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1.
Brain Nerve ; 72(11): 1135-1142, 2020 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-33191292

RESUMO

Dopamine (DA) plays an important role in the basal ganglia (BG) for motor control, and DA deficiency as seen in Parkinson's disease, causes movement disorders. DA activates the direct pathway nerve via the D1 receptor (D1R) and inhibits the indirect pathway nerve via the D2 receptor (D2R). To understand the role of DA signaling, we review recent studies of the roles of D1R and D2R with respect to motor control, neural activity and memory learning using genetically engineered mice, and investigate their involvement in the BG oscillation phenomenon.


Assuntos
Dopamina , Receptores de N-Metil-D-Aspartato , Animais , Gânglios da Base , Humanos , Camundongos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2
2.
Nat Commun ; 11(1): 4364, 2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32868781

RESUMO

Pathophysiological roles of cardiac dopamine system remain unknown. Here, we show the role of dopamine D1 receptor (D1R)-expressing cardiomyocytes (CMs) in triggering heart failure-associated ventricular arrhythmia. Comprehensive single-cell resolution analysis identifies the presence of D1R-expressing CMs in both heart failure model mice and in heart failure patients with sustained ventricular tachycardia. Overexpression of D1R in CMs disturbs normal calcium handling while CM-specific deletion of D1R ameliorates heart failure-associated ventricular arrhythmia. Thus, cardiac D1R has the potential to become a therapeutic target for preventing heart failure-associated ventricular arrhythmia.


Assuntos
Arritmias Cardíacas/etiologia , Insuficiência Cardíaca , Miócitos Cardíacos/metabolismo , Receptores de Dopamina D1/metabolismo , Animais , Arritmias Cardíacas/prevenção & controle , Perfilação da Expressão Gênica/métodos , Humanos , Camundongos , Camundongos Transgênicos , Ratos , Receptores de Dopamina D1/genética , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/prevenção & controle
3.
Proc Natl Acad Sci U S A ; 117(25): 14139-14149, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32503917

RESUMO

Agonist-activated G protein-coupled receptors (GPCRs) must correctly select from hundreds of potential downstream signaling cascades and effectors. To accomplish this, GPCRs first bind to an intermediary signaling protein, such as G protein or arrestin. These intermediaries initiate signaling cascades that promote the activity of different effectors, including several protein kinases. The relative roles of G proteins versus arrestins in initiating and directing signaling is hotly debated, and it remains unclear how the correct final signaling pathway is chosen given the ready availability of protein partners. Here, we begin to deconvolute the process of signal bias from the dopamine D1 receptor (D1R) by exploring factors that promote the activation of ERK1/2 or Src, the kinases that lead to cell growth and proliferation. We found that ERK1/2 activation involves both arrestin and Gαs, while Src activation depends solely on arrestin. Interestingly, we found that the phosphorylation pattern influences both arrestin and Gαs coupling, suggesting an additional way the cells regulate G protein signaling. The phosphorylation sites in the D1R intracellular loop 3 are particularly important for directing the binding of G protein versus arrestin and for selecting between the activation of ERK1/2 and Src. Collectively, these studies correlate functional outcomes with a physical basis for signaling bias and provide fundamental information on how GPCR signaling is directed.


Assuntos
Receptores de Dopamina D1/metabolismo , Transdução de Sinais , Arrestina/metabolismo , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Células HEK293 , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação , Domínios Proteicos , Receptores de Dopamina D1/química , Quinases da Família src/metabolismo
4.
J Pharmacol Sci ; 143(3): 226-233, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32446726

