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1.
Artigo em Inglês | MEDLINE | ID: mdl-33804403

RESUMO

Previous studies have identified that a behavior can occur through the strongest predictor intention, but there is a gap between intention and behavior. Dopamine receptor D2 (DRD2) is known to account for a variance in sporting behaviors in human and animal subjects. However, the relationship between DRD2 and sport participation has been poorly studied, and the limited available reports are inconsistent. The present study was performed to examine the impact of DRD2 on sport participation among Korean university students based on the integrated behavioral model (IBM). Data were collected from enrolled university students in Seoul (N = 45). Participants answered survey questions first, and then they gave investigators their hair to provide DNA information (i.e., the A1 allele of DRD2). DRD2 had a significant effect on sport participation, but only in male students. Male students who carried the A1 allele of DRD2 significantly participated in 105.10 min more sporting activities than male students who did not. Moreover, the effect of intention on sport participation was significantly decreased when considering DRD2. Despite the small sample size, the results of this study could be a preliminary case for a larger study and indicate the direction of future research. Our results suggest that DRD2 may have played an important role as the "actual skill" shown in the IBM.


Assuntos
Intenção , Esportes , Alelos , Humanos , Masculino , Receptores de Dopamina D2/genética , Seul
2.
Toxicol Lett ; 344: 1-10, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33647392

RESUMO

Methylphenidate (MPD) is used as a first-line treatment for attention-deficit/hyperactivity disorder (ADHD). The number of prescriptions for ADHD patients is increasing, suggesting that the number of fertile women using such medication might be also increasing. The purpose of this study was to clarify the effects of MPD exposure during the fetal period on infant development, behavior, learning, and memory in mice. Expression levels of candidate genes associated with ADHD were also determined in the brain of pups born to MDP-treated dams who were administered MPD orally at a dose of 2.5, 7.5, or 15 mg/kg daily from gestational day 1 to the day before delivery. Offspring aged 6-8 weeks were subjected to the spontaneous locomotor activity, elevated plus-maze, and passive avoidance tests and therapeutic treatments with MPD or atomoxetine. Fetal MPD exposure induced ADHD-like phenotypes, such as hyperactivity and impulsivity, in mouse offspring, which were suppressed by treatment with MPD and atomoxetine. These mice showed decreased Drd2 and Slc6a3 expression levels in the brain, which are often observed in ADHD model animals. Our results suggest that continuous use of MPD during pregnancy induces ADHD phenotypes in the offspring.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Metilfenidato/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Receptores de Dopamina D2/metabolismo , Animais , Animais Recém-Nascidos , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Aprendizagem , Masculino , Metilfenidato/administração & dosagem , Camundongos , Camundongos Endogâmicos ICR , Gravidez , Receptores de Dopamina D2/genética
3.
Gene ; 781: 145538, 2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-33631245

RESUMO

BACKGROUND: The genetics of binge-eating disorder (BED) is an emerging topic, with dopaminergic genes being implicated in its etiology due to the role that dopamine (DA) plays in food reward sensitivity and self-regulation of eating behavior. However, no study to date has examined if DA genes influence response to behavioral treatment of BED. OBJECTIVE: The primary objective of this study was to examine the ability of DA-associated polymorphisms to predict BED treatment response measured using binge frequency over 12 months. As secondary objectives, this study examined cross-sectional relationships between these polymorphisms and anthropometrics in women living with and without BED and obesity. METHODS: Women aged 18-64 years old were genotyped for the DA-related SNPs DRD2/ANKK1 Taq1A (rs1800497) and COMT (rs4680), as well as the DA-related uVNTRs DAT-1 (SLC6A3) and MAO-A. A multi-locus DA composite score was formed from these 4 polymorphisms using genotypes known to have a functional impact resulting in modified DA signaling. Binge frequency (Eating Disorder Examination - Interview) and body composition (Tanita BC-418) were assessed in a pre-post analysis to examine genetic predictors of treatment response in women living with obesity and BED. Secondary data analysis was conducted on a cross-sectional comparison of three groups of women enrolled in trial group treatment for BED: women living with obesity and BED (n = 72), obesity without BED (n = 27), and normal-weight without BED (n = 45). RESULTS: There were no significant genotype × time interactions related to anthropometrics or binge frequency for any individual DA genotypes, or to the composite score reflecting DA availability. At baseline, there were no significant between-group differences in frequencies of DA-related alleles, nor were there associations between genotypes and anthropometrics. CONCLUSIONS: Our study found no evidence to suggest that the DRD2/ANKK1 Taq1A, COMT, MAO-A, or DAT-1 polymorphisms are associated with response to behavioral intervention for BED as measured by changes in binge frequency. Future studies should examine a greater variety of dopaminergic polymorphisms, other candidate genes that target other neurotransmitter systems, as well as examine their impact on both behavioral and pharmacological-based treatment for BED.


