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1.
Chin J Physiol ; 64(1): 1-15, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33642339

RESUMO

Dopamine (DA) is important for the performance of operant behavior as revealed by psychopharmacological studies that manipulate the activity of DA subtype receptors. However, the effects of SKF83959, an atypical DA D1 receptor agonist, on operant behavior and the underlying pharmacological mechanisms remain unclear. The present study sought to determine whether blockade of DA D1- and D2-subtyped receptors would reverse the operant behavior altered by SKF83959. Male rats were trained to respond on either a fixed-interval 30 s (FI30) schedule or a differential reinforcement of low-rate response 10 s (DRL10) schedule, two timing-relevant tasks but with distinct reinforcement contingencies. Pharmacological evaluation was conducted with injection of a selective D1 (or D2) receptor antagonist alone or in combined with SKF83959 (1.0 mg/kg) following a stable baseline of behavioral performance. The results showed that SKF83959 treatment alone significantly disrupted the performance of FI30 and DRL10 behaviors mainly by showing the decreases of the response-related measures, and the distinct profiles of the behavior altered by the drug were manifested by the qualitative analysis of inter-response time data on both tasks. The effects of SKF83959 were not significantly affected/reversed by the pretreatment of either SCH23390 or eticlopride injected at the doses of 0.02 and 0.06 mg/kg; however, a subtle reversal effect was observed in the treatment of low-dose eticlopride. Despite that these results confirm the FI30 and DRL10 behaviors changed by SKF83959, the absence of pharmacological reversal effect by DA receptor antagonist suggests that either D1- or D2-subtyped receptors may not play a critical role in the alteration of timing-relevant operant behavior produced by SKF83959.


Assuntos
Agonistas de Dopamina , Receptores de Dopamina D1 , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/análogos & derivados , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Comportamento Animal , Agonistas de Dopamina/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley
2.
Eur J Med Chem ; 214: 113190, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33548637

RESUMO

Even today, the role of the histamine H2 receptor (H2R) in the central nervous system (CNS) is widely unknown. In previous research, many dimeric, high-affinity and subtype-selective carbamoylguanidine-type ligands such as UR-NK22 (5, pKi = 8.07) were reported as H2R agonists. However, their applicability to the study of the H2R in the CNS is compromised by their molecular and pharmacokinetic properties, such as high molecular weight and, consequently, a limited bioavailability. To address the need for more drug-like H2R agonists with high affinity, we synthesized a series of monomeric (thio)carbamoylguanidine-type ligands containing various spacers and side-chain moieties. This structural simplification resulted in potent (partial) agonists (guinea pig right atrium, [35S]GTPγS and ß-arrestin2 recruitment assays) with human (h) H2R affinities in the one-digit nanomolar range (pKi (139, UR-KAT523): 8.35; pKi (157, UR-MB-69): 8.69). Most of the compounds presented here exhibited an excellent selectivity profile towards the hH2R, e.g. 157 being at least 3800-fold selective within the histamine receptor family. The structural similarities of our monomeric ligands to pramipexole (6), a dopamine receptor agonist, suggested an investigation of the binding behavior at those receptors. The target compounds were (partial) agonists with moderate affinity at the hD2longR and agonists with high affinity at the hD3R (e.g. pKi (139, UR-KAT523): 7.80; pKi (157, UR-MB-69): 8.06). In summary, we developed a series of novel, more drug-like H2R and D3R agonists for the application in recombinant systems in which either the H2R or the D3R is solely expressed. Furthermore, our ligands are promising lead compounds in the development of selective H2R agonists for future in vivo studies or experiments utilizing primary tissue to unravel the role and function of the H2R in the CNS.


Assuntos
Agonistas de Dopamina/farmacologia , Guanidinas/farmacologia , Receptores de Dopamina D3/agonistas , Receptores Histamínicos H2/metabolismo , Animais , Células Cultivadas , Agonistas de Dopamina/síntese química , Agonistas de Dopamina/química , Relação Dose-Resposta a Droga , Guanidinas/síntese química , Guanidinas/química , Cobaias , Células HEK293 , Humanos , Ligantes , Estrutura Molecular , Relação Estrutura-Atividade
3.
Eur J Med Chem ; 212: 113151, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33450620

RESUMO

Employing two different alkyne-modified dopamine agonists to construct bivalent compounds via click chemistry resulted in the identification of a bivalent ligand (11c) for dopamine D2 receptor homodimer, which, compared to its parent monomeric alkyne, showed a 16-fold higher binding affinity for the dopamine D2 receptor and a 5-fold higher potency in a cAMP assay in HEK 293T cells stably expressing D2R. Molecular modeling revealed that 11c can indeed bridge the orthosteric binding sites of a D2R homodimer in a relaxed conformation via the TM5-TM6 interface and allows to largely rationalize the results of the receptor assays.