RESUMO

Renal ischemia/reperfusion (I/R) injury is a major cause of acute kidney injury (AKI), characterized by tubulointerstitial inflammation. Currently, progress in developing effective therapies to prevent or ameliorate AKI by anti-inflammation remains slow. Emerging studies have suggested that NLRP3 (the NOD-, LRR- and pyrin domain-containing 3) inflammasome plays a key role in a wide spectrum of kidney disease models including I/R injury. In this study, we investigated the renal protective effects of A68930, a specific agonist for the D-1 dopamine receptor (DRD1), which was recently recognized to downregulate NLRP3 inflammasome via DRD1 signaling. AKI was induced by renal I/R injury and A68930 was intraperitoneally injected 3 times after renal reperfusion. We showed that A68930 significantly ameliorated renal dysfunction. Meanwhile, A68930 markedly reduced macrophages and T cells infiltration, renal pro-inflammatory cytokines production (TNF-α, IL-6, IL-1ß), serum pro-inflammatory cytokine (TNF-α and IL-6) and NLRP3 inflammasome activation. Additionally, A68930 attenuated I/R-induced mitochondria injury, which was observed by transmission electron microscopy. In summary, our results demonstrated that activation of DRD1 by A68930 inhibited renal and systematic inflammation, and improved kidney function in I/R induced AKI model, which was probably related to the inhibition of the NLRP3 inflammasome activation.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/genética , Cromanos/farmacologia , Cromanos/uso terapêutico , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/metabolismo , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/prevenção & controle , Animais , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Rim/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/complicações , Fator de Necrose Tumoral alfa/metabolismo
5.
J Pharmacol Exp Ther ; 374(1): 6-15, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32265322

RESUMO

Rats eating high fat chow are more sensitive to the behavioral effects of dopaminergic drugs, including methamphetamine and the dopamine D2/D3 receptor agonist quinpirole, than rats eating standard chow. However, limited work has explored possible sex differences regarding the impact of diet on drug sensitivity. It is also unknown whether eating high fat chow enhances sensitivity of rats to other dopamine (e.g., D1) receptor agonists. To explore these possibilities, male and female Sprague-Dawley rats eating standard laboratory chow (17% kcal from fat) or high fat chow (60% kcal from fat) were tested once per week for 6 weeks with dopamine D1 receptor agonist SKF 82958 (0.01-3.2 mg/kg) or methamphetamine (0.1-3.2 mg/kg) using cumulative dosing procedures. Eating high fat chow increased sensitivity of male and female rats to methamphetamine-induced locomotion; however, only female rats eating high fat chow were more sensitive to SKF 82958-induced locomotion. SKF 82958-induced eye blinking was also marginally, although not significantly, enhanced among female rats eating high fat chow, but not males. Further, although dopamine D2 receptor expression was significantly increased for SKF 82958-treated rats eating high fat chow regardless of sex, no differences were observed in dopamine D1 receptor expression. Taken together, the present study suggests that although eating high fat chow enhances sensitivity of both sexes to dopaminergic drugs, the mechanism driving this effect might be different for males versus females. These data further demonstrate the importance of studying both sexes simultaneously when investigating factors that influence drug sensitivity. SIGNIFICANCE STATEMENT: Although it is known that diet can impact sensitivity to some dopaminergic drugs, sex differences regarding this effect are not well characterized. This report demonstrates that eating a high fat diet enhances sensitivity to methamphetamine, regardless of sex; however, sensitivity to dopamine D1 receptor agonist SKF 82958 is increased only among females eating high fat chow, but not males. This suggests that the mechanism(s) driving diet-induced changes in drug sensitivity might be different between sexes.


Assuntos
Benzazepinas/farmacologia , Dieta Hiperlipídica/efeitos adversos , Metanfetamina/farmacologia , Receptores de Dopamina D1/agonistas , Animais , Piscadela/efeitos dos fármacos , Interações Medicamentosas , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Ratos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo
6.
Nature ; 579(7800): 555-560, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32214250

RESUMO

Dopamine D2 receptors (D2Rs) are densely expressed in the striatum and have been linked to neuropsychiatric disorders such as schizophrenia1,2. High-affinity binding of dopamine suggests that D2Rs detect transient reductions in dopamine concentration (the dopamine dip) during punishment learning3-5. However, the nature and cellular basis of D2R-dependent behaviour are unclear. Here we show that tone reward conditioning induces marked stimulus generalization in a manner that depends on dopamine D1 receptors (D1Rs) in the nucleus accumbens (NAc) of mice, and that discrimination learning refines the conditioning using a dopamine dip. In NAc slices, a narrow dopamine dip (as short as 0.4 s) was detected by D2Rs to disinhibit adenosine A2A receptor (A2AR)-mediated enlargement of dendritic spines in D2R-expressing spiny projection neurons (D2-SPNs). Plasticity-related signalling by Ca2+/calmodulin-dependent protein kinase II and A2ARs in the NAc was required for discrimination learning. By contrast, extinction learning did not involve dopamine dips or D2-SPNs. Treatment with methamphetamine, which dysregulates dopamine signalling, impaired discrimination learning and spine enlargement, and these impairments were reversed by a D2R antagonist. Our data show that D2Rs refine the generalized reward learning mediated by D1Rs.


