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1.
Sci Rep ; 10(1): 9538, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32533080

RESUMO

Pannexin 1 (Panx1) forms ATP-permeable membrane channels that play roles in the nervous system. The analysis of roles in both standard and pathological conditions benefits from a model organism with rapid development and early onset of behaviors. Such a model was developed by ablating the zebrafish panx1a gene using TALEN technology. Here, RNA-seq analysis of 6 days post fertilization larvae were confirmed by Real-Time PCR and paired with testing visual-motor behavior and in vivo electrophysiology. Results demonstrated that loss of panx1a specifically affected the expression of gene classes representing the development of the visual system and visual processing. Abnormal swimming behavior in the dark and the expression regulation of pre-and postsynaptic biomarkers suggested changes in dopaminergic signaling. Indeed, altered visuomotor behavior in the absence of functional Panx1a was evoked through D1/D2-like receptor agonist treatment and rescued with the D2-like receptor antagonist Haloperidol. Local field potentials recorded from superficial areas of the optic tectum receiving input from the retina confirmed abnormal responses to visual stimuli, which resembled treatments with a dopamine receptor agonist or pharmacological blocking of Panx1a. We conclude that Panx1a functions are relevant at a time point when neuronal networks supporting visual-motor functions undergo modifications preparing for complex behaviors of freely swimming fish.


Assuntos
Conexinas/metabolismo , Dopamina/metabolismo , Neurônios/metabolismo , Transdução de Sinais/fisiologia , Visão Ocular/fisiologia , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Antagonistas dos Receptores de Dopamina D2/farmacologia , Haloperidol/farmacologia , Larva/efeitos dos fármacos , Larva/metabolismo , Neurônios/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Retina/efeitos dos fármacos , Retina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Colículos Superiores/efeitos dos fármacos , Colículos Superiores/metabolismo , Natação/fisiologia , Visão Ocular/efeitos dos fármacos
2.
Nature ; 579(7800): 555-560, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32214250

RESUMO

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


Assuntos
Espinhas Dendríticas/fisiologia , Aprendizagem por Discriminação/fisiologia , Receptores de Dopamina D2/metabolismo , Animais , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Condicionamento Clássico/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Aprendizagem por Discriminação/efeitos dos fármacos , Dopamina/metabolismo , Antagonistas dos Receptores de Dopamina D2/farmacologia , Extinção Psicológica/efeitos dos fármacos , Masculino , Metanfetamina/antagonistas & inibidores , Metanfetamina/farmacologia , Camundongos , Plasticidade Neuronal , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Optogenética , Receptor A2A de Adenosina/metabolismo , Receptores de Dopamina D1/metabolismo , Recompensa , Transdução de Sinais/efeitos dos fármacos , Sinapses/metabolismo
3.
Science ; 367(6484): 1362-1366, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32193325

RESUMO

Stimulants such as methylphenidate are increasingly used for cognitive enhancement but precise mechanisms are unknown. We found that methylphenidate boosts willingness to expend cognitive effort by altering the benefit-to-cost ratio of cognitive work. Willingness to expend effort was greater for participants with higher striatal dopamine synthesis capacity, whereas methylphenidate and sulpiride, a selective D2 receptor antagonist, increased cognitive motivation more for participants with lower synthesis capacity. A sequential sampling model informed by momentary gaze revealed that decisions to expend effort are related to amplification of benefit-versus-cost information attended early in the decision process, whereas the effect of benefits is strengthened with higher synthesis capacity and by methylphenidate. These findings demonstrate that methylphenidate boosts the perceived benefits versus costs of cognitive effort by modulating striatal dopamine signaling.


Assuntos
Cognição/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Metilfenidato/farmacologia , Motivação/efeitos dos fármacos , Sulpirida/farmacologia , Adolescente , Núcleo Caudado/metabolismo , Comportamento de Escolha , Tomada de Decisões , Dopamina/biossíntese , Antagonistas dos Receptores de Dopamina D2/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Feminino , Fixação Ocular , Humanos , Masculino , Memória , Recompensa , Movimentos Sacádicos , Transdução de Sinais/efeitos dos fármacos , Adulto Jovem
4.
J Biol Chem ; 295(12): 4001-4013, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32034092