Assuntos
Agonistas de Dopamina/farmacologia , Descoberta de Drogas , Receptores de Dopamina D2/agonistas , Células Cultivadas , Agonistas de Dopamina/síntese química , Agonistas de Dopamina/química , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
4.
Psychopharmacology (Berl) ; 238(4): 979-990, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33404734

RESUMO

INTRODUCTION: Cognitive function is closely linked to functional outcomes in psychiatric disorders such as schizophrenia, however developing effective treatments for cognitive dysfunction have proven elusive. Potential reasons for this may include the complexity of diseases, the absence of appropriate and translatable animal tests of cognitive dysfunction, and the reproducibility of findings. Attention is a key component of cognitive function traditionally assessed in the clinic using a variant of the continuous performance test (CPT). The 5-choice (5C)-CPT was developed as a translational cross-species version of this task. Given the association between glutamatergic abnormalities and cognitive dysfunction in schizophrenia, we hypothesized that the NMDA receptor antagonist MK-801 would impair 5C-CPT in rats across different laboratories, and determined whether the dopamine D1 receptor agonist SKF38393 or the nonspecific nicotinic agonist nicotine would remediate such deficits. METHOD: Rats were trained in the 5C-CPT at Beacon Discovery and UCSD. These rats were then treated with MK-801, agonist treatment, and combinations of the two. RESULTS: MK-801 produced 5C-CPT deficits in the same domains of rats across sites at similar doses. Neither nicotine nor SKF38393 treatment alone improved performance. Importantly, SKF38393, but not nicotine, remediated the MK-801-induced deficits. CONCLUSION: Convergent observation of MK-801-induced deficits in 5C-CPT was seen across laboratories, resulting in deficits consistent with those seen in people with schizophrenia. Treatment with SKF38393 but not nicotine reversed these deficits. More work is needed, but the 5C-CPT is a reliable method for detecting NMDA receptor disruption-induced deficits in attention.


Assuntos
Atenção/efeitos dos fármacos , Cognição/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Agonistas Nicotínicos/farmacologia , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Agonistas de Dopamina/farmacologia , Laboratórios , Masculino , Nicotina/farmacologia , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Esquizofrenia/fisiopatologia
5.
Psychopharmacology (Berl) ; 238(4): 991-1004, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33410986

RESUMO

RATIONALE: Optimal decision-making necessitates evaluation of multiple rewards that are each offset by distinct costs, such as high effort requirement or high risk of failure. The neurotransmitter dopamine is fundamental toward these cost-benefit analyses, and D1-like and D2-like dopamine receptors differently modulate the reward-discounting effects of both effort and risk. However, measuring the role of dopamine in regulating decision-making between options associated with distinct costs exceeds the scope of traditional rodent economic decision-making paradigms. OBJECTIVES: We developed the effort vs probability economic conflict task (EvP) to model multimodal economic decision-making in rats. This task measures choice between two rewards of uniform magnitude associated with either a high effort requirement or risk of reward omission. We then tested the modulatory effects of systemic cocaine and D1/D2 blockade or activation on the preference between high-effort and high-risk alternatives. METHODS: In the EvP, two reinforcers of equal magnitude are associated with either (1) an effort requirement that increases throughout the session (1, 5, 10, and 20 lever presses), or (2) a low probability of reward receipt (25% of probabilistic choices). Critically, the reinforcer for each choice is comparable (one pellet), which eliminates the influence of magnitude discrimination on the decision-making process. After establishing the task, the dopamine transporter blocker cocaine and D1/D2 antagonists and agonists were administered prior to EvP performance. RESULTS: Preference shifted away from either effortful or probabilistic choice when either option became more costly, and this preference was highly variable between subjects and stable over time. Cocaine, D1 activation, and D2 blockade produced limited, dose-dependent shifts in choice preference contingent on high or low effort conditions. In contrast, D2 activation across multiple doses evoked a robust shift from effortful to risky choice that was evident even when clearly disadvantageous. CONCLUSIONS: The EvP clearly demonstrates that rats can evaluate distinct effortful or risky costs associated with rewards of comparable magnitude, and shift preference away from either option with increasing cost. This preference is more tightly linked to D2 than D1 receptor manipulation, suggesting D2-like receptors as a possible therapeutic target for maladaptive biases toward risk-taking over effort.


