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1.
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
2.
Nat Commun ; 12(1): 6444, 2021 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-34750364

RESUMO

Synaptic pruning during adolescence is important for appropriate neurodevelopment and synaptic plasticity. Aberrant synaptic pruning may underlie a variety of brain disorders such as schizophrenia, autism and anxiety. Dopamine D2 receptor (Drd2) is associated with several neuropsychiatric diseases and is the target of some antipsychotic drugs. Here we generate self-reporting Drd2 heterozygous (SR-Drd2+/-) rats to simultaneously visualize Drd2-positive neurons and downregulate Drd2 expression. Time course studies on the developing anterior cingulate cortex (ACC) from control and SR-Drd2+/- rats reveal important roles of Drd2 in regulating synaptic pruning rather than synapse formation. Drd2 also regulates LTD, a form of synaptic plasticity which includes some similar cellular/biochemical processes as synaptic pruning. We further demonstrate that Drd2 regulates synaptic pruning via cell-autonomous mechanisms involving activation of mTOR signaling. Deficits of Drd2-mediated synaptic pruning in the ACC during adolescence lead to hyper-glutamatergic function and anxiety-like behaviors in adulthood. Taken together, our results demonstrate important roles of Drd2 in cortical synaptic pruning.


Assuntos
Giro do Cíngulo/fisiologia , Plasticidade Neuronal/fisiologia , Receptores de Dopamina D2/fisiologia , Transdução de Sinais/fisiologia , Animais , Animais Geneticamente Modificados , Espinhas Dendríticas/genética , Espinhas Dendríticas/fisiologia , Técnicas de Inativação de Genes , Giro do Cíngulo/citologia , Giro do Cíngulo/metabolismo , Heterozigoto , Potenciais Pós-Sinápticos Inibidores/genética , Potenciais Pós-Sinápticos Inibidores/fisiologia , Mutação , Plasticidade Neuronal/genética , Neurônios/citologia , Neurônios/metabolismo , Neurônios/fisiologia , Técnicas de Patch-Clamp/métodos , Ratos Sprague-Dawley , Receptores de Dopamina D2/genética , Transdução de Sinais/genética , Sinapses/genética , Sinapses/fisiologia , Fatores de Tempo
3.
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
4.
PLoS Comput Biol ; 17(9): e1009364, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34591840

RESUMO

In behavioral learning, reward-related events are encoded into phasic dopamine (DA) signals in the brain. In particular, unexpected reward omission leads to a phasic decrease in DA (DA dip) in the striatum, which triggers long-term potentiation (LTP) in DA D2 receptor (D2R)-expressing spiny-projection neurons (D2 SPNs). While this LTP is required for reward discrimination, it is unclear how such a short DA-dip signal (0.5-2 s) is transferred through intracellular signaling to the coincidence detector, adenylate cyclase (AC). In the present study, we built a computational model of D2 signaling to determine conditions for the DA-dip detection. The DA dip can be detected only if the basal DA signal sufficiently inhibits AC, and the DA-dip signal sufficiently disinhibits AC. We found that those two requirements were simultaneously satisfied only if two key molecules, D2R and regulators of G protein signaling (RGS) were balanced within a certain range; this balance has indeed been observed in experimental studies. We also found that high level of RGS was required for the detection of a 0.5-s short DA dip, and the analytical solutions for these requirements confirmed their universality. The imbalance between D2R and RGS is associated with schizophrenia and DYT1 dystonia, both of which are accompanied by abnormal striatal LTP. Our simulations suggest that D2 SPNs in patients with schizophrenia and DYT1 dystonia cannot detect short DA dips. We finally discussed that such psychiatric and movement disorders can be understood in terms of the imbalance between D2R and RGS.