RESUMO

The hallmark pathological features of Alzheimer's disease (AD) brains are senile plaques, comprising ß-amyloid (Aß) peptides, and neuronal inclusions formed from tau protein. These plaques form 10-20 years before AD symptom onset, whereas robust tau pathology is more closely associated with symptoms and correlates with cognitive status. This temporal sequence of AD pathology development, coupled with repeated clinical failures of Aß-directed drugs, suggests that molecules that reduce tau inclusions have therapeutic potential. Few tau-directed drugs are presently in clinical testing, in part because of the difficulty in identifying molecules that reduce tau inclusions. We describe here two cell-based assays of tau inclusion formation that we employed to screen for compounds that inhibit tau pathology: a HEK293 cell-based tau overexpression assay, and a primary rat cortical neuron assay with physiological tau expression. Screening a collection of ∼3500 pharmaceutical compounds with the HEK293 cell tau aggregation assay, we obtained only a low number of hit compounds. Moreover, these compounds generally failed to inhibit tau inclusion formation in the cortical neuron assay. We then screened the Prestwick library of mostly approved drugs in the cortical neuron assay, leading to the identification of a greater number of tau inclusion inhibitors. These included four dopamine D2 receptor antagonists, with D2 receptors having previously been suggested to regulate tau inclusions in a Caenorhabditis elegans model. These results suggest that neurons, the cells most affected by tau pathology in AD, are very suitable for screening for tau inclusion inhibitors.


Assuntos
Agregados Proteicos/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Antagonistas dos Receptores de Dopamina D2/química , Antagonistas dos Receptores de Dopamina D2/metabolismo , Antagonistas dos Receptores de Dopamina D2/farmacologia , Células HEK293 , Humanos , Camundongos , Microscopia de Fluorescência , Neurônios/citologia , Neurônios/metabolismo , Ratos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Proteínas tau/antagonistas & inibidores , Proteínas tau/genética
5.
Arch. Soc. Esp. Oftalmol ; 95(2): 84-89, feb. 2020. ilus, graf
Artigo em Espanhol | IBECS | ID: ibc-195331

RESUMO

La dopamina es sintetizada por la tirosina hidroxilasa y es considerada como una catecolamina mayor en la retina de los vertebrados, incluyendo el pez cebra. Sin embargo, se conoce poco sobre la función del receptor de dopamina D2 (DRD2) en la fisiología retiniana. Por lo tanto, para dilucidar el papel del DRD2 en el desarrollo y la función de los ojos en el pez cebra, los peces fueron expuestos a la flufenazina, quinpirol, o la combinación de ambos, y luego se evaluó el tamaño del ojo, el diámetro del nervio óptico (ONd) y la adaptación visual al fondo. Los resultados mostraron que la flufenazina (flufenazina, antagonista DRD2) disminuyó el tamaño del ojo y el diámetro del nervio óptico seguido de una interrupción de la función visual. La adición de quinpirol (quinpirol, agonista DRD2) invirtió los efectos causados por flufenazina, lo que implica que DRD2 es necesario para el desarrollo y la función normal del ojo en el pez cebra. Considerando el papel de las neuronas dopaminérgicas en el desarrollo y la función de la retina, la disfunción de las vías de señalización de las neuronas dopaminérgicas en la retina puede causar anormalidades visuales, particularmente en la participación de la dopamina en la regulación de la respuesta de la luz


Dopamine is synthesized by tyrosine hydroxylase and is considered as a major catecholamine in the vertebrate retina, including zebrafish. However, little is known about the role of dopamine D2 receptor (DRD2) in retinal physiology. Therefore, to elucidate the role of DRD2 in the eye development and function in zebrafish, fish were exposed to fluphenazine, quinpirole, or combination of both. Subsequently, the eye size, optic nerve diameter (ONd), and visual background adaptation were evaluated. The results showed that fluphenazine (fluphenazine, DRD2 antagonist) decreased eye size and optic nerve diameter followed by disruption of visual function. The addition of Quinpirole (quinpirole, DRD2 agonist) reversed the effects caused by fluphenazine, implying that DRD2 is necessary for normal eye development and function in zebrafish. Considering the role of dopaminergic neurons in retinal development and function, dysfunction of dopaminergic neuron signaling pathways in the retina may cause visual abnormalities, particularly in the involvement of dopamine in regulating light response


Assuntos
Animais , Antagonistas dos Receptores de Dopamina D2/farmacologia , Olho/embriologia , Fenômenos Fisiológicos Oculares , Receptores de Dopamina D2/fisiologia , Olho/anatomia & histologia , Olho/crescimento & desenvolvimento , Flufenazina/farmacologia , Imuno-Histoquímica , Tamanho do Órgão , Quimpirol/farmacologia
6.
Arch Soc Esp Oftalmol ; 95(2): 84-89, 2020 Feb.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31955999