Assuntos
Espinhas Dendríticas/fisiologia , Aprendizagem por Discriminação/fisiologia , Receptores de Dopamina D2/metabolismo , Animais , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Condicionamento Clássico/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Aprendizagem por Discriminação/efeitos dos fármacos , Dopamina/metabolismo , Antagonistas dos Receptores de Dopamina D2/farmacologia , Extinção Psicológica/efeitos dos fármacos , Masculino , Metanfetamina/antagonistas & inibidores , Metanfetamina/farmacologia , Camundongos , Plasticidade Neuronal , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Optogenética , Receptor A2A de Adenosina/metabolismo , Receptores de Dopamina D1/metabolismo , Recompensa , Transdução de Sinais/efeitos dos fármacos , Sinapses/metabolismo
7.
J Neurosci ; 40(14): 2868-2881, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32071139

RESUMO

The neuromodulator dopamine plays a key role in motivation, reward-related learning, and normal motor function. The different affinity of striatal D1 and D2 dopamine receptor types has been argued to constrain the D1 and D2 signaling pathways to phasic and tonic dopamine signals, respectively. However, this view assumes that dopamine receptor kinetics are instantaneous so that the time courses of changes in dopamine concentration and changes in receptor occupation are basically identical. Here we developed a neurochemical model of dopamine receptor binding taking into account the different kinetics and abundance of D1 and D2 receptors in the striatum. Testing a large range of behaviorally-relevant dopamine signals, we found that the D1 and D2 dopamine receptor populations responded very similarly to tonic and phasic dopamine signals. Furthermore, because of slow unbinding rates, both receptor populations integrated dopamine signals over a timescale of minutes. Our model provides a description of how physiological dopamine signals translate into changes in dopamine receptor occupation in the striatum, and explains why dopamine ramps are an effective signal to occupy dopamine receptors. Overall, our model points to the importance of taking into account receptor kinetics for functional considerations of dopamine signaling.SIGNIFICANCE STATEMENT Current models of basal ganglia function are often based on a distinction of two types of dopamine receptors, D1 and D2, with low and high affinity, respectively. Thereby, phasic dopamine signals are believed to mostly affect striatal neurons with D1 receptors, and tonic dopamine signals are believed to mostly affect striatal neurons with D2 receptors. This view does not take into account the rates for the binding and unbinding of dopamine to D1 and D2 receptors. By incorporating these kinetics into a computational model we show that D1 and D2 receptors both respond to phasic and tonic dopamine signals. This has implications for the processing of reward-related and motivational signals in the basal ganglia.


Assuntos
Encéfalo/metabolismo , Modelos Neurológicos , Neurônios/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Animais , Simulação por Computador , Dopamina/metabolismo , Humanos , Cinética
8.
J Neurosci ; 40(14): 2935-2942, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32102921

RESUMO

In Drosophila, dopamine signaling to the mushroom body intrinsic neurons, Kenyon cells (KCs), is critical to stabilize olfactory memory. Little is known about the downstream intracellular molecular signaling underlying memory stabilization. Here we address this question in the context of sugar-rewarded olfactory long-term memory (LTM). We show that associative training increases the phosphorylation of MAPK in KCs, via Dop1R2 signaling. Consistently, the attenuation of Dop1R2, Raf, or MAPK expression in KCs selectively impairs LTM, but not short-term memory. Moreover, we show that the LTM deficit caused by the knockdown of Dop1R2 can be rescued by expressing active Raf in KCs. Thus, the Dop1R2/Raf/MAPK pathway is a pivotal downstream effector of dopamine signaling for stabilizing appetitive olfactory memory.SIGNIFICANCE STATEMENT Dopaminergic input to the Kenyon cells (KCs) is pivotal to stabilize memory in Drosophila This process is mediated by dopamine receptors like Dop1R2. Nevertheless, little is known for its underlying molecular mechanism. Here we show that the Raf/MAPK pathway is specifically engaged in appetitive long-term memory in KCs. With combined biochemical and behavioral experiments, we reveal that activation of the Raf/MAPK pathway is regulated through Dop1R2, shedding light on how dopamine modulates intracellular signaling for memory stabilization.