Assuntos
Dopamina/fisiologia , Modelos Neurológicos , Receptores de Dopamina D2/fisiologia , Adenilil Ciclases/fisiologia , Animais , Biologia Computacional , Corpo Estriado/fisiologia , Distonia Muscular Deformante/fisiopatologia , Proteínas de Ligação ao GTP/fisiologia , Humanos , Aprendizagem/fisiologia , Potenciação de Longa Duração/fisiologia , Transtornos Mentais/fisiopatologia , Transtornos dos Movimentos/fisiopatologia , Neurônios/fisiologia , Recompensa , Esquizofrenia/fisiopatologia , Transdução de Sinais/fisiologia
5.
Eur J Pharmacol ; 912: 174517, 2021 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-34555394

RESUMO

Dopamine (DA) is an important modulator in nociception and analgesia. Spinal DA receptors are involved in descending modulation of the nociceptive transmission. Genetic variations within DA neurotransmission have been associated with altered pain sensitivity and development of chronic pain syndromes. The variant rs6277 in dopamine receptor 2 a (drd2a) has been associated with a decreased D2 receptor availability and increased nociception. The aim of this study is to further characterize the role of DA neurotransmission in nociception and the anti-nociceptive function of drd2a. The phenotype caused by rs6277 was modelled in zebrafish larvae using morpholino's and the effect on nociception was tested using a validated behavioural assay. The anti-nociceptive role of drd2a was tested using pharmacological intervention of D2 agonist Quinpirole. The experiments demonstrate that a decrease in drd2a expression results in a pro-nociceptive behavioural phenotype (P = 0.016) after a heat stimulus. Furthermore, agonism of drd2a with agonist Quinpirole (0.2 µM) results in dose-dependent anti-nociception (P = 0.035) after a heat stimulus. From these results it is concluded that the dopamine receptor drd2a is involved in anti-nociceptive behaviour in zebrafish. The model allows further screening and testing of genetic variation and treatment involved in nociception.


Assuntos
Dopamina/fisiologia , Nociceptividade/fisiologia , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/fisiologia , Transmissão Sináptica/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Temperatura Alta , Modelos Animais , Morfolinos/farmacologia , Nociceptividade/efeitos dos fármacos , Quimpirol/farmacologia , Receptores de Dopamina D2/agonistas , Transmissão Sináptica/efeitos dos fármacos , Peixe-Zebra
6.
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
7.
Mol Neurobiol ; 58(11): 5971-5985, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34432265

RESUMO

The dopaminergic system plays an essential role in maintaining homeostasis between the central nervous system (CNS) and the immune system. Previous studies have associated imbalances in the dopaminergic system to the pathogenesis of multiple sclerosis (MS). Here, we examined the protein levels of dopaminergic receptors (D1R and D2R) in different phases of the experimental autoimmune encephalomyelitis (EAE) model. We also investigated if the treatment with pramipexole (PPX)-a dopamine D2/D3 receptor-preferring agonist-would be able to prevent EAE-induced motor and mood dysfunction, as well as its underlying mechanisms of action. We report that D2R immunocontent is upregulated in the spinal cord of EAE mice 14 days post-induction. Moreover, D1R and D2R immunocontents in lymph nodes and the oxidative damage in the spinal cord and striatum of EAE animals were significantly increased during the chronic phase. Also, during the pre-symptomatic phase, axonal damage in the spinal cord of EAE mice could already be found. Surprisingly, therapeutic treatment with PPX failed to inhibit the progression of EAE. Of note, PPX treatment inhibited EAE-induced depressive-like while failed to inhibit anhedonic-like behaviors. We observed that PPX treatment downregulated IL-1ß levels and increased BNDF content in the spinal cord after EAE induction. Herein, we show that a D2/D3 receptor-preferred agonist mitigated EAE-induced depressive-like behavior, which could serve as a new possibility for further clinical trials on treating depressive symptoms in MS patients. Thus, we infer that D2R participates in the crosstalk between CNS and immune system during autoimmune and neuroinflammatory response induced by EAE, mainly in the acute and chronic phase of the disease.


Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologia , Anedonia/efeitos dos fármacos , Anedonia/fisiologia , Animais , Axônios/patologia , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Fator Neurotrófico Derivado do Encéfalo/genética , Corpo Estriado/metabolismo , Depressão/etiologia , Depressão/prevenção & controle , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/psicologia , Feminino , Interleucina-1beta/biossíntese , Interleucina-1beta/genética , Linfonodos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , /metabolismo , Estresse Oxidativo , Fragmentos de Peptídeos/biossíntese , Fragmentos de Peptídeos/genética , Pramipexol/farmacologia , Pramipexol/uso terapêutico , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/agonistas , Método Simples-Cego , Medula Espinal/metabolismo , Medula Espinal/patologia
8.
PLoS Biol ; 19(7): e3001055, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34197448

