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1.
Nat Commun ; 13(1): 3186, 2022 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-35676276

RESUMO

Dopamine receptors are widely distributed in the central nervous system and are important therapeutic targets for treatment of various psychiatric and neurological diseases. Here, we report three cryo-electron microscopy structures of the D1 dopamine receptor (D1R)-Gs complex bound to two agonists, fenoldopam and tavapadon, and a positive allosteric modulator LY3154207. The structure reveals unusual binding of two fenoldopam molecules, one to the orthosteric binding pocket (OBP) and the other to the extended binding pocket (EBP). In contrast, one elongated tavapadon molecule binds to D1R, extending from OBP to EBP. Moreover, LY3154207 stabilizes the second intracellular loop of D1R in an alpha helical conformation to efficiently engage the G protein. Through a combination of biochemical, biophysical and cellular assays, we further show that the broad conformation stabilized by two fenoldopam molecules and interaction between TM5 and the agonist are important for biased signaling of D1R.


Assuntos
Dopamina , Fenoldopam , Microscopia Crioeletrônica , Agonistas de Dopamina/química , Agonistas de Dopamina/farmacologia , Ligantes , Receptores de Dopamina D1/metabolismo
2.
ACS Chem Neurosci ; 13(12): 1818-1831, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35658399

RESUMO

Dopamine regulates normal functions such as movement, reinforcement learning, and cognition, and its dysfunction has been implicated in multiple psychiatric and neurological disorders. Dopamine acts through D1- (D1R and D5R) and D2-class (D2R, D3R, and D4R) receptors and activates both G protein- and ß-arrestin-dependent signaling pathways. Current dopamine receptor-based therapies are used to ameliorate motor deficits in Parkinson's disease or as antipsychotic medications for schizophrenia. These drugs show efficacy for ameliorating only some symptoms caused by dopamine dysfunction and are plagued by debilitating side effects. Studies in primates and rodents have shown that shifting the balance of dopamine receptor signaling toward the arrestin pathway can be beneficial for inducing normal movement, while reducing motor side effects such as dyskinesias, and can be efficacious at enhancing cognitive function compared to balanced agonists. Several structure-activity relationship (SAR) studies have embarked on discovering ß-arrestin-biased dopamine agonists, focused on D2 partial agonists, noncatechol D1 agonists, and mixed D1/D2R dopamine receptor agonists. Here, we describe an SAR study to identify novel D1R ß-arrestin-biased ligands using A-86929, a high-affinity D1R catechol agonist, as a core scaffold to identify chemical motifs responsible for ß-arrestin-biased activity at both D1 and D2Rs. Most of the A-86929 analogs screened were G protein-biased, but none of them were exclusively arrestin-biased. Additionally, various small-fragment molecular probes displayed weak bias toward the ß-arrestin pathway. Continued in-depth SFSR (structure-functional selectivity relationship) studies informed by structure determination, molecular modeling, and mutagenesis studies will facilitate the discovery of potent and efficacious arrestin-biased dopamine receptor ligands.


Assuntos
Agonistas de Dopamina , Dopamina , Animais , Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Proteínas de Ligação ao GTP/metabolismo , Ligantes , Quinolonas , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/metabolismo , Tiofenos , beta-Arrestinas/metabolismo
3.
PLoS One ; 17(6): e0269486, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35709159

RESUMO

Hordenine, a bioactive food compound, has several pharmacological properties and has recently been identified as a dopamine D2 receptor (D2R) agonist. Since the pharmacokinetic profile of hordenine has been described to a limited extent, the present study focused on the transfer and transport of hordenine across the intestinal epithelium and the blood-brain barrier (BBB) in vitro. Hordenine was quickly transferred through the Caco-2 monolayer in only a few hours, indicating a rapid oral uptake. However, the high bioavailability may be reduced by the observed efflux transport of hordenine from the bloodstream back into the intestinal lumen and by first pass metabolism in intestinal epithelial cells. To determine the biotransformation rate of hordenine, the metabolite hordenine sulfate was synthesized as reference standard for analytical purposes. In addition, transfer studies using primary porcine brain capillary endothelial cells (PBCEC) showed that hordenine is able to rapidly penetrate the BBB and potentially accumulate in the brain. Thus, a D2R interaction of hordenine and activation of dopaminergic signaling is conceivable, assuming that the intestinal barrier can be circumvented by a route of administration alternative to oral uptake.