RESUMO

Dopamine is synthesized by tyrosine hydroxylase and is considered as a major catecholamine in the vertebrate retina, including zebrafish. However, little is known about the role of dopamine D2 receptor (DRD2) in retinal physiology. Therefore, to elucidate the role of DRD2 in the eye development and function in zebrafish, fish were exposed to fluphenazine, quinpirole, or combination of both. Subsequently, the eye size, optic nerve diameter (ONd), and visual background adaptation were evaluated. The results showed that fluphenazine (fluphenazine, DRD2 antagonist) decreased eye size and optic nerve diameter followed by disruption of visual function. The addition of Quinpirole (quinpirole, DRD2 agonist) reversed the effects caused by fluphenazine, implying that DRD2 is necessary for normal eye development and function in zebrafish. Considering the role of dopaminergic neurons in retinal development and function, dysfunction of dopaminergic neuron signaling pathways in the retina may cause visual abnormalities, particularly in the involvement of dopamine in regulating light response.


Assuntos
Antagonistas dos Receptores de Dopamina D2/farmacologia , Olho/embriologia , Fenômenos Fisiológicos Oculares , Receptores de Dopamina D2/fisiologia , Animais , Olho/anatomia & histologia , Olho/crescimento & desenvolvimento , Flufenazina/farmacologia , Imuno-Histoquímica , Tamanho do Órgão , Quimpirol/farmacologia
7.
Neuropharmacology ; 163: 107591, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940535

RESUMO

Using molecular imaging techniques - positron emission tomography (PET) and single-photon emission computed tomography (SPECT) - in conjunction with an acute dopamine depletion challenge (alpha-methyl-para-tyrosine) it is possible to estimate endogenous dopamine levels occupying striatal dopamine D2 receptors (D2R) in humans in vivo. However, it is unclear what proportion of striatal D2R are occupied by endogenous dopamine under normal conditions. This is important since it has been suggested that in schizophrenia there may be a substantial proportion of striatal D2R which are occupied by endogenous dopamine and not accessible by therapeutic doses of antipsychotics. In order to clarify these issues, we conducted a meta-analysis of dopamine depletion studies using substituted benzamide radiotracers in healthy persons. This meta-analysis suggests that anywhere from 8 to 21% (weighted average 11%) of striatal D2R may be occupied by endogenous dopamine at baseline. Using these estimates, we propose an updated occupancy model and tentatively suggest that antipsychotics inhibit a smaller proportion of the total pool of striatal D2R in vivo than previously acknowledged. This article is part of the issue entitled 'Special Issue on Antipsychotics'.


Assuntos
Antagonistas dos Receptores de Dopamina D2/farmacologia , Dopamina/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Antipsicóticos , Humanos , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Receptores de Dopamina D3/metabolismo , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/metabolismo
8.
Neuropharmacology ; 162: 107818, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31647973

RESUMO

Emerging evidence suggest that appetite-regulating peptides modulate social behaviors. We here investigate whether the anorexigenic peptide neuromedin U (NMU) modulates sexual behavior in male mice. However, instead of modulating sexual behaviors, NMU administered into the third ventricle increased self-grooming behavior. In addition, NMU-treatment increased self-grooming behavior when exposed to other mice or olfactory social-cues, but not when exposed to non-social environments. As the neuropeptide oxytocin is released during social investigation and exogenous oxytocin induces self-grooming, its role in NMU-induced self-grooming behavior was investigated. In line with our hypothesis, the oxytocin receptor antagonist inhibited NMU-induced self-grooming behavior in mice exposed to olfactory social-cues. Moreover, dopamine in the mesocorticolimbic system is known to be a key regulator of self-grooming behavior. In line with this, we proved that infusion of NMU into nucleus accumbens increased self-grooming behavior in mice confronted with an olfactory social-cue and that this behavior was inhibited by antagonism of dopamine D2, but not D1/D5, receptors. Moreover repeated NMU treatment enhanced ex vivo dopamine levels and decreased the expression of dopamine D2 receptors in nucleus accumbens in socially housed mice. On the other hand, the olfactory stimuli-dependent NMU-induced self-grooming was not affected by a corticotrophin-releasing hormone antagonist, and NMU-treatment did not influence repetitive behaviors in the marble burying test. In conclusion, our results suggest that NMU treatment and, social cues - potentially triggering oxytocin release - together induce excessive grooming behavior in male mice. The mesolimbic dopamine system, including accumbal dopamine D2 receptors, was identified as a crucial downstream mechanism.