Assuntos
Tomada de Decisões/fisiologia , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Recompensa , Animais , Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Masculino , Probabilidade , Ratos , Ratos Long-Evans
6.
Psychopharmacology (Berl) ; 238(4): 1069-1085, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33432392

RESUMO

RATIONALE: There is an urgent need for novel drugs for treating cognitive deficits that are defining features of schizophrenia. The individual d- and l-enantiomers of the tetrahydroprotoberberine (THPB) d,l-govadine have been proposed for the treatment of cognitive deficiencies and positive symptoms of schizophrenia, respectively. OBJECTIVES: We examined the effects of d-, l-, or d,l-govadine on two distinct forms of cognitive flexibility perturbed in schizophrenia and compared them to those induced by a selective D1 receptor agonist and D2 receptor antagonist. METHODS: Male rats received d-, l-, or d,l-govadine (0.3, 0.5, and 1.0 mg/kg), D1 agonist SKF81297(0.1, 0.3, and 1.0 mg/kg), or D2 antagonist haloperidol (0.1-0.2 mg/kg). Experiment 1 used a strategy set-shifting task (between-subjects). In experiment 2, well-trained rats were tested on a probabilistic reversal task (within-subjects). RESULTS: d-Govadine improved set-shifting across all doses, whereas higher doses of l-govadine impaired set-shifting. SKF81297 reduced perseverative errors at the lowest dose. Low/high doses of haloperidol increased/decreased set-shifting errors, the latter "improvement" attributable to impaired retrieval of a previous acquired rule. Probabilistic reversal performance was less affected by these drugs, but d-govadine reduced errors during the first reversal, whereas l-govadine impaired initial discrimination learning. d,l-Govadine had no reliable cognitive effects but caused psychomotor slowing like l-govadine and haloperidol. CONCLUSIONS: These findings further highlight differences between two enantiomers of d,l-govadine that may reflect differential modulation of D1 and D2 receptors. These preclinical findings give further impetus to formal clinical evaluation of d-govadine as a treatment for cognitive deficiencies related to schizophrenia.


Assuntos
Alcaloides de Berberina/farmacologia , Cognição/efeitos dos fármacos , Dopaminérgicos/farmacologia , Animais , Benzazepinas/farmacologia , Alcaloides de Berberina/química , Aprendizagem por Discriminação/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Haloperidol/farmacologia , Aprendizagem/efeitos dos fármacos , Masculino , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Long-Evans , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Psicologia do Esquizofrênico , Estereoisomerismo
7.
Life Sci ; 261: 118349, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32853654

RESUMO

AIMS: Cerebral ischemic stroke leads to mitochondrial alterations which are key factors for initiation of various cascades resulting in neuronal damage. Dopamine D2 receptor (D2R) agonist, Sumanirole (SUM) has been reported to possess anti-inflammatory, anti-oxidant, and anti-apoptotic properties. However, the role of SUM in ischemic stroke (IS) has not been studied yet. The aim of the present study was to investigate the neuroprotective efficiency of SUM against ischemic injury and its possible effect on mitochondrial restorative mechanisms. MATERIALS AND METHODS: Transient middle cerebral artery occlusion (tMCAO) was performed in Wistar rats for 90 min occlusion and 22.5 h reperfusion to mimic ischemic stroke. Post- treatment with Sumanirole (0.1 mg/kg and 1 mg/kg; s.c.) was done at 1 h, 6 h, 12 hand 18 h after surgery. In addition, neurobehavioral analysis, mitochondrial reactive oxygen species and mitochondrial membrane potential by flow cytometric analysis, mitochondrial complexes analysis, infarct size evaluation and histological analysis were performed. KEY FINDINGS: Sumanirole restored behavioural alterations as measured by rotarod performance, grip strength, adhesive tape removal analysis and neurological deficits. In addition, it also refurbished mitochondrial dysfunction by decreasing mitochondrial reactive oxygen species production, elevating mitochondrial membrane potential and by protecting the activity of mitochondrial complexes along with histological alterations. As a result, infarct sizes were markedly reduced in tMCAO surgery animals. SIGNIFICANCE: Findings from the study provide evidence that SUM promotes neuronal survival in in vivo model of IS through mitochondria mediated neuroprotective features.


