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1.
Science ; 367(6477): 549-555, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32001651

RESUMO

Extinction learning allows animals to withhold voluntary actions that are no longer related to reward and so provides a major source of behavioral control. Although such learning is thought to depend on dopamine signals in the striatum, the way the circuits that mediate goal-directed control are reorganized during new learning remains unknown. Here, by mapping a dopamine-dependent transcriptional activation marker in large ensembles of spiny projection neurons (SPNs) expressing dopamine receptor type 1 (D1-SPNs) or 2 (D2-SPNs) in mice, we demonstrate an extensive and dynamic D2- to D1-SPN transmodulation across the striatum that is necessary for updating previous goal-directed learning. Our findings suggest that D2-SPNs suppress the influence of outdated D1-SPN plasticity within functionally relevant striatal territories to reshape volitional action.


Assuntos
Corpo Estriado/fisiologia , Neurônios Dopaminérgicos/fisiologia , Objetivos , Aprendizagem/fisiologia , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologia , Animais , Corpo Estriado/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nucleossomos/metabolismo , Racloprida/farmacologia , Receptores de Dopamina D1/antagonistas & inibidores
2.
J Neurochem ; 153(3): 334-345, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31985073

RESUMO

Brain endocannabinoids serve as retrograde neurotransmitters, being synthesized in post-synaptic neurons "on demand" and released to bind pre-synaptic cannabinoid receptors and suppress glutamatergic or GABAergic transmission. The most abundant brain endocannabinoid, 2 arachidonoyl glycerol (2-AG), is primarily synthesized by diacylglycerol lipase-α (DGLα), which is activated by poorly understood mechanisms in response to calcium influx following post-synaptic depolarization and/or the activation of Gq -coupled group 1 metabotropic glutamate receptors. However, the impact of other neurotransmitters and their downstream signaling pathways on synaptic 2-AG signaling has not been intensively studied. Here, we found that DGLα activity in membrane fractions from transfected HEK293T cells was significantly increased by in vitro phosphorylation using cyclic AMP-dependent protein kinase (PKA). Moreover, PKA directly phosphorylated DGLα at Ser798 in vitro. Elevation of cAMP levels in HEK293 cells expressing DGLα increased Ser798 phosphorylation, as detected using a phospho-Ser798-specific antibody, and enhanced DGLα activity; this in situ enhancement of DGLα activity was prevented by mutation of Ser798 to Ala. We investigated the impact of PKA on synaptic 2-AG mobilization in mouse striatal slices by manipulating D1-dopamine receptor (D1R) signaling and assessing depolarization-induced suppression of excitation, a DGLα- and 2-AG-dependent form of short-term synaptic depression. The magnitude of depolarization-enhanced suppression of excitation in direct pathway medium spiny neurons was increased by pre-incubation with a D1R agonist, and this enhancement was blocked by post-synaptic inhibition of PKA. Taken together, these findings provide new molecular insights into the complex mechanisms regulating synaptic endocannabinoid signaling.


Assuntos
Ácidos Araquidônicos/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Endocanabinoides/metabolismo , Glicerídeos/metabolismo , Lipase Lipoproteica/metabolismo , Receptores de Dopamina D1/metabolismo , Transdução de Sinais/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Cultura de Órgãos , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos
3.
Psychopharmacology (Berl) ; 237(4): 1107-1119, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31927604