RESUMO

It has been widely accepted that dopamine (DA) plays a major role in motivation, yet the specific contribution of DA signaling at D1-like receptor (D1R) and D2-like receptor (D2R) to cost-benefit trade-off remains unclear. Here, by combining pharmacological manipulation of DA receptors (DARs) and positron emission tomography (PET) imaging, we assessed the relationship between the degree of D1R/D2R blockade and changes in benefit- and cost-based motivation for goal-directed behavior of macaque monkeys. We found that the degree of blockade of either D1R or D2R was associated with a reduction of the positive impact of reward amount and increasing delay discounting. Workload discounting was selectively increased by D2R antagonism. In addition, blocking both D1R and D2R had a synergistic effect on delay discounting but an antagonist effect on workload discounting. These results provide fundamental insight into the distinct mechanisms of DA action in the regulation of the benefit- and cost-based motivation, which have important implications for motivational alterations in both neurological and psychiatric disorders.


Assuntos
Análise Custo-Benefício , Dopamina/metabolismo , Macaca mulatta/fisiologia , Motivação , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologia , Animais , Desvalorização pelo Atraso , Antagonistas de Dopamina/farmacologia , Macaca fuscata , Masculino , Tomografia por Emissão de Pósitrons , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Carga de Trabalho
9.
J Clin Invest ; 131(18)2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34264865

RESUMO

BACKGROUNDCertain components of rest-activity rhythms such as greater eveningness (delayed phase), physical inactivity (blunted amplitude), and shift work (irregularity) are associated with increased risk for drug use. Dopaminergic (DA) signaling has been hypothesized to mediate the associations, though clinical evidence is lacking.METHODSWe examined associations between rhythm components and striatal D1 (D1R) and D2/3 receptor (D2/3R) availability in 32 healthy adults (12 female, 20 male; age 42.40 ± 12.22 years) and its relationship to drug reward. Rest-activity rhythms were assessed by 1-week actigraphy combined with self-reports. [11C]NNC112 and [11C]raclopride positron emission tomography (PET) scans were conducted to measure D1R and D2/3R availability, respectively. Additionally, self-reported drug-rewarding effects of 60 mg oral methylphenidate were assessed.RESULTSWe found that delayed rhythm was associated with higher D1R availability in caudate, which was not attributable to sleep loss or so-called social jet lag, whereas physical inactivity was associated with higher D2/3R availability in nucleus accumbens (NAc). Delayed rest-activity rhythm, higher caudate D1R, and NAc D2/3R availability were associated with greater sensitivity to the rewarding effects of methylphenidate.CONCLUSIONThese findings reveal specific components of rest-activity rhythms associated with striatal D1R, D2/3R availability, and drug-rewarding effects. Personalized interventions that target rest-activity rhythms may help prevent and treat substance use disorders.TRIAL REGISTRATIONClinicalTrials.gov: NCT03190954.FUNDINGNational Institute on Alcohol Abuse and Alcoholism (ZIAAA000550).


Assuntos
Ritmo Circadiano/fisiologia , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologia , Recompensa , Transtornos Relacionados ao Uso de Substâncias/etiologia , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Actigrafia , Adulto , Estimulantes do Sistema Nervoso Central/administração & dosagem , Corpo Estriado/fisiologia , Feminino , Humanos , Masculino , Metilfenidato/administração & dosagem , Pessoa de Meia-Idade , Atividade Motora/fisiologia , Tomografia por Emissão de Pósitrons , Descanso/fisiologia , Adulto Jovem
10.
Psychopharmacology (Berl) ; 238(8): 2225-2234, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33891128

RESUMO

Episodic memory retrieval is fundamental for daily activities of humans and animals. Muscarinic cholinergic signaling is important for memory functioning and shows gender-dependent response in episodic memory retrieval. Dopamine D2 receptors influence memory formation and retrieval by influencing cholinergic signaling in the brain. This study aimed to determine the gender-dependent effects of D2 and muscarinic activity on memory retrieval. Male and female mice were trained for Morris water maze test and contextual fear conditioning. Memory retrieval was assessed following sub-chronic treatment (for 5 days) with D2 antagonist (risperidone 2.5 mg/kg) alone or in combination with scopolamine (1 mg/kg) or donepezil (1 mg/kg). Open field test was performed prior to the retrieval test to evaluate effects of risperidone treatment on locomotor activity and exploratory behavior. Risperidone co-treatment with donepezil impaired spatial memory retrieval in males only. Muscarinic and D2 simultaneous antagonism tend to impair fear retrieval in males but significantly enhanced retrieval of fear memories in female mice. These results suggest that D2 signaling influence muscarinic receptor activity during memory retrieval in gender-dependent manner.


