RESUMO
Steroid sex hormones produce physiological effects in reproductive and non-reproductive tissues, such as the brain. In the brain, sex hormones receptors are expressed in cortical, limbic and midbrain areas modulating memory, arousal, fear and motivation between other behaviors. One neurotransmitters system regulated by sex hormones is dopamine (DA), where during adulthood, sex hormones promote neurophysiological and behavioral effects on DA systems such as tuberoinfundibular (prolactin secretion), nigrostriatal (motor circuit regulation) and mesocorticolimbic (driving of motivated behavior). However, the long-term effects induced by neonatal exposure to sex hormones on DA release induced by D1 receptor activation and its expression in nucleus accumbens (NAcc) have not been fully studied. To answer this question, neurochemical, cellular and molecular techniques were used. The data show sex differences in NAcc DA extracellular levels induced by D1 receptor activation and protein content of this receptor in male and female control rats. In addition, neonatal programming with a single dose of TP increases the NAcc protein content of D1 receptors of adult male and female rats. Our results show new evidence related with sex differences that could explain the dependence to drug of abuse in males and females, which may be associated with increased reinforcing effects of drugs of abuse.
Assuntos
Dopamina/metabolismo , Ácido Glutâmico/metabolismo , Hormônios Esteroides Gonadais/farmacologia , Núcleo Accumbens/metabolismo , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Ácido gama-Aminobutírico/metabolismo , 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/farmacologia , Envelhecimento , Animais , Animais Recém-Nascidos , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/farmacologia , Estradiol/administração & dosagem , Estradiol/farmacologia , Feminino , Hormônios Esteroides Gonadais/administração & dosagem , Injeções , Masculino , Núcleo Accumbens/efeitos dos fármacos , Ratos Sprague-Dawley , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/efeitos dos fármacos , Fatores Sexuais , Propionato de Testosterona/administração & dosagem , Propionato de Testosterona/farmacologia , TempoRESUMO
Idiopathic pulmonary fibrosis (IPF) is the most common fatal interstitial lung disease, with limited therapeutic options. The abnormal and uncontrolled differentiation and proliferation of fibroblasts have been confirmed to play a crucial role in driving the pathogenesis of IPF. Therefore, effective and well-tolerated antifibrotic agents that interfere with fibroblasts would be an ideal treatment, but no such treatments are available. Remarkably, we found that dopamine (DA) receptor D1 (D1R) and DA receptor D2 (D2R) were both upregulated in myofibroblasts in lungs of IPF patients and a bleomycin (BLM)-induced mouse model. Then, we explored the safety and efficacy of DA, fenoldopam (FNP, a selective D1R agonist) and sumanirole (SMR, a selective D2R agonist) in reversing BLM-induced pulmonary fibrosis. Further data showed that DA receptor agonists exerted potent antifibrotic effects in BLM-induced pulmonary fibrosis by attenuating the differentiation and proliferation of fibroblasts. Detailed pathway analysis revealed that DA receptor agonists decreased the phosphorylation of Smad2 induced by TGF-ß1 in primary human lung fibroblasts (PHLFs) and IMR-90 cells. Overall, DA receptor agonists protected mice from BLM-induced pulmonary fibrosis and may be therapeutically beneficial for IPF patients in a clinical setting.
Assuntos
Antibióticos Antineoplásicos , Bleomicina , Agonistas de Dopamina/uso terapêutico , Fibroblastos/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Animais , Benzimidazóis/farmacologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Fenoldopam/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Elucidation of the mechanism of dopamine signaling to ERK that underlies plasticity in dopamine D1 receptor-expressing neurons leading to acquired cocaine preference is incomplete. NCS-Rapgef2 is a novel cAMP effector, expressed in neuronal and endocrine cells in adult mammals, that is required for D1 dopamine receptor-dependent ERK phosphorylation in mouse brain. In this report, we studied the effects of abrogating NCS-Rapgef2 expression on cAMP-dependent ERKâEgr-1/Zif268 signaling in cultured neuroendocrine cells; in D1 medium spiny neurons of NAc slices; and in either male or female mouse brain in a region-specific manner. NCS-Rapgef2 gene deletion in the NAc in adult mice, using adeno-associated virus-mediated expression of cre recombinase, eliminated cocaine-induced ERK phosphorylation and Egr-1/Zif268 upregulation in D1-medium spiny neurons and cocaine-induced behaviors, including locomotor sensitization and conditioned place preference. Abrogation of NCS-Rapgef2 gene expression in mPFC and BLA, by crossing mice bearing a floxed Rapgef2 allele with a cre mouse line driven by calcium/calmodulin-dependent kinase IIα promoter also eliminated cocaine-induced phospho-ERK activation and Egr-1/Zif268 induction, but without effect on the cocaine-induced behaviors. Our results indicate that NCS-Rapgef2 signaling to ERK in dopamine D1 receptor-expressing neurons in the NAc, but not in corticolimbic areas, contributes to cocaine-induced locomotor sensitization and conditioned place preference. Ablation of cocaine-dependent ERK activation by elimination of NCS-Rapgef2 occurred with no effect on phosphorylation of CREB in D1 dopaminoceptive neurons of NAc. This