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Several studies are published, that investigated dopamine receptor 2 (DRD2) gene TaqIA polymorphism as a risk factor for alcohol dependence (AD) with positive and negative associations. To derive a more precise estimation of the relationship, a meta-analysis of case-control studies that examined the association between DRD2 gene Taq1A polymorphism and alcohol dependence was performed. Eligible articles were identified through a search of databases including PubMed, Science Direct, Springer link, and Google Scholar. The association between the DRD2 TaqIA polymorphism and AD susceptibility was conducted using odds ratios (ORs) and 95% confidence intervals (95% CIs) as association measures. A total of 69 studies with 9125 cases and 9123 healthy controls were included in the current meta-analysis. Results of the present analysis showed significant association between DRD2 TaqIA polymorphism and AD risk using five genetic modes (allele contrast model-OR 1.22, 95% CI 1.13-1.32, p < 0.0001; homozygote model-OR 1.35, 95%CI 1.18-1.55; p ≤ 0.0001; dominant model-OR 1.29; 95% CI 1.20-1.39; p < 0.0001; recessive model-OR 1.21; 95% CI 1.08-1.36; p = 0.0006). There was no significant association found in subgroup analysis, TaqIA polymorphism was not significantly associated with AD risk in the Asian population under all genetic models, but in the Caucasian population, TaqIA polymorphism was significantly associated with AD risk. Overall, results support the hypothesis that DRD2 Taq1A polymorphism plays a role in alcohol dependence.
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BACKGROUND: The incidence of post-operative nausea and vomiting (PONV) remains at about 30% despite all therapeutic efforts to reduce it. The clinical risk factors guiding the prophylactic treatment are well established, but genetic factors associated with PONV remain poorly known. The aim of this study was to explore clinical and genetic factors impacting PONV by performing a genome-wide association study (GWAS) together with relevant clinical factors as covariates, and systematically attempt to replicate previously reported PONV associations. Relevant clinical factors are explored with logistic regression model. METHODS: This was an observational case control study in Helsinki University Hospital between 1 August 2006 and 31 December 2010. One thousand consenting women with elevated risk for PONV, undergoing breast cancer surgery with standardised propofol anaesthesia and antiemetics. After exclusions for clinical reasons and failed genotyping, 815 patients were included with 187 PONV cases and 628 controls. Emergence of PONV up to 7th post-operative day was recorded. PONV at 2-24 h after surgery was selected to be the primary outcome. The GWAS explored associations between PONV and 653 034 genetic variants. Replication attempts included 31 variants in 16 genes. RESULTS: The overall incidence of PONV up to 7th post-operative day was 35%, where 3% had PONV at 0-2 h and 23% at 2-24 h after surgery. Age, American Society of Anaesthesiologists status, the amount of oxycodone used in the post-anaesthesia care unit, smoking status, previous PONV, and history of motion sickness were statistically significant predictive factors in the logistic model. The receiver operating characteristic-area under the curve of 0.75 (95% CI 0.71-0.79) was calculated for the model. The GWAS identified six variants with suggestive association to PONV (p < 1 × 10-5 ). Of the previously reported variants, association with the DRD2 variant rs18004972 (TaqIA) was replicated (p = .028). CONCLUSIONS: Our GWAS approach did not identify any high-impact PONV susceptibility variants. The results provide some support for a role of dopamine D2 receptors in PONV.
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Anestesia , Antieméticos , Propofol , Humanos , Feminino , Náusea e Vômito Pós-Operatórios/epidemiologia , Náusea e Vômito Pós-Operatórios/genética , Propofol/uso terapêutico , Estudos de Casos e Controles , Estudo de Associação Genômica Ampla , Antieméticos/uso terapêutico , Fatores de RiscoRESUMO
BACKGROUND: The association between blunted dopaminergic neurotransmission and alcohol use disorder (AUD) is well-known. In particular, the impairment of postsynaptic dopamine 2 and 3 receptors (DRD2/3) in the ventral and dorsal striatum during the development and maintenance of alcohol addiction has been investigated in several positron emission tomography (PET) studies. However, it is unclear whether these changes are the result of adaptation or genetic predisposition. METHODS: Here we investigated the association between DRD2/ankyrin repeat and kinase domain-containing 1 (ANKK1) TaqIA allele (rs1800497) status and striatal DRD2/3 availability measured by 18F-fallypride PET in 12 AUD patients and 17 sex-matched healthy controls. Age and smoking status were included as covariates. RESULTS: Contrary to our expectations, TaqIA allele status was not associated with striatal DRD2/3 availability in either group and there was no significant difference between groups, possibly due to the relatively small sample size (N = 29). CONCLUSIONS: Nonetheless, this is the first in vivo study investigating the relationship between dopamine receptor availability and genetic factors in AUD. The pitfalls of assessing such relationships in a relatively small sample are discussed. CLINICAL TRIAL REGISTRATION: The published analysis is an additional, post hoc analysis to the preregistered trial with clinical trial number NCT01679145 available on https://clinical-trials.gov/ct2/show/NCT01679145.