Assuntos
Medo/fisiologia , Receptores de Dopamina D2/fisiologia , Receptores Muscarínicos/fisiologia , Caracteres Sexuais , Memória Espacial/fisiologia , Animais , Inibidores da Colinesterase/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Medo/efeitos dos fármacos , Medo/psicologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Antagonistas Muscarínicos/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos
11.
Biol Pharm Bull ; 44(3): 442-447, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33642553

RESUMO

The dopamine system plays an important role in regulating many brain functions, including the motor function. The blockade of dopamine receptors results in a serious motor dysfunction, such as catalepsy and Parkinsonism. However, the neuronal mechanism underlying the drug-induced motor dysfunction is not well understood. Here, we examine brain-wide activation patterns in Fos-enhanced green fluorescent protein reporter mice that exhibit cataleptic behavior induced by SCH39166, a dopamine D1-like receptor antagonist, and raclopride, a dopamine D2-like receptor antagonist. Support vector classifications showed that the orbital cortex (ORB) and striatum including the caudoputamen (CP) and nucleus accumbens (ACB), prominently contribute to the discrimination between brains of the vehicle-treated and both SCH39166- and raclopride-treated mice. Interregional correlations indicated that the increased functional connectivity of functional networks, including the ORB, CP, and ACB, is the common mechanism underlying SCH39166- and raclopride-induced cataleptic behavior. Moreover, the distinct mechanisms in the SCH39166- and raclopride-induced cataleptic behaviors are the decreased functional connectivity between three areas above and the cortical amygdala, and between three areas above and the anterior cingulate cortex, respectively. Thus, the alterations of functional connectivity in diverse brain regions, including the ORB, provide new insights on the mechanism underlying drug-induced movement disorders.


Assuntos
Benzazepinas/farmacologia , Catalepsia/induzido quimicamente , Corpo Estriado/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Racloprida/farmacologia , Animais , Catalepsia/fisiopatologia , Corpo Estriado/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Córtex Pré-Frontal/fisiologia , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologia
12.
PLoS Genet ; 17(2): e1009346, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33524034

RESUMO

Ethanol is a widely used drug, excessive consumption of which could lead to medical conditions with diverse symptoms. Ethanol abuse causes dysfunction of memory, attention, speech and locomotion across species. Dopamine signaling plays an essential role in ethanol dependent behaviors in animals ranging from C. elegans to humans. We devised an ethanol dependent assay in which mutants in the dopamine autoreceptor, dop-2, displayed a unique sedative locomotory behavior causing the animals to move in circles while dragging the posterior half of their body. Here, we identify the posterior dopaminergic sensory neuron as being essential to modulate this behavior. We further demonstrate that in dop-2 mutants, ethanol exposure increases dopamine secretion and functions in a DVA interneuron dependent manner. DVA releases the neuropeptide NLP-12 that is known to function through cholinergic motor neurons and affect movement. Thus, DOP-2 modulates dopamine levels at the synapse and regulates alcohol induced movement through NLP-12.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Etanol/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/fisiologia , Depressores do Sistema Nervoso Central/farmacologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/fisiologia , Humanos , Locomoção/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/fisiologia , Mutação , Neuropeptídeos/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/fisiologia , Transdução de Sinais/efeitos dos fármacos
13.
Alcohol ; 91: 61-73, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33429015