RESUMO

RATIONALE: Mesolimbic dopamine (DA) signaling is essential for the high maternal caregiving characteristic of the early postpartum period, but little is known about dopamine's role in the expression of maternal caregiving thereafter. OBJECTIVES: We tested the hypothesis that decreased mesolimbic dopaminergic signaling is particularly responsible for the natural decline in maternal caregiving that occurs as the postpartum period progresses. METHODS: Sprague-Dawley (SD) mother rats received intraperitoneal injections of either vehicle, the DA D1 receptor agonist SKF38393, the DA D2 receptor agonist quinpirole, or both agonists twice daily from postpartum days 9 to 15. In a separate experiment involving Long-Evans (LE) rats, we examined whether DA D1 and D2 receptor mRNAs in the nucleus accumbens (NA) shell and ventral tegmental area (VTA), along with DA turnover in the VTA, decline across the postpartum period in parallel with the decreasing maternal behavior. RESULTS: All drug treatments significantly maintained higher frequencies of active maternal behaviors (nesting, pup licking, retrieval) compared to vehicle. Furthermore, the majority of mothers treated with SKF38393 either alone or combined with quinpirole maintained full expression of maternal behavior during behavioral testing. D2 receptor mRNA levels were found to be lower in the late postpartum NA shell and VTA compared to early postpartum, but D1 receptor mRNA levels in the NA shell were higher in the late postpartum period. Furthermore, both late postpartum and recently parturient LE mothers had higher VTA DA turnover compared to nulliparae, suggesting changes in mesolimbic signal-to-noise ratio both at the end and beginning of motherhood. CONCLUSIONS: Collectively, our results suggest that alterations in mesolimbic DA is part of the neural substrate responsible for dynamic maternal caregiving across the entire postpartum period.


Assuntos
Dopamina/metabolismo , Comportamento Materno/fisiologia , Núcleo Accumbens/metabolismo , Período Pós-Parto/metabolismo , Transdução de Sinais/fisiologia , Área Tegmentar Ventral/metabolismo , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Animais Recém-Nascidos , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Feminino , Masculino , Comportamento Materno/efeitos dos fármacos , Comportamento Materno/psicologia , Núcleo Accumbens/efeitos dos fármacos , Período Pós-Parto/efeitos dos fármacos , Período Pós-Parto/psicologia , Gravidez , Quimpirol/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Área Tegmentar Ventral/efeitos dos fármacos
4.
Eur Arch Psychiatry Clin Neurosci ; 270(2): 271-275, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30927075

RESUMO

It is reported that dopamine D1 receptors in the medial prefrontal cortex play a role in the antidepressant actions of (R,S)-ketamine. However, its role in the antidepressant actions of (R)-ketamine, which is more potent than (S)-ketamine, is unknown. In the locomotion test, tail suspension test, forced swimming test and 1% sucrose preference test, pretreatment with dopamine D1 receptor antagonist SCH-23390 did not block the antidepressant effects of (R)-ketamine in the susceptible mice after chronic social defeat stress. These findings suggest that dopamine D1 receptors may not play a major role in the antidepressant actions of (R)-ketamine.


Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Ketamina/farmacologia , Receptores de Dopamina D1/antagonistas & inibidores , Estresse Psicológico/tratamento farmacológico , Animais , Benzazepinas/farmacologia , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Estresse Psicológico/metabolismo
5.
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
6.
Neurosci Lett ; 714: 134502, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31639423

RESUMO

The aim of this study was to investigate the relationship of dopamine D1 receptor (D1R) and its downstream factors with morphine withdrawal symptoms in rats. Rats were injected intraperitoneally with morphine in a dose-escalating manner. The midbrain periaqueductal gray (PAG) area was microinjected with D1R antagonist SCH23390 or D1R agonist SKF38393. Rats were intraperitoneally injected with naloxone (4 mg/kg) after the last morphine injection, and the withdrawal response was observed. The D1R antagonist reduced the withdrawal response in morphine-exposed rats and decreased the expression of Ca2+/calmodulin-dependent protein kinase II (CaMKII), phosphorylated extracellular signal-regulated kinase (p-ERK) and cAMP response element-binding protein (CREB) in the PAG. However, the ability of SKF38393 to increase the withdrawal response was weak and limited. Taken together, the results suggest that D1R antagonist decreased the withdrawal response in morphine-exposed rats by downregulating the downstream factors, CaMKII, p-ERK and CREB.