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Alcoolismo , Humanos , Alcoolismo/diagnóstico por imagem , Alcoolismo/genética , Alelos , Corpo Estriado/diagnóstico por imagem , Dopamina , Tomografia por Emissão de Pósitrons , Proteínas Serina-Treonina Quinases/genética , Receptores de Dopamina D2/genética , Masculino , FemininoRESUMO
Dopaminergic neurotransmission plays a pivotal role in appetitively motivated behavior in mammals, including humans. Notably, action and valence are not independent in motivated tasks, and it is particularly difficult for humans to learn the inhibition of an action to obtain a reward. We have previously observed that the carriers of the DRD2/ANKK1 TaqIA A1 allele, that has been associated with reduced striatal dopamine D2 receptor expression, showed a diminished learning performance when required to learn response inhibition to obtain rewards, a finding that was replicated in two independent cohorts. With our present study, we followed two aims: first, we aimed to replicate our finding on the DRD2/ANKK1 TaqIA polymorphism in a third independent cohort (N = 99) and to investigate the nature of the genetic effects more closely using trial-by-trial behavioral analysis and computational modeling in the combined dataset (N = 281). Second, we aimed to assess a potentially modulatory role of prefrontal dopamine availability, using the widely studied COMT Val108/158Met polymorphism as a proxy. We first report a replication of the above mentioned finding. Interestingly, after combining all three cohorts, exploratory analyses regarding the COMT Val108/158Met polymorphism suggest that homozygotes for the Met allele, which has been linked to higher prefrontal dopaminergic tone, show a lower learning bias. Our results corroborate the importance of genetic variability of the dopaminergic system in individual learning differences of action-valence interaction and, furthermore, suggest that motivational learning biases are differentially modulated by genetic determinants of striatal and prefrontal dopamine function.
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Catecol O-Metiltransferase , Dopamina , Animais , Viés , Catecol O-Metiltransferase/genética , Corpo Estriado , Genótipo , Humanos , Aprendizagem , Polimorfismo de Nucleotídeo Único/genética , Proteínas Serina-Treonina Quinases/genéticaRESUMO
The TaqIA single nucleotide variant (SNV) has been tested for association with addictions in a huge number of studies. TaqIA is located in the ankyrin repeat and kinase domain containing 1 gene (ANKK1) that codes for a receptor interacting protein kinase. ANKK1 maps on the NTAD cluster along with the dopamine receptor D2 (DRD2), the tetratricopeptide repeat domain 12 (TTC12) and the neural cell adhesion molecule 1 (NCAM1) genes. The four genes have been associated with addictions, although TTC12 and ANKK1 showed the strongest associations. In silico and in vitro studies revealed that ANKK1 is functionally related to the dopaminergic system, in particular with DRD2. In antisocial alcoholism, epistasis between ANKK1 TaqIA and DRD2 C957T SNVs has been described. This clinical finding has been supported by the study of ANKK1 expression in peripheral blood mononuclear cells of alcoholic patients and controls. Regarding the ANKK1 protein, there is direct evidence of its location in adult and developing central nervous system. Together, these findings of the ANKK1 gene and its protein suggest that the TaqIA SNV is a marker of brain differences, both in structure and in dopaminergic function, that increase individual risk to addiction development.