Assuntos
Barreira Hematoencefálica , Agonistas de Dopamina , Animais , Barreira Hematoencefálica/metabolismo , Células CACO-2 , Agonistas de Dopamina/farmacologia , Células Endoteliais/metabolismo , Humanos , Permeabilidade , Receptores de Dopamina D2/metabolismo , Suínos , Tiramina/análogos & derivados
4.
J Neural Transm (Vienna) ; 129(7): 889-894, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35503480

RESUMO

BACKGROUND: Twenty-four-hour treatment options could provide a continuous drug delivery strategy in advanced Parkinson's disease and can ameliorate motor and non-motor complications. Use of levodopa infusion is often limited to 12-16 h/day due to its cost. Adjunctive overnight rotigotine transdermal patch is a continuous drug delivery option successfully used in clinical practice coupled with apomorphine infusion. However, real-life data addressing the tolerability of transdermal dopamine agonist therapy with concomitant use of intrajejunal levodopa infusion in advanced Parkinson's disease are not available. OBJECTIVE: To evaluate the tolerability and beneficial effects of combined therapy with overnight rotigotine transdermal patch and intrajejunal levodopa infusion over a follow-up period of 12 months in advanced Parkinson's disease. METHOD: In this retrospective data analysis, data before and after the initiation of the continuous drug delivery combined therapy using overnight rotigotine transdermal patch and intrajejunal levodopa infusion were collected from the ongoing non-motor-international-longitudinal study (NILS) and local clinical practice at King's College Hospital (London, United Kingdom). 12 advanced Parkinson's disease patients on intrajejunal levodopa therapy who were additionally treated with overnight rotigotine transdermal patch (mean dose 5.67 ± 4.19 mg) are included. Tolerability over a 12-month period was assessed. In addition, changes in motor symptoms (SCales for Outcomes in Parkinson's disease, SCOPA-Motor), non-motor symptoms (Non-Motor Symptoms Scale, NMSS) and quality of life (Parkinson's disease Questionnaire-8, PDQ-8) before and 12-month after continuous drug delivery combined therapy initiation are evaluated. RESULTS: Tolerability was 100% irrespective of age, disease duration, stages of disease. (Treatment with overnight rotigotine transdermal patch that was maintained for a minimum of 6 months was considered "tolerated", primary tolerability). In addition, we noted a significant reduction of the NMSS total score (p = 0.009) and the NMSS domain 3 score (mood and apathy domain) (p = 0.028), although the latter did not remain statistically significant after correction for multiple testing (p2 = 0.252) at 12 months. CONCLUSION: Combination of intrajejunal levodopa infusion with overnight rotigotine transdermal patch is well tolerated and extend the beneficial effects of infusion with excellent tolerability; and also improved aspects of mood and apathy sustained at 12 months in advanced Parkinson's disease.


Assuntos
Levodopa , Doença de Parkinson , Administração Cutânea , Agonistas de Dopamina/farmacologia , Humanos , Levodopa/efeitos adversos , Estudos Longitudinais , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Qualidade de Vida , Estudos Retrospectivos , Tetra-Hidronaftalenos , Tiofenos , Adesivo Transdérmico
5.
Eur J Pharmacol ; 925: 175016, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35545150

RESUMO

(+)-4-Propyl-9-hydroxynaphthoxazine ((+)PHNO) is a high affinity, preferential dopamine D3 versus D2 agonist employed in view of its high specificity and excellent signal-to-noise ratio as a radiotracer for positron emission tomography (PET) imaging. Surprisingly, its profile at other classes of monoamine receptor remains undocumented. In addition to hD3 and hD2L receptors, (+)PHNO revealed high affinity at hD4.4 but not hD1 or hD5 receptors. It also revealed significant affinity for several other G protein-coupled monoaminergic receptors, in particular h5-HT1A and h5-HT7. (+)PHNO behaved as a full agonist at hD4.4 and h5-HT1A receptors with potencies comparable to its actions at hD3 and hD2L receptors, and with less potency at 5-HT7 receptors. In binding assays with membranes derived from cells co-expressing hD3 and hD2L receptors and labeled with [3H]Nemonapride or [3H]Spiperone, the proportion of high affinity binding sites recognized by (+)PHNO was higher than an equivalent mixture of membranes from cells expressing hD3or hD2L receptors, suggesting that (+)PHNO promotes formation of hD3-hD2L heterodimers. Further, in cells co-expressing hD3 and hD2L receptors, (+)PHNO showed higher efficacy for inhibiting forskolin stimulated adenylyl cyclase and inducing adenylyl cyclase super-sensitization than in cells transfected with only hD2L receptors. In conclusion, (+)PHNO is a potent agonist at hD4.4, h5-HT1A and h5-HT7 as well as hD3 and hD2L receptors, and it potently activates dopamine hD3-hD2L heterodimers. These interactions should be considered when interpreting PET studies with [11C](+)PHNO and may be relevant to its functional and potential clinical properties in Parkinson's disease and other disorders.


