work, the physiological effects of dopamine on the processing of surprising sensory information are yet to be addressed experimentally. In this study, we tested how dopamine modulates midbrain processing of unexpected tones. We recorded extracellular responses from the rat inferior colliculus to oddball and cascade sequences, before, during, and after the microiontophoretic application of dopamine or eticlopride (a D2-like receptor antagonist). Results demonstrate that dopamine reduces the net neuronal responsiveness exclusively to unexpected sensory input without significantly altering the processing of expected input. We conclude that dopaminergic projections from the thalamic subparafascicular nucleus to the inferior colliculus could encode the expected precision of unsigned PEs, attenuating via D2-like receptors the postsynaptic gain of sensory inputs forwarded by the auditory midbrain neurons. This direct dopaminergic modulation of sensory PE signaling has profound implications for both the predictive coding framework and the understanding of dopamine function.


Assuntos
Córtex Cerebral/fisiologia , Dopamina/farmacologia , Som , Estimulação Acústica , Adaptação Fisiológica , Animais , Córtex Cerebral/efeitos dos fármacos , Feminino , Ratos Long-Evans , Salicilamidas/farmacologia , Tálamo/fisiologia
4.
Zoolog Sci ; 37(1): 50-60, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32068374

RESUMO

The labial palps of bivalves are thought to be involved in suspension feeding. However, the function of their muscular movements and neural regulation are still unclear. In semi-intact preparations of Mytilus, in which one valve was removed, suspended particles were removed from the labial palps following two kinds of compound movements: torsional and rotational. Both of these compound movements are therefore thought to function in rejection during feeding. These movements were observed in reduced preparations of isolated labial palps with intact cerebral ganglia, and were maintained even after removal of the cerebral ganglia, suggesting that they are generated by the peripheral neural network. Stimulation of the anterior pallial nerve elicited tetanic contraction of the labial palp, followed by secondary responses, including torsional movement. Secondary responses were dramatically reduced by a high concentration of divalent cations, in which polysynaptic pathways were inhibited. Hence, the cerebral ganglia may play an excitatory role within the peripheral neural network and the labial palp musculature via the anterior pallial nerve. Administration of serotonin induced repetitive muscular movements, whereas dopamine did not induce muscular movements. Serotonin-induced muscular movements were not elicited under a high concentration of divalent cation condition. In histochemical experiments, both the serotonergic and dopaminergic neural processes and cell body-like structures were widely observed inside the labial palp, the anterior pallial nerve, and the cerebral ganglia. Serotonin may thus contribute to activation of polysynaptic peripheral pathways, which are involved in regulating compound movements.


Assuntos
Comportamento Alimentar , Músculos/inervação , Mytilus/fisiologia , Animais , Dopamina/farmacologia , Gânglios , Movimento/efeitos dos fármacos , Músculos/efeitos dos fármacos , Serotonina/farmacologia
5.
Sci Rep ; 10(1): 631, 2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959788

RESUMO

It is well established that astrocytes respond to the major neurotransmitters glutamate and GABA with cytosolic calcium rises, whereas less is known about the effect of dopamine on astroglial cells. In the present study, we used confocal calcium imaging in mouse brain slices of the olfactory bulb, a brain region with a large population of dopaminergic neurons, to investigate calcium signaling evoked by dopamine in astrocytes. Our results show that application of dopamine leads to a dose-dependent cytosolic calcium rise in astrocytes (EC50 = 76 µM) which is independent of neuronal activity and mainly mediated by PLC/IP3-dependent internal calcium release. Antagonists of both D1- and D2-class dopamine receptors partly reduce the dopaminergic calcium response, indicating that both receptor classes contribute to dopamine-induced calcium transients in olfactory bulb astrocytes.