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Comportamento Aditivo/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transtornos Relacionados ao Uso de Substâncias/genética , Comportamento Aditivo/metabolismo , Sistema Nervoso Central/metabolismo , Epistasia Genética , Humanos , Polimorfismo de Nucleotídeo Único , Receptores de Dopamina D2/metabolismo , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Distribuição TecidualRESUMO
TaqIA is a polymorphism associated with addictions and dopamine-related traits. It is located in the ankyrin repeat and kinase domain containing 1 gene (ANKK1) nearby the gene for the dopamine D2 receptor (D2R). Since ANKK1 function is unknown, TaqIA-associated traits have been explained only by differences in D2R. Here we report ANKK1 studies in mouse and human brain using quantitative real-time PCR, Western blot, immunohistochemistry, and flow cytometry. ANKK1 mRNA and protein isoforms vary along neurodevelopment in the human and mouse brain. In mouse adult brain ANKK1 is located in astrocytes, nuclei of postmitotic neurons and neural precursors from neurogenic niches. In both embryos and adults, nuclei of neural precursors show significant variation of ANKK1 intensity. We demonstrate a correlation between ANKK1 and the cell cycle. Cell synchronization experiments showed a significant increment of ANKK1-kinase in mitotic cells while ANKK1-kinase overexpression affects G1 and M phase that were found to be modulated by ANKK1 alleles and apomorphine treatment. Furthermore, during embryonic neurogenesis ANKK1 was expressed in slow-dividing neuroblasts and rapidly dividing precursors which are mitotic cells. These results suggest a role of ANKK1 during the cell cycle in neural precursors thus providing biological support to brain structure involvement in the TaqIA-associated phenotypes.
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Encéfalo/metabolismo , Ciclo Celular/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Células-Tronco Neurais/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Adolescente , Fatores Etários , Animais , Animais Recém-Nascidos , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Embrião de Mamíferos , Feto , Idade Gestacional , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Lactente , Camundongos , Pessoa de Meia-Idade , Neurogênese/fisiologia , Proteínas Serina-Treonina Quinases/genética , RNA Mensageiro/metabolismo , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismoRESUMO
In rodents, food-predictive cues elicit eating in the absence of hunger (Weingarten, 1983). This behavior is disrupted by the disconnection of amygdala pathways to the lateral hypothalamus (Petrovich et al., 2002). Whether this circuit contributes to long-term weight gain is unknown. Using fMRI in 32 healthy individuals, we demonstrate here that the amygdala response to the taste of a milkshake when sated but not hungry positively predicts weight change. This effect is independent of sex, initial BMI, and total circulating ghrelin levels, but it is only present in individuals who do not carry a copy of the A1 allele of the Taq1A polymorphism. In contrast, A1 allele carriers, who have decreased D2 receptor density (Blum et al., 1996), show a positive association between caudate response and weight change. Regardless of genotype, however, dynamic causal modeling supports unidirectional gustatory input from basolateral amygdala (BLA) to hypothalamus in sated subjects. This finding suggests that, as in rodents, external cues gain access to the homeostatic control circuits of the human hypothalamus via the amygdala. In contrast, during hunger, gustatory inputs enter the hypothalamus and drive bidirectional connectivity with the amygdala. These findings implicate the BLA-hypothalamic circuit in long-term weight change related to nonhomeostatic eating and provide compelling evidence that distinct brain mechanisms confer susceptibility to weight gain depending upon individual differences in dopamine signaling.
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Tonsila do Cerebelo/fisiologia , Sinais (Psicologia) , Fome , Saciação , Aumento de Peso/fisiologia , Adolescente , Adulto , Alelos , Feminino , Humanos , Hipotálamo/fisiologia , Masculino , Polimorfismo Genético , Receptores de Dopamina D2/genética , Aumento de Peso/genéticaRESUMO
AIMS/HYPOTHESIS: Variations in FTO are the strongest common genetic determinants of adiposity, and may partly act by influencing dopaminergic signalling in the brain leading to altered reward processing that promotes increased food intake. Therefore, we investigated the impact of such an interaction on body composition, and peripheral and brain insulin sensitivity. METHODS: Participants from the Tübingen Family study (n = 2245) and the Malmö Diet and Cancer study (n = 2921) were genotyped for FTO SNP rs8050136 and ANKK1 SNP rs1800497. Insulin sensitivity in the caudate nucleus, an important reward area in the brain, was assessed by fMRI in 45 participants combined with intranasal insulin administration. RESULTS: We found evidence of an interaction between variations in FTO and an ANKK1 polymorphism that associates with dopamine (D2) receptor density. In cases of reduced D2 receptor availability, as indicated by the ANKK1 polymorphism, FTO variation was associated with increased body fat and waist circumference and reduced peripheral insulin sensitivity. Similarly, altered central insulin sensitivity was observed in the caudate nucleus in individuals with the FTO obesity-risk allele and diminished D2 receptors. CONCLUSIONS/INTERPRETATION: The effects of variations in FTO are dependent on dopamine D2 receptor density (determined by the ANKK1 polymorphism). Carriers of both risk alleles might, therefore, be at increased risk of obesity and diabetes.