Assuntos
Transtorno da Compulsão Alimentar/genética , Dopamina/genética , Polimorfismo Genético , Adolescente , Adulto , Transtorno da Compulsão Alimentar/metabolismo , Catecol O-Metiltransferase/genética , Estudos Transversais , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Monoaminoxidase/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Dopamina D2/genética , Adulto Jovem
4.
Gene ; 777: 145466, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33524518

RESUMO

The dopamine - related genes, like dopamine D2 receptor (DRD2) gene and ankyrin repeat and kinase domain containing 1 (ANKK1) gene are implicated in neurological functions. Some polymorphisms of the DRD2/ANKK1 locus (TaqIA, TaqIB, TaqID) have been used to study genetic diversity and the evolution of human populations. The present investigation aims to assess the genetic diversity in seven North African populations in order to explore their genetic structure and to compare them to others worldwide populations studied for the same locus. Nine single nucleotide polymorphisms (SNPs) from the DRD2/ANKK1 locus (rs1800497 TaqIA, rs2242592, rs1124492, rs6277, rs6275, rs1079727, rs2002453, rs2234690 and rs1079597 TaqIB) were typed in 366 individuals from seven North African populations: six from Tunisia (Sousse, Smar, Kesra, Kairouan, Mehdia and Kerkennah) and one from Libya. The allelic frequencies of rs2002453 and rs2234690 were higher in the Smar population than in the other North African populations. More, the Smar population showed the lowest average heterozygosity (0.313). The principal component analysis (PCA) showed that the Smar population was clearly separated from others. Furthermore, linkage disequilibrium analysis shown a high linkage disequilibrium in the North African population and essentially in Smar population. Comparison with other world populations has shown that the heterozygosity of North African population was very close to that of the African and European populations. The PCA and the haplotypic analysis suggested the presence of an important Eurasian genetic component for the North African population. These results suggested that the Smar population was isolated from the others North Africans ones by its peculiar genetic structure because of isolation, endogamy and genetic drift. On the other hand, the North African population is characterized by a multi ancestral gene pool from Eurasia and sub-Saharan Africa due to human migration since prehistoric times.


Assuntos
Proteínas Serina-Treonina Quinases/genética , Receptores de Dopamina D2/genética , Adulto , África do Norte/etnologia , Grupo com Ancestrais do Continente Africano , Alelos , Grupos Étnicos/genética , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Genômica , Genótipo , Técnicas de Genotipagem , Haplótipos/genética , Heterozigoto , Migração Humana , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
5.
Gene ; 765: 145107, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32889058

RESUMO

AIM: The Lithuanian population has outstanding rates of alcohol consumption and alcohol related mortality. Alteration of brain dopaminergic system play a role in the risk for addiction disorders. We evaluated the association of one single nucleotide polymorphism rs1800497 in the Ankyrin Repeat and Kinase Domain Containing 1 - Dopamine Receptor D2 complex (ANKK1-DRD2) and a catechol-o-methyltransferase (COMT) rs4680 single nucleotide polymorphism with the risk for alcohol use disorder and impulsiveness in Lithuanian population. Both genetic polymorphisms are known to alter brain dopaminergic activity, thus we also investigated the possible interaction effect of these polymorphisms. METHODS: The study included 329 participants recruited from the local community. Hazardous alcohol use was evaluated using the Alcohol Use Disorder Identification Test (AUDIT). Impulsiveness was measured using the Barratt Impulsiveness Scale - 11 (BIS-11). Between group differences of AUDIT and BIS-11 scores were examined stratified by genetic polymorphisms and their combinations. The independent effect of each polymorphism and their interaction for hazardous alcohol use were evaluated using adjusted logistic regression analyses. RESULTS: The ANKK1-DRD2 rs1800497 polymorphism was associated with total AUDIT score, but not with the hazardous use of alcohol, as indicated by the AUDIT test cut-off of 8. The COMT rs4680 GG genotype was associated with the hazardous use of alcohol (adjusted OR = 2.094, p = 0.029), but this association was not statistically significant after adjustment for multiple comparisons. Presence of both COMT rs4680 and ANKK1-DRD2 rs1800497 GGxCT/TT polymorphisms was associated with significantly increased risk for hazardous use of alcohol (adjusted OR = 5.016, p = 0.005). The COMT rs4680 and ANKK1-DRD2 rs1800497 genetic polymorphisms, and their combination were not associated with impulsiveness. CONCLUSIONS: Our study demonstrated that the interaction of COMT rs4680 and ANKK1-DRD2 rs1800497 genetic polymorphisms is associated with a hazardous use of alcohol.