Assuntos
Dopamina/metabolismo , Asseio Animal/efeitos dos fármacos , Neuropeptídeos/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Ocitocina/metabolismo , Comportamento Sexual Animal/efeitos dos fármacos , Animais , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Infusões Intraventriculares , Masculino , Camundongos , Núcleo Accumbens/metabolismo , Odorantes , Estimulação Física , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D5/antagonistas & inibidores , Receptores de Ocitocina/antagonistas & inibidores , Olfato , Comportamento Social , Terceiro Ventrículo
10.
Pharmacology ; 105(1-2): 19-27, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31645049

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM) is a common and lethal cancer of the central nervous system. This cancer is difficult to treat because most anticancer therapeutics do not readily penetrate into the brain due to the tight control at the cerebrovascular barrier. Numerous studies have suggested that dopamine D2 receptor (D2R) antagonists, such as first generation antipsychotics, may have anticancer efficacy in vivo and in vitro. The role of the D2R itself in the anticancer effects is unclear, but there is evidence suggesting that D2R activation promotes stem-like and spheroid forming behaviors in GBM. OBJECTIVES: We aimed to observe the role of the dopamine D2R and its modulators (at selective concentrations) in spheroid formation and stemness of GBM cell line, U87MG, to clarify the validity of the D2R as a therapeutic target for cancer therapy. METHODS: Spheroid formation assays and Western blotting of the glioblastoma cell line, U87MG, were used to observe responses to treatment with the D2R agonists sumanirole, ropinirole, and 4-propyl-9-hydroxynaphthoxazine (PHNO); and the D2R antagonists thioridazine, pimozide, haloperidol, and remoxipride. Extreme limiting dilution analysis was done to determine the impact of sumanirole and remoxipride treatment on sphere-forming cell frequency. Proliferation was also measured by crystal violet staining. Stable lentiviral transduction of DRD2 or shDRD2 was used to validate the role of the D2R in assay behaviors. RESULTS: D2R antagonists thioridazine, pimozide, haloperidol, and remoxipride decrease spheroid formation behaviors at a selective 100 nmol/L concentration, while D2R agonists PHNO, sumanirole, and ropinirole increase the formation of spheroids. Similarly, 100 nmol/L remoxipride decreased sphere-forming cell frequency. These results were recapitulated with genetic overexpression and knockdown of the D2R, and combination experiments indicate that the D2R is required for the effects of the pharmacological modulators. Furthermore, spheroid proliferation and invasive capacity increased under treatment with 100 nmol/L sumanirole and decreased under treatment with 100 nmol/L thioridazine. Expression levels of the stemness markers Nestin and Sox2, as well as those of differentiation marker glial fibrillary acidic protein, were not altered by 100 nmol/L thioridazine or sumanirole for 72 h or continuous treatment with these compounds for 7 days during a spheroid formation assay. CONCLUSIONS: Signaling activity of the dopamine D2R may be involved in the spheroid formation phenotype in the context of the U87MG cell line. However, this modulation may not be due to alterations in stemness marker expression, but due to other factors that may contribute to spheroid formation, such as cell-cell adhesion or EGFR signaling.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Receptores de Dopamina D2/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2/farmacologia , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Fenótipo , RNA Interferente Pequeno/genética , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/genética , Esferoides Celulares
11.
Eur J Pharm Sci ; 143: 105152, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31740395

RESUMO

Vesicular acetylcholine transporter (VAChT) is a promising target for a PET measure of cholinergic deficits which contribute to cognitive impairments. Dopamine D2-like agonists and antagonists are frequently used in the elderly and could alter cholinergic function and VAChT level. Therefore, pretreatment with dopamine D2-like drugs may interfere with PET measures using [18F]VAT, a specific VAChT radioligand. Herein, we investigated the impact of dopaminergic D2-like antagonist/agonist on VAChT level in the brain of macaques using [18F]VAT PET. PET imaging studies were carried out on macaques at baseline or pretreatment conditions. For pretreatment, animals were injected using a VAChT inhibitor (-)-vesamicol, a D2-like antagonist (-)-eticlopride, and a D2-like agonist (-)-quinpirole, separately. (-)-Vesamicol was injected at escalating doses of 0.025, 0.05, 0.125, 0.25 and 0.35 mg/kg; (-)-eticlopride was injected at escalating doses of 0.01, 0.10 and 0.30 mg/kg; (-)-quinpirole was injected at escalating doses of 0.20, 0.30, and 0.50 mg/kg. PET data showed [18F]VAT uptake declined in a dose-dependent manner by (-)-vesamicol pretreatment, demonstrating [18F]VAT uptake is sensitive to reflect the availability of VAChT binding sites. Furthermore, (-)-eticlopride increased [18F]VAT striatal uptake in a dose-dependent manner, while (-)-quinpirole decreased its uptake, suggesting striatal VAChT levels can be regulated by D2-like drug administration. Our findings confirmed [18F]VAT offers a reliable tool to in vivo assess the availability of VAChT binding sites. More importantly, PET with [18F]VAT successfully quantified the impact of dopaminergic D2-like drugs on striatal VAChT level, suggesting [18F]VAT has great potential for investigating the interaction between dopaminergic and cholinergic systems in vivo.