Assuntos
Astrócitos/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Cálcio/metabolismo , Dopamina/farmacologia , Bulbo Olfatório/citologia , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Camundongos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo
6.
Eur J Med Chem ; 189: 112048, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31954881

RESUMO

Currently, influenza PAN endonuclease has become an attractive target for development of new drugs to treat influenza infections. Herein we report the discovery of new PAN endonuclease inhibitors derived from a chelating agent dopamine moiety. A series of dopamine amide derivatives and their conformationally constrained 1,2,3,4-tetrahydroisoquinoline-6,7-diol-based analogs were elaborated and assayed against influenza virus A/WSN/33 (H1N1). Most compounds exhibited moderate to excellent antiviral activities, generating a preliminary SARs. Among them, compounds 14 and 19 showed stronger anti-IAV activity compared with the reference Peramivir. Moreover, 14 and 19 demonstrated a concentration-dependent inhibition of PAN endonuclease based on both FRET assay and SPR assay. Docking studies were also performed to elucidate the binding mode of 14 and 19 with the PAN protein and to identify amino acids involved in their mechanism of action, which were well consistent with the biological data. This finding was beneficial to laying the foundation for the rational development of more effective PAN endonuclease inhibitors.


Assuntos
Antivirais/farmacologia , Dopamina/análogos & derivados , Dopamina/farmacologia , Endonucleases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Proteínas Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/metabolismo , Dopamina/metabolismo , Desenho de Fármacos , Endonucleases/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Vírus da Influenza A Subtipo H1N1/enzimologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , Proteínas Virais/metabolismo
7.
ACS Appl Mater Interfaces ; 12(5): 5658-5670, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31986005

RESUMO

Alzheimer's disease (AD) is one of the common causes of dementia and mild cognitive impairments, which is progressively expanding among the elderly population worldwide. A short Amyloid-ß (Aß) peptide generated after amyloidogenic processing of amyloid precursor protein exist as intermolecular ß-sheet rich oligomeric, protofibriler, and fibrillar structures and believe to be toxic species which instigate neuronal pathobiology in the brain and deposits as senile plaque. Enormous efforts are being made to develop an effective anti-AD therapy that can target Aß processing, aggregation, and propagation and provide a synergistic neuroprotective effect. However, a nanodrug prepared from natural origin can confer a multimodal synergistic chemo/photothermal inhibition of Aß pathobiology is not yet demonstrated. In the present work, we report a dopamine-melatonin nanocomposite (DM-NC), which possesses a synergistic near-infrared (NIR) responsive photothermal and pharmacological modality. The noncovalent interaction-mediated self-assembly of melatonin and dopamine oxidative intermediates leads to the evolution of DM-NCs that can withstand variable pH and peroxide environment. NIR-activated melatonin release and photothermal effect collectively inhibit Aß nucleation, self-seeding, and propagation and can also disrupt the preformed Aß fibers examined using in vitro Aß aggregation and Aß-misfolding cyclic amplification assays. The DM-NCs display a higher biocompatibility to neuroblastoma cells, suppress the AD-associated generation of intracellular reactive oxygen species, and are devoid of any negative impact on the axonal growth process. In okadaic acid-induced neuroblastoma and ex vivo midbrain slice culture-based AD model, DM-NCs exposure suppresses the intracellular Aß production, aggregation, and accumulation. Therefore, this nature-derived nanocomposite demonstrates a multimodal NIR-responsive synergistic photothermal and pharmacological modality for effective AD therapy.


Assuntos
Peptídeos beta-Amiloides/química , Dopamina/química , Melatonina/química , Nanocompostos/efeitos da radiação , Neurônios/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Amiloide/efeitos dos fármacos , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Química Encefálica , Linhagem Celular Tumoral , Dopamina/farmacologia , Feminino , Humanos , Raios Infravermelhos , Melatonina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Nanocompostos/química , Neuroblastoma , Neurônios/metabolismo , Espécies Reativas de Oxigênio/metabolismo
8.
Mater Sci Eng C Mater Biol Appl ; 108: 110459, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31924031