Assuntos
Benzimidazóis/farmacologia , Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Benzimidazóis/administração & dosagem , Isquemia Encefálica/patologia , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Infarto da Artéria Cerebral Média , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Fármacos Neuroprotetores/administração & dosagem , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Acidente Vascular Cerebral/patologia , Fatores de Tempo
8.
Clin Exp Hypertens ; 42(7): 675-679, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-32478610

RESUMO

BACKGROUND: Bromocriptine, a dopamine agonist, used for the treatment of hyperprolactinemia, type 2 diabetes, ovarian hyper-stimulation syndrome, has also effects on the cardiac remodeling process, but the mechanism of action is unknown. The aim of this work was to determinate the effect during hypertrophic process through molecular mechanisms that include prolactin receptor (Prlr) and receptor of dopamine 2 (D2 r) expression. METHODS: We used a model of cardiac hypertrophy induced by an aortocaval fistula (ACF) surgery in rats. Protein concentrations of D2 r and Prlr were determined by western blotting. The treatment consisted in water (control), captopril (50 mg/kg/day), bromocriptine (3 mg/kg/day), and ACF group (n = 6 per group). RESULTS: Our results showed that bromocriptine treatment decreases the hypertrophy index. Treatment with bromocriptine increases the protein expression of Prlr and D2 r in the cardiac tissue of rats with cardiac hypertrophy. CONCLUSIONS: We concluded that bromocriptine has a protective effect on cardiac hypertrophy, and due to this effect, it may modulate the expression of Prlr and D2 r, which are involved in the development of cardiac hypertrophy.


Assuntos
Bromocriptina/farmacologia , Cardiomegalia/metabolismo , Agonistas de Dopamina/farmacologia , Miocárdio/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores da Prolactina/metabolismo , Animais , Bromocriptina/metabolismo , Bromocriptina/uso terapêutico , Cardiomegalia/prevenção & controle , Masculino , Ratos , Receptores de Dopamina D2/agonistas
9.
J Neurosci ; 40(27): 5273-5282, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32457071

RESUMO

The mesolimbic dopaminergic system exerts a crucial influence on incentive processing. However, the contribution of dopamine in dynamic, ecological situations where reward rates vary, and decisions evolve over time, remains unclear. In such circumstances, current (foreground) reward accrual needs to be compared continuously with potential rewards that could be obtained by traveling elsewhere (background reward rate), to determine the opportunity cost of staying versus leaving. We hypothesized that dopamine specifically modulates the influence of background, but not foreground, reward information when making a dynamic comparison of these variables for optimal behavior. On a novel foraging task based on an ecological account of animal behavior (marginal value theorem), human participants of either sex decided when to leave locations in situations where foreground rewards depleted at different rates, either in rich or poor environments with high or low background reward rates. In line with theoretical accounts, people's decisions to move from current locations were independently modulated by changes in both foreground and background reward rates. Pharmacological manipulation of dopamine D2 receptor activity using the agonist cabergoline significantly affected decisions to move on, specifically modulating the effect of background reward rates. In particular, when on cabergoline, people left patches in poor environments much earlier. These results demonstrate a role of dopamine in signaling the opportunity cost of rewards, not value per se. Using this ecologically derived framework, we uncover a specific mechanism by which D2 dopamine receptor activity modulates decision-making when foreground and background reward rates are dynamically compared.SIGNIFICANCE STATEMENT Many decisions, across economic, political, and social spheres, involve choices to "leave". Such decisions depend on a continuous comparison of a current location's value, with that of other locations you could move on to. However, how the brain makes such decisions is poorly understood. Here, we developed a computerized task, based around theories of how animals make decisions to move on when foraging for food. Healthy human participants had to decide when to leave collecting financial rewards in a location, and travel to collect rewards elsewhere. Using a pharmacological manipulation, we show that the activity of dopamine in the brain modulates decisions to move on, with people valuing other locations differently depending on their dopaminergic state.