Assuntos
Benzazepinas/farmacologia , Morfina/efeitos adversos , Substância Cinzenta Periaquedutal/metabolismo , Síndrome de Abstinência a Substâncias/prevenção & controle , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/administração & dosagem , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Benzazepinas/administração & dosagem , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação para Baixo/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Masculino , Microinjeções , Morfina/antagonistas & inibidores , Naloxona/farmacologia , Ratos , Receptores de Dopamina D1/antagonistas & inibidores
7.
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
8.
J Physiol Sci ; 69(6): 1019-1028, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31664642

RESUMO

We aimed to identify the neurotransmitters and brain regions involved in exercise efficiency in mice during continuous complicated exercises. Male C57BL/6J mice practiced treadmill running with intermittent obstacles on a treadmill for 8 days. Oxygen uptake (VO2) during treadmill running was measured as exercise efficiency. After obstacle exercise training, the VO2 measured during treadmill running with obstacles decreased significantly. Obstacle exercise-induced c-Fos expressions and dopamine turnover (DOPAC/dopamine) in the septum after obstacle exercise training were significantly higher than that before training. The dopamine turnover was correlated with exercise efficiency on the 3rd day after exercise training. Furthermore, the training effect on exercise efficiency was significantly decreased by injection of dopamine receptor antagonists into the septum and was associated with decreased c-Fos expressions in the septum and hippocampus of the mice. These results suggest that dopaminergic function in the septum is involved in exercise efficiency during continuous complicated exercises.


Assuntos
Dopamina/farmacologia , Consumo de Oxigênio/fisiologia , Condicionamento Físico Animal/fisiologia , Septo do Cérebro/efeitos dos fármacos , Animais , Benzazepinas/farmacologia , Biomarcadores , Antagonistas de Dopamina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Genes fos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Dopamina D1/antagonistas & inibidores , Corrida , Serotonina/metabolismo , Sulpirida/farmacologia
9.
Biochem Biophys Res Commun ; 519(3): 547-552, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31537386

RESUMO

This study investigated dopaminergic function in the lateral hypothalamus (LH) in the regulation of feeding behavior. Refeeding increased dopamine levels in the LH. Glucose injection also increased dopamine levels in the LH. When the retrograde tracer Fluoro-Gold (FG) was injected into the LH, FG-positive cells were found in the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNC), which were mostly tyrosine hydroxylase-positive. Injection of the dopamine D1 receptor agonist SKF 38393, but not the antagonist SCH 23390, into the LH increased food intake. Similarly, injection of the dopamine D2 receptor agonist quinpirole, but not the antagonist l-sulpiride, into the LH increased food intake. The effect of each agonist was blocked by its respective antagonist. Furthermore, injection of quinpirole, but not SKF 38393, decreased the mRNA level of preproorexin. In addition, injection of SKF 38393 decreased the mRNA levels of neuropeptide Y and agouti-related peptide, whereas the injection of quinpirole increased the mRNA level of proopiomelanocortin. These results indicate that food intake activates dopamine neurons projecting from the VTA/SNC to the LH through an increase in blood glucose levels, which terminates food intake by stimulation of dopamine D1 and D2 receptors. It is also possible that stimulation of dopamine D1 and D2 receptors in the LH inhibits feeding behavior through different neuropeptides.


Assuntos
Dopaminérgicos/farmacologia , Dopamina/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Região Hipotalâmica Lateral/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Neuropeptídeos/farmacologia , Receptores de Dopamina D1/antagonistas & inibidores , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Agonistas de Dopamina/farmacologia , Região Hipotalâmica Lateral/metabolismo , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Quimpirol/farmacologia , Ratos , Ratos Wistar , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo
10.
Eur J Neurosci ; 50(11): 3689-3701, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31423669