Assuntos
Dopamina , Receptores de Dopamina D2 , Adenilil Ciclases , Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Oxazinas , Tomografia por Emissão de Pósitrons/métodos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo
6.
Cells ; 11(7)2022 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-35406766

RESUMO

Pathological angiogenesis is correlated with many ophthalmic diseases. The most common are exudative age-related macular degeneration and proliferative diabetic retinopathy. The current treatment for these diseases is based on regularly administered anti-VEGF antibodies injections. In the study, we investigated selected D2 dopaminergic receptor agonists, namely bromocriptine, cabergoline and pergolide, on hypoxia-induced neovascularization. We used the zebrafish laboratory model, specifically three-day post fertilization (dpf) Tg(fli-1: EGFP) zebrafish larvae. To induce abnormal angiogenesis of hyaloid-retinal vessels (HRVs) and intersegmental vessels (ISVs), the larvae were treated with cobalt chloride (II) (CoCl2) (a hypoxia-inducing agent) from 24 h post fertilization. The inhibitory role of D2 dopaminergic receptor agonists was investigated using confocal microscopy and qPCR. Additionally, the results were compared to those obtained in the group treated with CoCl2 followed by bevacizumab, the well-known antiangiogenic agent. Confocal microscopy analyses revealed severe deformation of vessels in the CoCl2 treated group, while co-incubation with bromocriptine, cabergoline, pergolide and bevacizumab, respectively, significantly inhibited abnormalities of angiogenesis. The qPCR analyses supported the protective role of the chosen dopaminergic agonists by demonstrating their influence on CoCl2-derived upregulation of vegfaa expression. The present results suggest that the D2 receptor agonists can be considered as a new direction in research for antiangiogenic therapy.


Assuntos
Agonistas de Dopamina , Peixe-Zebra , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Bevacizumab , Bromocriptina/metabolismo , Bromocriptina/farmacologia , Cabergolina/metabolismo , Agonistas de Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Agonistas de Dopamina/uso terapêutico , Hipóxia/patologia , Larva/metabolismo , Neovascularização Patológica/metabolismo , Pergolida/metabolismo , Pergolida/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Peixe-Zebra/metabolismo
7.
Pharmacol Res ; 179: 106223, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35429668

RESUMO

Dopamine D3 receptors (D3R) have a causal role in neurological and psychiatric disorders. We have developed a novel class of G-protein biased (GPB) signaling D3R agonists with minimal ß-arrestin2 (ßarr2) recruitment and demonstrated efficacy in rodent model of Parkinson's disease. This contrasts with unbiased (UB) D3R agonists like Pramipexole which recruit both ß-arrestin and G-proteins for signaling. In this study, we investigated the effects of GPB and UB agonists on D3R mediated activation of mono and dual phosphorylation of ERK1/2. We used the neuronal-like SH-SY5Y cells stably expressing D3R and ßarr2 knockdown (ßarr2KD) to delineate the roles of Gi/o and ßarr2 on phosphorylation patterns of ERK1/2 induced by D3R agonists. Results indicate GPB and UB agonists promote similar early and late phase mono activation patterns of ERK1/2. On the contrary, GPB and UB agonists promote either early or early and late phase dual activation of ERK1/2, respectively. The early phase dual activation of ERK1/2 is predominantly promoted by Gi/o while the late phase dual activation by ßarr2 recruitment. PKC plays a significant role in both the early and late phase dual phosphorylation of ERK1/2. ßarr2KD significantly increased short- and long-term dual phosphorylation levels of ERK1/2 induced by GPB agonists which was inhibited by a combination of Gi/o and PKC inhibitors. Interestingly, ßarr2KD significantly reduced the short and long-term dual phosphorylation of ERK1/2 by UB agonists. Overall, this study highlights that biased signaling agonists of D3R have differential effects on ERK1/2 which may be advantageous to develop better drugs.


Assuntos
Sistema de Sinalização das MAP Quinases , Receptores de Dopamina D3 , Agonistas de Dopamina/farmacologia , Proteínas de Ligação ao GTP , Humanos , Receptores de Dopamina D3/metabolismo , Transdução de Sinais , beta-Arrestina 2 , beta-Arrestinas
8.
Sci Rep ; 12(1): 4540, 2022 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-35296748