Assuntos
Comportamento Apetitivo/fisiologia , Proteínas de Drosophila/metabolismo , Memória de Longo Prazo/fisiologia , Neurônios/metabolismo , Receptores de Dopamina D1/metabolismo , Transdução de Sinais/fisiologia , Animais , Drosophila , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Masculino , Corpos Pedunculados/fisiologia , Quinases raf/metabolismo
9.
Sci Rep ; 10(1): 1838, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-32020036

RESUMO

The medial prefrontal cortex (mPFC) is a critical component of a cortico-basal ganglia-thalamo-cortical loop regulating limbic and cognitive functions. Within this circuit, two distinct nucleus accumbens (NAc) output neuron types, dopamine D1 or D2 receptor-expressing neurons, dynamically control the flow of information through basal ganglia nuclei that eventually project back to the mPFC to complete the loop. Thus, chronic dysfunction of the NAc may result in mPFC transcriptomal changes, which in turn contribute to disease conditions associated with the mPFC and basal ganglia. Here, we used RNA sequencing to analyse differentially expressed genes (DEGs) in the mPFC following a reversible neurotransmission blocking technique in D1 or D2 receptor-expressing NAc neurons, respectively (D1-RNB, or D2-RNB). Gene Set Enrichment Analysis revealed that gene sets of layer 5b and 6 pyramidal neurons were enriched in DEGs of the mPFC downregulated in both NAc D1- and D2-RNB mice. In contrast, gene sets of layer 5a pyramidal neurons were enriched in upregulated DEGs of the mPFC in D1-RNB mice, and downregulated DEGs of the mPFC in D2-RNB mice. These findings reveal for the first time that NAc output pathways play an important role in controlling mPFC gene expression.


Assuntos
Vias Neurais/metabolismo , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/metabolismo , Animais , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/fisiologia , Regulação da Expressão Gênica , Camundongos , Vias Neurais/fisiologia , Núcleo Accumbens/fisiologia , Células Piramidais/metabolismo , Células Piramidais/fisiologia , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Transcriptoma
10.
J Neurochem ; 153(3): 297-299, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32091130

RESUMO

Endocannabinoids (eCBs) play key roles in short-term and long-term synaptic plasticity in the corticostriatal circuit. By activating cannabinoid receptors expressed in the central nervous system, eCBs regulate several neural functions and behaviors. The major eCB 2-arachidonoyl-glycerol (2-AG) is particularly important for triggering a short-term form of synaptic plasticity (depolarization-induced suppression of excitatory transmission or DSE) on cortical glutamatergic afferents inputting the striatum. The neurotransmitter dopamine, through the action of D1 and D2 receptors, is also critically involved in corticostriatal plasticity. This Editorial highlights the study by Shonesy et al., which presents evidence that activation of dopamine D1 receptor and its classical downstream target cAMP-dependent protein kinase (PKA) are involved in increasing the synthesis of 2-AG in striatal medium spiny neurons (MSN) to drive DSE in the corticostriatal circuit, as schematically outlined in Figure 1. The authors used a set of complementary approaches and identified a putative serine (Ser) residue phosphorylated by PKA in diacylglycerol lipase (DGL) alpha that is required for generating 2-AG, providing a mechanistic clue into how the canonical D1 pathway in MSN might fine-tune short-term plasticity in the corticostriatal circuit. Besides, the work by Shonesy et al. may pave the way for further studies exploring the signaling interplay between canonical dopamine D1 receptor pathway and eCBs to control other forms of synaptic plasticity in different brain circuits with possible pathological relevance.


Assuntos
Corpo Estriado/metabolismo , Endocanabinoides/metabolismo , Plasticidade Neuronal/fisiologia , Receptores de Dopamina D1/metabolismo , Animais , Ácidos Araquidônicos/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Glicerídeos/metabolismo , Humanos , Lipase Lipoproteica/metabolismo , Sinapses/metabolismo
11.
Behav Pharmacol ; 31(2&3): 196-206, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32040018