RESUMO

In this work, a new pH-responsive nanohybrid carrier was prepared with chelating ZnO-dopamine (Zn-d) on the surface of graphene oxide. Doxorubicin (DOX) as a model drug was loaded on the resulted nanohybrid. The characteristics of Zn-d-rGO nanohybrid (NH) determined using Fourier transformed infrared spectroscopy (FT-IR), X-ray Diffraction spectroscopy (XRD), UV-Visible spectroscopy, Scanning Electron Microscope (SEM), EDX and AFM. The BET analysis showed a specific surface area of 37.16 m2/g and the obtained nanohybrid indicated a high loading capacity of DOX up to 99.7%, and the release profile displayed a pH-dependent discharge in the acidic environment for14 days. The cytotoxicity of the prepared nanohybrid was measured against T47D and MCF10A cells and it confirmed that as-prepared nanohybrid has high toxicity against cancer cells and lower effect against human breast cell. Meanwhile, the prepared nanohybrids showed well antimicrobial activity against gram-positive and negative bacteria. The obtained results showed that the prepared nanohybrid (Zn-d-rGO) could potentially be used as a safe carrier for drug delivery systems.


Assuntos
Antibacterianos , Quelantes , Dopamina , Doxorrubicina , Portadores de Fármacos , Grafite , Nanopartículas/química , Óxido de Zinco , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Linhagem Celular Tumoral , Quelantes/química , Quelantes/farmacocinética , Quelantes/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Dopamina/química , Dopamina/farmacocinética , Dopamina/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Grafite/química , Grafite/farmacocinética , Grafite/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Óxido de Zinco/química , Óxido de Zinco/farmacocinética , Óxido de Zinco/farmacologia
9.
Plant Physiol Biochem ; 148: 260-272, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31982861

RESUMO

Water shortage is one of the main limiting factors in apple (Malus domestica Borkh.) production. Although dopamine is produced in plants and has been linked with response to abiotic stress, the underlying mechanism remains unknown. In this study, physiological analyses revealed that pretreatment with 100 µM dopamine alleviated drought stress in apple seedlings. Dopamine inhibited the degradation of photosynthetic pigments and increased net photosynthetic rate under drought stress. Dopamine also reduced H2O2 content, possibly through direct scavenging and by mediating the antioxidant enzyme activity. Seedlings pretreated with dopamine had higher sucrose and malic acid contents but lower starch accumulation in their leaves. RNA-Seq analysis identified 1052 differentially expressed genes (DEGs) between non-treated and dopamine-pretreated plants under drought. An in-depth analysis of these DEGs revealed that dopamine regulated the expression of genes related to metabolism of nitrogen, secondary compounds, and amino acids under drought stress. In addition, dopamine may improve apple drought tolerance by activating Ca2+ signaling pathways through increased expression of CNGC and CAM/CML family genes. Moreover, analysis of transcription factor expression suggested that dopamine affected drought tolerance mainly through the regulation of WRKY, ERF, and NAC transcription factors.


Assuntos
Secas , Malus , Estresse Fisiológico , Transcriptoma , Dopamina/farmacologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Malus/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos
10.
Eur J Pharmacol ; 866: 172826, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31790652