RESUMO

Parkinson's disease (PD) is a neurodegenerative condition caused by the loss of dopaminergic neurons in the substantia nigra pars compacta. As activation of dopaminergic receptors is fundamentally involved in the micturition reflex in PD, the objective of this study was to determine the effect of a single dose of rotigotine ([-]2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin) on intercontraction interval (ICI) and voiding pressure (VP) in a rat model of PD. We used 27 female rats, PD was induced by injecting 6-hydroxydopamine (6-OHDA; 8 µg in 2 µL of 0.9% saline containing 0.3% ascorbic acid), and rotigotine was administrated at doses of 0.125, 0.25, or 0.5 mg/kg, either intravenous or subcutaneous injection. In rats with 6-OHDA-induced PD, intravenous injection of 0.25 or 0.5 mg/kg rotigotine led to a significantly lower ICI than after vehicle injection (p < 0.05). Additionally, VP was significantly lower in animals administered rotigotine compared to those injected with vehicle (p < 0.05). Compared to vehicle-injected animals, subcutaneous administration of rotigotine (0.125, 0.25, or 0.5 mg/kg) led to a significantly higher ICI at 2 h after injection (p < 0.05); however, there was no change in ICI after injection with (+)-SCH23390 hydrochloride. Dermal administration of rotigotine in a rat model of PD could suppress an overactive bladder.


Assuntos
Agonistas de Dopamina , Doença de Parkinson , Animais , Modelos Animais de Doenças , Agonistas de Dopamina/farmacologia , Neurônios Dopaminérgicos , Feminino , Masculino , Oxidopamina/farmacologia , Doença de Parkinson/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Substância Negra , Tetra-Hidronaftalenos , Tiofenos , Bexiga Urinária
9.
J Exp Biol ; 225(6)2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35320357

RESUMO

The subjugation strategy employed by the jewel wasp is unique in that it manipulates the behavior of its host, the American cockroach, rather than inducing outright paralysis. Upon envenomation directly into the central complex (CX), a command center in the brain for motor behavior, the stung cockroach initially engages in intense grooming behavior, then falls into a lethargic sleep-like state referred to as hypokinesia. Behavioral changes evoked by the sting are due at least in part to the presence of the neurotransmitter dopamine in the venom. In insects, dopamine receptors are classified as two families, the D1-like and the D2-like receptors. However, specific roles played by dopamine receptor subtypes in venom-induced behavioral manipulation by the jewel wasp remain largely unknown. In the present study, we used a pharmacological approach to investigate roles of D1-like and D2-like receptors in behaviors exhibited by stung cockroaches, focusing on grooming. Specifically, we assessed behavioral outcomes of focal CX injections of dopamine receptor agonists and antagonists. Both specific and non-specific compounds were used. Our results strongly implicate D1-like dopamine receptors in venom-induced grooming. Regarding induction of hypokinesia, our findings demonstrate that dopamine signaling is necessary for induction of long-lasting hypokinesia caused by brain envenomation.


Assuntos
Baratas , Vespas , Animais , Comportamento Animal , Baratas/fisiologia , Dopamina/farmacologia , Agonistas de Dopamina/farmacologia , Humanos , Hipocinesia/induzido quimicamente , Instinto , Receptores Dopaminérgicos , Receptores de Dopamina D1 , Venenos de Vespas/efeitos adversos , Vespas/fisiologia
10.
Biotechnol J ; 17(6): e2100561, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35332995

RESUMO

Electrical stimulation of brain or muscle activities has gained attention for studying the molecular and cellular mechanisms involved in electric-induced responses. We recently showed zebrafish's response to electricity. Here, we hypothesized that this response is affected by the dopaminergic signaling pathways. The effects of multiple dopamine agonists and antagonists on the electric response of 6 days-postfertilization zebrafish larvae were investigated using a microfluidic device with enhanced control of experimentation and throughput. All dopamine antagonists decreased locomotor activities, while dopamine agonists did not induce similar behaviors. The D2-selective dopamine agonist quinpirole enhanced the movement. Exposure to nonselective and D1-selective dopamine agonists apomorphine and SKF-81297 caused no significant change in the electric response. Exposing larvae that were pretreated with nonselective and D2-selective dopamine antagonists butaclamol and haloperidol to apomorphine and quinpirole, respectively, restored the electric locomotion. These results reveal a correlation between electric response and dopamine signaling pathway. Furthermore, they demonstrate that electric-induced zebrafish larvae locomotion can be conditioned by modulating dopamine receptor functions. Our electrofluidic assay has profound application potential for fundamental electric-induced response research and brain disorder studies especially those related to the dopamine imbalance and as a chemical screening method when investigating biological pathways and behaviors.