RESUMO

Relapsing to drugs of abuse is a challenging problem in treatment of addiction and stress is believed to be a major risk factor in relapse to drugs. The hippocampus region and dopamine signaling play a critical role in reward-related behaviors. The purpose of this study is to identify the involvement of D1- and D2-like receptors in the CA1 region of hippocampus in the reinstatement induced by a combination of food deprivation stress and a sub-threshold dose of morphine in extinguished morphine-conditioning place preference in rats. Adult male rats treated with one specific doses of SCH-23390 or sulpiride (0.5, 2 and 4 µg/0.5 µl vehicle/side) as D1- and D2-like receptors antagonists into the CA1 in separate groups, following the conditioning and extinction phase of morphine-conditioning place preference, before initiating the food deprivation stress on the last day of extinction. Then, the food deprived animals examined for reinstatement by injection of the sub-threshold dose of morphine (0.5 mg/kg, s.c.) on reinstatement day. Conditioning place preference scores and locomotor activities were recorded during test. Our results showed that combination of food deprivation stress and a sub-threshold dose of morphine induced the reinstatement of morphine-conditioning place preference. The induced reinstatement was decreased by two higher doses of SCH-23390 (2 and 4 µg/0.5 µl vehicle/side). However, the sulpiride (0.5, 2 and 4 µg/0.5 µl vehicle/side) could not reduce the reinstatement. Results showed that the role of D1-like receptor in the CA1 region was more prominent than D2-like receptor in reinstatement induced by food deprivation stress and re-exposure to morphine. Therefore the D1-like receptor in the CA1 might be a potential therapeutic target for treatment of opiate addiction.


Assuntos
Região CA1 Hipocampal/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Receptores de Dopamina D1/metabolismo , Animais , Benzazepinas/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Privação de Alimentos , Hipocampo/efeitos dos fármacos , Masculino , Morfina/farmacologia , Entorpecentes/farmacologia , Ratos , Ratos Wistar , Receptores de Dopamina D2/metabolismo , Sulpirida/farmacologia
12.
J Clin Invest ; 130(3): 1168-1184, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32039920

RESUMO

Dopamine receptor D1 modulates glutamatergic transmission in cortico-basal ganglia circuits and represents a major target of L-DOPA therapy in Parkinson's disease. Here we show that D1 and metabotropic glutamate type 5 (mGlu5) receptors can form previously unknown heteromeric entities with distinctive functional properties. Interacting with Gq proteins, cell-surface D1-mGlu5 heteromers exacerbated PLC signaling and intracellular calcium release in response to either glutamate or dopamine. In rodent models of Parkinson's disease, D1-mGlu5 nanocomplexes were strongly upregulated in the dopamine-denervated striatum, resulting in a synergistic activation of PLC signaling by D1 and mGlu5 receptor agonists. In turn, D1-mGlu5-dependent PLC signaling was causally linked with excessive activation of extracellular signal-regulated kinases in striatal neurons, leading to dyskinesia in animals treated with L-DOPA or D1 receptor agonists. The discovery of D1-mGlu5 functional heteromers mediating maladaptive molecular and motor responses in the dopamine-denervated striatum may prompt the development of new therapeutic principles for Parkinson's disease.


Assuntos
Corpo Estriado/metabolismo , Sistema de Sinalização das MAP Quinases , Neurônios/metabolismo , Doença de Parkinson Secundária/metabolismo , Receptor de Glutamato Metabotrópico 5/metabolismo , Receptores de Dopamina D1/metabolismo , Animais , Corpo Estriado/patologia , Células HEK293 , Humanos , Camundongos , Camundongos Knockout , Complexos Multiproteicos/agonistas , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Neurônios/patologia , Doença de Parkinson Secundária/tratamento farmacológico , Doença de Parkinson Secundária/genética , Doença de Parkinson Secundária/patologia , Ratos , Receptor de Glutamato Metabotrópico 5/genética , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/genética
13.
Biol Sex Differ ; 11(1): 8, 2020 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-32087746

RESUMO

Depression and anxiety are more common among females than males and represent a leading cause of disease-related disability in women. Since the dopamine D1-D2 heteromer is involved in depression- and anxiety-like behavior, the possibility that the receptor complex may have a role in mediating sex differences in such behaviors and related biochemical signaling was explored.In non-human primate caudate nucleus and in rat striatum, females expressed higher density of D1-D2 heteromer complexes and a greater number of D1-D2 expressing neurons compared to males. In rat, the sex difference in D1-D2 expression levels occurred even though D1 receptor expression was lower in female than in male with no difference in D2 receptor expression. In behavioral tests, female rats showed faster latency to depressive-like behavior and a greater susceptibility to the pro-depressive and anxiogenic-like effects of D1-D2 heteromer activation by low doses of SKF 83959, all of which were ameliorated by the selective heteromer disrupting peptide, TAT-D1. The sex difference observed in the anxiety test correlated with differences in low-frequency delta and theta oscillations in the nucleus accumbens. Analysis of signaling pathways revealed that the sex difference in D1-D2 heteromer expression led to differences in basal and heteromer-stimulated activities of two important signaling pathways, BDNF/TrkB and Akt/GSK3/ß-catenin.These results suggest that the higher D1-D2 heteromer expression in female may significantly increase predisposition to depressive-like and anxiety-like behavior in female animals.