RESUMO

Many reports have indicated that dopamine has immunomodulatory effects on peripheral immune cells. The purpose of this study was to reveal the immunomodulatory effect of dopamine on the expression of proinflammatory cytokines in microglial cells, which are the immune cells of the central nervous system. In murine microglial cell line BV-2 cells, pretreatment with dopamine for 24 h attenuated the lipopolysaccharide (LPS)-induced expression of proinflammatory cytokines such as tumor-necrosis factor-α, interleukin-1ß, and interleukin-6. Neither (5R)-8-chloro-3-methyl-5-phenyl-1,2,4,5-tetrahydro-3-benzazepin-7-ol; hydrochloride (SCH-23390) nor sulpiride, which are dopamine D1-like and D2-like receptor antagonists, respectively, affected the attenuation of LPS-induced expression of cytokines by dopamine. In addition, pretreatment with neither (-)-(6aR,12bR)-4,6,6a,7,8,12b-Hexahydro-7-methylindolo[4,3-a]phenanthridin (CY208-243) nor bromocriptine, dopamine D1-like and D2-like receptor agonists, respectively, was effective in doing so. However, N-acetylcysteine (NAC), which inhibits dopamine oxidation to dopamine quinone, did inhibit this attenuated expression. Dopamine increased the level of quinoproteins, and this increase was inhibited by NAC. Western blot and immunocytochemical analyses revealed that dopamine inhibited LPS-induced nuclear translocation of nuclear factor-kappa B (NF-κB) p65. Dopamine also attenuated the expression of cytokines and the nuclear translocation of NF-κB p65 induced by LPS in mouse microglial cells in primary culture. These results suggest that dopamine attenuated LPS-induced expression of cytokines by inhibiting the nuclear translocation of NF-κB p65 through the formation of dopamine quinone in microglial cells.


Assuntos
Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Citocinas/metabolismo , Dopamina/análogos & derivados , Dopamina/farmacologia , Microglia/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Linhagem Celular , Dopamina/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/citologia , Microglia/metabolismo
11.
Am J Physiol Regul Integr Comp Physiol ; 318(1): R173-R181, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31746629

RESUMO

We examined the contribution of the carotid chemoreceptors to insulin-mediated increases in muscle sympathetic nerve activity (MSNA) in healthy humans. We hypothesized that reductions in carotid chemoreceptor activity would attenuate the sympathoexcitatory response to hyperinsulinemia. Young, healthy adults (9 male/9 female, 28 ± 1 yr, 24 ± 1 kg/m2) completed a 30-min euglycemic baseline followed by a 90-min hyperinsulinemic (1 mU·kg fat-free mass-1·min-1), euglycemic infusion. MSNA (microneurography of the peroneal nerve) was continuously measured. The role of the carotid chemoreceptors was assessed at baseline and during hyperinsulinemia via 1) acute hyperoxia, 2) low-dose dopamine (1-4 µg·kg-1·min-1), and 3) acute hyperoxia + low-dose dopamine. MSNA burst frequency increased from baseline during hyperinsulinemia (P < 0.01). Acute hyperoxia had no effect on MSNA burst frequency at rest (P = 0.74) or during hyperinsulinemia (P = 0.83). The insulin-mediated increase in MSNA burst frequency (P = 0.02) was unaffected by low-dose dopamine (P = 0.60). When combined with low-dose dopamine, acute hyperoxia had no effect on MSNA burst frequency at rest (P = 0.17) or during hyperinsulinemia (P = 0.85). Carotid chemoreceptor desensitization in young, healthy men and women does not attenuate the sympathoexcitatory response to hyperinsulinemia. Our data suggest that the carotid chemoreceptors do not contribute to acute insulin-mediated increases in MSNA in young, healthy adults.


Assuntos
Artérias Carótidas/fisiologia , Células Quimiorreceptoras/metabolismo , Insulina/farmacologia , Adulto , Glicemia , Estudos Cross-Over , Dopamina/farmacologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Músculo Esquelético , Sistema Nervoso Simpático/fisiologia
12.
Biochem Biophys Res Commun ; 522(4): 1041-1045, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-31818461

RESUMO

The orphan G protein-coupled receptor 6 (GPR6) is highly expressed in the striatum and has been linked to multiple striatal pathologies. The identification of endogenous ligands and their mechanisms of action at GPR6 will help to elucidate the physiological and pathological roles of the receptor. In the current study, we tested the concentration-dependent effects of a variety of endocannabinoid-like N-acylamides on GPR6 signaling. Here, we demonstrate for the first time that N-arachidonoyl dopamine, N-docosahexaenoyl dopamine, N-oleoyl dopamine and N-palmitoyl dopamine exert inverse agonism at GPR6. This effect was concentration-dependent, with potencies in the micromolar range, and functionally selective for ß-arrestin2 recruitment. Structure-activity relationship studies demonstrate that both the N-acyl side chain and the dopamine head group are important for these ligands to act on GPR6. Our discovery of these N-acyl dopamines as endogenous inverse agonists for GPR6 moves us one step further in understanding the roles GPR6 play in neurodegenerative and neuropsychiatric disorders related to striatal dysfunction.