Assuntos
Dopamina , Peixe-Zebra , Animais , Apomorfina/farmacologia , Dopamina/metabolismo , Dopamina/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Eletricidade , Larva/metabolismo , Quimpirol/farmacologia , Transdução de Sinais , Peixe-Zebra/metabolismo
11.
Neurotoxicology ; 89: 121-126, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35104500

RESUMO

BACKGROUND: Motor symptoms of Parkinson's disease (PD) are characterized by bradykinesia, resting tremor, rigidity, slow movement, impaired gait and postural instability, resulting from progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Atractylon is a natural furan compound in Atractylodes rhizomes, exhibiting anticancer, anti-inflammation, antiviral and gastroprotective activities, and so on. However, it is still unknown whether atractylon is beneficial to motor dysfunctions of PD. METHODS: GPCR-targeted piggyBac-TANGO compound screening system, cAMP assay, and immunostaining of p-CREB and BDNF were used to identify dopamine 2 receptor (DRD2) activation. The effects of atractylon on motor deficits and gait disturbances, as well as tyrosine hydroxylase (TH) in the SNpc were investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. RESULTS: Atractylon treatment increased the eGFP expression in dose-dependent manner in piggyBac-TANGO assay, decreased cAMP production, and enhanced the levels of p-CREB and BDNF in DRD2 highly expresseding SY-SY5Y cells. In MPTP-induced mice, atractylon improved the slow movement, diminished voluntary locomotion, and abnormal gait parameters, such as duration, cadence, average speed, step cycle, stride length, and so on. Moreover, atractylon rescued the TH positive cells in SNpc and TH positive nerve fibers in striatum. CONCLUSIONS: Atractylon could effectively activate DRD2, attenuate motor deficits and gait disorders, and protect dopaminergic neurons in MPTP-induced PD mice. Our findings stretch out the therapeutic potential of atractylon for motor symptoms of PD.


Assuntos
Agonistas de Dopamina , Transtornos Parkinsonianos , Sesquiterpenos , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Corpo Estriado , Modelos Animais de Doenças , Agonistas de Dopamina/farmacologia , Neurônios Dopaminérgicos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/tratamento farmacológico , Sesquiterpenos/farmacologia , Substância Negra , Tirosina 3-Mono-Oxigenase/metabolismo
12.
Brain Res Bull ; 181: 157-166, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35122898

RESUMO

Pramipexole is a potent agonist of D3 and D2 dopamine receptors, currently approved for clinical use in Parkinson's disease (PD) and restless leg syndrome. Several studies have shown that pramipexole significantly increases the risk of pathological gambling and impulse-control disorders. While these iatrogenic complications can impose a severe social and financial burden, their treatment poses serious clinical challenges. Our group previously reported that the steroidogenic inhibitor finasteride reduced pathological gambling severity in PD patients who developed this complication following pramipexole treatment. To study the mechanisms underlying these effects, here we tested the impact of finasteride in a rat model of pramipexole-induced alterations of probability discounting. We previously showed that, in rats exposed to low doses of the monoamine-depleting agent reserpine (1 mg/kg/day, SC), pramipexole (0.3 mg/kg/day, SC) increased the propensity to engage in disadvantageous choices. This effect was paralleled by a marked D3 receptor upregulation in the nucleus accumbens. First, we tested how finasteride (25-50 mg/kg, IP) intrinsically affects probability discounting. While the highest dose of finasteride produced a marked lack of interest in lever pressing (manifested as a significant increase in omissions), the 25 mg/kg (IP) dose did not intrinsically modify probability discounting. However, this finasteride regimen significantly reduced the adverse effects of reserpine and pramipexole in probability discounting by diminishing rats' propensity to engage in highly disadvantageous probabilistic choices. The same regimen also reversed the upregulation of D3 receptors in the nucleus accumbens induced by reserpine and pramipexole. These findings confirm that finasteride opposes the impulsivity caused by pramipexole and suggest that this effect may be underpinned by a normalizing effect on D3 receptor expression in the nucleus accumbens.


Assuntos
Inibidores de 5-alfa Redutase/farmacologia , Comportamento de Escolha/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Finasterida/farmacologia , Comportamento Impulsivo/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Pramipexol/farmacologia , Aprendizagem por Probabilidade , Receptores de Dopamina D3/efeitos dos fármacos , Receptores de Dopamina D3/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Ratos , Receptores de Dopamina D3/agonistas
13.
Neurosci Res ; 178: 93-97, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35150767

RESUMO

Intermittent administration of L-dopa in Parkinson's disease is associated with L-dopa-induced dyskinesia (LID). Long-acting dopamine agonists may reduce the risk of LID by continuous dopaminergic stimulation. We examined the LID-like behavior, preprodynorphin messenger ribonucleic acid (mRNA) expression in the striatum (a neurochemical LID hallmark), and the volume of the entopeduncular nucleus (a pathological LID hallmark) in Parkinson's disease rat models that were treated with L-dopa and cabergoline. Cabergoline co-treatment with L-dopa reduced LID, striatal preprodynorphin mRNA expression, and hypertrophy of the entopeduncular nucleus, indicating that cabergoline has an anti-LID effect independent of the L-dopa-sparing effect.