Assuntos
Alcoolismo/genética , Catecol O-Metiltransferase/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Dopamina D2/genética , Adulto , Alcoolismo/epidemiologia , Alelos , Repetição de Anquirina/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação/genética , Lituânia/epidemiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Dopamina D2/metabolismo , Fatores de Risco
6.
Phytomedicine ; 81: 153439, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33352493

RESUMO

BACKGROUND: Depression and stress-related disorders are leading causes of death worldwide. Standard treatments elevating serotonin or noradrenaline levels are not sufficiently effective and cause adverse side effects. A connection between dopamine pathways and stress-related disorders has been suggested. Compounds derived from herbal medicine could be a promising alternative. We examined the neuroprotective effects of ursolic acid (UA) by focusing on dopamine signalling. METHODS: Trolox equivalent capacity assay was used to determine the antioxidant activities of UA in vitro. C. elegans N2 wildtype and dopamine receptor-knockout mutants (dop1-deficient RB665 and dop3-deficient LX703 strains) were used as in vivo models. H2DCFDA and acute juglone assays were applied to determine the antioxidant activity in dependency of dopamine pathways in vivo. Stress was assessed by heat and acute osmotic stress assays. The influence of UA on overall survival was analyzed by a life span assay. The dop1 and dop3 mRNA expression was determined by real time RT-PCR. We also examined the binding affinity of UA towards C. elegans Dop1 and Dop3 receptors as well as human dopamine receptors D1 and D3 by molecular docking. RESULTS: Antioxidant activity assays showed that UA exerts strong antioxidant activity. UA increased resistance towards oxidative, osmotic and heat stress. Additionally, UA increased life span of nematodes. Moreover, dop1 and dop3 gene expression was significantly enhanced upon UA treatment. Docking analysis revealed stronger binding affinity of UA to C. elegans and human dopamine receptors than the natural ligand, dopamine. Binding to Dop1 was stronger than to Dop3. CONCLUSION: UA reduced stress-dependent ROS generation and acted through Dop1 and to a lesser extent through Dop3 to reduce stress and prolong life span in C. elegans. These results indicate that UA could be a promising lead compound for the development of new antidepressant medications.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/efeitos dos fármacos , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/genética , Estresse Fisiológico/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Antioxidantes/farmacologia , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/metabolismo , Dopamina/metabolismo , Técnicas de Inativação de Genes , Humanos , Longevidade/efeitos dos fármacos , Simulação de Acoplamento Molecular , Mutação , Espécies Reativas de Oxigênio/metabolismo , Receptores de Dopamina D1/química , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/química , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/química , Receptores de Dopamina D3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Fisiológico/genética , Triterpenos/química
7.
Sci Rep ; 10(1): 22347, 2020 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-33339892

RESUMO

Recent evidence suggests that the central nervous system (CNS) regulates plasma glucose levels, but the underlying mechanism is unclear. The present study investigated the role of dopaminergic function in the CNS in regulation of plasma glucose levels in mice. I.c.v. injection of neither the dopamine D1 receptor agonist SKF 38393 nor the antagonist SCH 23390 influenced plasma glucose levels. In contrast, i.c.v. injection of both the dopamine D2 receptor agonist quinpirole and the antagonist l-sulpiride increased plasma glucose levels. Hyperglycemia induced by quinpirole and l-sulpiride was absent in dopamine D2 receptor knockout mice. I.c.v. injection of quinpirole and l-sulpiride each increased mRNA levels of hepatic glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, which are the key enzymes for hepatic gluconeogenesis. Systemic injection of the ß2 adrenoceptor antagonist ICI 118,551 inhibited hyperglycemia induced by l-sulpiride, but not by quinpirole. In contrast, hyperglycemia induced by quinpirole, but not by l-sulpiride, was inhibited by hepatic vagotomy. These results suggest that stimulation of central dopamine D2 receptors increases plasma glucose level by increasing hepatic glucose production through parasympathetic nerves, whereas inhibition of central dopamine D2 receptors increases plasma glucose level by increasing hepatic glucose production through sympathetic nerves.