Assuntos
Tomada de Decisões/fisiologia , Dopamina/fisiologia , Comportamento Alimentar/fisiologia , Adulto , Cabergolina/farmacologia , Tomada de Decisões/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Método Duplo-Cego , Meio Ambiente , Comportamento Alimentar/efeitos dos fármacos , Feminino , Humanos , Masculino , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/fisiologia , Recompensa , Adulto Jovem
10.
J Endocrinol ; 244(2): 415-429, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32395971

RESUMO

Among all the hormone-secreting pituitary tumours, prolactinomas are the most frequently found in the clinic. Since dopamine is the primary inhibitor of lactotroph function, dopamine agonists represent the first-line therapy. However, a subset of patients exhibits resistance to these drugs, and therefore, alternative treatments are desired. As activins inhibit prolactin gene expression through the inhibition of Pit-1 involving the p38MAPK pathway, in the present work, we studied the local activin system as an alternative inhibitory system for lactotroph hyperplasia treatment. We used two different mouse models of prolactinoma: transgenic mice with overexpression of the human chorionic gonadotropin ß-subunit (hCGß) and mice lacking dopamine receptor type 2. In both models, females, but not males, develop lactotroph hyperplasia from the fourth month of life. We found reduced expression of pituitary activin subunits and activin receptors in hyperplastic pituitaries from both models compared with wild-type counterparts. Consequently, hyperplastic pituitaries presented a reduced activin-inhibitory action on prolactin secretion. Additionally, while female wild-type lactotrophs presented high levels of phospho-p38MAPK, it was lost in prolactinomas, concomitant with decreased activin expression, increased Pit-1 expression and tumour development. In contrast, male pituitaries express higher mRNA levels of activin subunits ßA and ßB, which would suggest a stronger activin inhibitory function on lactotrophs, protecting this sex from tumour development, despite genotype. The present results highlight the importance of the activin inhibitory action on lactotroph function and place the local activin system as a new target for the treatment of dopamine agonist-resistant prolactinomas.


Assuntos
Ativinas/metabolismo , Lactotrofos/metabolismo , Neoplasias Hipofisárias/genética , Prolactinoma/genética , Animais , Agonistas de Dopamina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Genótipo , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Camundongos Transgênicos , Hipófise/metabolismo , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/tratamento farmacológico , Prolactinoma/complicações , Prolactinoma/tratamento farmacológico , RNA Mensageiro/metabolismo , Fatores Sexuais , Fator de Transcrição Pit-1/metabolismo
11.
Am J Physiol Endocrinol Metab ; 319(1): E133-E145, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32459527

RESUMO

Bromocriptine mesylate treatment was examined in dogs fed a high fat diet (HFD) for 8 wk. After 4 wk on HFD, daily bromocriptine (Bromo; n = 6) or vehicle (CTR; n = 5) injections were administered. Oral glucose tolerance tests were performed before beginning HFD (OGTT1), 4 wk after HFD began (Bromo only), and after 7.5 wk on HFD (OGTT3). After 8 wk on HFD, clamp studies were performed, with infusion of somatostatin and intraportal replacement of insulin (4× basal) and glucagon (basal). From 0 to 90 min (P1), glucose was infused via peripheral vein to double the hepatic glucose load; and from 90 to 180 min (P2), glucose was infused via the hepatic portal vein at 4 mg·kg-1·min-1, with the HGL maintained at 2× basal. Bromo decreased the OGTT glucose ΔAUC0-30 and ΔAUC0-120 by 62 and 27%, respectively, P < 0.05 for both) without significantly altering the insulin response. Bromo dogs exhibited enhanced net hepatic glucose uptake (NHGU) compared with CTR (~33 and 21% greater, P1 and P2, respectively, P < 0.05). Nonhepatic glucose uptake (non-HGU) was increased ~38% in Bromo in P2 (P < 0.05). Bromo vs. CTR had higher (P < 0.05) rates of glucose infusion (36 and 30%) and non-HGU (~40 and 27%) than CTR during P1 and P2, respectively. In Bromo vs. CTR, hepatic 18:0/16:0 and 16:1/16:0 ratios tended to be elevated in triglycerides and were higher (P < 0.05) in phospholipids, consistent with a beneficial effect of bromocriptine on liver fat accumulation. Thus, bromocriptine treatment improved glucose disposal in a glucose-intolerant model, enhancing both NHGU and non-HGU.


