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1.
Elife ; 112022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35289748

RESUMO

Some theories of human cultural evolution posit that humans have social-specific learning mechanisms that are adaptive specialisations moulded by natural selection to cope with the pressures of group living. However, the existence of neurochemical pathways that are specialised for learning from social information and individual experience is widely debated. Cognitive neuroscientific studies present mixed evidence for social-specific learning mechanisms: some studies find dissociable neural correlates for social and individual learning, whereas others find the same brain areas and, dopamine-mediated, computations involved in both. Here, we demonstrate that, like individual learning, social learning is modulated by the dopamine D2 receptor antagonist haloperidol when social information is the primary learning source, but not when it comprises a secondary, additional element. Two groups (total N = 43) completed a decision-making task which required primary learning, from own experience, and secondary learning from an additional source. For one group, the primary source was social, and secondary was individual; for the other group this was reversed. Haloperidol affected primary learning irrespective of social/individual nature, with no effect on learning from the secondary source. Thus, we illustrate that dopaminergic mechanisms underpinning learning can be dissociated along a primary-secondary but not a social-individual axis. These results resolve conflict in the literature and support an expanding field showing that, rather than being specialised for particular inputs, neurochemical pathways in the human brain can process both social and non-social cues and arbitrate between the two depending upon which cue is primarily relevant for the task at hand.


Assuntos
Dopamina , Haloperidol , Sinais (Psicologia) , Dopamina/metabolismo , Antagonistas dos Receptores de Dopamina D2/farmacologia , Haloperidol/farmacologia , Humanos , Receptores de Dopamina D2 , Recompensa
2.
Proc Natl Acad Sci U S A ; 119(11): e2118570119, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35263227

RESUMO

SignificanceDespite the identification of neural circuits and circulating hormones in olfactory regulation, the peripheral targets for olfactory modulation remain relatively unexplored. Here we show that dopamine D2 receptor (DRD2) is expressed in the cilia and somata of mature olfactory sensory neurons (OSNs), while nasal dopamine (DA) is mainly released from the sympathetic nerve terminals, which innervate the mouse olfactory mucosa (OM). We further demonstrate that DA-DRD2 signaling in the nose plays important roles in regulating olfactory function using genetic and pharmacological approaches. Moreover, the local DA synthesis in mouse OM is reduced during hunger, which contributes to starvation-induced olfactory enhancement. Altogether, we demonstrate that nasal DA and DRD2 receptor can serve as the potential peripheral targets for olfactory modulation.


Assuntos
Dopamina , Neurônios Receptores Olfatórios , Receptores de Dopamina D2 , Animais , Dopamina/metabolismo , Antagonistas dos Receptores de Dopamina D2/farmacologia , Humanos , Camundongos , Neurônios Receptores Olfatórios/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Transdução de Sinais , Olfato
3.
Molecules ; 27(4)2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-35209087

RESUMO

Long-chain arylpiperazine scaffold is a versatile template to design central nervous system (CNS) drugs that target serotonin and dopamine receptors. Here we describe the synthesis and biological evaluation of ten new arylpiperazine derivatives designed to obtain an affinity profile at serotonin 5-HT1A, 5-HT2A, 5-HT7 receptor, and dopamine D2 receptor of prospective drugs to treat the core symptoms of autism spectrum disorder (ASD) or psychosis. Besides the structural features required for affinity at the target receptors, the new compounds incorporated structural fragments with antioxidant properties to counteract oxidative stress connected with ASD and psychosis. All the new compounds showed CNS MultiParameter Optimization score predictive of desirable ADMET properties and cross the blood-brain barrier. We identified compound 12a that combines an affinity profile compatible with antipsychotic activity (5-HT1AKi = 41.5 nM, 5-HT2AKi = 315 nM, 5-HT7Ki = 42.5 nM, D2Ki = 300 nM), and compound 9b that has an affinity profile consistent with studies in the context of ASD (5-HT1AKi = 23.9 nM, 5-HT2AKi = 39.4 nM, 5-HT7Ki = 45.0 nM). Both compounds also had antioxidant properties. All compounds showed low in vitro metabolic stability, the only exception being compound 9b, which might be suitable for studies in vivo.