Assuntos
Glicemia/genética , Quimpirol/farmacologia , Receptores de Dopamina D2/genética , Sulpirida/farmacologia , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Vias Autônomas/efeitos dos fármacos , Vias Autônomas/metabolismo , Benzazepinas/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2/farmacologia , Humanos , Camundongos , Camundongos Knockout , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D2/agonistas
8.
Sci Rep ; 10(1): 21842, 2020 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-33318558

RESUMO

Fluorescent ligands are versatile tools for the study of G protein-coupled receptors. Depending on the fluorophore, they can be used for a range of different applications, including fluorescence microscopy and bioluminescence or fluorescence resonance energy transfer (BRET or FRET) assays. Starting from phenylpiperazines and indanylamines, privileged scaffolds for dopamine D2-like receptors, we developed dansyl-labeled fluorescent ligands that are well accommodated in the binding pockets of D2 and D3 receptors. These receptors are the target proteins for the therapy for several neurologic and psychiatric disorders, including Parkinson's disease and schizophrenia. The dansyl-labeled ligands exhibit binding affinities up to 0.44 nM and 0.29 nM at D2R and D3R, respectively. When the dansyl label was exchanged for sterically more demanding xanthene or cyanine dyes, fluorescent ligands 10a-c retained excellent binding properties and, as expected from their indanylamine pharmacophore, acted as agonists at D2R. While the Cy3B-labeled ligand 10b was used to visualize D2R and D3R on the surface of living cells by total internal reflection microscopy, ligand 10a comprising a rhodamine label showed excellent properties in a NanoBRET binding assay at D3R.


Assuntos
Carbocianinas/química , Corantes Fluorescentes/química , Receptores de Dopamina D2 , Receptores de Dopamina D3 , Animais , Células CHO , Cricetulus , Células HEK293 , Humanos , Receptores de Dopamina D2/química , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/química , Receptores de Dopamina D3/genética , Receptores de Dopamina D3/metabolismo
9.
Nat Commun ; 11(1): 4448, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895370

RESUMO

Substance abuse disorders are linked to alteration of circadian rhythms, although the molecular and neuronal pathways implicated have not been fully elucidated. Addictive drugs, such as cocaine, induce a rapid increase of dopamine levels in the brain. Here, we show that acute administration of cocaine triggers reprogramming in circadian gene expression in the striatum, an area involved in psychomotor and rewarding effects of drugs. This process involves the activation of peroxisome protein activator receptor gamma (PPARγ), a nuclear receptor involved in inflammatory responses. PPARγ reprogramming is altered in mice with cell-specific ablation of the dopamine D2 receptor (D2R) in the striatal medium spiny neurons (MSNs) (iMSN-D2RKO). Administration of a specific PPARγ agonist in iMSN-D2RKO mice elicits substantial rescue of cocaine-dependent control of circadian genes. These findings have potential implications for development of strategies to treat substance abuse disorders.


Assuntos
Relógios Circadianos/efeitos dos fármacos , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Cocaína/efeitos adversos , Núcleo Accumbens/efeitos dos fármacos , PPAR gama/metabolismo , Receptores de Dopamina D2/metabolismo , Administração Oral , Animais , Relógios Circadianos/fisiologia , Cocaína/administração & dosagem , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Dopamina/metabolismo , Injeções Intraperitoneais , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Knockout , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Núcleo Accumbens/fisiopatologia , PPAR gama/agonistas , Pioglitazona/administração & dosagem , Receptores de Dopamina D2/genética , Recompensa , Transdução de Sinais
10.
Gen Physiol Biophys ; 39(4): 393-398, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32902408