study reveals a new cAMP-dependent signaling pathway for cocaine-induced behavioral adaptations, mediated through NCS-Rapgef2/phospho-ERK activation, independently of PKA/CREB signaling.SIGNIFICANCE STATEMENT ERK phosphorylation in dopamine D1 receptor-expressing neurons exerts a pivotal role in psychostimulant-induced neuronal gene regulation and behavioral adaptation, including locomotor sensitization and drug preference in rodents. In this study, we examined the role of dopamine signaling through the D1 receptor via a novel pathway initiated through the cAMP-activated guanine nucleotide exchange factor NCS-Rapgef2 in mice. NCS-Rapgef2 in the NAc is required for activation of ERK and Egr-1/Zif268 in D1 dopaminoceptive neurons after acute cocaine administration, and subsequent enhanced locomotor response and drug seeking behavior after repeated cocaine administration. This novel component in dopamine signaling provides a potential new target for intervention in psychostimulant-shaped behaviors, and new understanding of how D1-medium spiny neurons encode the experience of psychomotor stimulant exposure.
Assuntos
Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Receptores de Dopamina D1/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , AMP Cíclico/fisiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína 1 de Resposta de Crescimento Precoce/efeitos dos fármacos , Feminino , Fatores de Troca do Nucleotídeo Guanina/efeitos dos fármacos , Fatores de Troca do Nucleotídeo Guanina/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Accumbens/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Estriado Ventral/efeitos dos fármacosRESUMO
BACKGROUND: We recently showed that striatal overexpression of brain derived neurotrophic factor (BDNF) by adeno-associated viral (AAV) vector exacerbated L-DOPA-induced dyskinesia (LID) in 6-OHDA-lesioned rats. An extensive sprouting of striatal serotonergic terminals accompanied this effect, accounting for the increased susceptibility to LID. OBJECTIVE: We set to investigate whether the BDNF effect was restricted to LID, or extended to dyskinesia induced by direct D1 receptor agonists. METHODS: Unilaterally 6-OHDA-lesioned rats received a striatal injection of an AAV vector to induce BDNF or GFP overexpression. Eight weeks later, animals received daily treatments with a low dose of SKF82958 (0.02âmg/kg s.c.) and development of dyskinesia was evaluated. At the end of the experiment, D1 and D3 receptors expression levels and D1 receptor-dependent signaling pathways were measured in the striatum. RESULTS: BDNF overexpression induced significant worsening of dyskinesia induced by SKF82958 compared to the GFP group and increased the expression of D3 receptor at striatal level, even in absence of pharmacological treatment; by contrast, D1 receptor levels were not affected. In BDNF-overexpressing striata, SKF82958 administration resulted in increased levels of D1-D3 receptors co-immunoprecipitation and increased phosphorylation levels of Thr34 DARPP-32 and ERK1/2. CONCLUSION: Here we provide evidence for a functional link between BDNF, D3 receptors and D1-D3 receptor close interaction in the augmented susceptibility to dyskinesia in 6-OHDA-lesioned rats. We suggest that D1-D3 receptors interaction may be instrumental in driving the molecular alterations underlying the appearance of dyskinesia; its disruption may be a therapeutic strategy for treating dyskinesia in PD patients.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corpo Estriado/metabolismo , Agonistas de Dopamina/farmacologia , Discinesia Induzida por Medicamentos/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D3/metabolismo , Animais , Benzazepinas/farmacologia , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Modelos Animais de Doenças , Suscetibilidade a Doenças/induzido quimicamente , Discinesia Induzida por Medicamentos/etiologia , Imunoprecipitação , Oxidopamina , Ratos , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D3/efeitos dos fármacosRESUMO
The biochemical and molecular substrates of methamphetamine (METH) use disorder remain to be elucidated. In rodents, increased METH intake is associated with increased expression of dopamine D1 receptors (D1R) in the dorsal striatum. The present study assessed potential effects of inhibiting striatal D1R activity on METH self-administration (SA) by rats. We microinjected Cre-activated adeno-associated viruses to deliver the inhibitory DREADD construct, hM4D (Gi) - mCherry, into neurons that expressed Cre-recombinase (D1-expressing neurons) in the dorsal striatum of male and female transgenic Long Evans rats (Drd1a-iCre#3). Two weeks later, we trained rats to self-administer METH. Once this behavior was acquired, intraperitoneal injections of clozapine-N-Oxide (CNO) or its vehicle (sterile water) were given to rats before each METH SA session to determine the effect of DREADD-mediated inhibition on METH intake. After the end of the experiments, histology was performed to confirm DREADD delivery into the dorsal striatum. There were no significant effects of the inhibitory DREADD on METH SA by male or female rats. Post-mortem histological assessment revealed DREADD expression in the dorsal striatum. Our results suggest that inhibition of D1R in the dorsal striatum does not suppress METH SA. It remains to be determined if activating D1R-expressing neurons might have differential behavioral effects. Future studies will also assess if impacting D1R activity in other brain regions might influence METH SA.