RESUMO

The rising popularity of alcohol mixed with energy drinks (AmEDs) has become a significant public health concern, with AmED users reporting higher levels of alcohol intake than non-AmED users. One mechanism proposed to explain this heightened level of alcohol intake in AmED users is that the high levels of caffeine found in energy drinks may increase the positive reinforcing properties of alcohol, an effect that may be dependent on interactions between adenosine receptor signaling pathways and the dopamine D2 receptor. Therefore, the purpose of the current study was to confirm whether caffeine does increase the positive reinforcing effects of alcohol using both fixed ratio (FR) and progressive ratio (PR) designs, and to investigate a potential role of the dopamine D2 receptor to caffeine-induced increases in alcohol self-administration. Male Long-Evans rats were trained to self-administer a sweetened alcohol solution (10% v/v alcohol + 2% w/v sucrose) on an FR2 schedule of reinforcement, and the effects of caffeine (0, 5, 10, and 20 mg/kg, i. p. [intraperitoneally]) on the maintenance of alcohol self-administration and alcohol break point were examined. Parallel experiments in rats trained to self-administer sucrose (0.8% w/v) were conducted to determine whether caffeine's reinforcement-enhancing effects extended to a non-drug reinforcer. Caffeine pretreatment (5-10 mg/kg) significantly increased sweetened alcohol self-administration and motivation for a sweetened alcohol reinforcer. However, similar increases in self-administration of a non-drug reinforcer were not observed. Contrary to our hypothesis, the D2 receptor antagonist eticlopride did not block a caffeine-induced increase in sweetened alcohol self-administration, nor did it alter caffeine-induced increases in motivation for a sweetened alcohol reinforcer. Taken together, these results support the hypothesis that caffeine increases the positive reinforcing effects of alcohol, which may explain caffeine-induced increases in alcohol intake. However, the reinforcement-enhancing effects of caffeine appear to be independent of D2 receptor function.


Assuntos
Consumo de Bebidas Alcoólicas , Cafeína , Etanol/administração & dosagem , Receptores de Dopamina D2/fisiologia , Animais , Cafeína/farmacologia , Condicionamento Operante , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Long-Evans , Autoadministração
14.
Neurosci Lett ; 742: 135514, 2021 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-33227368

RESUMO

The spinal cord contains a highly collateralized network of descending dopamine (DA) fibers that stem from the dorso-posterior hypothalamic A11 region in the brain, however, the modulatory actions of DA have generally only been assessed in lumbar segments L2-L5. In contrast to these exclusively sensorimotor segments, spinal cords segments T1-L2 and, in mouse, L6-S2, additionally contain the intermediolateral (IML) nucleus, the origin of autonomic nervous system (ANS). Here, we tested if the different spinal circuits in sensorimotor and IML-containing segments react differently to the modulation of the monosynaptic reflex (MSR) by DA. Bath-application of DA (1 µM) led to a decrease of MSR amplitude in L3-L5 segments; however, in IML-containing segments (T10-L2, and S1/2) the MSR response was facilitated. We did not observe any difference in the response between thoracic (sympathetic) and lumbosacral (parasympathetic) segments. Application of the D2-receptor agonists bromocriptine or quinpirole mimicked the effects of DA, while blocking D2 receptor pathways with raclopride or application with the D1-receptor agonist SKF 38393 led to an increase of the MSR in L3-L5 segments and a decrease of the MSR in IML-containing segments. In contrast, in the presence of the gap-junction blockers, carbenoloxone and quinine, DA modulatory actions in IML-containing segments were similar to those of sensorimotor L3-L5 segments. We suggest that DA modulates MSR amplitudes in the spinal cord in a segment-specific manner, and that the differential outcome observed in ANS segments may be a result of gap junctions in the IML.


Assuntos
Sistema Nervoso Autônomo/fisiologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Dopamina/farmacologia , Receptores de Dopamina D2/fisiologia , Reflexo/fisiologia , Medula Espinal/fisiologia , Animais , Sistema Nervoso Autônomo/efeitos dos fármacos , Estimulação Elétrica/métodos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Cultura de Órgãos , Receptores de Dopamina D2/agonistas , Reflexo/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos
15.
J Neurosci Res ; 99(3): 947-965, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33271630