Assuntos
Encéfalo/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Tomografia por Emissão de Pósitrons/métodos , Receptores de Dopamina D2/agonistas , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismo , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Radioisótopos de Flúor , Macaca , Masculino , Piperidinas/farmacologia , Quimpirol/farmacologia , Salicilamidas/farmacologia
12.
Sci Rep ; 9(1): 19512, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31862967

RESUMO

Emotional hyperthermia is the increase in body temperature that occurs as a response to an animal detecting a salient, survival-relevant stimulus. Brown adipose tissue (BAT) thermogenesis, controlled via its sympathetic innervation, contributes to this temperature increase. Here, we have used an intruder rat experimental model to determine whether quinpirole-mediated activation of dopamine D2 receptors attenuates emotional hyperthermia in conscious rats. In anesthetized rats, we determined whether systemic quinpirole reduces BAT nerve discharge induced by activation of the medullary raphé and the lateral habenula (LHb). We measured BAT and body temperature with chronically implanted thermistors in conscious, freely moving, individually housed, male rats (resident rats). Either vehicle or quinpirole was administered, intraperitoneally, to the resident rat 30 min before introduction of a caged intruder rat. Quinpirole, in a dose-dependent manner, reduced intruder-elicited increases in BAT and body temperature. Pre-treatment with the D2 antagonist spiperone, but not the selective D1 antagonist SCH-23390, prevented this quinpirole-elicited decrease. In anesthetized rats, quinpirole abolished BAT sympathetic nerve discharge elicited by bicuculline-mediated activation of the LHb, but not the medullary raphé. Thus, activation of dopamine D2 receptors reduces the BAT thermogenesis that contributes to emotional hyperthermia. We provide evidence that these dopamine D2 receptors are located in the thermogenic pathway between the LHb and the lower brainstem pre-sympathetic control centre in the medullary raphé.


Assuntos
Tecido Adiposo Marrom/metabolismo , Habenula/metabolismo , Receptores de Dopamina D2/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Animais , Benzazepinas/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Masculino , Quimpirol/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/antagonistas & inibidores , Espiperona/farmacologia , Estresse Psicológico/metabolismo , Temperatura , Termogênese/efeitos dos fármacos
13.
Behav Neurosci ; 133(6): 545-555, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31414832

RESUMO

Addiction to opioids is an important global problem. Published research has indicated the powerful rewarding effects of drug use, which in the case of opiates like morphine may lead to drug addiction and maladaptive decision making with negative social consequences. In-depth comprehension of the role of responsible mechanisms in addiction can lead us to better and more effective treatments for drug dependence. Continuing previous work in our laboratory, in this study we aimed to investigate the role of dopamine D1- and D2-like receptors in the dentate gyrus (DG) on the reinstatement of drug-seeking behavior induced by the combination of forced swim stress and a subthreshold dose of morphine on extinguished morphine-conditioned place preference in rats. The rats were bilaterally implanted with 2 separate cannulas into the DG region. After the extinction phase of morphine-conditioned place preference, the animals received different doses (0.5, 2, and 4 µg per 0.5 µL vehicle/side) of SCH-23390 or sulpiride on the reinstatement day and were tested for the combination of forced swim stress and a subthreshold dose of morphine in discrete groups. Our findings indicated that D1- and D2-like receptor antagonists attenuated the reinstatement induced by the combination of FSS and the subthreshold dose of morphine. The reduction was more robust in groups of animals that received sulpiride as compared with SCH-23390. Our results showed a role for DG dopamine receptors in relapse to drugs of abuse, the activity of which may be induced by exposure to a stressor like forced swim stress. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Giro Denteado/efeitos dos fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Analgésicos Opioides/farmacologia , Animais , Benzazepinas/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Psicológico , Giro Denteado/metabolismo , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Morfina/farmacologia , Entorpecentes/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de Dopamina D1/antagonistas & inibidores , Recompensa , Estresse Psicológico , Sulpirida/farmacologia , Natação
14.
Behav Neurosci ; 133(6): 556-562, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31424230