Assuntos
Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Inibição Psicológica , Metanfetamina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Corpo Estriado/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Feminino , Substância Cinzenta/efeitos dos fármacos , Substância Cinzenta/metabolismo , Masculino , Ratos Long-Evans , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D1/metabolismo , AutoadministraçãoRESUMO
BACKGROUND: Faster off-rate competitive enzyme inhibitors are generally more sensitive than slower off-rate ones to binding inhibition by enzyme substrates. We previously reported that the cyclic adenosine monophosphate concentration in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) may be higher than that in D2-MSNs. Consequently, compared with slower off-rate phosphodiesterase 10A inhibitors, faster off-rate ones comparably activated D2-MSNs but partially activated D1-MSNs. We further investigated the pharmacological profiles of phosphodiesterase 10A inhibitors with different off-rates. METHODS: Phosphodiesterase 10A inhibitors with slower (T-609) and faster (T-773) off-rates were used. D1- and D2-MSN activation was assessed by substance P and enkephalin mRNA induction, respectively, in rodents. Antipsychotic-like effects were evaluated by MK-801- and methamphetamine-induced hyperactivity and prepulse inhibition in rodents. Cognition was assessed by novel object recognition task and radial arm maze in rats. Prefrontal cortex activation was evaluated by c-Fos immunohistochemistry in rats. Gene translations in D1- and D2-MSNs were evaluated by translating ribosome affinity purification and RNA sequencing in mice. RESULTS: Compared with T-609, T-773 comparably activated D2-MSNs but partially activated D1-MSNs. Haloperidol (a D2 antagonist) and T-773, but not T-609, produced antipsychotic-like effects in all paradigms. T-773, but not T-609 or haloperidol, activated the prefrontal cortex and improved cognition. Overall gene translation patterns in D2-MSNs by all drugs and those in D1-MSNs by T-773 and T-609 were qualitatively similar. CONCLUSIONS: Differential pharmacological profiles among those drugs could be attributable to activation balance of D1- and D2-MSNs. The "balanced activation" of MSNs by faster off-rate phosphodiesterase 10A inhibitors may be favorable to treat schizophrenia.
Assuntos
Antipsicóticos/farmacologia , Corpo Estriado/efeitos dos fármacos , Neurônios GABAérgicos/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Nootrópicos/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases , Córtex Pré-Frontal/efeitos dos fármacos , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Reconhecimento Psicológico/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Ratos , Ratos Long-Evans , Ratos Sprague-DawleyRESUMO
Dopamine receptors are important G protein-coupled receptors (GPCRs) with therapeutic opportunities for treating Parkinson's Disease (PD) motor and cognitive deficits. Biased D1 dopamine ligands that differentially activate G protein over ß-arrestin recruitment pathways are valuable chemical tools for dissecting positive versus negative effects in drugs for PD. Here, we reveal an iterative approach toward modification of a D1-selective noncatechol scaffold critical for G protein-biased agonism. This approach provided enhanced understanding of the structural components critical for activity and signaling bias and led to the discovery of several novel compounds with useful pharmacological properties, including three highly GS-biased partial agonists. Administration of a potent, balanced, and brain-penetrant lead compound from this series results in robust antiparkinsonian effects in a rodent model of PD. This study suggests that the noncatechol ligands developed through this approach are valuable tools for probing D1 receptor signaling biology and biased agonism in models of neurologic disease.