RESUMO

It is known that early-life stress events induce profound consequences on emotional brain regions including amygdala, involved in emotional processing and the ventral tegmental area (VTA), which contains neuron cell bodies of the mesolimbic dopaminergic system. The aim of this study is to test the hypothesis that stress induced by long-term social isolation from weaning in female rats is associated with alterations in amygdalar dopamine receptor gene expression and VTA dopamine concentrations. Rats were weaned on postnatal day 21 and then exposed to stress of chronic isolation for 9 weeks. Control animals were housed socially. Amygdalar dopamine D1 but not D2 receptor gene expression was decreased in isolated rats compared to controls. Dopamine concentrations in the VTA were enhanced following chronic isolation. A negative correlation was observed between amygdalar D1 gene expression and dopamine concentrations in the VTA. In conclusion, a reduction of dopamine D1 receptor gene expression in the amygdala in response to stress induced by chronic isolation in female rats was accompanied by an increase in dopamine concentration in the VTA. Further studies are needed to understand the physiological significance, if any, of negative association of amygdalar dopamine receptor D1 gene expression and dopamine concentrations in the VTA.


Assuntos
Dopamina/análise , Receptores de Dopamina D2 , Isolamento Social , Estresse Psicológico , Área Tegmentar Ventral , Desmame , Animais , Emoções , Feminino , Ratos , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Área Tegmentar Ventral/metabolismo
11.
Ann Agric Environ Med ; 27(2): 260-268, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32588603

RESUMO

INTRODUCTION: Marijuana is one of the most widely used psychoactive substance. There is evidence of genetic predisposition for addiction. OBJECTIVE: The aim of the study is to evaluate personality traits measured by the NEO Five-Factor Inventory and State-Trait Anxiety Inventory, combined with analysis of Tag1B rs1079597 and Tag1D rs1800498 located in the DRD2 gene. MATERIAL AND METHODS: The study group consisted of 214 rural cannabinoid users and 301 controls. The same psychometric test and real-time PCR genotyping were performed in both studied groups. RESULTS: The values of Anxiety state, Anxiety trait, NEO FFI: Neuroticism and Openness in the rural cannabis using group were significantly higher than in the control group. On the other hand, lower values were observed among rural people using cannabis compared to the control group for NEO FFI: Extraversion, Agreeability and Conscientiousness. In the Anxiety trait subscale, a 2% association with the polymorphism DRD2 Tag1B rs1079597 was detected in subjects using cannabis. However, for the DRD2 Tag1D rs1800498, there was no effect on the differences in personality traits between rural cannabis users and the control group. CONCLUSIONS: The study shows differences in personality traits between the cannabis using group and controls. Interaction between genetic factors and personality traits was also detected. The association showing the combination of psychological characteristics and genetic variants can bring us closer to the overall picture of the issue of marijuana addiction.


Assuntos
Cannabis , Usuários de Drogas/psicologia , Personalidade/genética , Polimorfismo Genético , Receptores de Dopamina D2/genética , População Rural/estatística & dados numéricos , Adulto , Humanos , Masculino , Testes de Personalidade , Polônia , Receptores de Dopamina D2/metabolismo , Adulto Jovem
12.
Ann Agric Environ Med ; 27(2): 269-273, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32588604

RESUMO

INTRODUCTION: Substance abuse significantly influences human health and may induce problems with social functioning worldwide. Numerous genetic and environmental risk factors, as well as their interactions, accelerate the development of drug addiction. Etiologically, the dopaminergic mesocorticolimbic reward pathways are related to psychoactive substance addiction, and the reward properties of heroin are connected with changes in the mesolimbic dopaminergic system. OBJECTIVE: The aim of this study is a haplotypic analysis of subjects addicted to polysubstance. However, with the knowledge that this is not a homogenous subgroup, it was decided to separate and analyze homogenous subgroups of subjects in order to find specific haplotypic variants among them. The subjects in the subgroups were addicted to heroin, and subjects with more than two relapses in the past two years. MATERIAL AND METHODS: The study group comprised of 301 polysubstance addicted rural male subjects. From this group, 2 homogenous subgroups of subjects were isolated and additionally analyzed: (1) a group of heroin addicted subjects (n=61), and (2) a group of heroin-addicted subjects with at least two relapses in the last two years (n=21). The group consisting of all polysubstance addicted rural subjects and both homogenous subgroups were analyzed against a control group of non-addicted subjects (n=300), matching gender and age. Five polymorphisms in the DRD2/ANKK1 region were analyzed: rs1076560, rs1800498, rs1079597, rs6276 in the DRD2 gene, and rs1800497 in the ANKK1 gene. RESULTS: A statistically significant haplotype association was found in analysis of the heroin addicted subjects, compared to controls, and two possible trends - when comparing the whole group of addicted subjects to controls, and in relapse subgroups, compared to the controls. CONCLUSIONS: The results obtained showed that haplotypes indicate a part of the biological component of addiction.