Assuntos
Técnicas de Química Sintética , Desenho de Fármacos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2 , Humanos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Receptores Dopaminérgicos/química , Receptores Dopaminérgicos/metabolismo , Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , Relação Estrutura-Atividade
4.
Behav Brain Res ; 422: 113748, 2022 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-35038463

RESUMO

Repetitive motor behaviors are repetitive and invariant movements with no apparent function, and are common in several neurological and neurodevelopmental disorders, including autism spectrum disorders (ASD). However, the neuropathology associated with the expression of these abnormal stereotypic movements is not well understood, and effective treatments are lacking. The ketogenic diet (KD) has been used for almost a century to treat intractable epilepsy and, more recently, disorders associated with inflexibility of behavioral routines. Here, we show a novel application for KD to reduce an abnormal repetitive circling behavior in a rodent model. We then explore potential mediation through the striatum, as dysregulation of cortico-basal ganglia circuitry has previously been implicated in repetitive motor behavior. In Experiments 1 and 2, adult FVB mice were assessed for levels of repetitive circling across a 3-week baseline period. Mice were then switched to KD and repetitive circling was assessed for an additional 3 weeks. In Experiment 1, time on KD was associated with reduced repetitive behavior. In Experiment 2, we replicated these benefits of KD and assessed dendritic spine density in the striatum as one potential mechanism for reducing repetitive behavior, which yielded no differences. In Experiment 3, adult female circling mice were given a single administration of a dopamine D2 receptor antagonist (L-741,646) that was associated with reduced repetitive behavior over time. Future research will explore the relationship between KD and dopamine within basal ganglia nuclei that may be influencing the benefits of KD on repetitive behavior.


Assuntos
Comportamento Animal , Sintomas Comportamentais/dietoterapia , Sintomas Comportamentais/tratamento farmacológico , Dieta Cetogênica , Antagonistas dos Receptores de Dopamina D2/farmacologia , Comportamento Estereotipado , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Antagonistas dos Receptores de Dopamina D2/administração & dosagem , Feminino , Masculino , Camundongos , Comportamento Estereotipado/efeitos dos fármacos , Comportamento Estereotipado/fisiologia
5.
Behav Brain Res ; 417: 113611, 2022 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-34592376

RESUMO

Fear extinction (FExt) is used to treat patients with posttraumatic stress disorder (PTSD). However, fear related to traumatic events can be persistent and return even after successful extinction. The neurochemical control of extinction seems to be performed by several neurotransmitters, including dopamine (DA), through D1 and D2 receptors. Recently, we showed that intranasally applied DA (IN-DA) facilitated the FExt, but the mechanisms by which it promoted this effect are still unknown. This study focused on investigating whether these effects are mediated by the action of DA on D2-like receptors since these receptors seem to be related to neurochemical and molecular changes underlying extinction. Also, we investigated whether IN-DA treatment would affect conditioned fear-induced antinociception (Fear-IA). Rats treated with IN-DA (1 mg/kg) twenty-five minutes after sulpiride (SUL; 40 mg/kg, i.p., D2-antagonist) were subjected to the extinction of contextual fear. IN-DA applied before the extinction session induced the FExt and prevented Fear-IA. These effects were impaired by pre-treatment with SUL, suggesting that the IN-DA effects are mediated by DA on D2-like receptors. SUL per se also facilitated the FExt but did not affect Fear-IA. These data suggest IN-DA as a promising pharmacological tool to supplement the psychotherapy of patients suffering from PTSD.


Assuntos
Condicionamento Psicológico/fisiologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Dopamina/farmacologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Receptores de Dopamina D2/fisiologia , Sulpirida/farmacologia , Administração Intranasal , Animais , Condicionamento Psicológico/efeitos dos fármacos , Dopaminérgicos/farmacologia , Extinção Psicológica/efeitos dos fármacos , Masculino , Ratos , Sulpirida/antagonistas & inibidores
6.
Pharmacol Res Perspect ; 10(1): e00903, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34918875

