In Vivo Imaging of Cerebral Dopamine D3 Receptors in Alcoholism

PubMed Central

Erritzoe, David; Tziortzi, Andri; Bargiela, David; Colasanti, Alessandro; Searle, Graham E; Gunn, Roger N; Beaver, John D; Waldman, Adam; Nutt, David J; Bani, Massimo; Merlo-Pich, Emilio; Rabiner, Eugenii A; Lingford-Hughes, Anne

2014-01-01

Animal studies support the role of the dopamine D3 receptor (DRD3) in alcohol reinforcement or liking. Sustained voluntary alcohol drinking in rats has been associated with an upregulation of striatal DRD3 gene expression and selective blockade of DRD3 reduces ethanol preference, consumption, and cue-induced reinstatement. In vivo measurement of DRD3 in the living human brain has not been possible until recently owing to a lack of suitable tools. In this study, DRD3 status was assessed for the first time in human alcohol addiction. Brain DRD3 availability was compared between 16 male abstinent alcohol-dependent patients and 13 healthy non-dependent age-matched males using the DRD3-preferring agonist positron emission tomography (PET) radioligand [11C]PHNO with and without blockade with a selective DRD3 antagonist (GSK598809 60 mg p.o.). In striatal regions of interest, where the [11C]PHNO PET signal represents primarily DRD2 binding, no differences were seen in [11C]PHNO binding between the groups at baseline. However, baseline [11C]PHNO binding was higher in alcohol-dependent patients in hypothalamus (VT: 16.5±4 vs 13.7±2.9, p=0.040), a region in which the [11C]PHNO signal almost entirely reflects DRD3 availability. The reductions in regional receptor binding (VT) following a single oral dose of GSK598809 (60 mg) were consistent with those observed in previous studies across all regions. There were no differences in regional changes in VT following DRD3 blockade between the two groups, indicating that the regional fractions of DRD3 are similar in the two groups, and the increased [11C]PHNO binding in the hypothalamus in alcohol-dependent patients is explained by elevated DRD3 in this group. Although we found no difference between alcohol-dependent patients and controls in striatal DRD3 levels, increased DRD3 binding in the hypothalamus of alcohol-dependent patients was observed. This may be relevant to the development of future therapeutic strategies to treat alcohol abuse. PMID:24469594

Cloning of the neurodegeneration gene drop-dead and characterization of additional phenotypes of its mutation.

PubMed

Blumenthal, Edward M

2008-01-01

Mutations in the Drosophila gene drop-dead (drd) result in early adult lethality and neurodegeneration, but the molecular identity of the drd gene and its mechanism of action are not known. This paper describes the characterization of a new X-linked recessive adult-lethal mutation, originally called lot's wife (lwf(1)) but subsequently identified as an allele of drd (drd(lwf)); drd(lwf) mutants die within two weeks of eclosion. Through mapping and complementation, the drd gene has been identified as CG33968, which encodes a putative integral membrane protein of unknown function. The drd(lwf) allele is associated with a nonsense mutation that eliminates nearly 80% of the CG33968 gene product; mutations in the same gene were also found in two previously described drd alleles. Characterization of drd (lwf) flies revealed additional phenotypes of drd, most notably, defects in food processing by the digestive system and in oogenesis. Mutant flies store significantly more food in their crops and defecate less than wild-type flies, suggesting that normal transfer of ingested food from the crop into the midgut is dependent upon the DRD gene product. The defect in oogenesis results in the sterility of homozygous mutant females and is associated with a reduction in the number of vitellogenic egg chambers. The disruption in vitellogenesis is far more severe than that seen in starved flies and so is unlikely to be a secondary consequence of the digestive phenotype. This study demonstrates that mutation of the drd gene CG33968 results in a complex phenotype affecting multiple physiological systems within the fly.

The role of the dopamine D1 receptor in social cognition: studies using a novel genetic rat model.

PubMed

Homberg, Judith R; Olivier, Jocelien D A; VandenBroeke, Marie; Youn, Jiun; Ellenbroek, Arabella K; Karel, Peter; Shan, Ling; van Boxtel, Ruben; Ooms, Sharon; Balemans, Monique; Langedijk, Jacqueline; Muller, Mareike; Vriend, Gert; Cools, Alexander R; Cuppen, Edwin; Ellenbroek, Bart A

2016-10-01

Social cognition is an endophenotype that is impaired in schizophrenia and several other (comorbid) psychiatric disorders. One of the modulators of social cognition is dopamine, but its role is not clear. The effects of dopamine are mediated through dopamine receptors, including the dopamine D1 receptor (Drd1). Because current Drd1 receptor agonists are not Drd1 selective, pharmacological tools are not sufficient to delineate the role of the Drd1. Here, we describe a novel rat model with a genetic mutation in Drd1 in which we measured basic behavioural phenotypes and social cognition. The I116S mutation was predicted to render the receptor less stable. In line with this computational prediction, this Drd1 mutation led to a decreased transmembrane insertion of Drd1, whereas Drd1 expression, as measured by Drd1 mRNA levels, remained unaffected. Owing to decreased transmembrane Drd1 insertion, the mutant rats displayed normal basic motoric and neurological parameters, as well as locomotor activity and anxiety-like behaviour. However, measures of social cognition like social interaction, scent marking, pup ultrasonic vocalizations and sociability, were strongly reduced in the mutant rats. This profile of the Drd1 mutant rat offers the field of neuroscience a novel genetic rat model to study a series of psychiatric disorders including schizophrenia, autism, depression, bipolar disorder and drug addiction. © 2016. Published by The Company of Biologists Ltd.