RESUMO

As prairie voles (Microtus ochrogaster) display spontaneous biparental care, and the ventromedial hypothalamus (VMH) has been implicated in reproductive behaviour, we conducted experiments to test the hypothesis that the VMH neurochemical circuitry is involved in alloparental behaviours in male prairie voles. We compared alloparental behaviours of adult, sexually naïve male and female voles-both displayed licking/grooming, huddling and retrieving behaviours towards conspecific pups. We also stained for the immediate-early gene encoded early growth protein Egr-1 in the vole brain. The pup-exposed animals showed levels of Egr-1 staining that was higher in the VMH but lower in the amygdala compared to animals exposed to a pup-sized piece of plastic (control). A retrograde tracer, Fluoro-Gold (FG), was injected into the VMH of male voles that were subsequently tested in the pup exposure or control condition. More FG/Egr-1 cells were detected for glutamatergic (GLU) staining in the ventral bed nucleus of the stria terminalis (BNSTv) and medial amygdala (MeA), whereas less FG/Egr-1 cells were stained for gamma-aminobutyric acid (GABA) in the MeA of the pup-exposed group compared to the control group. Further, the ratio of GLU:GABA expression in FG/Egr-1 projection neurons from both the BNSTv and MeA to the VMH was increased following pup exposure. Finally, pharmacological blockade of either dopamine D1 receptor or oxytocin receptor in the VMH impaired the onset of male alloparental behaviour. Together, these data suggest that the VMH may be involved in the onset of alloparental care and play a role in regulating social approach in male prairie voles.


Assuntos
Rede Nervosa/metabolismo , Apego ao Objeto , Caracteres Sexuais , Comportamento Social , Núcleo Hipotalâmico Ventromedial/metabolismo , Animais , Arvicolinae , Antagonistas de Dopamina/farmacologia , Feminino , Masculino , Rede Nervosa/efeitos dos fármacos , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/metabolismo , Receptores de Ocitocina/antagonistas & inibidores , Receptores de Ocitocina/metabolismo , Roedores , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacos
11.
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
12.
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
13.
Ann Clin Psychiatry ; 31(3): 164-168, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31369655

RESUMO

BACKGROUND: Stuttering, also known as childhood-onset fluency disorder, is a chronic neurodevelopmental disorder that affects 1% of the population and can greatly impact an individual's social, occupational, and academic functioning. Prior research has shown dopamine D2 antagonists are effective in reducing the severity of stuttering symptoms, but these compounds can be associated with metabolic and movement disorder adverse effects. Ecopipam is an investigational medication that acts as a selective dopamine D1 receptor antagonist. This mechanism should reduce the likelihood of metabolic and movement disorder adverse effects of D2 antagonists. METHOD: This open-label pilot study investigated ecopipam in the treatment of adults who stutter. RESULTS: The results showed that a majority of participants demonstrated improvement in their stuttering. The medication was well tolerated. CONCLUSIONS: These positive, preliminary findings suggest that a doubleblind, randomized controlled clinical trial to examine the efficacy of ecopipam in the treatment of stuttering is warranted.


Assuntos
Benzazepinas/farmacologia , Antagonistas de Dopamina/farmacologia , Receptores de Dopamina D1/antagonistas & inibidores , Gagueira/tratamento farmacológico , Adulto , Benzazepinas/administração & dosagem , Benzazepinas/efeitos adversos , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Resultado do Tratamento
14.
Life Sci ; 233: 116712, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31377325

RESUMO

AIMS: Previous researches demonstrated that genetics and environment are two essential factors to prone individuals to drug abuse. Our previous data showed that dopaminergic system changed in the offspring of morphine-abstinent rats. In the present study, we evaluated whether blocking the D1-like dopamine receptors (DR) in the nucleus accumbens (NAC) affect the rewarding effect of morphine in the offspring of morphine-abstinent rats. MAIN METHODS: In the study, male and female Wistar rats received morphine orally for 21 days. Ten days after last morphine administration, animals prepared to mate either with a morphine abstinent or a drug-naive rat. Adult male offspring were chosen for further evaluation. SCH23390 (0.01 µg/rat) was administrated intra-NAC during the conditioning phase in the CPP paradigm (morphine 7.5 mg/kg). KEY FINDINGS: Obtained data showed that morphine administration (7.5 mg/kg) did not induce conditioning in the offspring of the morphine-abstinent parent(s) (p < 0.001) compared with the control group. However, when SCH23390 injected in the NAC during the induction phase, the offspring of morphine-abstinent rats were conditioned with the same dose of morphine. SIGNIFICANCE: Previous studies showed that the offspring of morphine-abstinent rats are more prone to opioid consumption, and also developed tolerance to the rewarding effect of morphine. Current data indicated that blockade of D1-like DR in the NAC could prevent morphine-induced tolerance in these offspring. Therefore, inhibition of D1-like DR in the NAC might be a new candidate against morphine-reinforcing effect in the offspring of morphine-abstinent parent(s).