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Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Dopamina D2/genética , Tecido Adiposo/metabolismo , Administração Intranasal , Adulto , Feminino , Predisposição Genética para Doença , Genótipo , Teste de Tolerância a Glucose , Humanos , Insulina/administração & dosagem , Resistência à Insulina/genética , Resistência à Insulina/fisiologia , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Obesidade/genética , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
BACKGROUND: Polymorphism of the dopamine D2 receptor TaqIA gene is related to reward response, relapse risks and effect of therapy for drug addiction. Whether the cue-induced craving and brain response was related to dopamine D2 receptor TaqIA gene is unknown. METHODS: Forty-nine male heroin-dependent individuals [31 with A1 allele of the TaqIA (A1+), 18 A2 allele carriers (A1-)] under methadone maintenance treatment and 20 healthy control subjects performed a heroin cue-reactivity task during functional magnetic resonance imaging. Cue-elicited craving was measured. Difference in cue induced craving and brain response were analyzed among the three groups. Correlation analyses between craving and differential brain response, heroin use and treatment history were performed within A1+ and A1- group respectively. RESULTS: Compared with A1- group, A1+ group showed greater cue-induced response in the ventrolateral prefrontal cortex, medial orbitofrontal gyrus, dorsomedial prefrontal cortex, pallidum, putamen, thalamus, superior parietal lobule and superior occipital gyrus. No difference in craving was found. The response in right thalamus positively correlated with daily heroin and methadone dose in A1+ group. For A1- group, response in left ventral orbitofrontal cortex, medial orbitofrontal gyrus, ventral anterior cingulate cortex, caudate, precuneus, calcarine and bilateral pallidum negatively correlated with duration of heroin use. The response in left ventral orbitofrontal cortex, medial orbitofrontal gyrus, bilateral calcarine and right cerebellum negatively correlated with duration of methadone maintenance treatment in A1- group. CONCLUSIONS: The findings supported that A1 allele of the TaqIA is associated with higher salience allocation to heroin-related cues in heroin-dependent patients.
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Analgésicos Opioides/farmacologia , Dependência de Heroína/genética , Metadona/farmacologia , Tratamento de Substituição de Opiáceos , Receptores de Dopamina D2/genética , Adulto , Alelos , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Fissura/efeitos dos fármacos , Sinais (Psicologia) , Heroína/farmacologia , Dependência de Heroína/tratamento farmacológico , Dependência de Heroína/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Variantes Farmacogenômicos , Polimorfismo Genético , Recidiva , RecompensaRESUMO
BACKGROUND: Persistent postural-perceptual dizziness (PPPD) is a chronic dizziness, its pathogenesis is unknown by now. OBJECTIVE: To study the relationship between the DRD2 gene TaqIA polymorphisms and PPPD, and further to explore the molecular mechanism underlying this disease. METHODS: 43 patients diagnosed with PPPD and 45 randomly selected cases (matched by age and sex) were included in the study and control group, respectively. DRD2 gene TaqIA polymorphisms were detected in all participants by polymerase chain reaction (PCR)combined with the restriction fragment length polymorphism (RFLP) method. RESULTS: In the study group, frequencies of the A1 and A2 TaqIA alleles (65.1% and 34.9%, respectively) were significantly different to those in the control group (46.7% and 53.3%, respectively; Pâ<â0.05). The allele frequency in the study group for the A1/A1 genotype was 34.9%, for A1/A2 was 60.5%, and for A2/A2 was 4.6%, all of which were significantly higher than the control group (24.4%, 44.5%. and 31.1%, respectively; Pâ<â0.01). CONCLUSIONS: Our findings indicate that the DRD2 TaqIA A1 allele is possibly the susceptibility polymorphism for PPPD, and that the A2/A2 genotype has a potentially protective role for PPPD. However, larger independent studies are required for further validation.