Assuntos
Discinesia Induzida por Medicamentos , Doença de Parkinson , Animais , Antiparkinsonianos/efeitos adversos , Cabergolina/metabolismo , Cabergolina/farmacologia , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Agonistas de Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Discinesia Induzida por Medicamentos/tratamento farmacológico , Discinesia Induzida por Medicamentos/metabolismo , Levodopa/efeitos adversos , Oxidopamina , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley
14.
Int J Mol Sci ; 23(3)2022 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-35163699

RESUMO

Endometrial mesenchymal stromal cells (E-MSCs) extensively contribute to the establishment and progression of endometrial ectopic lesions through formation of the stromal vascular tissue, and support to its growth and vascularization. As E-MSCs lack oestrogen receptors, endometriosis eradication cannot be achieved by hormone-based pharmacological approaches. Quinagolide is a non-ergot-derived dopamine receptor 2 agonist reported to display therapeutic effects in in vivo models of endometriosis. In the present study, we isolated E-MSCs from eutopic endometrial tissue and from ovarian and peritoneal endometriotic lesions, and we tested the effect of quinagolide on their proliferation and matrix invasion ability. Moreover, the effect of quinagolide on E-MSC endothelial differentiation was assessed in an endothelial co-culture model of angiogenesis. E-MSC lines expressed dopamine receptor 2, with higher expression in ectopic than eutopic ones. Quinagolide inhibited the invasive properties of E-MSCs, but not their proliferation, and limited their endothelial differentiation. The abrogation of the observed effects by spiperone, a dopamine receptor antagonist, confirmed specific dopamine receptor activation. At variance, no involvement of VEGFR2 inhibition was observed. Moreover, dopamine receptor 2 activation led to downregulation of AKT and its phosphorylation. Of interest, several effects were more prominent on ectopic E-MSCs with respect to eutopic lines. Together with the reported effects on endometrial and endothelial cells, the observed inhibition of E-MSCs may increase the rationale for quinagolide in endometriosis treatment.


Assuntos
Aminoquinolinas/farmacologia , Proliferação de Células , Endometriose/tratamento farmacológico , Células-Tronco Mesenquimais/efeitos dos fármacos , Adulto , Aminoquinolinas/uso terapêutico , Agonistas de Dopamina/farmacologia , Endometriose/fisiopatologia , Endométrio/efeitos dos fármacos , Feminino , Humanos , Células-Tronco Mesenquimais/fisiologia , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-akt , Receptor 2 de Fatores de Crescimento do Endotélio Vascular
15.
Addict Biol ; 27(2): e13133, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35032086

RESUMO

Circadian genes, including Per1, in the medial shell region of nucleus accumbens (mNAcSh), regulate binge alcohol consumption. However, the upstream mechanism regulating circadian genes-induced alcohol consumption is not known. Since activation of dopamine D2 receptors (D2R) increases Per1 gene expression, we hypothesised that local infusion of quinpirole, a D2R agonist, by increasing Per1 gene expression in the mNAcSh, will increase binge alcohol consumption in mice. We performed two experiments on male C57BL/6J mice, instrumented with bilateral guide cannulas above the mNAcSh, and exposed to a 4-day drinking-in-dark (DID) paradigm. The first experiment determined the effects of bilateral infusion of quinpirole (100 ng/300 nl/site) or DMSO (Vehicle group) in the mNAcSh on Per1 gene expression and alcohol consumption. The second experiment determined the effect of antisense-induced downregulation of Per1 in the mNAcSh on the quinpirole-induced increase in alcohol consumption. Control experiments were performed by exposing the animals to sucrose (10% w/v). After the experiment, animals were euthanised, brains removed and processed for localisation of injection sites and analysis of Per1 gene expression in the mNAcSh. As compared with the DMSO, local bilateral infusion of quinpirole significantly increased the expression of Per1 in the mNAcSh along with an increase in the amount of alcohol consumed in mice exposed to DID paradigm. In addition, local antisense-induced downregulation of Per1 significantly attenuated the effects of intro-accumbal infusion of quinpirole on alcohol consumption. Our results suggest that Per1 in the mNAcSh mediates D2R activation-induced increase in alcohol consumption.