Assuntos
Condicionamento Clássico/efeitos dos fármacos , Condicionamento Operante/fisiologia , Dependência de Morfina/metabolismo , Morfina/farmacologia , Núcleo Accumbens/metabolismo , Receptores de Dopamina D1/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Benzazepinas/farmacologia , Condicionamento Operante/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Feminino , Masculino , Morfina/administração & dosagem , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de Dopamina D1/antagonistas & inibidores
15.
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
16.
eNeuro ; 6(4)2019.
Artigo em Inglês | MEDLINE | ID: mdl-31358512

RESUMO

One way that drugs of abuse perturb the dopamine system is by triggering large amounts of extracellular dopamine to efflux into limbic regions. The basolateral (BLA) and central (CeA) nuclei of the amygdala have been shown to play distinct roles in value representation of primary and conditioned reward. However, the precise role of dopaminergic receptors in the BLA and the CeA during reward-related behaviors remains to be determined. Here we investigate the effects of dopamine D1 receptor blockade in the BLA and the CeA during asymptotic performance of cocaine self-administration and in a novel application of contextual renewal under continued access conditions. After more than three weeks of chained seek-take self-administration of cocaine, male Long Evans rats were given a bilateral intra-BLA or intra-CeA infusion of the D1 antagonist SCH-23390 (2 µg/0.3 µl) for multiple days. Intra-BLA D1 receptor blockade before, but not after the self-administration session, gradually suppressed drug seeking and taking responses and persisted with a change in context with continued D1 blockade. In contrast, intra-CeA D1 receptor blockade caused a rapid reduction in self-administration that showed renewal with a change in context with continued D1 blockade. Further, conditioned place aversion developed with intra-BLA but not intra-CeA infusions. Collectively, these results demonstrate that dopamine D1 receptors in the BLA and CeA both contribute to drug seeking and taking, but may do so through distinct mechanisms.


Assuntos
Complexo Nuclear Basolateral da Amígdala/fisiologia , Núcleo Central da Amígdala/fisiologia , Cocaína/administração & dosagem , Comportamento de Procura de Droga/fisiologia , Receptores de Dopamina D1/fisiologia , Animais , Núcleo Central da Amígdala/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Comportamento de Procura de Droga/efeitos dos fármacos , Masculino , Ratos Long-Evans , Receptores de Dopamina D1/antagonistas & inibidores
17.
Dev Neurosci ; 41(1-2): 44-55, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31212274

RESUMO

Methamphetamine (MA) abuse is a worldwide issue that produces health and cognitive effects in the user. MA is abused by some women who then become pregnant and expose their developing child to the drug. Preclinical rodent models demonstrate cognitive deficits following developmental MA exposure, an effect observed in children exposed to MA in utero. To determine if the dopamine receptor D1 (DRD1) is involved in the learning and memory deficits following MA exposure, male Sprague-Dawley rats were treated 4 times daily at 2 h intervals with 0 (saline) or 10 mg/kg of MA from postnatal day (P)6-15, 30 min after 0.5, 1.0, or 2.0 mg/kg SCH23390. Cincinnati water maze testing began on P30, and the high dose of SCH23390 blocked the learning deficits induced by MA with no effect from the lower doses. Morris water maze (MWM) learning deficits following MA were not protected by SCH23390, although there was a non-dose dependent effect in the acquisition phase. Locomotor deficits induced by MA were reversed by all doses of SCH23390. There were no effects of MA on criterion to trial passive avoidance. Taken together, these data show that behaviors that are dependent on the striatum are better protected with the DRD1 antagonist during MA treatment than the hippocampally mediated spatial learning in the MWM. This suggests that multiple mechanisms exist for the deficits induced by neonatal MA administration.