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Desoxirribonucleases de Sítio Específico do Tipo II/metabolismo , Tontura/genética , Polimorfismo de Fragmento de Restrição , Receptores de Dopamina D2/genética , Vertigem/genética , Adulto , Idoso , Estudos de Casos e Controles , Tontura/epidemiologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Vertigem/epidemiologia , Adulto JovemRESUMO
This study aimed to screen relevant interactions between DRD2/ANKK1 TaqIA polymorphism and dietary intakes with reference to phenotypical features in patients with T2D from western Mexico. In this cross-sectional study, a total of 175 T2D patients were enrolled. Dietary intake was evaluated using 3-day food records and appropriate software. Glycemic and blood lipid profiles were measured by standardized methods. Genotyping of the DRD2/ANKK1 TaqIA polymorphism was performed by the RFLP method. Gene-diet interactions regarding anthropometric and metabolic phenotypes were screened by adjusted multiple linear regression analyses. Genotype frequencies of the DRD2/ANKK1 TaqIA polymorphism were A1A1 (16.0%), A1A2 (52.6%), and A2A2 (31.4%). Statistically significant interactions between the DRD2/ANKK1 TaqIA genotypes and dietary factors in relation to blood triglyceride (TG) levels were found. Carriers of the A1 allele (A1A1 homozygotes plus A1A2 heterozygotes) were protected from TG increases by maltose intake (P int. = 0.023). Instead, A2A2 homozygotes were susceptible to TG rises through consumptions of total fat (P int. = 0.041), monounsaturated fatty acids (P int. = 0.001), and dietary cholesterol (P int. = 0.019). This study suggests that the interactions between DRD2/ANKK1 TaqIA polymorphism and dietary factors (sugar and fats) influence TG levels in diabetic patients.
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Diabetes Mellitus Tipo 2/sangue , Proteínas Serina-Treonina Quinases/genética , Receptores de Dopamina D2/genética , Triglicerídeos/sangue , Idoso , Estudos Transversais , Dieta/efeitos adversos , Gorduras na Dieta/administração & dosagem , Açúcares da Dieta/administração & dosagem , Ingestão de Energia , Feminino , Genótipo , Humanos , Masculino , México , Pessoa de Meia-Idade , Fenótipo , Polimorfismo Genético , Análise de RegressãoRESUMO
Dopamine is critically important in the neural manifestation of motivated behavior, and alterations in the human dopaminergic system have been implicated in the etiology of motivation-related psychiatric disorders, most prominently addiction. Patients with chronic addiction exhibit reduced dopamine D2 receptor (DRD2) availability in the striatum, and the DRD2 TaqIA (rs1800497) and C957T (rs6277) genetic polymorphisms have previously been linked to individual differences in striatal dopamine metabolism and clinical risk for alcohol and nicotine dependence. Here, we investigated the hypothesis that the variants of these polymorphisms would show increased reward-related memory formation, which has previously been shown to jointly engage the mesolimbic dopaminergic system and the hippocampus, as a potential intermediate phenotype for addiction memory. To this end, we performed functional magnetic resonance imaging (fMRI) in 62 young, healthy individuals genotyped for DRD2 TaqIA and C957T variants. Participants performed an incentive delay task, followed by a recognition memory task 24 h later. We observed effects of both genotypes on the overall recognition performance with carriers of low-expressing variants, namely TaqIA A1 carriers and C957T C homozygotes, showing better performance than the other genotype groups. In addition to the better memory performance, C957T C homozygotes also exhibited a response bias for cues predicting monetary reward. At the neural level, the C957T polymorphism was associated with a genotype-related modulation of right hippocampal and striatal fMRI responses predictive of subsequent recognition confidence for reward-predicting items. Our results indicate that genetic variations associated with DRD2 expression affect explicit memory, specifically for rewarded stimuli. We suggest that the relatively better memory for rewarded stimuli in carriers of low-expressing DRD2 variants may reflect an intermediate phenotype of addiction memory.