Assuntos
Descoberta de Drogas , Receptores Acoplados a Proteínas-G/agonistas , Animais , Células CHO , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Dopamina/química , Dopamina/farmacologia , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , beta-Arrestina 2/metabolismo
13.
Dev Comp Immunol ; 102: 103473, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31437524

RESUMO

Dopamine (DA) is an important neuroendocrine factor, which can act as neurotransmitter and neurohormone. In this study, we explored the immune defense mechanism in Litopenaeus vannamei with injection of dopamine at 10-7 and 10-6 mol shrimp-1, respectively. The genes expressions of dopamine receptor (DAR), G proteins (Gs, Gi, Gq), phagocytosis and exocytosis-related proteins, as well as intracellular signaling pathway factors, and immune defense parameters were measured. Results showed that mRNA expression levels of dopamine receptor D4 (D4), Gi, nuclear transcription factors and exocytosis-related proteins decreased significantly and reached the minimum at 3 h, while the genes expressions of Gs, Gq and phagocytosis-related proteins reached the highest and lowest levels at 3 h and 6 h, respectively. The second messenger synthetases increased significantly in treatment groups within 3 h. Simultaneously, the second messengers and protein kinases shared a similar trend, which were significantly elevated and reached the peak value at 3 h. Ultimately lead to the total hemocyte count (THC), proPO activity and phagocytic activity decreased significantly, reaching minimum values at 3 h, 3 h and 6 h, respectively. While PO activity showed obvious peak changes, which maximum value reached at 3 h. These results suggested that DA receptor could couple with G protein after DA injection and might regulate immunity through cAMP-PKA, DAG-PKC or CaM pathway.


Assuntos
Dopamina/farmacologia , Exocitose/efeitos dos fármacos , Hemócitos/efeitos dos fármacos , Penaeidae/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Exocitose/genética , Proteínas de Ligação ao GTP/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Hemócitos/imunologia , Hemócitos/patologia , Imunidade Inata/efeitos dos fármacos , Penaeidae/imunologia , Fagocitose/genética , Receptores Dopaminérgicos/genética , Transdução de Sinais/imunologia , Fatores de Transcrição/genética
14.
Psychopharmacology (Berl) ; 237(1): 33-43, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31392358

RESUMO

RATIONALE: Effort-based decision-making tasks offer animals choices between preferred reinforcers that require high effort to obtain vs. low effort/low reward options. The neural mechanisms of effort-based choice are widely studied in rats, and evidence indicates that mesolimbic dopamine (DA) and related neural systems play a key role. Fewer studies of effort-based choice have been performed in mice. OBJECTIVES: The present studies used touchscreen operant procedures (Bussey-Saksida boxes) to assess effort-based choice in mice. METHODS: CD1 mice were assessed on a concurrent fixed ratio 1 panel pressing/choice procedure. Mice were allowed to choose between rearing to press an elevated panel on the touchscreen for a preferred food (strawberry milkshake) vs. consuming a concurrently available less preferred alternative (high carbohydrate pellets). RESULTS: The DA D2 antagonist haloperidol (0.05-0.15 mg/kg IP) produced a dose-related decrease in panel pressing. Intake of food pellets was not reduced by haloperidol, and in fact, there was a significant quadratic trend, indicating a tendency for pellet intake to increase at low/moderate doses. In contrast, reinforcer devaluation by removing food restriction substantially decreased both panel pressing and pellet intake. In free-feeding choice tests, mice strongly preferred milkshake vs. pellets. Haloperidol did not affect food intake or preference. CONCLUSION: Haloperidol reduced the tendency to work for food, but this reduction was not due to decreases in primary food motivation or preference. Mouse touchscreen procedures demonstrate effects of haloperidol that are similar but not identical to those shown in rats. These rodent studies may be relevant for understanding motivational dysfunctions in humans.