Assuntos
Dependência de Heroína/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Dopamina D2/genética , População Rural/estatística & dados numéricos , Adulto , Dependência de Heroína/etiologia , Dependência de Heroína/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Polônia , Recidiva
13.
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
14.
PLoS One ; 15(5): e0226790, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32365120

RESUMO

Patients with DYT1 dystonia caused by the mutated TOR1A gene exhibit risk neutral behaviour compared to controls who are risk averse in the same reinforcement learning task. It is unclear whether this behaviour can be linked to changes in cortico-striatal plasticity demonstrated in animal models which share the same TOR1A mutation. We hypothesised that we could reproduce the experimental risk taking behaviour using a model of the basal ganglia under conditions where cortico-striatal plasticity was abnormal. As dopamine exerts opposing effects on cortico-striatal plasticity via different receptors expressed on medium spiny neurons (MSN) of the direct (D1R dominant, dMSNs) and indirect (D2R dominant, iMSNs) pathways, we tested whether abnormalities in cortico-striatal plasticity in one or both of these pathways could explain the patient's behaviour. Our model could generate simulated behaviour indistinguishable from patients when cortico-striatal plasticity was abnormal in both dMSNs and iMSNs in opposite directions. The risk neutral behaviour of the patients was replicated when increased cortico-striatal long term potentiation in dMSN's was in combination with increased long term depression in iMSN's. This result is consistent with previous observations in rodent models of increased cortico-striatal plasticity at in dMSNs, but contrasts with the pattern reported in vitro of dopamine D2 receptor dependant increases in cortico-striatal LTP and loss of LTD at iMSNs. These results suggest that additional factors in patients who manifest motor symptoms may lead to divergent effects on D2 receptor dependant cortico-striatal plasticity that are not apparent in rodent models of this disease.


Assuntos
Dopamina/genética , Distonia Muscular Deformante/genética , Chaperonas Moleculares/genética , Receptores de Dopamina D2/genética , Animais , Gânglios da Base/metabolismo , Gânglios da Base/fisiologia , Comportamento Animal/fisiologia , Ciências Biocomportamentais , Corpo Estriado/metabolismo , Corpo Estriado/fisiologia , Dopamina/metabolismo , Distonia Muscular Deformante/psicologia , Feminino , Humanos , Aprendizagem/fisiologia , Potenciação de Longa Duração/genética , Potenciação de Longa Duração/fisiologia , Masculino , Rigidez Muscular/genética , Rigidez Muscular/patologia , Mutação/genética , Vias Neurais/metabolismo , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Reforço Psicológico , Assunção de Riscos , Roedores/genética , Roedores/fisiologia , Sinapses/genética
15.
Nat Commun ; 11(1): 1957, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32327644

RESUMO

Action control is a key brain function determining the survival of animals in their environment. In mammals, neurons expressing dopamine D2 receptors (D2R) in the dorsal striatum (DS) and the nucleus accumbens (Acb) jointly but differentially contribute to the fine regulation of movement. However, their region-specific molecular features are presently unknown. By combining RNAseq of striatal D2R neurons and histological analyses, we identified hundreds of novel region-specific molecular markers, which may serve as tools to target selective subpopulations. As a proof of concept, we characterized the molecular identity of a subcircuit defined by WFS1 neurons and evaluated multiple behavioral tasks after its temporally-controlled deletion of D2R. Consequently, conditional D2R knockout mice displayed a significant reduction in digging behavior and an exacerbated hyperlocomotor response to amphetamine. Thus, targeted molecular analyses reveal an unforeseen heterogeneity in D2R-expressing striatal neuronal populations, underlying specific D2R's functional features in the control of specific motor behaviors.