RESUMO

Metopimazine (MPZ) is a peripherally restricted, dopamine D2 receptor antagonist used for four decades to treat acute nausea and vomiting. MPZ is currently under clinical investigation for the treatment of gastroparesis (GP). MPZ undergoes high first-pass metabolism that produces metopimazine acid (MPZA), the major circulating metabolite in humans. Despite a long history of use, the enzymes involved in the metabolism of MPZ have not been identified. Here we report a series of studies designed to identify potential MPZ metabolites in vitro, determine their clinical relevance in humans, and elucidate the enzymes responsible for their formation. The findings demonstrated that the formation of MPZA was primarily catalyzed by human liver microsomal amidase. Additionally, human liver cytosolic aldehyde oxidase (AO) catalyzes the formation of MPZA, in vitro, although to a much lesser extent. Neither cytochrome P450 enzymes nor flavin-monooxygenases (FMO) were involved in the formation MPZA, although two minor oxidative pathways were catalyzed by CYP3A4 and CYP2D6 in vitro. Analysis of plasma samples from subjects dosed 60 mg of MPZ verified that these oxidative pathways are very minor and that CYP enzyme involvement was negligible compared to microsomal amidase/hydrolase in overall MPZ metabolism in humans. The metabolism by liver amidase, an enzyme family not well defined in small molecule drug metabolism, with minimal metabolism by CYPs, differentiates this drug from current D2 antagonists used or in development for the treatment of GP.


Assuntos
Amidoidrolases/metabolismo , Antagonistas dos Receptores de Dopamina D2/metabolismo , Ácidos Isonipecóticos/metabolismo , Microssomos Hepáticos/metabolismo , Adolescente , Adulto , Animais , Antieméticos/metabolismo , Estudos de Coortes , Sistema Enzimático do Citocromo P-450/metabolismo , Cães , Método Duplo-Cego , Feminino , Humanos , Masculino , Microssomos Hepáticos/enzimologia , Pessoa de Meia-Idade , Ratos , Ratos Sprague-Dawley , Adulto Jovem
7.
Physiol Rep ; 9(21): e15088, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34762352

RESUMO

Neuronal networks cause changes in behaviorally important information processing through the vesicular release of neurotransmitters governed by the rate and timing of action potentials (APs). Herein, we provide evidence that dopamine (DA), nonquantally released from the cytoplasm, may exert similar effects in vivo. In mouse slice preparations, (+/-)-3,4-methylenedioxy-methamphetamine (MDMA, or ecstasy) and ß-phenylethylamine (ß-PEA)-induced DA release in the striatum and nucleus accumbens (NAc), two regions of the brain involved in reward-driven and social behavior and inhibited the axonal stimulation-induced release of tritiated acetylcholine ([3 H]ACh) in the striatum. The DA transporter (DAT) inhibitor (GBR-12909) prevented MDMA and ß-PEA from causing DA release. GBR-12909 could also restore some of the stimulated acetylcholine release reduced by MDMA or ß-PEA in the striatum confirming the fundamental role of DAT. In addition, hypothermia could prevent the ß-PEA-induced release in the striatum and in the NAc. Sulpiride, a D2 receptor antagonist, also prevented the inhibitory effects of MDMA or ß-PEA on stimulated ACh release, suggesting they act indirectly via binding of DA. Reflecting the neurochemical interactions in brain slices at higher system level, MDMA altered the social behavior of rats by preferentially enhancing passive social behavior. Similar to the in vitro effects, GBR-12909 treatment reversed specific elements of the MDMA-induced changes in behavior, such as passive social behavior, while left others including social play unchanged. The changes in behavior by the high level of extracellular DA-- a significant amount originating from cytoplasmic release--suggest that in addition to digital computation through synapses, the brain also uses analog communication, such as DA signaling, to mediate some elements of complex behaviors, but in a much longer time scale.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Dopamina/metabolismo , Serotonina/metabolismo , Transdução de Sinais , Comportamento Social , Animais , Corpo Estriado/citologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Antagonistas dos Receptores de Dopamina D2/farmacologia , Masculino , Camundongos , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Núcleo Accumbens/citologia , Núcleo Accumbens/metabolismo , Fenetilaminas/farmacologia , Psicotrópicos/farmacologia , Ratos , Ratos Wistar , Receptores de Dopamina D2/metabolismo , Sulpirida/farmacologia
8.
Neurobiol Learn Mem ; 186: 107538, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34737042