Assuntos
Comportamento de Escolha/efeitos dos fármacos , Tomada de Decisões/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Haloperidol/farmacologia , Animais , Dopamina/farmacologia , Masculino , Camundongos
15.
Mol Pharmacol ; 97(2): 123-131, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31734646

RESUMO

The dopamine D2 receptor (D2R) is a G protein-coupled receptor (GPCR) expressed in regions of the brain that control motor function, cognition, and motivation. As a result, D2R is involved in the pathophysiology of disorders such as schizophrenia and drug addiction. Understanding the signaling pathways activated by D2R is crucial to finding new therapeutic targets for these disorders. D2R stimulation by its agonist, dopamine, causes desensitization and internalization of the receptor. A previous study found that inhibitors of the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) blocked D2R desensitization in neurons in the ventral tegmental area of the brain. In the present study, using a cell-based system, we investigated whether ALK regulates D2R internalization. The ALK inhibitor alectinib completely inhibited dopamine-induced D2R internalization. Since GPCRs can transactivate receptor tyrosine kinases, we also examined if D2R stimulation activated ALK signaling. ALK phosphorylation increased by almost 2-fold after dopamine treatment and ALK coimmunoprecipitated with D2R. To identify the signaling pathways downstream of ALK that might regulate D2R internalization, we used pharmacological inhibitors of proteins activated by ALK signaling. Protein kinase Cγ was activated by dopamine in an ALK-dependent manner, and a protein kinase C inhibitor completely blocked dopamine-induced D2R internalization. Taken together, these results identify ALK as a receptor tyrosine kinase transactivated by D2R that promotes its internalization, possibly through activation of protein kinase C. ALK inhibitors could be useful in enhancing D2R signaling. SIGNIFICANCE STATEMENT: Receptor internalization is a mechanism by which receptors are desensitized. In this study we found that agonist-induced internalization of the dopamine D2 receptor is regulated by the receptor tyrosine kinase ALK. ALK was also transactivated by and associated with dopamine D2 receptor. Dopamine activated protein kinase C in an ALK-dependent manner and a PKC inhibitor blocked dopamine D2 receptor internalization. These results indicate that ALK regulates dopamine D2 receptor trafficking, which has implications for psychiatric disorders involving dysregulated dopamine signaling.


Assuntos
Quinase do Linfoma Anaplásico/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptores de Dopamina D2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Carbazóis/farmacologia , Dopamina/farmacologia , Células HEK293 , Humanos , Fosforilação/efeitos dos fármacos , Piperidinas/farmacologia , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , RNA Interferente Pequeno/metabolismo , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
16.
Biochem Biophys Res Commun ; 521(4): 997-1002, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31727364

RESUMO

Laccases (benzenediol: oxygen oxidoreductases, EC1.10.3.2) can oxidize various substrates, and those which are tolerant to and even activated by salts have attracted a lot of attention due to their application potential in certain industries. The mechanism of the salt activation of laccases is awaiting to be elucidated yet. Our previous study (Li, Xie et al. 2018) supposed that the salt activation of marine laccase Lac15 might be attributed to Cl- ion specifically binding to some local sites to interfere substrate binding and/or electron transfer. In this study, we found two sites whose mutations resulted in elimination of the salt activation of Lac15's activity towards catechol and dopamine respectively, and revealed that the mutations affected the activity by altering both Em and kcat, demonstrating the supposed mechanism. A model for the salt activation of laccases was accordingly proposed, albeit some details are to be elucidated.