RESUMO

Cognitive decline in Parkinson's disease (PD) is a common sequela of the disorder that has a large impact on patient well-being. Its physiological etiology, however, remains elusive. Our study used graph theory analysis to investigate the large-scale topological patterns of the extrastriatal dopamine D2 receptor network. We used positron emission tomography with [11 C]FLB-457 to measure the binding potential of cortical dopamine D2 receptors in two networks: the meso-cortical dopamine network and the meso-limbic dopamine network. We also investigated the application of partial volume effect correction (PVEC) in conjunction with graph theory analysis. Three groups were investigated in this study divided according to their cognitive status as measured by the Montreal Cognitive Assessment score, with a score ≤25 considered cognitively impaired: (a) healthy controls (n = 13, 11 female), (b) cognitively unimpaired PD patients (PD-CU, n = 13, 5 female), and (c) PD patients with mild cognitive impairment (PD-MCI, n = 17, 4 female). In the meso-cortical network, we observed increased small-worldness, normalized clustering, and local efficiency in the PD-CU group compared to the PD-MCI group, as well as a hub shift in the PD-MCI group. Compensatory reorganization of the meso-cortical dopamine D2 receptor network may be responsible for some of the cognitive preservation observed in PD-CU. These results were found without PVEC applied and PVEC proved detrimental to the graph theory analysis. Overall, our findings demonstrate how graph theory analysis can be used to detect subtle changes in the brain that would otherwise be missed by regional comparisons of receptor density.


Assuntos
Encéfalo/fisiologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Doença de Parkinson/fisiopatologia , Receptores de Dopamina D2/fisiologia , Idoso , Mapeamento Encefálico , Dopamina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rede Nervosa , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Receptores de Dopamina D2/metabolismo
16.
Neuropharmacology ; 175: 108163, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32479812

RESUMO

Adolescence is characterized by changes in behavior, such as increases in sensation seeking and risk taking, and increased vulnerability to developing a range of psychiatric disorders, including substance abuse disorders (SUD) and mood disorders. The mesolimbic dopamine system plays an essential role in mediating these behaviors and disorders. Therefore, it is imperative to understand how the dopamine system and its regulation are changing during this period of development. Here, we used ex vivo fast scan cyclic voltammetry to compare stimulated dopamine release and its local circuitry regulation between early adolescent and adult male and female Sprague-Dawley rats. We found that, compared to adults, adolescent males have decreased stimulated dopamine release in the NAc core, while adolescent females have increased dopamine release in the NAc shell, NAc core, and DMS. We also found sex- and region-specific differences in other dopamine dynamics, including maximal dopamine uptake (Vmax), release across a range of stimulation frequencies, and autoreceptor regulation of dopamine release. Better understanding how the dopamine system develops during adolescence will be imperative for understanding what mediates adolescent vulnerability to developing psychiatric disorders and how disruptions during this period of reorganization could alter behaviors and vulnerability into adulthood.


Assuntos
Corpo Estriado/fisiologia , Dopamina/fisiologia , Receptores de Dopamina D2/fisiologia , Fatores Etários , Animais , Feminino , Masculino , Neurônios/fisiologia , Núcleo Accumbens/fisiologia , Ratos Sprague-Dawley
17.
Nutr. hosp ; 37(3): 524-533, mayo-jun. 2020. tab, graf
Artigo em Inglês | IBECS | ID: ibc-193860

RESUMO

BACKGROUND: food is a powerful reinforcer that motivates people to eat. The TaqI A1 polymorphism (rs1800497; T>C) downstream of the dopamine D2 receptor (DRD2) gene has been associated with diminished DRD2 receptor density, higher food reinforcement, and impaired eating behavior in adults. OBJECTIVE: to evaluate the association between the rs1800497 polymorphism and the reinforcing value of food and eating in the absence of hunger in Chilean children. MATERIAL AND METHOD: nineteen Chilean children (aged 8-12 years) who were carriers of the A1-allele and 19 age- and gender-matched non-carriers (A2-allele) were evaluated on the reinforcing value of food and eating in the absence of hunger. Anthropometric measures were performed by standard procedures. Briefly, children received a standard pre-load lunch followed by an ad-libitum exposure to palatable foods. RESULTS: no differences were found between A1-allele carriers and non-carriers, whether obese or non-obese, in ad libitum energy intake, macronutrient consumption, or the relative reinforcing value of food (p > 0.05). In obese children, A1 carriers reported significantly lower satiety and fullness before lunch (p < 0.05). However, in children with normal weight A1 carriers were found to exhibit trends for greater satiety and fullness before lunch when compared to non-carriers, but this trend reversed after lunch such that carriers exhibited lower satiety and fullness (p = 0.06). CONCLUSIONS: although TaqI A1 may play an important role in some eating behavior-related traits such as satiety and fullness, especially in obese children, our findings indicate that this polymorphism does not appear to affect eating in the absence of hunger or food reinforcement in children