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The ankyrin repeat and kinase domain containing 1 (ANKK1) TaqIA polymorphism has been extensively studied as a marker of the gene for dopamine receptor D2 (DRD2) in addictions and other dopamine-associated traits. In vitro mRNA and protein studies have shown a potential connection between ANKK1 and the dopaminergic system functioning. Here, we have investigated whether Ankk1 expression in the brain is regulated by treatment with dopaminergic agonists. We used quantitative RT-PCR of total brain and Western blots of specific brain areas to study Ankk1 in murine brain after dopaminergic treatments. We found that Ankk1 mRNA was upregulated after activation of D1R-like dopamine receptors with SKF38393 (2.660 ± 1.035-fold; t: 4.066, df: 11, P = 0.002) and apomorphine (2.043 ± 0.595-fold; t: 3.782, df: 8, P = 0.005). The D2R-like agonist quinelorane has no effect upon Ankk1 mRNA (1.004 ± 0.580-fold; t: 0.015, df: 10, P = 0.9885). In contrast, mice treatment with the D2R-like agonists 7-OH-DPAT and aripiprazole caused a significant Ankk1 mRNA downregulation (0.606 ± 0.057-fold; t: 2.786, df: 10, P = 0.02 and 0.588 ± 0.130-fold; t: 2.394, df: 11, P = 0.036, respectively). With respect the Ankk1 proteins profile, no effects were found after SKF38393 (t: 0.54, df: 2, P = 0.643) and Quinelorane (t: 0.286, df: 8, P = 0.782) treatments. In contrast, the D2R-like agonist 7-OH-DPAT (±) caused a significant increment of Ankk1 in the striatum (t: 2.718, df: 7; P = 0.03) when compared to the prefrontal cortex. The activation of D1R-like and D2-R-like leads to opposite transcriptional regulation of Ankk1 by specific pathways.
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Encéfalo/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/administração & dosagem , Animais , Apomorfina , Aripiprazol , Encéfalo/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Serina-Treonina Quinases/genética , Quinolinas , RNA Mensageiro/metabolismo , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , Tetra-Hidronaftalenos , Regulação para Cima/efeitos dos fármacosRESUMO
Previous receptor binding studies suggest dopamine function is altered in the basal ganglia circuitry in task-specific dystonia, a condition characterized by contraction of agonist and antagonist muscles while performing specific tasks. Dopamine plays a role in reward-based learning. Using fMRI, this study compared 31 right-handed writer's cramp patients to 35 controls in reward-based learning of a probabilistic reversal-learning task. All subjects chose between two stimuli and indicated their response with their left or right index finger. One stimulus response was rewarded 80%, the other 20%. After contingencies reversal, the second stimulus response was rewarded in 80%. We further linked the DRD2/ANKK1-TaqIa polymorphism, which is associated with 30% reduction of the striatal dopamine receptor density with reward-based learning and assumed impaired reversal learning in A + subjects. Feedback learning in patients was normal. Blood-oxygen level dependent (BOLD) signal in controls increased with negative feedback in the insula, rostral cingulate cortex, middle frontal gyrus and parietal cortex (pFWE < 0.05). In comparison to controls, patients showed greater increase in BOLD activity following negative feedback in the dorsal anterior cingulate cortex (BA32). The genetic status was not correlated with the BOLD activity. The Brodmann area 32 (BA32) is part of the dorsal anterior cingulate cortex (dACC) that plays an important role in coordinating and integrating information to guide behavior and in reward-based learning. The dACC is connected with the basal ganglia-thalamo-loop modulated by dopaminergic signaling. This finding suggests disturbed integration of reinforcement history in decision making and implicate that the reward system might contribute to the pathogenesis in writer's cramp.
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Encéfalo/fisiopatologia , Cognição/fisiologia , Distúrbios Distônicos/genética , Distúrbios Distônicos/fisiopatologia , Feedback Formativo , Reversão de Aprendizagem/fisiologia , Adaptação Fisiológica , Adulto , Idoso , Gânglios da Base/fisiopatologia , Mapeamento Encefálico , Feminino , Genótipo , Giro do Cíngulo/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/genética , Receptores de Dopamina D2/genética , Adulto JovemRESUMO
[This corrects the article on p. 140 in vol. 8, PMID: 25147510.].