Assuntos
Agonistas de Dopamina/farmacologia , Dopamina/metabolismo , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/efeitos dos fármacos , Animais , Antiparkinsonianos/farmacologia , Arrestinas/metabolismo , AMP Cíclico/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores Acoplados a Proteínas G/metabolismoRESUMO
CD8+ T regulatory/suppressor cells (Treg) affect peripheral tolerance and may be involved in autoimmune diseases as well as in cancer. In view of our previous data showing the ability of DA to affect adaptive immune responses, we investigated the dopaminergic phenotype of human CD8+ Treg as well as the ability of DA to affect their generation and activity. Results show that CD8+ T cells express both D1-like and D2-like dopaminergic receptors (DR), tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of DA, and vesicular monoamine transporter (VMAT) 2 and contain high levels of intracellular DA. Preferential upregulation of DR mRNA levels in the CD8+CD28- T cell compartment occurs during generation of CD8+ Treg, which is reduced by DA and by the D1-like DR agonist SKF-38393. DA and SKF-38393 also reduce the suppressive activity of CD8+ Treg on human peripheral blood mononuclear cells. Treg are crucial for tumor escape from the host immune system, thus the ability of DA to inhibits Treg function supports dopaminergic pathways as a druggable targets to develop original and innovative antitumor strategies.
Assuntos
Dopamina/farmacologia , Receptores de Dopamina D1/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Citometria de Fluxo , Humanos , Neuroimunomodulação/fisiologia , RNA Mensageiro/biossíntese , Receptores de Dopamina D1/análise , Receptores de Dopamina D1/biossíntese , Receptores de Dopamina D1/genética , Linfócitos T Reguladores/metabolismo , Tirosina 3-Mono-Oxigenase/biossíntese , Tirosina 3-Mono-Oxigenase/genética , Proteínas Vesiculares de Transporte de Monoamina/biossíntese , Proteínas Vesiculares de Transporte de Monoamina/genéticaRESUMO
BACKGROUND The aim of this study was to investigate the effects of electroacupuncture (EA) on expression of the D1 receptor (D1R), phosphorylation of extracellular-regulated protein kinase 1/2 (p-ERK1/2) and c-Fos in the insular cortex (IC) of ketamine-addicted rats. MATERIAL AND METHODS Sprague-Dawley rats were randomly divided into 7 groups: the normal group, the normal saline (NS) group, the ketamine (Ket) group, the U0126+Ket group, the SCH23390+Ket group, the Ket+acupoints EA (EA1) group, and the Ket+ non-acupoints EA (EA2) group. We used immunohistochemistry to detect the expression of D1R, p-ERK1/2, and c-Fos. We also used Nissl staining techniques to study the morphology of IC neurons. RESULTS Our study demonstrated that the ketamine group had sparsely distributed neurons, large intracellular vacuoles, nuclei shift, and unclear nucleolus. The number of Nissl-positive (neuronal) cells in the ketamine group were decreased than in the normal group. Our results also indicated that there was significantly lower expression of D1R, p-ERK1/2, and c-Fos in the IC of the U0126+Ket group, SCH23390+Ket group, and Ket+EA1 group as compared with that of the Ket group. CONCLUSIONS Ketamine addiction induces c-Fos overexpression in the IC by increasing the expression of D1R and p-ERK1/2. Acupoints EA downregulate D1R and p-ERK1/2 by reducing the overexpression of c-Fos.
Assuntos
Córtex Cerebral/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Receptores de Dopamina D1/efeitos dos fármacos , Pontos de Acupuntura , Animais , Butadienos/farmacologia , Eletroacupuntura/métodos , Genes fos/efeitos dos fármacos , Genes fos/fisiologia , Ketamina/farmacologia , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Neurônios/efeitos dos fármacos , Nitrilas/farmacologia , Fosforilação , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/metabolismoRESUMO
While the role of the ascending dopaminergic system in brain function and dysfunction has been a subject of extensive research, the role of the descending dopaminergic system in spinal cord function and dysfunction is just beginning to be understood. Adenosine plays a key role in the inhibitory control of the ascending dopaminergic system, largely dependent on functional complexes of specific subtypes of adenosine and dopamine receptors. Combining a selective destabilizing peptide strategy with a proximity ligation assay and patch-clamp electrophysiology in slices from male mouse lumbar spinal cord, the present study demonstrates the existence of adenosine A1-dopamine D1 receptor heteromers in the spinal motoneuron by which adenosine tonically inhibits D1 receptor-mediated signaling. A1-D1 receptor heteromers play a significant control of the motoneuron excitability, represent main targets for the excitatory effects of caffeine in the spinal cord and can constitute new targets for the pharmacological therapy after spinal cord injury, motor aging-associated disorders and restless legs syndrome.
Assuntos
Cafeína/farmacologia , Neurônios Motores/efeitos dos fármacos , Receptores de Dopamina D1/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Adenosina/farmacologia , Células Cultivadas , Dopamina/farmacologia , Humanos , Neurônios Eferentes/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacosRESUMO
In the search for efficacious pharmacotherapies to treat cocaine addiction much attention has been given to agents targeting dopamine D1 or D3 receptors because of the involvement of these receptors in drug-related behaviors. D1-like and D3 receptor partial agonists and antagonists have been shown to reduce drug reward, reinstatement of drug seeking and conditioned place preference in rodents and non-human primates. However, translation of these encouraging results to clinical settings has been limited due to a number of factors including toxicity, poor pharmacokinetic properties and extrapyramidal and sedative side effects. This review highlights the role of D1 and D3 receptors in drug reward and seeking, the discovery of D1-D3 heteromers and their potential as targets in the treatment of addiction.