RESUMO

We evaluated interactions between dopamine D2 receptor and nitric oxide (NO) actions on the regulation of anxiety and memory in the 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease (PD). A unilateral guide cannula was stereotaxically implanted over the right striatum. Elevated plus-maze test (EPM) test-retest protocol was employed to evaluate anxiety and memory in mice. The results revealed that injection of L-NAME (9 mg/kg) induced anxiolytic and amnesic effects, while L-arginine (9 mg/kg) produced anxiogenic and memory-improvement effects in the 6-OHDA mouse model of PD. Administration of sulpiride (20 mg/kg) induced anxiogenic and memory-improvement effects, whereas quinpirole (20 mg/kg) caused anxiolytic and amnesic effects in PD mice. Co-injection of sulpiride (5, 10, and 20 mg/kg) plus L-NAME (3 mg/kg) induced anxiolytic and amnesic effects. Co-injection of sulpiride (20 mg/kg) plus L-arginine (3 mg/kg) induced anxiogenic and memory-improvement effects. Co-administrations of quinpirole (20 mg/kg) and L-NAME (3 mg/kg) induced anxiolytic effect, but co-administration of quinpirole (20 mg/kg) plus L-arginine (3 mg/kg) caused anxiogenic and memory-improvement effects. The isobologram analysis revealed that there is a synergistic effect between sulpiride and L-arginine as well as quinpirole and L-NAME upon induction of anxiogenic and anxiolytic effects, respectively in PD mice. Our results suggested: (1) NO and dopamine D2 receptor mechanisms affect anxiety and memory in PD mice; (2) L-NAME reversed anxiogenic and memory-improvement effect induced by sulpiride; (3) Anxiolytic and amnesic effects induced by quinpirole reversed by L-arginine; (4) There is a synergistic effect between dopamine D2 receptor and NO systems on the modulation of anxiety and memory.


Assuntos
Arginina/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Inibidores Enzimáticos/farmacologia , Doença de Parkinson/fisiopatologia , Quimpirol/farmacologia , Sulpirida/farmacologia , Adrenérgicos/farmacologia , Animais , Ansiedade/tratamento farmacológico , Ansiedade/fisiopatologia , Modelos Animais de Doenças , Antagonistas dos Receptores de Dopamina D2/farmacologia , Quimioterapia Combinada , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Camundongos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/farmacologia , Oxidopamina/farmacologia , Receptores de Dopamina D2/fisiologia
9.
eNeuro ; 8(5)2021.
Artigo em Inglês | MEDLINE | ID: mdl-34556558

RESUMO

Dopaminergic modulation is essential for the control of voluntary movement; however, the role of dopamine in regulating the neural excitability of the primary motor cortex (M1) is not well understood. Here, we investigated two modes by which dopamine influences the input/output function of M1 neurons. To test the direct regulation of M1 neurons by dopamine, we performed whole-cell recordings of excitatory neurons and measured excitability before and after local, acute dopamine receptor blockade. We then determined whether chronic depletion of dopaminergic input to the entire motor circuit, via a mouse model of Parkinson's disease, was sufficient to shift M1 neuron excitability. We show that D1 receptor (D1R) and D2R antagonism altered subthreshold and suprathreshold properties of M1 pyramidal neurons in a layer-specific fashion. The effects of D1R antagonism were primarily driven by changes to intrinsic properties, while the excitability shifts following D2R antagonism relied on synaptic transmission. In contrast, chronic depletion of dopamine to the motor circuit with 6-hydroxydopamine induced layer-specific synaptic transmission-dependent shifts in M1 neuron excitability that only partially overlapped with the effects of acute D1R antagonism. These results suggest that while acute and chronic changes in dopamine modulate the input/output function of M1 neurons, the mechanisms engaged are distinct depending on the duration and origin of the manipulation. Our study highlights the broad influence of dopamine on M1 excitability by demonstrating the consequences of local and global dopamine depletion on neuronal input/output function.


Assuntos
Dopamina , Córtex Motor , Animais , Antagonistas dos Receptores de Dopamina D2 , Camundongos , Córtex Motor/metabolismo , Neurônios/metabolismo , Células Piramidais/metabolismo , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo
10.
Elife ; 102021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-34542411

RESUMO

Social behavior is a hallmark of complex animal systems; however, some species appear to have secondarily lost this social ability. In these non-social species, whether social abilities are permanently lost or suppressed is unclear. The blind cavefish Astyanax mexicanus is known to be asocial. Here, we reveal that cavefish exhibited social-like interactions in familiar environments but suppressed these interactions in stress-associated unfamiliar environments. Furthermore, the level of suppression in sociality was positively correlated with that of stereotypic repetitive behavior, as seen in mammals. Treatment with a human antipsychotic drug targeting the dopaminergic system induced social-like interactions in cavefish, even in unfamiliar environments, while reducing repetitive behavior. Overall, these results suggest that the antagonistic association between repetitive and social-like behaviors is deeply shared from teleosts through mammals.