Assuntos
Neostriado/citologia , Neurônios/fisiologia , Núcleo Accumbens/citologia , Receptores de Dopamina D2/metabolismo , Anfetamina/farmacologia , Animais , Biomarcadores/metabolismo , Corpo Estriado/citologia , Corpo Estriado/metabolismo , Corpo Estriado/fisiologia , Dopaminérgicos/farmacologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Neostriado/metabolismo , Neostriado/fisiologia , Vias Neurais , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiologia , Receptores de Dopamina D2/genética
16.
Psychiatr Danub ; 32(1): 84-91, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32303037

RESUMO

BACKGROUND: Symptomatic remission is an achievable goal in the treatment of schizophrenia. The type of antipsychotic medication and particular genetic variants of the dopaminergic system might be associated with remission. Potential pharmacogenetic markers of the treatment response to antipsychotic medication are missing. This study assessed the possible association between dopamine receptor type 2 (DRD2 rs1800497) and dopamine transporter (DAT1 rs28363170) gene variants with symptomatic remission in schizophrenia. SUBJECTS AND METHODS: Olanzapine (5-20 mg/d) monotherapy was administered for 6 months to 150 male Caucasian subjects with schizophrenia. Remission was evaluated according to "Remission in Schizophrenia Working Group" criteria. Genotyping was performed by PCR-RFLP. RESULTS: Symptomatic remission was found in 31% of patients. DRD2 rs1800497 and DAT1 rs28363170 gene variants were not significantly associated with symptomatic remission. The limitations are a relatively small sample size of patients with schizophrenia (N=150), especially of group with symptomatic remission (N=45). However, the study had moderate but adequate sample sizes for most of the comparisons. Only two dopaminergic polymorphisms were analyzed, and plasma concentration of olanzapine was not determined. CONCLUSION: These results revealed a lack of association between DRD2 rs1800497 and DAT1 rs28363170 genetic variants and symptomatic remission in male patients treated with olanzapine, suggesting that these genetic variants could not be used to predict symptomatic remission to olanzapine monotherapy. Negative results should be further confirmed or rejected in the larger samples, including haplotype analyses, to detect clinically useful and easy obtainable pharmacogenetic markers that might predict therapeutic response or remission in schizophrenia.


Assuntos
Antipsicóticos/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Mutação , Olanzapina/administração & dosagem , Olanzapina/uso terapêutico , Receptores de Dopamina D2/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Adulto , Antipsicóticos/administração & dosagem , Grupo com Ancestrais do Continente Europeu/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento
17.
Nat Commun ; 11(1): 941, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32071304

RESUMO

Oxidative stress is a major pathogenic mechanism in Parkinson's disease (PD). As an important cellular antioxidant, glutathione (GSH) balances the production and incorporation of free radicals to protect neurons from oxidative damage. GSH level is decreased in the brains of PD patients. Hence, clarifying the molecular mechanism of GSH deficiency may help deepen our knowledge of PD pathogenesis. Here we report that the astrocytic dopamine D2 receptor (DRD2) regulates GSH synthesis via PKM2-mediated Nrf2 transactivation. In addition we find that pyridoxine can dimerize PKM2 to promote GSH biosynthesis. Further experiments show that pyridoxine supplementation increases the resistance of nigral dopaminergic neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in wild-type mice as well as in astrocytic Drd2 conditional knockout mice. We conclude that dimerizing PKM2 may be a potential target for PD treatment.


Assuntos
Glutationa/biossíntese , Intoxicação por MPTP/patologia , Fator 2 Relacionado a NF-E2/genética , Fármacos Neuroprotetores/administração & dosagem , Piruvato Quinase/metabolismo , Receptores de Dopamina D2/metabolismo , Animais , Astrócitos , Técnicas de Observação do Comportamento , Comportamento Animal/efeitos dos fármacos , Células Cultivadas , Dopamina/metabolismo , Neurônios Dopaminérgicos , Intoxicação por MPTP/diagnóstico , Intoxicação por MPTP/tratamento farmacológico , Camundongos Knockout , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Cultura Primária de Células , Multimerização Proteica/efeitos dos fármacos , Piridoxina/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Receptores de Dopamina D2/genética , Substância Negra/citologia , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Ativação Transcricional
18.
Nat Commun ; 11(1): 782, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034128

RESUMO

Food addiction is linked to obesity and eating disorders and is characterized by a loss of behavioral control and compulsive food intake. Here, using a food addiction mouse model, we report that the lack of cannabinoid type-1 receptor in dorsal telencephalic glutamatergic neurons prevents the development of food addiction-like behavior, which is associated with enhanced synaptic excitatory transmission in the medial prefrontal cortex (mPFC) and in the nucleus accumbens (NAc). In contrast, chemogenetic inhibition of neuronal activity in the mPFC-NAc pathway induces compulsive food seeking. Transcriptomic analysis and genetic manipulation identified that increased dopamine D2 receptor expression in the mPFC-NAc pathway promotes the addiction-like phenotype. Our study unravels a new neurobiological mechanism underlying resilience and vulnerability to the development of food addiction, which could pave the way towards novel and efficient interventions for this disorder.