Assuntos
Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Antagonistas de Dopamina/uso terapêutico , Dopamina/farmacologia , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Animais , Transtornos Relacionados ao Uso de Cocaína/psicologia , Comportamento de Procura de Droga , HumanosRESUMO
To investigate the difference in results according to the mode of levodopa administration and the effect of zonisamide (ZNS), we analyzed the mRNA expression of dopaminergic and non-dopaminergic receptors in the striatum of Parkinson model rats in relation to the development of levodopa-induced dyskinesia (LID). Unilateral Parkinson model rats were subdivided into 4 groups and treated as follows: no medication (group N), continuous levodopa infusion (group C), intermittent levodopa injection (group I), and intermittent levodopa and ZNS injection (group Z). Two weeks after the treatment, LID was observed in group I and Z, but less severe in group Z. The level of both D1 and D2 receptor mRNAs was elevated in groups I and Z, but only D2 receptor mRNA expression was elevated in group C. Adenosine A2A receptor mRNA showed increased expression only in group I. The level of endocannabinoid CB1 receptor mRNA was elevated in groups N, C, and I, but not in group Z. Intermittent injection of levodopa caused LID, in association with elevated expression of D1 and A2A receptors. ZNS ameliorated the development of LID and inhibited up-regulation of A2A and CB1 receptors. Modulation of these receptors may lead to therapeutic approaches for dyskinesia.
Assuntos
Anticonvulsivantes/farmacologia , Corpo Estriado/efeitos dos fármacos , Dopaminérgicos/farmacologia , Discinesia Induzida por Medicamentos/tratamento farmacológico , Expressão Gênica/efeitos dos fármacos , Isoxazóis/farmacologia , Levodopa/farmacologia , Doença de Parkinson/tratamento farmacológico , Receptor A2A de Adenosina/efeitos dos fármacos , Receptor CB1 de Canabinoide/efeitos dos fármacos , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Animais , Anticonvulsivantes/administração & dosagem , Dopaminérgicos/administração & dosagem , Dopaminérgicos/efeitos adversos , Discinesia Induzida por Medicamentos/metabolismo , Feminino , Isoxazóis/administração & dosagem , Levodopa/administração & dosagem , Levodopa/efeitos adversos , Ratos , Ratos Sprague-Dawley , ZonisamidaRESUMO
Nicotine is one of the most addictive substances known, targeting multiple memory systems, including the ventral and dorsal striatum. One form of neuroplasticity commonly associated with nicotine is dendrite remodeling. Nicotine-induced dendritic remodeling of ventral striatal medium spiny neurons (MSNs) is well-documented. Whether MSN dendrites in the dorsal striatum undergo a similar pattern of nicotine-induced structural remodeling is unknown. A morphometric analysis of Golgi-stained MSNs in rat revealed a natural asymmetry in dendritic morphology across the mediolateral axis, with larger, more complex MSNs found in the dorsolateral striatum (DLS). Chronic nicotine produced a lasting (at least 21day) expansion in the dendritic complexity of MSNs in the DLS, but not dorsomedial striatum (DMS). Given prior evidence that MSN subtypes can be distinguished based on dendritic morphology, MSNs were segregated into morphological subpopulations based on the number of primary dendrites. Analysis of these subpopulations revealed that DLS MSNs with more primary dendrites were selectively remodeled by chronic nicotine exposure and remodeling was specific to the distal-most portions of the dendritic arbor. Co-administration of the dopamine D1 receptor (D1R) antagonist SCH23390 completely reversed the selective effects of nicotine on DLS MSN dendrite morphology, supporting a causal role for dopamine signaling at D1 receptors in nicotine-induced dendrite restructuring. Considering the functional importance of the DLS in shaping and expressing habitual behavior, these data support a model in which nicotine induces persistent and selective changes in the circuit connectivity of the DLS that may promote and sustain addiction-related behavior.