Assuntos
Comportamento Animal , Characidae/fisiologia , Comportamento Social , Comportamento Estereotipado , Animais , Antipsicóticos/farmacologia , Aripiprazol/farmacologia , Comportamento Animal/efeitos dos fármacos , Cegueira , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/fisiologia , Ecossistema , Sistema da Linha Lateral/fisiologia , Mecanorreceptores/fisiologia , Mecanotransdução Celular , Reconhecimento Psicológico , Comportamento Estereotipado/efeitos dos fármacos , Natação , Fatores de Tempo , Gravação em Vídeo
11.
Am J Emerg Med ; 50: 376-380, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34474267

RESUMO

INTRODUCTION: Headache is one of the most common neurological conditions among emergency department visits (ED), although the best therapy has not been identified yet. Therefore, in the current study, we aimed to compare the pain-relieving effect of metoclopramide and ketorolac in acute primary headaches patients. METHODS: This double-blind, randomised clinical trial was conducted at Golestan Hospital, Ahvaz, Iran. This research involved all adult patients with acute primary (migraine or tension-type) headaches presented to the ED. Pain intensity was assessed with 0 to 10 verbal Numeric Rating Scales (NRS). The subjects were randomised into 10 mg intravenous (IV) metoclopramide or 30 mg IV ketorolac groups. Pain score and drug adverse reactions were compared between the two groups at baseline, 15, 30, and 60 min after baseline. RESULTS: 108 patients completed this trial and were equally divided into two groups (mean age of 34 ± 8.54 years; 57.4% female). Before treatment, the mean pain score was 6.9 and 6.8 in metoclopramide and ketorolac groups, respectively (p > 0.05). Metoclopramide failed to provide more improvement in pain score at 30 min (p = 0.55) and 60 min (p = 0.15) from baseline. There were no serious adverse events in this study. Only five patients required rescue medication which four of them were in ketorolac group. CONCLUSION: We were unable to reject the null hypothesis that there would be no difference in pain outcomes between metoclopramide and ketorolac.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Antagonistas dos Receptores de Dopamina D2/administração & dosagem , Cefaleia/tratamento farmacológico , Cetorolaco/administração & dosagem , Metoclopramida/administração & dosagem , Administração Intravenosa , Adulto , Serviço Hospitalar de Emergência , Feminino , Humanos , Masculino , Medição da Dor
12.
Neuropharmacology ; 200: 108786, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34516984

RESUMO

Impulsive action can be defined as the inability to withhold a response and represents one of the dimensions of the broad construct impulsivity. Here, we characterized a modified differential reinforcement of low rates of responding (DRL) task developed in our laboratory, in which impulsive action is measured in ad libitum fed/watered subjects. Specifically, we first determined the effects of both sex and estrous cycle on impulsive action by systematically comparing male and estrous-synchronized female subjects. In addition, we evaluated the convergent validity of this modified DRL task by testing the effects of the D2R/5HT2AR antagonist, aripiprazole, and the noncompetitive NMDAR antagonist, MK-801. Finally, we tested the effects of the selective antagonist BD-1063 and agonist PRE-084 of Sigma-1 receptor (Sig-1R) on impulsive action using this modified DRL task. We found that female rats showed and increased inability to withhold a response when compared to males, and this effect was driven by the metestrus/diestrus phase of the estrous cycle. In addition, aripiprazole and MK-801 fully retained their capability to reduce and increase impulsive action, respectively. Finally, the selective Sig-1R antagonist, BD-1063 dose-dependently reduced the inability to withhold a response in both sexes, though more potently in female rats. In summary, we show that impulsive action, as measured in a modified DRL task which minimizes energy-homeostatic influences, is a function of both sex and estrous cycle. Furthermore, we validate the convergent validity of the task and provide evidence that Sig-1R antagonism may represent a novel pharmacological strategy to reduce impulsive action.


Assuntos
Aripiprazol/farmacologia , Comportamento Animal/efeitos dos fármacos , Maleato de Dizocilpina/farmacologia , Comportamento Impulsivo/efeitos dos fármacos , Piperazinas/farmacologia , Receptores sigma/efeitos dos fármacos , Animais , Comportamento de Escolha/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2/farmacologia , Ciclo Estral/efeitos dos fármacos , Feminino , Masculino , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia
13.
Mol Neurobiol ; 58(11): 5667-5681, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34387814