ANTECEDENTES: los alimentos son un poderoso reforzador de la alimentación. El polimorfismo TaqI A1 (rs1800497; T> C) del gen del receptor 2 de dopamina (DRD2) se ha asociado con una menor densidad de DRD2, un mayor refuerzo alimentario y un comportamiento alimentario alterado en adultos. OBJETIVO: evaluar la asociación entre el polimorfismo rs1800497, el valor reforzador del alimento y la conducta de comer en ausencia de hambre en niños chilenos. MATERIAL Y MÉTODO: treinta y ocho niños chilenos, 19 portadores del alelo A1 y 19 no portadores (alelo A2), pareados por género y edad, fueron evaluados en condiciones de laboratorio para determinar el valor reforzador del alimento y la conducta de comer en ausencia de hambre. Las mediciones antropométricas se realizaron por procedimientos estándar. Brevemente, los niños recibieron un almuerzo estándar seguido de una exposición ad-libitum a alimentos sabrosos. RESULTADOS: no hubo diferencias en la ingesta ad libitum de energía, ni en el consumo de macronutrientes, ni en el valor reforzador del alimento entre los portadores del alelo A1 frente a los no portadores (p > 0,05). Entre los niños obesos, los portadores del alelo A1 reportaron un menor nivel de saciedad y plenitud pre-almuerzo (p < 0,05). Sin embargo, entre los niños con normopeso se observó que los portadores de A1 tenían tendencia a presentar un mayor grado de saciedad y plenitud (pre-almuerzo) frente a los no portadores. Esta tendencia se invirtió post-almuerzo, de modo que los portadores exhibieron menor saciedad y plenitud (p = 0,06). CONCLUSIONES: la variante TaqI A1 podría desempeñar un papel importante en algunos rasgos relacionados con la conducta alimentaria, como la saciedad y la plenitud


Assuntos
Humanos , Masculino , Feminino , Criança , Fome/fisiologia , Variação Genética/genética , Comportamento Alimentar/fisiologia , Ingestão de Energia/genética , Obesidade/genética , Receptores de Dopamina D2/genética , Chile , Variação Genética/efeitos dos fármacos , Polimorfismo Genético/genética , Antropometria , Peso Corporal/genética , Ingestão de Energia/fisiologia , Receptores de Dopamina D2/fisiologia
18.
Cells ; 9(5)2020 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-32349279

RESUMO

In the 1980s and 1990s, the concept was introduced that molecular integration in the Central Nervous System could develop through allosteric receptor-receptor interactions in heteroreceptor complexes presents in neurons. A number of adenosine-dopamine heteroreceptor complexes were identified that lead to the A2A-D2 heteromer hypothesis of schizophrenia. The hypothesis is based on strong antagonistic A2A-D2 receptor-receptor interactions and their presence in the ventral striato-pallidal GABA anti-reward neurons leading to reduction of positive symptoms. Other types of adenosine A2A heteroreceptor complexes are also discussed in relation to this disease, such as A2A-D3 and A2A-D4 heteroreceptor complexes as well as higher order A2A-D2-mGluR5 and A2A-D2-Sigma1R heteroreceptor complexes. The A2A receptor protomer can likely modulate the function of the D4 receptors of relevance for understanding cognitive dysfunction in schizophrenia. A2A-D2-mGluR5 complex is of interest since upon A2A/mGluR5 coactivation they appear to synergize in producing strong inhibition of the D2 receptor protomer. For understanding the future of the schizophrenia treatment, the vulnerability of the current A2A-D2like receptor complexes will be tested in animal models of schizophrenia. A2A-D2-Simag1R complexes hold the highest promise through Sigma1R enhancement of inhibition of D2R function. In line with this work, Lara proposed a highly relevant role of adenosine for neurobiology of schizophrenia.