Assuntos
Glicemia/efeitos dos fármacos , Bromocriptina/farmacologia , Dieta Hiperlipídica , Agonistas de Dopamina/farmacologia , Intolerância à Glucose/metabolismo , Fígado/efeitos dos fármacos , Animais , Glicemia/metabolismo , Cães , Ácidos Graxos não Esterificados/metabolismo , Glucagon/efeitos dos fármacos , Glucagon/metabolismo , Glucose/metabolismo , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Glicogênio/metabolismo , Veias Hepáticas , Insulina/metabolismo , Ácido Láctico/metabolismo , Fígado/metabolismo , Veia Porta , Somatostatina
12.
Am J Physiol Gastrointest Liver Physiol ; 318(6): G1000-G1012, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32308041

RESUMO

Trypsinogen activation is the hallmark of acute pancreatitis (AP) independent of intra-acinar NF-κB activation and inflammation. We previously found that dopamine (DA) receptor 2 (DRD2) activation controls inflammation during AP via PP2A-dependent NF-κB activation. In this study, we sought to examine whether DRD2 signaling mediates trypsinogen activation and the underlying mechanisms. Pancreatic acinar cells were stimulated with cholecystokinin-8 in vitro. AP was induced by intraperitoneal injections of caerulein and LPS or l-arginine. Pancreatitis severity was assessed biochemically and histologically. We found that activation of DRD2 by quinpirole, a potent DRD2 agonist, resulted in the reduction of trypsinogen activation and the upregulation of HSP70 in vitro and in vivo. Mechanistically, we found that quinpirole induced dephosphorylation of heat shock factor 1 (HSF1), a master transcription factor of HSP70, leading to increased nuclear translocation of HSF1 in a PP2A-dependent pathway. Furthermore, DRD2 activation restored lysosomal pH and, therefore, maintained lysosomal cathepsin B activity in a HSP70-dependent manner. VER155008, a potent HSP70 antagonist, abolished the protective effects observed with DRD2 activation in vitro and in two experimental models of AP. Our data showed that besides controlling NF-κB activation, DRD2 activation prevented trypsinogen activation during acute pancreatitis via PP2A-dependent upregulation of HSP70 and further support that DRD2 agonist could be a promising therapeutic strategy for treating AP.NEW & NOTEWORTHY The current study demonstrated that activation of DRD2 by quinpirole protects against trypsinogen activation in the in vitro and in vivo setting of acute pancreatitis by upregulating HSP70 and restoring lysosomal degradation via a PP2A-dependent manner, therefore leading to reduced pancreatic injury. These findings provide a new mechanistic insight on the protective effect of DRD2 activation in acute pancreatitis.


Assuntos
Proteínas de Choque Térmico HSP72/metabolismo , Pancreatite/tratamento farmacológico , Quimpirol/farmacologia , Receptores de Dopamina D2/agonistas , Tripsinogênio/metabolismo , Animais , Ceruletídeo/farmacologia , Agonistas de Dopamina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP72/genética , Fatores de Transcrição de Choque Térmico/genética , Fatores de Transcrição de Choque Térmico/metabolismo , Lisossomos , Camundongos , Camundongos Endogâmicos C57BL , Pâncreas/citologia , Pancreatite/metabolismo , Fosforilação , Proteína Fosfatase 2/metabolismo , Regulação para Cima
13.
J Med Chem ; 63(10): 5526-5567, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32342685

RESUMO

To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a ß-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated ß-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.


Assuntos
Agonistas de Dopamina/química , Agonistas de Dopamina/farmacologia , Descoberta de Drogas/métodos , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/química , Animais , Células CHO , Cricetulus , Agonistas de Dopamina/metabolismo , Relação Dose-Resposta a Droga , Células HEK293 , Células Hep G2 , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Secundária de Proteína , Receptores de Dopamina D3/metabolismo
14.
Brain ; 143(2): 701-710, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32040562

RESUMO

The efficacy of dopamine agonists in treating major depressive disorder has been hypothesized to stem from effects on ventrostriatal dopamine and reward function. However, an important question is whether dopamine agonists are most beneficial for patients with reward-based deficits. This study evaluated whether measures of reward processing and ventrostriatal dopamine function predicted response to the dopamine agonist, pramipexole (ClinicalTrials.gov Identifier: NCT02033369). Individuals with major depressive disorder (n = 26) and healthy controls (n = 26) (mean ± SD age = 26.5 ± 5.9; 50% female) first underwent assessments of reward learning behaviour and ventrostriatal prediction error signalling (measured using functional MRI). 11C-(+)-PHNO PET before and after oral amphetamine was used to assess ventrostriatal dopamine release. The depressed group then received open-label pramipexole treatment for 6 weeks (0.5 mg/day titrated to a maximum daily dose of 2.5 mg). Symptoms were assessed weekly, and reward learning was reassessed post-treatment. At baseline, relative to controls, the depressed group showed lower reward learning (P = 0.02), a trend towards blunted reward-related prediction error signals (P = 0.07), and a trend towards increased amphetamine-induced dopamine release (P = 0.07). Despite symptom improvements following pramipexole (Cohen's d ranging from 0.51 to 2.16 across symptom subscales), reward learning did not change after treatment. At a group level, baseline reward learning (P = 0.001) and prediction error signalling (P = 0.004) were both associated with symptom improvement, albeit in a direction opposite to initial predictions: patients with stronger pretreatment reward learning and reward-related prediction error signalling improved most. Baseline D2/3 receptor availability (P = 0.02) and dopamine release (P = 0.05) also predicted improvements in clinical functioning, with lower D2/3 receptor availability and lower dopamine release predicting greater improvements. Although these findings await replication, they suggest that measures of reward-related mesolimbic dopamine function may hold promise for identifying depressed individuals likely to respond favourably to dopaminergic pharmacotherapy.