RESUMO

The activity of the midbrain dopamine system reflects the valence of environmental events and modulates various brain structures to modify an organism's behavior. A series of recent studies reported that the direct and indirect pathways in the striatum are critical for instrumental learning, but the dynamic changes in dopamine neuron activity that occur during negative reinforcement learning are still largely unclear. In the present study, by using a negative reinforcement learning paradigm employing foot shocks as aversive stimuli, bidirectional changes in substantia nigra pars compacta (SNc) dopamine neuron activity in the learning and habituation phases were observed. The results showed that in the learning phase, before mice had mastered the skill of escaping foot shocks, the presence of foot shocks induced a transient reduction in the activity of SNc dopamine neurons; however, in the habituation phase, in which the learned skill was automated, it induced a transient increase. Microinjection of a dopamine D1 receptor (D1R) or D2 receptor (D2R) antagonist into the dorsomedial striatum (DMS) significantly impaired learning behavior, suggesting that the modulatory effects of dopamine on both the direct and indirect pathways are required. Moreover, during the learning phase, excitatory synaptic transmission to DMS D2R-expressing medium spiny neurons (D2-MSNs) was potentiated. However, upon completion of the learning and habituation phases, the synapses onto D1R-expressing medium spiny neurons (D1-MSNs) were potentiated, and those onto D2-MSNs were restored to normal levels. The bidirectional changes in both SNc dopamine neuron activity and DMS synaptic plasticity might be the critical neural correlates for negative reinforcement learning.


Assuntos
Dopamina/fisiologia , Neurônios Dopaminérgicos/fisiologia , Mesencéfalo/fisiologia , Reforço Psicológico , Animais , Benzazepinas/farmacologia , Corpo Estriado/fisiologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Eletrochoque , Vetores Genéticos/administração & dosagem , Vetores Genéticos/farmacologia , Ácido Glutâmico/metabolismo , Habituação Psicofisiológica/efeitos dos fármacos , Habituação Psicofisiológica/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologia , Proteínas Recombinantes/metabolismo , Análise de Célula Única , Sacarose , Transmissão Sináptica
15.
Neurogastroenterol Motil ; 33(8): e14237, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34399024

RESUMO

BACKGROUND: Gastroparesis is a condition characterized by epigastric symptoms and delayed gastric emptying (GE) rate in the absence of any mechanical obstruction. The condition is challenging in clinical practice by the lack of guidance concerning diagnosis and management of gastroparesis. METHODS: A Delphi consensus was undertaken by 40 experts from 19 European countries who conducted a literature summary and voting process on 89 statements. Quality of evidence was evaluated using grading of recommendations assessment, development, and evaluation criteria. Consensus (defined as ≥80% agreement) was reached for 25 statements. RESULTS: The European consensus defined gastroparesis as the presence of symptoms associated with delayed GE in the absence of mechanical obstruction. Nausea and vomiting were identified as cardinal symptoms, with often coexisting postprandial distress syndrome symptoms of dyspepsia. The true epidemiology of gastroparesis is not known in detail, but diabetes, gastric surgery, certain neurological and connective tissue diseases, and the use of certain drugs recognized as risk factors. While the panel agreed that severely impaired gastric motor function is present in these patients, there was no consensus on underlying pathophysiology. The panel agreed that an upper endoscopy and a GE test are required for diagnosis. Only dietary therapy, dopamine-2 antagonists and 5-HT4 receptor agonists were considered appropriate therapies, in addition to nutritional support in case of severe weight loss. No consensus was reached on the use of proton pump inhibitors, other classes of antiemetics or prokinetics, neuromodulators, complimentary, psychological, or more invasive therapies. Finally, there was consensus that gastroparesis adversely impacts on quality of life and healthcare costs and that the long-term prognosis of gastroparesis depends on the cause. CONCLUSIONS AND INFERENCES: A multinational group of European experts summarized the current state of consensus on definition, symptom characteristics, pathophysiology, diagnosis, and management of gastroparesis.