Assuntos
Lacase/metabolismo , Cloreto de Sódio/farmacologia , Sítios de Ligação , Catecóis/farmacologia , Dopamina/farmacologia , Ativação Enzimática/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Cinética , Lacase/química , Lacase/genética , Mutação/genética , Espectrometria de Fluorescência , Especificidade por Substrato/efeitos dos fármacos
17.
Arch Dis Child ; 105(4): 390-394, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31471281

RESUMO

OBJECTIVE: To evaluate whether changing dopamine infusions every 12 hours and preparing these infusions 30 min before administration reduces blood pressure fluctuations in preterm and term neonates. DESIGN: This was a retrospective study using data from live patients on the neonatal unit and prospective study exploring stability of infusions in a laboratory-based neonatal ward simulation. SETTING: Single-centre study in a tertiary neonatal surgical unit in a university teaching hospital. PATIENTS: Neonates who received more than one subsequent dopamine infusion and had invasive arterial blood pressure monitoring, during their admission in the neonatal unit, were included. INTERVENTIONS: As part of the Quality Improvement project, the standard operating procedure (SOP) was changed, and dopamine infusions were prepared by nursing staff and left to rest for 30 min before administering to the neonate. Additionally, infusions were replaced every 12 hours. MAIN OUTCOME MEASURES: The percentage change in mean arterial pressure (MAP) and the percentage loss in the drug concentration during infusion during changeover. RESULTS: Our findings indicate that up to 15% of the initial dopamine concentration is lost after 24 hours. This results in a sharp variation in the dopamine concentration during infusion changeover that correlates with observed rapid fluctuations in MAP. In changing the SOP, no significant difference in the concentration of dopamine and MAP were observed over 12 hours. CONCLUSIONS: Delaying administration of dopamine infusions by 30 min after preparation combined with changing infusions 12 hourly has reduced MAP fluctuations. Therefore, the risks associated with MAP fluctuations, including intraventricular haemorrhages, are reduced.


Assuntos
Pressão Arterial/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Dopamina/administração & dosagem , Hipotensão/tratamento farmacológico , Terapia Intensiva Neonatal , Dopamina/farmacologia , Feminino , Hemodinâmica , Humanos , Hipotensão/fisiopatologia , Recém-Nascido , Infusões Intravenosas , Masculino , Estudos Prospectivos , Estudos Retrospectivos
18.
Biomed Res Int ; 2019: 6467134, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31828112

RESUMO

For several years, research has been carried out on the effectiveness of solutions for perfusion and preservation of organs, including the liver. There is a search for an optimal pharmacological composition of these solutions, allowing to preserve or improve vital functions of the organ for as long as possible until it is transplanted into a recipient. Hormones due to their properties, often resulting from their pleiotropic effects, may be a valuable component for optimizing the composition of liver perfusion and preservation solutions. The paper presents the current state of knowledge on liver perfusion and preservation solutions modified with hormones. It also shows the characteristics of the hormones evaluated, taking into account their physiological functions in the body.


Assuntos
Hormônios/farmacologia , Fígado/efeitos dos fármacos , Soluções para Preservação de Órgãos/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Dopamina/farmacologia , Glucagon/farmacologia , Hormônios/química , Humanos , Transplante de Fígado/normas , Melatonina/farmacologia , Soluções para Preservação de Órgãos/química , Prolactina/farmacologia , Sobrevivência de Tecidos/efeitos dos fármacos
19.
Sci Rep ; 9(1): 19338, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31853095