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Motivational salience plays an important role in shaping human behavior, but recent studies demonstrate that human performance is not uniformly improved by motivation. Instead, action has been shown to dominate valence in motivated tasks, and it is particularly difficult for humans to learn the inhibition of an action to obtain a reward, but the neural mechanism behind this behavioral specificity is yet unclear. In all mammals, including humans, the monoamine neurotransmitter dopamine is particularly important in the neural manifestation of appetitively motivated behavior, and the human dopamine system is subject to considerable genetic variability. The well-studied TaqIA restriction fragment length polymorphism (rs1800497) has previously been shown to affect striatal dopamine metabolism. In this study we investigated a potential effect of this genetic variation on motivated action/inhibition learning. Two independent cohorts consisting of 87 and 95 healthy participants, respectively, were tested using the previously described valenced go/no-go learning paradigm in which participants learned the reward-associated no-go condition significantly worse than all other conditions. This effect was modulated by the TaqIA polymorphism, with carriers of the A1 allele showing a diminished learning-related performance enhancement in the rewarded no-go condition compared to the A2 homozygotes. This result highlights a modulatory role for genetic variability of the dopaminergic system in individual learning differences of action-valence interaction.
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Dopamine has been implicated in the fine-tuning of complex cognitive and motor function and also in the anticipation of future rewards. This dual function of dopamine suggests that dopamine might be involved in the generation of active motivated behavior. The DRD2 TaqIA polymorphism of the dopamine D2 receptor gene (rs1800497) has previously been suggested to affect striatal function with carriers of the less common A1 allele exhibiting reduced striatal D2 receptor density and increased risk for addiction. Here we aimed to investigate the influences of DRD2 TaqIA genotype on the modulation of interference processing by reward and punishment. Forty-six young, healthy volunteers participated in a behavioral experiment, and 32 underwent functional magnetic resonance imaging (fMRI). Participants performed a flanker task with a motivation manipulation (monetary reward, monetary loss, neither, or both). Reaction times (RTs) were shorter in motivated flanker trials, irrespective of congruency. In the fMRI experiment motivation was associated with reduced prefrontal activation during incongruent vs. congruent flanker trials, possibly reflecting increased processing efficiency. DRD2 TaqIA genotype did not affect overall RTs, but interacted with motivation on the congruency-related RT differences, with A1 carriers showing smaller interference effects to reward alone and A2 homozygotes exhibiting a specific interference reduction during combined reward (REW) and punishment trials (PUN). In fMRI, anterior cingulate activity showed a similar pattern of genotype-related modulation. Additionally, A1 carriers showed increased anterior insula activation relative to A2 homozygotes. Our results point to a role for genetic variations of the dopaminergic system in individual differences of cognition-motivation interaction.
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Objective To analyze the association ofdopamine receptor D2 (DRD2) TaqIA gene polymorphism with persistent postural-perceptual dizziness (PPPD) and explore the molecular mechanism of this disease.Methods The study group consisted of 43 patients diagnosed as having PPPD was chosen in our hospital from January 2017 to June 2017;45 gender-and age-matched control subjects were selected randomly from acute vertigo patients who were fully recovered within 3 months without selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) medication and were normal at 6 months of follow up.Personality characteristics of the two groups were analyzed by adult Essen personality inventory.Frequencies of DRD2 TaqIA gene polymorphism were detected with polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP).Results Percentage of neurotic individuals in study group (67.4%) was significant higher than that of control subjects (37.8%,P<0.05).Genotype distribution ofA1/A1,A1/A2,and A2/A2 showed significant difference between the two groups (P<0.05).In the study group,A1 and A2 allele frequencies in the DRD2 TaqIA gene were 65.1% and 34.9% respectively,which had significantly difference as compared with those of control subjects (46.7% and 53.3%,P<0.05).Conclusion A 1 allele in DRD2 TaqIA gene may be the susceptibility gene for PPPD.
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Objective:to explore the relation of a marker (TaqIA) located DRD 2 gene and heroin dependence.Method:to compare the genotypes and allele frequencies between 66 patients with heroin dependence and 132 normal controls by PCR-RELP. TABPQ was used to measure the characters of patient's behavior.Result:There were significant differences in allele frequencies between patients and controls. No behavior difference was found between patients with different genotypes. Conclusion:There is an association between the marker (TaqIA) and heroin dependence. The data suggest that patients with A1 allele confers susceptibility to heroin dependence.