Assuntos
Dependência de Alimentos/fisiopatologia , Núcleo Accumbens/fisiologia , Córtex Pré-Frontal/fisiologia , Receptores de Dopamina D2/genética , Animais , Modelos Animais de Doenças , Comportamento Alimentar/fisiologia , Dependência de Alimentos/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Camundongos Knockout , Vias Neurais/fisiologia , Receptor CB1 de Canabinoide/genética , Transmissão Sináptica , Regulação para Cima
19.
Neuron ; 106(1): 76-89.e8, 2020 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-32004439

RESUMO

Unbiased in vivo genome-wide genetic screening is a powerful approach to elucidate new molecular mechanisms, but such screening has not been possible to perform in the mammalian central nervous system (CNS). Here, we report the results of the first genome-wide genetic screens in the CNS using both short hairpin RNA (shRNA) and CRISPR libraries. Our screens identify many classes of CNS neuronal essential genes and demonstrate that CNS neurons are particularly sensitive not only to perturbations to synaptic processes but also autophagy, proteostasis, mRNA processing, and mitochondrial function. These results reveal a molecular logic for the common implication of these pathways across multiple neurodegenerative diseases. To further identify disease-relevant genetic modifiers, we applied our screening approach to two mouse models of Huntington's disease (HD). Top mutant huntingtin toxicity modifier genes included several Nme genes and several genes involved in methylation-dependent chromatin silencing and dopamine signaling, results that reveal new HD therapeutic target pathways.


Assuntos
Sobrevivência Celular/genética , Proteína Huntingtina/genética , Doença de Huntington/genética , Neostriado/metabolismo , Neurônios/metabolismo , Animais , Comportamento Animal , Sistemas CRISPR-Cas , Técnicas de Silenciamento de Genes , Biblioteca Gênica , Genes Essenciais/genética , Camundongos , Camundongos Transgênicos , Nucleosídeo NM23 Difosfato Quinases/genética , Nucleosídeo Difosfato Quinase D/genética , Agregados Proteicos , Interferência de RNA , RNA Guia , RNA Interferente Pequeno , Receptores de Dopamina D2/genética , Análise de Sequência de RNA
20.
Sci Rep ; 10(1): 647, 2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959776

RESUMO

Accumulating evidence suggests AKT1 and DRD2-AKT-GSK3 signaling involvement in schizophrenia. AKT1 activity is also required for lithium, a GSK3 inhibitor, to modulate mood-related behaviors. Notably, GSK3 inhibitor significantly alleviates behavioral deficits in Akt1-/- female mice, whereas typical/atypical antipsychotics have no effect. In agreement with adjunctive therapy with lithium in treating schizophrenia, our data mining indicated that the average utilization rates of lithium in the Taiwan National Health Insurance Research Database from 2002 to 2013 are 10.9% and 6.63% in inpatients and outpatients with schizophrenia, respectively. Given that lithium is commonly used in clinical practice, it is of great interest to evaluate the effect of lithium on alleviating Akt1-related deficits. Taking advantage of Akt1+/- mice to mimic genetic deficiency in patients, behavioral impairments were replicated in female Akt1+/- mice but were alleviated by subchronic lithium treatment for 13 days. Lithium also effectively alleviated the observed reduction in phosphorylated GSK3α/ß expression in the brains of Akt1+/- mice. Furthermore, inhibition of Akt expression using an Akt1/2 inhibitor significantly reduced neurite length in P19 cells and primary hippocampal cell cultures, which was also ameliorated by lithium. Collectively, our findings implied the therapeutic potential of lithium and the importance of the AKT1-GSK3 signaling pathway.


Assuntos
Bases de Dados Factuais , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Seguro Saúde , Compostos de Lítio/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Transdução de Sinais , Adolescente , Adulto , Idoso , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Humanos , Compostos de Lítio/farmacologia , Masculino , Camundongos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Taiwan , Adulto Jovem
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