RESUMO

Previous studies on drug abuse have shown that response to drug-associated cues exist during prolonged abstinence. In succession to previous investigations in our laboratory on morphine dependence and our research on acquisition and expression phases of morphine-conditioned place preference (CPP), in this study we attempt to determine the effects of intraaccumbal administration of SCH-23390, as a D1-like receptor antagonist, and sulpiride, as a D2-like receptor antagonist, in the maintenance of morphine-induced CPP in rats. Seventy-nine adult male Wistar rats weighing 200-280 g were bilaterally implanted with cannulas into the nucleus accumbens. During the 3-day conditioning phase, the animals received daily subcutaneous administration of morphine (5 mg/kg). CPP score and locomotor activity of animals were recorded by Ethovision software. Different doses (0.25, 1, 4 µg per 0.5 µL vehicle) of D1- and D2-like antagonists were bilateral injected daily after the expression phase and during the extinction phase. Our findings revealed that intraaccumbal administration of D1-like and D2-like antagonists after the CPP test shortened the extinction phase in the rats. The results suggested that the existence of the dopamine receptors in the nucleus accumbens was important for the maintenance of morphine-rewarding properties during the extinction phase. Therefore, dopamine receptors may be considered as a promising therapeutic agent in preventing the maintenance of morphine-rewarding effects in dependent individuals. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Núcleo Accumbens/efeitos dos fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Analgésicos Opioides/farmacologia , Animais , Benzazepinas , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Psicológico , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Comportamento de Procura de Droga/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Masculino , Morfina/administração & dosagem , Morfina/farmacologia , Entorpecentes/farmacologia , Núcleo Accumbens/metabolismo , Ratos , Ratos Wistar , Receptores de Dopamina D1/antagonistas & inibidores , Recompensa , Sulpirida
15.
FEBS Open Bio ; 9(9): 1580-1588, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31301124

RESUMO

Drug repositioning has garnered attention as an alternative strategy to the discovery and development of novel anticancer drug candidates. In this study, we screened 321 FDA-approved drugs against nonirradiated and irradiated MCF-7 cells, revealing that aripiprazole, a dopamine receptor D2 (D2R) partial agonist, enhances the radiosensitivity of MCF-7 cells. Unexpectedly, D2R-selective antagonist treatment significantly enhanced the radiosensitizing effects of aripiprazole and prevented aripiprazole-induced 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. Direct AMPK activation with A769662 treatment blunted the radiosensitizing effects of aripiprazole. These results indicate that aripiprazole has potential as a radiosensitizing drug. Furthermore, prevention of D2R/AMPK activation might enhance these anticancer effects of aripiprazole in breast cancer cells.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos/farmacologia , Aripiprazol/antagonistas & inibidores , Antagonistas dos Receptores de Dopamina D2/farmacologia , Pironas/farmacologia , Receptores de Dopamina D2/metabolismo , Tiofenos/farmacologia , Apoptose/efeitos dos fármacos , Aripiprazol/farmacologia , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Ativação Enzimática , Humanos , Células MCF-7 , Fosforilação/efeitos dos fármacos , Receptores de Dopamina D2/agonistas , Células Tumorais Cultivadas
16.
Psychopharmacology (Berl) ; 236(12): 3497-3512, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31273401

RESUMO

RATIONALE: Analysis of lick pattern for sucrose and NaCl and of the forced swimming response after dopamine antagonist administration led us to suggest that dopamine on D1-like receptors is involved in behavioural activation, and the level of activation is "reboosted" on the basis of an evaluation process involving D2-like receptors. Although some studies investigated licking microstructure for water after dopamine antagonists, the within-session time course of their effect was never investigated. OBJECTIVES: The aims of this study were to further investigate the role of dopamine receptors in the mechanisms governing water ingestion, focussing on the within-session time course of the microstructure parameters, and to test the proposed hypothesis. MATERIALS AND METHODS: The effects of the dopamine D1-like receptor antagonist SCH 23390 (0.01-0.04 mg/kg) and of the dopamine D2-like receptor antagonist raclopride (0.025-0.25 mg/kg) on licking microstructure for water were examined in 20-h water-deprived rats in 30-min sessions. RESULTS: As previously observed with sucrose and NaCl, SCH 23390 reduced licking by reducing burst number, suggesting reduced behavioural activation. Moreover, it resulted in an increased burst size. Raclopride reduced the size of licking bursts, while their number was either increased or decreased depending on the dose. CONCLUSION: The results support the suggestion that D1 receptors are involved in behavioural activation and D2 receptors are involved in a related evaluation process. Within the framework of the proposed hypothesis, the increased burst size after D1-like receptor blockade might be interpreted as a pro-hedonic effect consequent to the increased cost of the activation of the licking response.