RESUMO

IFNγ enhances allograft immunogenicity and facilitates T-cell mediated rejection. This may cause interstitial fibrosis and tubular atrophy (IFTA), contributing to chronic allograft loss. We assessed if inhibition of T-cell activation by N-octanoyl dopamine (NOD) impairs adherence of activated T-cells to endothelial cells and the ability of activated T-cells to produce IFNγ. We also assessed if NOD affects IFNγ mediated gene expression in endothelial cells. The presence of NOD during T-cell activation significantly blunted their adhesion to unstimulated and cytokine stimulated HUVEC. Supernatants of these T-cells displayed significantly lower concentrations of TNFα and IFNγ and were less capable to facilitate T-cell adhesion. In the presence of NOD VLA-4 (CD49d/CD29) and LFA-1 (CD11a/CD18) expression on T-cells was reduced. NOD treatment of IFNγ stimulated HUVEC reduced the expression of MHC class II transactivator (CIITA), of MHC class II and its associated invariant chain CD74. Since IFTA is associated with T-cell mediated rejection and IFNγ to a large extent regulates immunogenicity of allografts, our current data suggest a potential clinical use of NOD in the treatment of transplant recipients. Further in vivo studies are warranted to confirm these in vitro findings and to assess the benefit of NOD on IFTA in clinically relevant models.


Assuntos
Moléculas de Adesão Celular/metabolismo , Dopamina/análogos & derivados , Antígenos de Histocompatibilidade Classe II/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Interferon gama/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Linfócitos T/imunologia , Antígenos de Diferenciação de Linfócitos B/metabolismo , Adesão Celular/efeitos dos fármacos , Dopamina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Antígenos HLA-DR/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Integrina alfa4beta1/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Antígeno-1 Associado à Função Linfocitária/metabolismo , Proteínas Nucleares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Transativadores/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo
20.
Biomed Res Int ; 2019: 1767203, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31815123

RESUMO

Neurological diseases particularly Alzheimer's disease (AD), Parkinson's disease (PD), stroke, and epilepsy are on the rise all around the world causing morbidity and mortality globally with a common symptom of gradual loss or impairment of motor behaviour. Striatum, which is a component of the basal ganglia, is involved in facilitating voluntary movement while the cerebellum is involved in the maintenance of balance and coordination of voluntary movements. Dopamine, serotonin, gamma-aminobutyric acid (GABA), and glutamate, to name a few, interact in regulating the excitation and inhibition of motor neurons. In another hand, interestingly, the motor loss associated with neurological diseases is possibly resulted from neuroinflammation induced by the neuroimmune system. Toll-like receptors (TLRs) are present in the central nervous system (CNS), specifically and primarily expressed in microglia and are also found on neurons and astrocytes, functioning mainly in the regulation of proinflammatory cytokine production. TLRs are always found to be associated or involved in the induction of neuroinflammation in neurodegenerative diseases. Activation of toll-like receptor 4 (TLR4) through TLR4 agonist, lipopolysaccharide (LPS), stimulation initiate a signaling cascade whereby the TLR4-LPS interaction has been found to result in physiological and behavioural changes including retardation of motor activity in the mouse model. TLR4 inhibitor TAK-242 was reflected in the reduction of the spinal cord pathology along with the motor improvement in ALS mouse. There is cross talk with neuroinflammation and neurochemicals. For example, TLR4 activation by LPS is noted to release proinflammatory cytokines, IL-1ß, from microglia that subsequently suppresses GABA receptor activities at the postsynaptic site and reduces GABA synthesis at the presynaptic site. Glial glutamate transporter activities are also found to be suppressed, showing the association between TLR4 activation and the related neurotransmitters and corresponding receptors and transporters in the event of neuroinflammation. This review is helpful to understand the connection between neurotransmitter and neuroinflammation in striatum- and cerebellum-mediated motor behaviour.


Assuntos
Cerebelo/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Inflamação , Neurônios Motores/efeitos dos fármacos , Neurotransmissores/farmacologia , Animais , Astrócitos/metabolismo , Sistema Nervoso Central/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Dopamina/farmacologia , Ácido Glutâmico/farmacologia , Humanos , Interleucina-1beta , Lipopolissacarídeos/efeitos adversos , Camundongos , Microglia/metabolismo , Serotonina/farmacologia , Receptor 4 Toll-Like , Receptores Toll-Like , Ácido gama-Aminobutírico/farmacologia
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