Assuntos
Corpo Estriado/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Nicotina/farmacologia , Receptores de Dopamina D1/efeitos dos fármacos , Animais , Corpo Estriado/metabolismo , Masculino , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Ratos Sprague-Dawley , Receptores de Dopamina D1/metabolismoRESUMO
Dopamine (DA) modulates glutamatergic synaptic transmission and its plasticity in the striatum; however it is not well known how DA modulates long-term plasticity of striatal GABAergic inhibitory synapses. This work focused on the analysis of both dopaminergic modulation of inhibitory synapses and the synaptic plasticity established between GABAergic afferents to medium spiny neurons (MSNs). Our results showed that low and high DA concentrations mainly reduced the amplitude of inhibitory synaptic response; however detailed analysis of the D1 and D2 participation in this modulation displayed a wide variability in synaptic response. Analyzing DA participation in striatal GABAergic plasticity we observed that high frequency stimulation (HFS) of GABAergic interneurons in the presence of DA at a low concentration (200 nM) favored the expression of inhibitory striatal LTD, whereas higher concentration of DA (20 µM) primarily induced LTP. Interestingly, the plasticity induced in an animal model of striatal degeneration mimicked that induced in the presence of DA at a high concentration, which was not abolished with D2 antagonist but was prevented by PKA blocker.
Assuntos
Dopamina/fisiologia , Potenciação de Longa Duração/fisiologia , Neostriado/fisiologia , Plasticidade Neuronal/fisiologia , Transmissão Sináptica/fisiologia , Animais , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Estimulação Elétrica , Fenômenos Eletrofisiológicos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios Aferentes/fisiologia , Inibidores de Proteínas Quinases , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/fisiologia , Sinapses/fisiologia , Ácido gama-Aminobutírico/fisiologiaRESUMO
Dopamine replacement therapy in Parkinson's disease is associated with several unwanted effects, of which dyskinesia is the most disabling. The development of new therapeutic interventions to reduce the impact of dyskinesia in Parkinson's disease is therefore a priority need. This review summarizes the key molecular mechanisms that underlie dyskinesia. The role of dopamine receptors and their associated signaling mechanisms including dopamine-cAMP-regulated neuronal phosphoprotein, extracellular signal-regulated kinase, mammalian target of rapamycin, mitogen and stress-activated kinase-1 and Histone H3 are summarized, along with an evaluation of the role of cannabinoid and nicotinic acetylcholine receptors. The role of synaptic plasticity and animal behavioral results on dyskinesia are also evaluated. The most recent therapeutic advances to treat Parkinson's disease are discussed, with emphasis on the possibilities and limitations of non-pharmacological interventions such as physical activity, deep brain stimulation, transcranial magnetic field stimulation and cell replacement therapy. The review suggests new prospects for the management of Parkinson's disease-associated motor symptoms, especially the development of dyskinesia. This review aims at summarizing the key molecular mechanisms underlying dyskinesia and the most recent therapeutic advances to treat Parkinson's disease with emphasis on non-pharmacological interventions such as physical activity, deep brain stimulation (DBS), transcranial magnetic field stimulation (TMS) and cell replacement therapy. These new interventions are discussed from both the experimental and clinical point of view, describing their current strength and limitations.
Assuntos
Discinesias/etiologia , Discinesias/terapia , Doença de Parkinson/complicações , Doença de Parkinson/terapia , Animais , Canabinoides/farmacologia , Transplante de Células , Cromatina/efeitos dos fármacos , Estimulação Encefálica Profunda , Dopaminérgicos/uso terapêutico , Fosfoproteína 32 Regulada por cAMP e Dopamina/fisiologia , Discinesias/fisiopatologia , Histonas/metabolismo , Humanos , Levodopa/farmacologia , Levodopa/uso terapêutico , Atividade Motora/fisiologia , Doença de Parkinson/fisiopatologia , Fosforilação , Desempenho Psicomotor/fisiologia , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estimulação Magnética TranscranianaRESUMO
AIMS: Chronic administration of cocaine attenuates delta opioid receptor (DOPR) signaling in the striatum and the desensitization is mediated by the indirect actions of cocaine on dopamine D1 receptors (D1R). In addition, DOPR and D1R co-exist in some rat striatal neurons. In the present study, we examined the underlying mechanism of DOPR desensitization by D1R activation. MAIN METHODS: NG 108-15 cells stably expressing HA-rat D1 receptor (HA-D1R) and Chinese hamster ovary (CHO) cells stably expressing both FLAG-mouse DOPR (FLAG-DOPR) and HA-D1R were used as the cell models. Receptor binding, [(35)S]GTPγS binding, receptor phosphorylation and western blot were conducted to examine DOPR affinity, expression, internalization, downregulation, desensitization, phosphorylation and phosphorylated ERK1/2. KEY FINDINGS: Pretreatment with either the DOPR agonist DPDPE or the D1R agonist SKF-82958 for 30min attenuated DPDPE-stimulated [(35)S]GTPγS binding to G proteins, demonstrating homologous and heterologous desensitization of the DOPR, respectively. SKF-82958 pretreatment did not affect the level of DOPR or affinity of DOPR antagonist or agonists, nor did it induce phosphorylation, internalization or down-regulation of the DOPR in the CHO-FLAG-DOPR/HA-D1R cells. Pretreatment of cells with inhibitors of PKA, MEK1 and PI3K, but not PKC, attenuated SKF-82958-induced desensitization of the DOPR. The D1R agonist SKF-82958 enhanced phosphorylation of ERK1/2, and pretreatment with inhibitors of MEK1 and PI3K, but not PKA and PKC, reduced the effect. These results indicate that activation of ERK1/2 and/or PKA, but not PKC, is involved in D1 receptor-induced heterologous desensitization of the DOPR. SIGNIFICANCE: This study provides possible mechanisms underlying D1R activation-induced DOPR desensitization.
Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Receptores de Dopamina D1/fisiologia , Receptores Opioides delta/fisiologia , Animais , Benzamidas/farmacologia , Benzazepinas/farmacologia , Western Blotting , Células CHO , Linhagem Celular , Cocaína/farmacologia , Cricetinae , Proteínas Quinases Dependentes de AMP Cíclico/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Fosforilação , Piperazinas/farmacologia , Ratos , Receptores de Dopamina D1/efeitos dos fármacos , Receptores Opioides delta/efeitos dos fármacosRESUMO
BACKGROUND: Huntington's disease (HD) is a neurological disorder caused by mutations in the huntingtin (HTT) gene, the product of which leads to selective and progressive neuronal cell death in the striatum and cortex. Transcriptional dysregulation has emerged as a core pathologic feature in the CNS of human and animal models of HD. It is still unclear whether perturbations in gene expression are a consequence of the disease or importantly, contribute to the pathogenesis of HD. OBJECTIVE: To examine if transcriptional dysregulation can be ameliorated with antisense oligonucleotides that reduce levels of mutant Htt and provide therapeutic benefit in the YAC128 mouse model of HD. METHODS: Quantitative real-time PCR analysis was used to evaluate dysregulation of a subset of striatal genes in the YAC128 mouse model. Transcripts were then evaluated following ICV delivery of antisense oligonucleotides (ASO). Rota rod and Porsolt swim tests were used to evaluate phenotypic deficits in these mice following ASO treatment. RESULTS: Transcriptional dysregulation was detected in the YAC128 mouse model and appears to progress with age. ICV delivery of ASOs directed against mutant Htt resulted in reduction in mutant Htt levels and amelioration in behavioral deficits in the YAC128 mouse model. These improvements were correlated with improvements in the levels of several dysregulated striatal transcripts. CONCLUSIONS: The role of transcriptional dysregulation in the pathogenesis of Huntington's disease is not well understood, however, a wealth of evidence now strongly suggests that changes in transcriptional signatures are a prominent feature in the brains of both HD patients and animal models of the disease. Our study is the first to show that a therapeutic agent capable of improving an HD disease phenotype is concomitantly correlated with normalization of a subset of dysregulated striatal transcripts. Our data suggests that correction of these disease-altered transcripts may underlie, at least in part, the therapeutic efficacy shown associated with ASO-mediated correction of HD phenotypes and may provide a novel set of early biomarkers for evaluating future therapeutic concepts for HD.
Assuntos
Comportamento Animal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Doença de Huntington/genética , Destreza Motora/efeitos dos fármacos , Neostriado/efeitos dos fármacos , Proteínas do Tecido Nervoso/efeitos dos fármacos , Proteínas Nucleares/efeitos dos fármacos , Oligonucleotídeos Antissenso/farmacologia , Animais , Modelos Animais de Doenças , Fosfoproteína 32 Regulada por cAMP e Dopamina/efeitos dos fármacos , Fosfoproteína 32 Regulada por cAMP e Dopamina/genética , Encefalinas/efeitos dos fármacos , Encefalinas/genética , Proteína Huntingtina , Hipoxantina Fosforribosiltransferase/efeitos dos fármacos , Hipoxantina Fosforribosiltransferase/genética , Infusões Intraventriculares , Camundongos , Neostriado/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptor CB1 de Canabinoide/efeitos dos fármacos , Receptor CB1 de Canabinoide/genética , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/genéticaRESUMO
Cocaine abuse leads to adaptations in brain reward circuits, where dopaminergic neurotransmission is a fundamental component. We hypothesized that chronic cocaine self-administration could influence dopamine D1 and D2 receptor activation of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) and cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation. Male Sprague Dawley rats were exposed to cocaine self-administration for 6-11 weeks. Brains from sham controls and cocaine rats were extracted 1 day after the last session, and slices obtained from the striatum and nucleus accumbens (NAc) were incubated in vitro with or without the D1R agonist SKF38393 or the D2R agonist quinpirole. We found that cocaine self-administration led to a reduction in the capacity of D1R to activate ERK1/2 phosphorylation as compared with control rats. Cocaine self-administration also reduced D1R agonist-induced CREB phosphorylation in striatal slices, suggesting a downregulation of D1R signaling. D2R-induced ERK1/2 phosphorylation appeared blunted in striatal slices from cocaine rats. In contrast, surprisingly, cocaine self-administration strongly potentiated D2R agonist-induced CREB phosphorylation selectively in the NAc portion of the slices. Altered agonist-induced signaling was independent of total ERK1/2 and CREB expression. Our finding that selected cellular D2R responses to CREB were strengthened by cocaine self-administration could be relevant to understand how dopaminergic receptors participate in cocaine-induced behaviors.