Assuntos
Núcleo Accumbens , Receptores de Dopamina D2 , Consumo de Bebidas Alcoólicas/genética , Animais , Agonistas de Dopamina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Quimpirol/farmacologia , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo
16.
Sci Rep ; 12(1): 367, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013368

RESUMO

The posterior pallial amygdala (PoA) is located on the basolateral caudal telencephalon, including the basal division of PoA (PoAb) and the compact division of PoA (PoAc). PoA plays a vital role in emotion regulation and is considered a part of the amygdala in birds. However, the regulatory functions responsible for motor behaviors and emotions between PoAb and PoAc are poorly understood. Therefore, we studied the structure and function of PoA by tract-tracing methods, constant current electrical stimulation, and different dopamine receptor drug injections in pigeons (Columba livia domestica). PoAb connects reciprocally with two nuclear groups in the cerebrum: 1) a continuum comprising the temporo-parieto-occipitalis, corticoidea dorsolateralis, hippocampus, and parahippocampalis areas and 2) rostral areas of the hemisphere, including the nucleus septalis lateralis and nucleus taeniae amygdalae. Extratelencephalic projections of PoAb terminate in the lateral hypothalamic nucleus and are scattered in many limbic midbrain regions. PoAb and PoAc mainly mediated the turning movement. In the 'open-field' test, D1 agonist and D2 antagonist could significantly reduce the latency period for entering into the central area and increase the residence time in the central area, whereas D1 antagonist and D2 agonist had the opposite effect. PoAb and PoAc are important brain areas that mediate turning behavior.


Assuntos
Tonsila do Cerebelo/fisiologia , Comportamento Animal , Columbidae/fisiologia , Atividade Motora , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Columbidae/metabolismo , Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Neurônios Dopaminérgicos/fisiologia , Estimulação Elétrica , Feminino , Masculino , Atividade Motora/efeitos dos fármacos , Técnicas de Rastreamento Neuroanatômico , Teste de Campo Aberto , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo
17.
Neuropharmacology ; 207: 108942, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35026287

RESUMO

INTRODUCTION: Brain imaging studies have highlighted that the density of dopamine D2 receptors markedly fluctuates across the stages of Parkinson's disease and in response to pharmacological treatment. Moreover, receptor density constitutes a molecular determinant for the signaling profile of D2 receptor ligands. We therefore hypothesized that variations in receptor expression could influence D2 receptor response to antiparkinsonian drugs, most notably with respect to the recruitment bias between Gi1 and ß-arrestin2. METHODS: The recruitment bias of dopamine, pramipexole, ropinirole, and rotigotine was examined using a nanoluciferase-based biosensor for probing the interactions of the D2L receptor with either Gi1 or ß-arrestin2. The characterization of the functional selectivity of these D2 receptor agonists was performed at two distinct D2L receptor densities by taking advantage of a cell model carrying an inducible system that enables the overexpression of the D2L receptor when exposed to doxycycline. RESULTS: A high receptor density oriented the balanced signaling profile of dopamine towards a preferential recruitment of Gi1. It also moderated the marked Gi1 and ß-arrestin2 biases of pramipexole and rotigotine, respectively. At variance, the Gi1 bias of ropinirole appeared as not being influenced by D2L receptor density. CONCLUSIONS: Taken together, these observations highlight receptor density as a key driver of the signaling transducer recruitment triggered by antiparkinsonian agents. Moreover, given the putative beneficial properties of ß-arrestin2 in promoting locomotion, this study provides molecular insights that position the arrestin-biased ligand rotigotine as a putatively more beneficial D2 receptor agonist for the treatment of early and late Parkinson's disease.


Assuntos
Antiparkinsonianos/farmacologia , Agonistas de Dopamina/farmacologia , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Receptores Acoplados a Proteínas G/efeitos dos fármacos , beta-Arrestina 2/efeitos dos fármacos , Técnicas Biossensoriais , Dopamina/farmacologia , Humanos , Indóis/farmacologia , Luciferases , Pramipexol/farmacologia , Receptores de Dopamina D2/agonistas , Tetra-Hidronaftalenos/farmacologia , Tiofenos/farmacologia
18.
Neuropharmacology ; 207: 108967, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35077763

RESUMO

Dopamine D1 receptor (D1R) agonists are frequently used to study the role of D1Rs in neurotransmission and behaviour. They have been repeatedly shown to modulate glutamatergic NMDAR currents in the prefrontal cortex (PFC), giving rise to the idea that D1R activation tunes glutamatergic networks by regulating NMDAR activity. We report that the widely used D1R agonist SKF81297 potentiates NMDAR currents in a dose-dependent manner, independently of D1R activation in mPFC slices, cortical neuron cultures and NMDAR-expressing recombinant HEK293 cells. SKF81297 potentiated NMDAR currents through both GluN2A and GluN2B subtypes in the absence of D1R expression, while inhibiting NMDAR currents through GluN2C and GluN2D subtypes. In contrast, the D1R ligands SKF38393, dopamine and SCH23390 inhibited GluN2A- and GluN2B-containing NMDAR currents. SKF81297 also inhibited GluN2A- and GluN2B-containing NMDAR currents at higher concentrations and when glutamate/glycine levels were high, exhibiting bidirectional modulation. To our knowledge, these findings are the first report of a D1R-independent positive modulatory effect of a D1R ligand on NMDA receptors. Importantly, our results further emphasize the possibility of off-target effects of many D1R ligands, which has significant implications for interpreting the large body of research relying on these compounds to examine dopamine functions.