Assuntos
Comportamento de Ingestão de Líquido/fisiologia , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologia , Privação de Água/fisiologia , Água/administração & dosagem , Animais , Benzazepinas/farmacologia , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Ingestão de Alimentos/psicologia , Masculino , Racloprida/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/antagonistas & inibidores
17.
Psychopharmacology (Berl) ; 236(8): 2337-2358, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31324936

RESUMO

RATIONALE: Disorders of compulsivity such as stimulant use disorder (SUD) and obsessive-compulsive disorder (OCD) are characterised by deficits in behavioural flexibility, some of which have been captured using probabilistic reversal learning (PRL) paradigms. OBJECTIVES: This study used computational modelling to characterise the reinforcement learning processes underlying patterns of PRL behaviour observed in SUD and OCD and to show how the dopamine D2/3 receptor agonist pramipexole and the D2/3 antagonist amisulpride affected these responses. METHODS: We applied a hierarchical Bayesian method to PRL data across three groups: individuals with SUD, OCD, and healthy controls. Participants completed three sessions where they received placebo, pramipexole, and amisulpride, in a double-blind placebo-controlled, randomised design. We compared seven models using a bridge sampling estimate of the marginal likelihood. RESULTS: Stimulus-bound perseveration, a measure of the degree to which participants responded to the same stimulus as before irrespective of outcome, was significantly increased in SUD, but decreased in OCD, compared to controls (on placebo). Individuals with SUD also exhibited reduced reward-driven learning, whilst both the SUD and OCD groups showed increased learning from punishment (nonreward). Pramipexole and amisulpride had similar effects on the control and OCD groups; both increased punishment-driven learning. These D2/3-modulating drugs affected the SUD group differently, remediating reward-driven learning and reducing aspects of perseverative behaviour, amongst other effects. CONCLUSIONS: We provide a parsimonious computational account of how perseverative tendencies and reward- and punishment-driven learning differentially contribute to PRL in SUD and OCD. D2/3 agents modulated these processes and remediated deficits in SUD in particular, which may inform therapeutic effects.


Assuntos
Transtorno Obsessivo-Compulsivo/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Reforço Psicológico , Reversão de Aprendizagem/fisiologia , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Adulto , Estimulantes do Sistema Nervoso Central/uso terapêutico , Cognição/efeitos dos fármacos , Cognição/fisiologia , Agonistas de Dopamina/farmacologia , Agonistas de Dopamina/uso terapêutico , Antagonistas de Dopamina/farmacologia , Antagonistas de Dopamina/uso terapêutico , Antagonistas dos Receptores de Dopamina D2/farmacologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Neurológicos , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/psicologia , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/antagonistas & inibidores , Reversão de Aprendizagem/efeitos dos fármacos , Recompensa , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adulto Jovem
18.
Expert Rev Gastroenterol Hepatol ; 13(8): 711-721, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31314613

RESUMO

Introduction: Gastroparesis is a chronic disorder of the stomach characterized by delayed gastric emptying without mechanical obstruction. Diabetes is the most commonly known cause of gastroparesis. Management of diabetic gastroparesis involves lifestyle modifications, glycemic control, pharmacological drugs, and for refractory cases surgical treatments. Metoclopramide remains the only drug approved by the Food and Drug Administration for diabetic gastroparesis. The aim of this article is to provide a concise review of the pharmacology, clinical efficacy and tolerability of metoclopramide. Areas covered: We searched PubMed using the key words 'metoclopramide', 'diabetic gastroparesis', and 'gastric emptying'. The relevant articles and their bibliography were reviewed. Metoclopramide acts on several different receptors; primarily as a dopamine receptor antagonist, both peripherally improving gastric emptying, and centrally resulting in an anti-emetic effect. Metoclopramide side effects, mostly related to its ability to cross the blood-brain barrier, include drowsiness, restlessness, hyperprolactinemia, and tardive dyskinesia (TD), a movement disorder that may be irreversible. Expert opinion: Metoclopramide carries a black box warning for use >12 weeks due to the risk of TD. However, gastroparesis patients experience chronic symptoms often requiring prolonged treatments. Physicians and patients look forward to FDA approval of new agents for gastroparesis with better efficacy and safety profile.


Assuntos
Complicações do Diabetes/complicações , Antagonistas dos Receptores de Dopamina D2/uso terapêutico , Esvaziamento Gástrico/efeitos dos fármacos , Gastroparesia/tratamento farmacológico , Metoclopramida/uso terapêutico , Trato Gastrointestinal Superior/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2/efeitos adversos , Antagonistas dos Receptores de Dopamina D2/farmacologia , Gastroparesia/etiologia , Humanos , Metoclopramida/efeitos adversos , Metoclopramida/farmacologia , Resultado do Tratamento , Trato Gastrointestinal Superior/inervação
19.
Psychopharmacology (Berl) ; 236(8): 2307-2323, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31218428