Assuntos
Estimulantes do Sistema Nervoso Central/toxicidade , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Metanfetamina/toxicidade , Receptores de Dopamina D1/antagonistas & inibidores , Animais , Animais Recém-Nascidos , Benzazepinas/farmacologia , Antagonistas de Dopamina/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Tempo
18.
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
19.
Psychopharmacology (Berl) ; 236(9): 2699-2712, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30972447

RESUMO

RATIONALE: Nucleus accumbens (NAc) dopamine (DA) plays an integral role in overcoming effort costs, as blockade of D1 and D2 receptors reduces the choice of larger, more-costly rewards. Similarly, the stress neuropeptide corticotropin-releasing factor (CRF) modulates DA transmission and mediates stress-induced alterations in effort-related choice. OBJECTIVES: The current study explored how excessive stimulation of different DA receptors within the NAc core and shell alters effort-related decision-making and compared these effects to those induced by CRF stimulation. METHODS: Male Long Evans rats were well-trained on an effort-discounting task wherein they choose between a low-effort/low-reward and a high-effort/high-reward lever where the effort requirement increased over blocks (2-20 presses). Dopamine D1 (SKF 81297, 0.2-2 µg), D2/3 (quinpirole, 1-10 µg), or D3 (PD 128,907, 1.5-3 µg) receptor agonists, or CRF (0.5 µg), were infused into the NAc core or shell prior to testing. RESULTS: Stimulation of D2/3 receptors with quinpirole in the NAc core or shell markedly reduced the choice of high-effort option and increase choice latencies, without altering preference for larger vs smaller rewards. Stimulation of D1 or D3 receptors did not alter choice, although SKF 81297 infusions into the shell reduced response vigor. In comparison, core infusions of CRF flattened the discounting curve, reducing effortful choice when costs were low and increasing it when costs were high. CONCLUSIONS: Excessive stimulation of NAc D2 receptors has detrimental effects on effort-related decision-making. Furthermore, CRF stimulation induces dissociable effects on decision-making compared with those induced the effects of stimulation of different DA receptors.


Assuntos
Tomada de Decisões/fisiologia , Núcleo Accumbens/metabolismo , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Animais , Tomada de Decisões/efeitos dos fármacos , Agonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/administração & dosagem , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Microinjeções , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Long-Evans , Receptores de Hormônio Liberador da Corticotropina/agonistas , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/antagonistas & inibidores , Recompensa
20.
FEBS Lett ; 593(7): 732-742, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30821397

RESUMO

Dysfunction of the dopaminergic pathway is linked to numerous diseases of the nervous system. The D1-D2 receptor heteromer is known to play a role in certain neuropsychiatric disorders, such as depression. Here, we synthesized an eight amino acid residue peptide, EAARRAQE, derived from the third intracellular loop of the D2 receptor and show that the peptide binds to the D1 receptor with comparable efficiency as that of the full-length D2 receptor protein. Moreover, immunoprecipitation studies show the existence of a heteromeric complex formed both in vitro and in total protein derived from temporal and frontal lobe tissue from normal and depressed subjects. The efficiency of the peptide to block the D1-D2 heteromeric complex was comparable in all the samples tested.


Assuntos
Antagonistas dos Receptores de Dopamina D2/farmacologia , Neurônios/metabolismo , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/genética , Animais , Mapeamento Encefálico , Depressão/genética , Depressão/patologia , Dopamina/genética , Dopamina/metabolismo , Antagonistas dos Receptores de Dopamina D2/síntese química , Lobo Frontal/metabolismo , Humanos , Imunoprecipitação , Neurônios/efeitos dos fármacos , Neurônios/patologia , Peptídeos/síntese química , Peptídeos/farmacologia , Ligação Proteica/genética , Ratos , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D2/química , Lobo Temporal/metabolismo
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