Assuntos
Antagonistas dos Receptores de Dopamina D2/uso terapêutico , Gastroparesia/diagnóstico , Antagonistas do Receptor 5-HT4 de Serotonina/uso terapêutico , Consenso , Endoscopia do Sistema Digestório , Gastroparesia/dietoterapia , Gastroparesia/tratamento farmacológico , Humanos , Apoio Nutricional , Qualidade de Vida
16.
Mol Pharmacol ; 100(4): 372-387, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34353882

RESUMO

ONC201 is a first-in-class imipridone compound that is in clinical trials for the treatment of high-grade gliomas and other advanced cancers. Recent studies identified that ONC201 antagonizes D2-like dopamine receptors at therapeutically relevant concentrations. In the current study, characterization of ONC201 using radioligand binding and multiple functional assays revealed that it was a full antagonist of the D2 and D3 receptors (D2R and D3R) with low micromolar potencies, similar to its potency for antiproliferative effects. Curve-shift experiments using D2R-mediated ß-arrestin recruitment and cAMP assays revealed that ONC201 exhibited a mixed form of antagonism. An operational model of allostery was used to analyze these data, which suggested that the predominant modulatory effect of ONC201 was on dopamine efficacy with little to no effect on dopamine affinity. To investigate how ONC201 binds to the D2R, we employed scanning mutagenesis coupled with a D2R-mediated calcium efflux assay. Eight residues were identified as being important for ONC201's functional antagonism of the D2R. Mutation of these residues followed by assessing ONC201 antagonism in multiple signaling assays highlighted specific residues involved in ONC201 binding. Together with computational modeling and simulation studies, our results suggest that ONC201 interacts with the D2R in a bitopic manner where the imipridone core of the molecule protrudes into the orthosteric binding site, but does not compete with dopamine, whereas a secondary phenyl ring engages an allosteric binding pocket that may be associated with negative modulation of receptor activity. SIGNIFICANCE STATEMENT: ONC201 is a novel antagonist of the D2 dopamine receptor with demonstrated efficacy in the treatment of various cancers, especially high-grade glioma. This study demonstrates that ONC201 antagonizes the D2 receptor with novel bitopic and negative allosteric mechanisms of action, which may explain its high selectivity and some of its clinical anticancer properties that are distinct from other D2 receptor antagonists widely used for the treatment of schizophrenia and other neuropsychiatric disorders.


Assuntos
Antineoplásicos/metabolismo , Antagonistas dos Receptores de Dopamina D2/metabolismo , Imidazóis/metabolismo , Piridinas/metabolismo , Pirimidinas/metabolismo , Receptores de Dopamina D2/metabolismo , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Células CHO , Cricetinae , Cricetulus , Antagonistas dos Receptores de Dopamina D2/química , Antagonistas dos Receptores de Dopamina D2/farmacologia , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Imidazóis/química , Imidazóis/farmacologia , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Estrutura Secundária de Proteína , Piridinas/química , Piridinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Receptores de Dopamina D2/química
17.
Eur J Pharmacol ; 910: 174443, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34464604

RESUMO

Rotigotine-loaded microspheres (RoMS), a sustained-release formulation with a continuous release of rotigotine for more than 7 days in vivo, have been conducted a clinical trial for the treatment of Parkinson's disease (PD). Previous work from our laboratory showed that RoMS exerted an antinociceptive effect in rat models of inflammatory pain. The purpose of this study was to investigate the mechanisms of action underlying the antinociceptive effect of RoMS. A rat model of inflammatory pain was prepared by an intraplantar injection of carrageenan. The hot plate test and the Randall-Selitto test were used to evaluate the effect of domperidone (selective D2 receptor antagonist), D2D3 shRNA, and naloxone (nonselective opioid receptor antagonist) on RoMS-mediated antinociceptive efficacy. The expressions of D2 and D3 receptors in the striatum and periaqueductal gray were measured by Western blotting. Intracerebroventricular injection of domperidone abated the antinociceptive effect of RoMS. However, intraperitoneal injection of domperidone had no significant effect on the antinociceptive action of RoMS. Intracerebroventricular injection with D2D3 shRNA significantly attenuated the expressions of D2 and D3 receptors in the striatum and the periaqueductal gray. D2 and D3 receptors silence significantly weakened RoMS-mediated antinociceptive effect. Intracerebroventricular injection of naloxone also alleviated the antinociceptive effect of RoMS. The results suggest that RoMS-mediated antinociceptive efficacy is associated with activating central dopamine D2 and D3 receptors. Opioid receptors play a role in the antinociceptive effect of RoMS.