Assuntos
Depressão/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Pramipexol/farmacologia , Recompensa , Adulto , Transtorno Depressivo Maior/fisiopatologia , Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Feminino , Humanos , Aprendizagem/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade
15.
Psychopharmacology (Berl) ; 237(6): 1671-1680, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32107571

RESUMO

Trust is central to bonding and cooperation. In many social interactions, individuals need to trust another person exclusively on the basis of their subjective impressions of the other's trustworthiness. Such impressions can be formed from social information from faces (e.g., facial trustworthiness and attractiveness) and guide trusting behaviors via activations of dopaminergic brain regions. However, the specific dopaminergic effects on impression-based trust are to date elusive. Here, in a double-blind, placebo-controlled, within-subject design, we administrated a D2/D3 dopamine agonist (pramipexole) to 28 healthy females who subsequently played a one-shot trust game with partners of varying facial trustworthiness. Our results show that by minimizing facial attractiveness information, we could isolate the specific effects of facial trustworthiness on trust in unknown partners. Despite no modulation of trustworthiness impressions, pramipexole intake significantly impacted trusting behaviors. Notably, these effects of pramipexole on trusting behaviors interacted with participants' hormonal contraceptive use. In particular, after pramipexole intake, trust significantly decreased in hormonal contraceptive non-users. This study fills an important gap in the experimental literature on trust and its neural dynamics, unearthing the cognitive and neural modulations of trusting behaviors based on trustworthiness impressions of others.


Assuntos
Agonistas de Dopamina/farmacologia , Expressão Facial , Relações Interpessoais , Estimulação Luminosa/métodos , Confiança/psicologia , Adulto , Atitude , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Método Duplo-Cego , Feminino , Humanos , Pramipexol/farmacologia , Distribuição Aleatória , Adulto Jovem
16.
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
17.
Invest Ophthalmol Vis Sci ; 61(1): 4, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31999819

RESUMO

Purpose: Neurotrophic keratopathy is a degenerative disease that may be improved by nerve growth factor (NGF). Our aim was to investigate the use of pergolide, a dopamine (D1 and D2) receptor agonist known to increase the synthesis and release of NGF for regeneration of damaged corneal nerve fibers. Methods: Pergolide function was evaluated by measuring axon length and NGF levels by enzyme-linked immunosorbent assay in cultured chicken dorsal root ganglion (DRG) cells with serial doses of pergolide (10, 25, 50, 150, and 300 µg/ml) and with different concentrations of a D1 antagonist. Pergolide function was further evaluated by cornea nerve fiber density and wound healing in a cornea scratch mouse model. Results: Pergolide increased DRG axon length significantly at a dose between 50 and 300 µg/ml. Different concentrations of D1 antagonist (12, 24, 48, and 96 µg/ml) inhibited DRG axon length growth with pergolide (300 µg/ml). Pergolide (50 µg/ml) upregulated NGF expression in DRG cells at both 24 hours and 48 hours. Pergolide improved cornea nerve fiber density at both 1 week and 2 weeks. Pergolide also improved cornea wound healing. Conclusions: We demonstrated that pergolide can act to promote an increase in NGF which promotes corneal nerve regeneration and would therefore improve corneal sensation and visual acuity in eyes with peripheral neurotrophic keratopathy.