Assuntos
Benzazepinas/farmacologia , Agonistas de Dopamina/farmacologia , Neurônios/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Receptores de Dopamina D1/agonistas , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Células HEK293 , Humanos
19.
CNS Drugs ; 36(2): 143-165, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35006557

RESUMO

Apathy is a highly prevalent symptom of dementia. Despite its association with faster cognitive and functional decline, decreased quality of life and increased mortality, no therapies are currently approved to treat apathy. The objective of this review was to summarize the drugs that have been studied for apathy treatment in patients with dementia (specifically Alzheimer's disease [AD], Huntington's disease [HD] and Parkinson's disease [PD] dementia; dementia with Lewy bodies [DLB]; vascular dementia [VaD]; and frontotemporal dementia [FTD]) based on their putative mechanisms of action. A search for relevant studies was performed using ClinicalTrials.gov and PubMed. Eligible studies were randomized controlled trials that were available in English and included at least one drug intervention and an apathy measure scale. A total of 52 studies that included patients with AD (n = 33 studies), PD (n = 5), HD (n = 1), DLB (n = 1), FTD (n = 3), VaD (n = 1), VaD and AD (n = 4), VaD and mixed dementia (n = 1), and AD, VaD and mixed dementia (n = 3) were eligible for inclusion. These studies showed that methylphenidate, olanzapine, cholinesterase inhibitors, choline alphoscerate, citalopram, memantine, and mibampator are the only beneficial drugs in AD-related apathy. For PD-related apathy, only methylphenidate, rotigotine and rivastigmine showed benefits. Regarding FTD- and DLB-related apathy, initial studies with agomelatine and rivastigmine showed benefits, respectively. As for HD- and only-VaD-related apathy, no drugs demonstrated benefits. With regards to mixed populations, memantine, galantamine and gingko biloba showed effects on apathy in the AD plus VaD populations and nimodipine in the VaD plus mixed dementia populations. Of the drugs with positive results, some are already prescribed to patients with dementia to target other symptoms, some have characteristics-such as medical contraindications (e.g., cardiovascular) and adverse effects (e.g., gastrointestinal disturbances)-that limit their clinical use and some require further study. Future studies should investigate apathy as a primary outcome, making use of appropriate sample sizes and study durations to ensure durability of results. There should also be a consensus on using scales with high test/retest and interrater reliabilities to limit the inconsistencies between clinical trials. In conclusion, there are currently no US FDA-approved drugs that target apathy in dementia, so there is an ongoing need for the development of such drugs.


Assuntos
Apatia/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Demência , Demência/classificação , Demência/tratamento farmacológico , Demência/psicologia , Agonistas de Dopamina/farmacologia , Desenvolvimento de Medicamentos , Humanos , Seleção de Pacientes , Ensaios Clínicos Controlados Aleatórios como Assunto , Risco Ajustado/métodos , Inibidores de Captação de Serotonina/farmacologia
20.
Behav Brain Res ; 422: 113759, 2022 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-35051488

RESUMO

Conditioned avoidance responses (CAR) behavior is a classical instrumental response paradigm, which is widely used to study aversive conditioning and defensive motivation behavior. Previous studies have shown that dopamine D1 and D2 receptors are involved in CAR behavior; however, it is unclear in which brain regions that dopamine evokes CAR behavior. The aim of the study is to investigate whether dopamine triggers CAR behavior via activating dopamine D1 or D2 receptors in the shell of nucleus accumbens or dorsolateral striatum. The present study found that infusion of the dopamine D2 receptor agonist quinpirole, but not D1 receptor agonist SKF38393, into the shell of nucleus accumbens evoked CAR behavior in reserpine-treated rats. Whereas, infusion of neither SKF38393 nor quinpirole into the dorsolateral striatum evoked CAR behavior. In addition, infusion of quinpirole into the shell of nucleus accumbens enhanced CAR behavior in the unsuccessful trained rats without affecting the motor function in the balance beam and locomotor tests. In conclusion, activation of dopamine D2, but not D1 receptors in the shell of nucleus accumbens evokes CAR behavior. However, activation of dopamine D1 and D2 receptors in the dorsolateral striatum does not evoke CAR behavior. It is suggested that the shell of nucleus accumbens is the critical brain region for dopamine to invoke CAR behavior, and activation of dopamine D2 receptors in the shell of nucleus accumbens is sufficient and necessary to evoke CAR behavior.


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Animais , Masculino , Neostriado/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/efeitos dos fármacos
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