Assuntos
Receptor A2A de Adenosina/metabolismo , Receptores de Dopamina D2/metabolismo , Esquizofrenia/metabolismo , Adenosina/metabolismo , Encéfalo/metabolismo , Sistema Nervoso Central/metabolismo , Dopamina/metabolismo , Humanos , Neurônios/metabolismo , Receptor A2A de Adenosina/fisiologia , Receptores de Dopamina D2/fisiologia , Esquizofrenia/fisiopatologia
19.
Invest Ophthalmol Vis Sci ; 61(5): 10, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32396631

RESUMO

Purpose: A burst in phagocytosis of spent photoreceptor outer fragments by RPE is a rhythmic process occurring 1 to 2 hours after the onset of light. This phenomenon is considered crucial for the health of the photoreceptors and RPE. We have recently reported that dopamine, via dopamine 2 receptor (D2R), shifts the circadian rhythm in the RPE. Methods: Here, we first investigated the impact of the removal of D2R on the daily peak of phagocytosis by RPE and then we analyzed the function and morphology of retina and RPE in the absence of D2R. Results: D2R knockout (KO) mice do not show a daily burst of phagocytic activity after the onset of light. RNA sequencing revealed a total of 394 differentially expressed genes (DEGs) between ZT 23 and ZT 1 in the control mice, whereas in D2R KO mice, we detected 1054 DEGs. Pathway analysis of the gene expression data implicated integrin signaling to be one of the upregulated pathways in control but not in D2R KO mice. Consistent with the gene expression data, phosphorylation of focal adhesion kinase (FAK) did not increase significantly in KO mice at ZT 1. No difference in retinal thickness, visual function, or morphology of RPE cells was observed between wild-type (WT) and D2R KO mice at the age of 3 and 12 months. Conclusions: Our data suggest that removal of D2R prevents the burst of phagocytosis and a related increase in the phosphorylation of FAK after light onset. The pathway analysis points toward a putative role of D2R in controlling integrin signaling, which is known to play an important role in the control of the daily burst of phagocytosis by the RPE. Our data also indicate that the absence of the burst of phagocytic activity in the early morning does not produce any apparent deleterious effect on the retina or RPE up to 1 year of age.


Assuntos
Fagocitose , Receptores de Dopamina D2/fisiologia , Epitélio Pigmentado da Retina/patologia , Transdução de Sinais/fisiologia , Animais , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Integrinas/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagossomos/patologia , Fosforilação/fisiologia , Tomografia de Coerência Óptica , Regulação para Cima/fisiologia
20.
Horm Behav ; 124: 104777, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32439347

RESUMO

Neuropeptide oxytocin (OT) is involved in the regulation of social and non-social behaviour. The central nucleus of amygdala (CeA), part of the limbic system, plays an important role in learning, memory, anxiety and reinforcing mechanisms. CeA has been shown to be rich in OT receptors in rodents. Our previous findings indicated that OT in the rat CeA has a dose dependent rewarding and anxiolytic effect. The aim of our present study was to examine in the CeA the possible interaction of OT and D2 dopamine (DA) receptor antagonist Sulpiride on reinforcement in place preference test and on anxiety in elevated plus maze test. Wistar rats were microinjected bilaterally with 10 ng OT. In different group of animals 4 µg D2 DA receptor antagonist was applied. Other animals received D2 DA receptor antagonist 15 min before 10 ng OT treatment or vehicle solution into the CeA. Rats receiving 10 ng OT spent significantly longer time in the treatment quadrant during the test session in conditioned place preference test. Prior treatment with D2 DA receptor antagonist blocked the rewarding effects of OT. Antagonist in itself did not influence the time rats spent in the treatment quadrant. In elevated plus maze test, rats receiving 10 ng OT spent significantly longer time on the open arms. Prior treatment with D2 DA receptor antagonist blocked the effects of OT. Our results show that DA system plays a role in positive reinforcing and anxiolytic effects of OT because D2 DA receptor antagonist can block these actions.


Assuntos
Ansiolíticos/farmacologia , Ocitocina/farmacologia , Receptores de Dopamina D2/fisiologia , Comportamento Espacial/efeitos dos fármacos , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2/farmacologia , Medo/efeitos dos fármacos , Reação de Congelamento Cataléptica/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Ocitocina/metabolismo , Receptores de Ocitocina/fisiologia , Reforço Psicológico , Recompensa , Sulpirida/farmacologia
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