Assuntos
Lesões da Córnea/tratamento farmacológico , Agonistas de Dopamina/uso terapêutico , Fibras Nervosas/efeitos dos fármacos , Pergolida/uso terapêutico , Animais , Axônios/efeitos dos fármacos , Galinhas , Agonistas de Dopamina/farmacologia , Gânglios Espinais/efeitos dos fármacos , Camundongos , Regeneração Nervosa , Pergolida/farmacologia , Cicatrização/fisiologia
18.
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
19.
Biochem Pharmacol ; 174: 113791, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31917245

RESUMO

Protein kinase C (PKC) is one of the major effectors involved in the heterologous regulatory pathways of G protein-coupled receptors (GPCRs). On the other hand, GRK2 and ß-arrestins are the players of homologous regulatory pathway of GPCRs that affect the receptor functions in agonist-selective manner. Even though two pathways can occur independently, crosstalks between two pathways add more diverse modes of regulations on GPCR functions. Even if extensive studies have been conducted, a commonly applicable molecular mechanism involved in the crosstalks between two regulatory pathways has yet to be elucidated. Here we show that PKCßII was phosphorylated at its activation loop of kinase domain (T500) through constitutive interaction with phosphoinositide-dependent kinase 1 (PDK1) that is phosphorylated at S214. With agonist stimulation, dopamine D2 receptor interacted with 14-3-3η in GRK2/ß-arrestin2-dependent manner, resulting in the recruitment of PDK1. The PDK1 recruited to 14-3-3η was dephosphorylated at S241 and dissociated from PKCßII, abrogating the phosphorylation of PKCßII at T500. This signaling cascade resulted in the inhibition of PKCßII functions, including its phosphorylation in the C-terminal tail, intracellular translocation, and kinase activity. Thus, this study revealed a novel and commonly applicable molecular mechanism involved in the inhibition of PKCßII functions through GRK2/ß-arrestin2-mediated homologous pathway of GPCRs. The results obtained in this study could be expanded to other GPCRs and provide new strategies for the treatment of PKCßII-related disorders.


Assuntos
Proteínas Quinases Dependentes de 3-Fosfoinositídeo/metabolismo , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Proteína Quinase C beta/metabolismo , Receptores de Dopamina D2/metabolismo , beta-Arrestina 2/metabolismo , Proteínas 14-3-3/metabolismo , Agonistas de Dopamina/farmacologia , Células HEK293 , Humanos , Fosforilação , Transdução de Sinais
20.
Am J Physiol Endocrinol Metab ; 318(1): E62-E71, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31794265

RESUMO

Bromocriptine, a dopamine D2 receptor agonist originally used for the treatment of hyperprolactinemia, is largely successful in reducing hyperglycemia and improving glucose tolerance in type 2 diabetics. However, the mechanism behind bromocriptine's effect on glucose intolerance is unclear. Here, we tested three hypotheses, that bromocriptine may exert its effects on glucose metabolism by 1) decreasing prolactin secretion, 2) indirectly increasing activity of key melanocortin receptors in the central nervous system, or 3) improving/restoring circadian rhythms. Using a diet-induced obese (DIO) mouse model, we established that a 2-wk treatment of bromocriptine is robustly effective at improving glucose tolerance. We then demonstrated that bromocriptine is effective at improving the glucose tolerance of both DIO prolactin-deficient and melanocortin-4 receptor (MC4R)-deficient mice, pointing to bromocriptine's ability to affect glucose tolerance independently of prolactin or MC4R signaling. Finally, we tested bromocriptine's dependence on the circadian system by testing its effectiveness in environmental (e.g., repeated shifts to the light-dark cycle) and genetic (e.g., the Clock mutant mouse) models of circadian disruption. In both models of circadian disruption, bromocriptine was effective at improving glucose tolerance, indicating that a functional or well-aligned endogenous clock is not necessary for bromocriptine's effects on glucose metabolism. Taken together, these results do not support the role of prolactin, MC4R, or the circadian clock as integral to bromocriptine's underlying mechanism. Instead, we find that bromocriptine is a robust diabetic treatment and resilient to genetically induced obesity, diabetes, and circadian disruption.


Assuntos
Glicemia/efeitos dos fármacos , Bromocriptina/farmacologia , Agonistas de Dopamina/farmacologia , Obesidade/metabolismo , Animais , Glicemia/metabolismo , Proteínas CLOCK/genética , Ritmo Circadiano , Dieta Hiperlipídica , Modelos Animais de Doenças , Teste de Tolerância a Glucose , Insulina/metabolismo , Camundongos , Camundongos Knockout , Mutação , Prolactina/genética , Receptor Tipo 4 de Melanocortina/genética
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