Assuntos
Cocaína/farmacologia , Corpo Estriado/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Animais , Cocaína/administração & dosagem , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Inibidores da Captação de Dopamina/administração & dosagem , Masculino , Núcleo Accumbens/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacosRESUMO
Markers of dopamine D(1) receptor activation were determined to elucidate intracellular mechanisms associated with the combined effects of caffeine and 3,4 methylenedioxymethamphetamine (MDMA), reported previously to produce increased toxicity, when compared with either drug alone. Caffeine (10 mg/kg) and MDMA (15 mg/kg) were administered to male Sprague Dawley rats alone and in combination. One hour after drug administration, core body temperature and phosphorylation of the dopamine D(1) -related intracellular markers, cAMP response element binding protein (CREB), the dopamine and c-AMP-regulated phosphoprotein of 32 kDa (DARPP-32) and expression of the immediate early gene and cellular activation marker c-fos were determined in the hypothalamus. Co-administration of caffeine with MDMA increased core body temperature when compared with MDMA or caffeine treatment alone. Pre-treatment with the dopamine D(1) receptor antagonist SCH 23390 (1 mg/kg, i.p.), 30 min. prior to caffeine and MDMA administration, produced a hypothermic response to MDMA that was unaffected by caffeine. Co-administration of caffeine with MDMA increased p-CREB, p-DARPP-32 and c-fos expression when compared with either treatment alone. Pre-treatment with SCH-23390 attenuated the changes in p-CREB, p-DARPP and c-fos. The results show an enhanced intracellular response when caffeine is combined with MDMA but not with either agent alone suggestive of synergistic intracellular actions convergent on a dopamine D(1) receptor signalling pathway. A dopamine-related synergy associated with the combined administration of caffeine and MDMA may have important use and safety implications for recreational drug users.
Assuntos
Cafeína/farmacologia , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Receptores de Dopamina D1/efeitos dos fármacos , Animais , Temperatura Corporal/efeitos dos fármacos , Cafeína/administração & dosagem , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Fosfoproteína 32 Regulada por cAMP e Dopamina/genética , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Sinergismo Farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , N-Metil-3,4-Metilenodioxianfetamina/administração & dosagem , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Renal dopamine D(1)-like receptors (D(1)Rs) and angiotensin type 2 receptors (AT(2)Rs) are important natriuretic receptors counterbalancing angiotensin type 1 receptor-mediated tubular sodium reabsorption. Here we explore the mechanisms of D(1)R and AT(2)R interactions in natriuresis. In uninephrectomized, sodium-loaded Sprague-Dawley rats, direct renal interstitial infusion of the highly selective D(1)R agonist fenoldopam induced a natriuretic response that was abolished by the AT(2)R-specific antagonist PD-123319 or by microtubule polymerization inhibitor nocodazole but not by actin polymerization inhibitor cytochalasin D. By confocal microscopy and immunoelectron microscopy, fenoldopam translocated AT(2)Rs from intracellular sites to the apical plasma membranes of renal proximal tubule cells, and this translocation was abolished by nocodazole. Because D(1)R activation induces natriuresis via an adenylyl cyclase/cAMP signaling pathway, we explored whether this pathway is responsible for AT(2)R recruitment and AT(2)R-mediated natriuresis. Renal interstitial coinfusion of the adenylyl cyclase activator forskolin and 3-isobutly-1-methylxanthine induced natriuresis that was abolished either by PD-123319 or nocodazole but was unaffected by specific the D(1)R antagonist SCH-23390. Coadministration of forskolin and 3-isobutly-1-methylxanthine also translocated AT(2)Rs to the apical plasma membranes of renal proximal tubule cells; this translocation was abolished by nocodazole but was unaffected by SCH-23390. The results demonstrate that D(1)R-induced natriuresis requires AT(2)R recruitment to the apical plasma membranes of renal proximal tubule cells in a microtubule-dependent manner involving an adenylyl cyclase/cAMP signaling pathway. These studies provide novel insights regarding the mechanisms whereby renal D(1)Rs and AT(2)Rs act in concert to promote sodium excretion in vivo.