Assuntos
Analgésicos/farmacologia , Dopaminérgicos/farmacologia , Dopamina/metabolismo , Microesferas , Dor/tratamento farmacológico , Tetra-Hidronaftalenos/farmacologia , Tiofenos/farmacologia , Analgésicos/administração & dosagem , Animais , Carragenina/toxicidade , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Domperidona/administração & dosagem , Domperidona/farmacologia , Dopaminérgicos/administração & dosagem , Antagonistas dos Receptores de Dopamina D2/administração & dosagem , Antagonistas dos Receptores de Dopamina D2/farmacologia , Inflamação/tratamento farmacológico , Inflamação/etiologia , Injeções , Masculino , Naloxona/administração & dosagem , Naloxona/farmacologia , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/farmacologia , Dor/etiologia , Substância Cinzenta Periaquedutal/metabolismo , Ratos Sprague-Dawley , Receptores de Dopamina D2/genética , Receptores de Dopamina D3/genética , Estresse Mecânico , Temperatura , Tetra-Hidronaftalenos/administração & dosagem , Tiofenos/administração & dosagem
19.
Behav Brain Res ; 414: 113488, 2021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-34329670

RESUMO

In humans, adverse childhood experiences are associated with an increased risk of developing a neuropsychiatric disorder. Changes in social behavior and cognitive function are hallmarks of numerous neuropsychiatric disorders. Here we examined the effects of exposure to variable stress during the juvenile period on social behavior, reward, and cognitive function (as measured in the 5-choice serial reaction time task (5CSRTT)) in rats. From postnatal days (PND) 25-29 male and female rats were exposed to a variable stress protocol. In adulthood, social interactions and sucrose preference were assessed prior to training on the 5CSRTT. Once successfully trained, rats were challenged with different task versions, and then the effects of cocaine (0, 10, or 20 mg/kg, IP) on performance were assessed. A follow-up experiment examined the ability of the D2 receptor antagonist eticlopride (0.0, 0.025, 0.05 mg/kg, IP) to block the effects of cocaine on 5CSRTT performance in female rats. Male rats exposed to juvenile stress tended to engage in less social behavior and had an increased correct response latency in the 5CSRTT following cocaine administration. Female rats exposed to juvenile stress exhibited a trend towards increased social behavior and demonstrated increased cocaine-induced impulsivity. The increase in impulsivity was not blocked by co-administration of eticlopride. Juvenile stress had minimal effects on adult behavior in male rats, but increased cocaine-induced impulsivity in female rats. Such an effect could contribute to the enhanced escalation of drug-use observed in females that experience juvenile stress. This possibility awaits further testing.


Assuntos
Comportamento Animal , Cocaína/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Comportamento Impulsivo , Comportamento Social , Fatores Etários , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Cocaína/administração & dosagem , Antagonistas dos Receptores de Dopamina D2/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Feminino , Comportamento Impulsivo/efeitos dos fármacos , Comportamento Impulsivo/fisiologia , Masculino , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Ratos , Ratos Sprague-Dawley , Salicilamidas/farmacologia , Fatores Sexuais , Estresse Psicológico
20.
Int J Neuropsychopharmacol ; 24(11): 867-878, 2021 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-34197589

RESUMO

BACKGROUND: Drug-induced alterations to the dopamine system in stimulant use disorder (SUD) are hypothesized to impair reinforcement learning (RL). Computational modeling enables the investigation of the latent processes of RL in SUD patients, which could elucidate the nature of their impairments. METHODS: We investigated RL in 44 SUD patients and 41 healthy control participants using a probabilistic RL task that assesses learning from reward and punishment separately. In an independent sample, we determined the modulatory role of dopamine in RL following a single dose of the dopamine D2/3 receptor antagonist amisulpride (400 mg) and the agonist pramipexole (0.5 mg) in a randomised, double-blind, placebo-controlled, crossover design. We analyzed task performance using computational modelling and hypothesized that RL impairments in SUD patients would be differentially modulated by a dopamine D2/3 receptor antagonist and agonist. RESULTS: Computational analyses in both samples revealed significantly reduced learning rates from punishment in SUD patients compared with healthy controls, whilst their reward learning rates were not measurably impaired. In addition, the dopaminergic receptor agents modulated RL parameters differentially in both groups. Both amisulpride and pramipexole impaired RL parameters in healthy participants, but ameliorated learning from punishment in SUD patients. CONCLUSION: Our findings suggest that RL impairments seen in SUD patients are associated with altered dopamine function.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Dopamina/metabolismo , Reforço Psicológico , Adulto , Estimulantes do Sistema Nervoso Central/farmacologia , Simulação por Computador , Corpo Estriado/metabolismo , Estudos Cross-Over , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2/uso terapêutico , Método Duplo-Cego , Retroalimentação , Humanos , Masculino , Pramipexol/farmacologia , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Recompensa
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