Assuntos
Ansiedade/metabolismo , Núcleo Caudado/metabolismo , Depressão/metabolismo , Núcleo Accumbens/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Caracteres Sexuais , Transdução de Sinais , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/administração & dosagem , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/análogos & derivados , Animais , Ansiedade/fisiopatologia , Comportamento Animal , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Núcleo Caudado/efeitos dos fármacos , Chlorocebus aethiops , Depressão/fisiopatologia , Feminino , Quinase 3 da Glicogênio Sintase/metabolismo , Masculino , Núcleo Accumbens/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Receptor trkB/metabolismo , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , Transdução de Sinais/efeitos dos fármacos , beta Catenina/metabolismo
14.
Psychopharmacology (Berl) ; 237(4): 1107-1119, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31927604

RESUMO

RATIONALE: Mesolimbic dopamine (DA) signaling is essential for the high maternal caregiving characteristic of the early postpartum period, but little is known about dopamine's role in the expression of maternal caregiving thereafter. OBJECTIVES: We tested the hypothesis that decreased mesolimbic dopaminergic signaling is particularly responsible for the natural decline in maternal caregiving that occurs as the postpartum period progresses. METHODS: Sprague-Dawley (SD) mother rats received intraperitoneal injections of either vehicle, the DA D1 receptor agonist SKF38393, the DA D2 receptor agonist quinpirole, or both agonists twice daily from postpartum days 9 to 15. In a separate experiment involving Long-Evans (LE) rats, we examined whether DA D1 and D2 receptor mRNAs in the nucleus accumbens (NA) shell and ventral tegmental area (VTA), along with DA turnover in the VTA, decline across the postpartum period in parallel with the decreasing maternal behavior. RESULTS: All drug treatments significantly maintained higher frequencies of active maternal behaviors (nesting, pup licking, retrieval) compared to vehicle. Furthermore, the majority of mothers treated with SKF38393 either alone or combined with quinpirole maintained full expression of maternal behavior during behavioral testing. D2 receptor mRNA levels were found to be lower in the late postpartum NA shell and VTA compared to early postpartum, but D1 receptor mRNA levels in the NA shell were higher in the late postpartum period. Furthermore, both late postpartum and recently parturient LE mothers had higher VTA DA turnover compared to nulliparae, suggesting changes in mesolimbic signal-to-noise ratio both at the end and beginning of motherhood. CONCLUSIONS: Collectively, our results suggest that alterations in mesolimbic DA is part of the neural substrate responsible for dynamic maternal caregiving across the entire postpartum period.


Assuntos
Dopamina/metabolismo , Comportamento Materno/fisiologia , Núcleo Accumbens/metabolismo , Período Pós-Parto/metabolismo , Transdução de Sinais/fisiologia , Área Tegmentar Ventral/metabolismo , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Animais Recém-Nascidos , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Feminino , Masculino , Comportamento Materno/efeitos dos fármacos , Comportamento Materno/psicologia , Núcleo Accumbens/efeitos dos fármacos , Período Pós-Parto/efeitos dos fármacos , Período Pós-Parto/psicologia , Gravidez , Quimpirol/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Área Tegmentar Ventral/efeitos dos fármacos
15.
Trends Pharmacol Sci ; 41(4): 230-232, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31964511

RESUMO

To investigate how opioid exposure alters dopamine (DA) responses in medium spiny neurons (MSNs), Muntean et al. used a novel cAMP sensor to track cAMP dynamics and report a coordinated effort of adaptations in D1- and D2-MSNs to integrate DA inputs and shift signaling strengths in various states of opioid dependence.