RESUMO

RATIONALE: Dopamine D2-like receptors (D2R) are important drug targets in schizophrenia and Parkinson's disease, but D2R ligands also cause cognitive inflexibility such as poor reversal learning. The specific role of D2R in reversal learning remains unclear. OBJECTIVES: We tested the hypotheses that D2R agonism impairs reversal learning by blocking negative feedback and that antagonism of D1-like receptors (D1R) impairs learning from positive feedback. METHODS: Male Lister Hooded rats were trained on a novel visual reversal learning task. Performance on "probe trials", during which the correct or incorrect stimulus was presented with a third, probabilistically rewarded (50% of trials) and therefore intermediate stimulus, revealed individual learning curves for the processes of positive and negative feedback. The effects of D2R and D1R agonists and antagonists were evaluated. A separate cohort was tested on a spatial probabilistic reversal learning (PRL) task after D2R agonism. Computational reinforcement learning modelling was applied to choice data from the PRL task to evaluate the contribution of latent factors. RESULTS: D2R agonism with quinpirole dose-dependently impaired both visual reversal and PRL. Analysis of the probe trials on the visual task revealed a complete blockade of learning from negative feedback at the 0.25 mg/kg dose, while learning from positive feedback was intact. Estimated parameters from the model that best described the PRL choice data revealed a steep and selective decrease in learning rate from losses. D1R antagonism had a transient effect on the positive probe trials. CONCLUSIONS: D2R stimulation impairs reversal learning by blocking the impact of negative feedback.


Assuntos
Retroalimentação Fisiológica/fisiologia , Estimulação Luminosa/métodos , Receptores de Dopamina D2/metabolismo , Reversão de Aprendizagem/fisiologia , Percepção Espacial/fisiologia , Animais , Dopamina/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Retroalimentação Fisiológica/efeitos dos fármacos , Masculino , Ratos , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/agonistas , Reversão de Aprendizagem/efeitos dos fármacos , Percepção Espacial/efeitos dos fármacos , Percepção Visual/efeitos dos fármacos , Percepção Visual/fisiologia
20.
Psychopharmacology (Berl) ; 236(11): 3169-3182, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31172225

RESUMO

RATIONALE: Levo-tetrahydropalmatine (l-THP), an active ingredient of Corydalis yanhusuo, has been reported to be a partial agonist for dopamine D1 receptors (D1R) and an antagonist for D2R. Although it has been safely used clinically in China for decades as an analgesic with sedative/hypnotic properties, there are few studies that address the mechanisms by which l-THP exerts its beneficial effects in chronic pain-induced sleep disturbance. OBJECTIVES: To investigate the effects and mechanisms of l-THP on sleep disturbance in a neuropathic pain-like condition. METHODS: A mouse model of chronic neuropathic pain induced by partial sciatic nerve ligation (PSNL) was employed. The antinociceptive and hypnotic effects of l-THP were evaluated by measurement of mechanical allodynia, thermal hyperalgesia, and electroencephalogram (EEG) recordings in PSNL mice. Pharmacological approaches and c-Fos expression were used to clarify the mechanisms of l-THP. RESULTS: Intraperitoneal injection of l-THP at 5 and 10 mg/kg not only significantly increased the mechanical threshold by 134.4% and 174.8%, and prolonged the thermal latency by 49.4% and 69.2%, but also increased non-rapid eye movement sleep by 17.5% and 29.6%, and decreased sleep fragmentation in PSNL mice, compared with the vehicle control. Moreover, the antinociceptive effect of l-THP was prevented by D1R antagonist SCH23390 or D2R agonist quinpirole; meanwhile, the hypnotic effect of l-THP was blocked by quinpirole rather than by SCH23390. Immunohistochemistry demonstrated that l-THP inhibited c-Fos overexpression induced by PSNL in the cingulate cortex and the periaqueductal gray. CONCLUSIONS: These findings indicated that l-THP exerted analgesic effects by agonism D1R and antagonism D2R, and the antagonism of D2R mediated the hypnotic effect of l-THP in PSNL mice.


Assuntos
Analgésicos não Entorpecentes/uso terapêutico , Alcaloides de Berberina/uso terapêutico , Hipnóticos e Sedativos/uso terapêutico , Neuralgia/tratamento farmacológico , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologia , Analgésicos não Entorpecentes/farmacologia , Animais , Alcaloides de Berberina/farmacologia , Modelos Animais de Doenças , Antagonistas dos Receptores de Dopamina D2/farmacologia , Antagonistas dos Receptores de Dopamina D2/uso terapêutico , Eletroencefalografia/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuralgia/fisiopatologia , Receptores de Dopamina D1/agonistas
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