Assuntos
Núcleo Accumbens , Receptores de Dopamina D1 , Analgésicos Opioides , Corpo Estriado/metabolismo , Núcleo Accumbens/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo
16.
Exp Cell Res ; 388(2): 111849, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31954110

RESUMO

Diabetic nephropathy (DN) is a major microvascular complication of diabetes that can lead to end-stage renal disease. Podocytes constitute the last barrier of glomerular filtration, whose damage are the direct cause of proteinuria. Dopamine receptors are involved in the regulation of diabetes-induced glomerular hyperfiltration, and only dopamine 1 receptor (D1R) can be amplified in cultured mouse podocytes. However, the exact effect of D1R on diabetic podocytes remains unclear. This study aims to investigate the protective role of D1R activation on diabetic podocytes injury in vivo and vitro as well as its potential mechanism. We observed D1R protective effect respectively in streptozotocin (STZ)-induced type 1 diabetes (T1D) mice as well as mouse podocytes (MPC5) cultured in high glucose (HG, 40 mM) medium. It showed that D1R and podocyte-associated proteins (Podocin, CD2AP and Nephrin) expression were significantly decreased both in the T1D mice (fed for 8 and 12 weeks) and HG-cultured MPC5 cells, while the NOX-5 expression increased. In T1D mice, the levels of 24-h urine protein, serum creatinine and urinary 8-OHdG were increased in a time-dependent manner, at the same time, hematoxylin-eosin (HE) staining and electron microscope observed the kidney lesion and podocytes injury. In vitro, HG induced podocytes oxidative stress and apoptosis, which could be inhibited by SKF38393 (a D1R agonist) and N-acetyl-l-cysteine (NAC, a reactive oxygen species scavenger). Furthermore, there was a decreasing Podocin expression and a significant increasing NOX-5 expression in podocytes transfected with D1R-small interfering RNA (siRNA). More importantly, the expression of phospho-CREB (the PKA downstream transcription factor) was decreased and phospho-p38 MAPK was increased in HG-induced podocytes, which can respectively be activated or blocked by SKF38393, 8-Bromo-CAMP (a PKA activator), NAC, and SB20380 (a p38 MAPK inhibitor). In conclusion, D1R activation can protect diabetic podocytes from apoptosis and oxidative damage, in part through the PKA/NOX-5/p38 MAPK pathway.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/prevenção & controle , NADPH Oxidase 5/metabolismo , Podócitos/metabolismo , Receptores de Dopamina D1/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Apoptose , Proteínas Quinases Dependentes de AMP Cíclico/genética , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Regulação da Expressão Gênica , Glucose/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidase 5/genética , Podócitos/patologia , Substâncias Protetoras , Espécies Reativas de Oxigênio/metabolismo , Receptores de Dopamina D1/genética , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/genética
17.
J Neurochem ; 153(3): 334-345, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31985073

RESUMO

Brain endocannabinoids serve as retrograde neurotransmitters, being synthesized in post-synaptic neurons "on demand" and released to bind pre-synaptic cannabinoid receptors and suppress glutamatergic or GABAergic transmission. The most abundant brain endocannabinoid, 2 arachidonoyl glycerol (2-AG), is primarily synthesized by diacylglycerol lipase-α (DGLα), which is activated by poorly understood mechanisms in response to calcium influx following post-synaptic depolarization and/or the activation of Gq -coupled group 1 metabotropic glutamate receptors. However, the impact of other neurotransmitters and their downstream signaling pathways on synaptic 2-AG signaling has not been intensively studied. Here, we found that DGLα activity in membrane fractions from transfected HEK293T cells was significantly increased by in vitro phosphorylation using cyclic AMP-dependent protein kinase (PKA). Moreover, PKA directly phosphorylated DGLα at Ser798 in vitro. Elevation of cAMP levels in HEK293 cells expressing DGLα increased Ser798 phosphorylation, as detected using a phospho-Ser798-specific antibody, and enhanced DGLα activity; this in situ enhancement of DGLα activity was prevented by mutation of Ser798 to Ala. We investigated the impact of PKA on synaptic 2-AG mobilization in mouse striatal slices by manipulating D1-dopamine receptor (D1R) signaling and assessing depolarization-induced suppression of excitation, a DGLα- and 2-AG-dependent form of short-term synaptic depression. The magnitude of depolarization-enhanced suppression of excitation in direct pathway medium spiny neurons was increased by pre-incubation with a D1R agonist, and this enhancement was blocked by post-synaptic inhibition of PKA. Taken together, these findings provide new molecular insights into the complex mechanisms regulating synaptic endocannabinoid signaling.


Assuntos
Ácidos Araquidônicos/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Endocanabinoides/metabolismo , Glicerídeos/metabolismo , Lipase Lipoproteica/metabolismo , Receptores de Dopamina D1/metabolismo , Transdução de Sinais/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Cultura de Órgãos , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos
18.
Psychopharmacology (Berl) ; 237(1): 155-165, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31435690

RESUMO

In the majority of Parkinson's disease (PD) patients, long-term dopamine (DA) replacement therapy leads to dyskinesia characterized by abnormal involuntary movements (AIMs). There are various mechanisms of dyskinesia, such as the sensitization of striatal DA D1 receptors (D1R) and upregulation of DA D3 receptors (D3R). These receptors interact physically and functionally in D1R-bearing medium spiny neurons to synergistically drive dyskinesia. However, the cross-receptor-mediated effects due to D1R-D3R cooperativity are still poorly understood. In pursuit of this, we examined whether or not pharmacological D1R or D3R stimulation sensitizes the dyskinetic response to the appositional agonist, a process known as cross-sensitization. First, we established D1R-D3R behavioral synergy in a cohort of 6-OHDA-lesioned female adult Sprague-Dawley rats. Then, in a new cohort, we tested for cross-sensitization in a between-subject design. Five groups received a sub-chronic regimen of either saline, the D1R agonist SKF38393 (1.0 mg/kg), or the D3R agonist PD128907 (0.3 mg/kg). For the final injection, each group received an acute injection of the other agonist. AIMs were monitored following each injection. Sub-chronic administration of both SKF38393 and PD128907 induced the development of dyskinesia. More importantly, cross-agonism tests revealed reciprocal cross-sensitization; chronic treatment with either SKF38393 or PD128907 induced sensitization to a single administration of the other agonist. This reciprocity was not marked by changes to either D1R or D3R striatal mRNA expression. The current study provides key behavioral data demonstrating the role of D3R in dyskinesia and provides behavioral evidence of D1R and D3R functional interactions.


Assuntos
Corpo Estriado/metabolismo , Agonistas de Dopamina/farmacologia , Discinesia Induzida por Medicamentos/metabolismo , Doença de Parkinson Secundária/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D3/metabolismo , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Benzopiranos/farmacologia , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Feminino , Oxazinas/farmacologia , Oxidopamina , Doença de Parkinson Secundária/induzido quimicamente , Ratos , Ratos Sprague-Dawley
19.
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
20.
Clin Exp Hypertens ; 42(2): 99-104, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30698033

RESUMO

Objective:Environmental cold stress is an important factor that leads to hypertension. The role and the mechanisms of in-utero cold stress in hypertension in adult offspring remain unknown.Methods: The pregnant rats were housed in cold (4°C) rooms from 14 to 21 days of gestation for prenatal cold exposure. The blood pressure and vascular response offspring of control and cold exposure were measured. And the receptor expression, phosphorylation and internalization were checked by immunoblotting or immunoprecipitation.Results: In the present study, we report that prenatal cold stress elevated the blood pressure via decreasing D1 receptor-associated vasodilation, which is ascribed to decreased D1 receptor expression and function. Moreover, the artery G protein-coupled receptor kinase 4 (GRK4) expression has been found to be higher in the prenatal cold stress treated offspring than the controls, which could cause the increased phosphorylation and internalization of D1 receptor in mesenteric artery from prenatal cold stress treated offspring, and led to receptor desensitization and vascular dysfunction.Conclusion: The results illustrate a new paradigm for the developmental origins of hypertension and imply that GRK4 and dopamine D1 receptor may be crucial determinants for the maternal hypertension.


Assuntos
Resposta ao Choque Frio/fisiologia , Dopamina/fisiologia , Hipertensão/prevenção & controle , Complicações Cardiovasculares na Gravidez/fisiopatologia , Animais , Pressão Sanguínea/fisiologia , Feminino , Quinase 4 de Receptor Acoplado a Proteína G/metabolismo , Hipertensão/fisiopatologia , Artérias Mesentéricas/fisiologia , Fosforilação/fisiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos Sprague-Dawley , Receptores de Dopamina D1/metabolismo , Vasodilatação/fisiologia
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