Transcriptomic context of DRD1 is associated with prefrontal activity and behavior during working memory.

PubMed

Fazio, Leonardo; Pergola, Giulio; Papalino, Marco; Di Carlo, Pasquale; Monda, Anna; Gelao, Barbara; Amoroso, Nicola; Tangaro, Sabina; Rampino, Antonio; Popolizio, Teresa; Bertolino, Alessandro; Blasi, Giuseppe

2018-05-22

Dopamine D 1 receptor (D 1 R) signaling shapes prefrontal cortex (PFC) activity during working memory (WM). Previous reports found higher WM performance associated with alleles linked to greater expression of the gene coding for D 1 Rs ( DRD1 ). However, there is no evidence on the relationship between genetic modulation of DRD1 expression in PFC and patterns of prefrontal activity during WM. Furthermore, previous studies have not considered that D 1 Rs are part of a coregulated molecular environment, which may contribute to D 1 R-related prefrontal WM processing. Thus, we hypothesized a reciprocal link between a coregulated (i.e., coexpressed) molecular network including DRD1 and PFC activity. To explore this relationship, we used three independent postmortem prefrontal mRNA datasets (total n = 404) to characterize a coexpression network including DRD1 Then, we indexed network coexpression using a measure (polygenic coexpression index- DRD1 -PCI) combining the effect of single nucleotide polymorphisms (SNPs) on coexpression. Finally, we associated the DRD1 -PCI with WM performance and related brain activity in independent samples of healthy participants (total n = 371). We identified and replicated a coexpression network including DRD1 , whose coexpression was correlated with DRD1 -PCI. We also found that DRD1 -PCI was associated with lower PFC activity and higher WM performance. Behavioral and imaging results were replicated in independent samples. These findings suggest that genetically predicted expression of DRD1 and of its coexpression partners stratifies healthy individuals in terms of WM performance and related prefrontal activity. They also highlight genes and SNPs potentially relevant to pharmacological trials aimed to test cognitive enhancers modulating DRD1 signaling.

Dopamine Genes (DRD2/ANKK1-TaqA1 and DRD4-7R) and Executive Function: Their Interaction with Obesity

PubMed Central

Ariza, Mar; Garolera, Maite; Jurado, Maria Angeles; Garcia-Garcia, Isabel; Hernan, Imma; Sánchez-Garre, Consuelo; Vernet-Vernet, Maria; Sender-Palacios, Maria Jose; Marques-Iturria, Idoia; Pueyo, Roser; Segura, Barbara; Narberhaus, Ana

2012-01-01

Obesity is a multifactorial disease caused by the interaction between genotype and environment, and it is considered to be a type of addictive alteration. The A1 allele of the DRD2/ANKK1-TaqIA gene has been associated with addictive disorders, with obesity and with the performance in executive functions. The 7 repeat allele of the DRD4 gene has likewise been associated with the performance in executive functions, as well as with addictive behaviors and impulsivity. Participants were included in the obesity group (N = 42) if their body mass index (BMI) was equal to or above 30, and in the lean group (N = 42) if their BMI was below 25. The DRD2/ANKK1-TaqIA and DRD4 VNTR polymorphisms were obtained. All subjects underwent neuropsychological assessment. Eating behavior traits were evaluated. The ‘DRD2/ANKK1-TaqIA A1-allele status’ had a significant effect on almost all the executive variables, but no significant ‘DRD4 7R-allele status’ effects were observed for any of the executive variables analyzed. There was a significant ‘group’ x ‘DRD2/ANKK1-TaqIA A1-allele status’ interaction effect on LN and ‘group’ x ‘DRD4 7R-allele status’ interaction effect on TMT B-A score. Being obese and a carrier of the A1 allele of DRD2/ANKK1-TaqIA or the 7R allele of DRD4 VNTR polymorphisms could confer a weakness as regards the performance of executive functions. PMID:22848508

Spent nuclear fuel project cold vacuum drying facility operations manual

DOE Office of Scientific and Technical Information (OSTI.GOV)

IRWIN, J.J.

This document provides the Operations Manual for the Cold Vacuum Drying Facility (CVDF). The Manual was developed in conjunction with HNF-SD-SNF-SAR-002, Safety Analysis Report for the Cold Vacuum Drying Facility, Phase 2, Supporting Installation of Processing Systems (Garvin 1998) and, the HNF-SD-SNF-DRD-002, 1997, Cold Vacuum Drying Facility Design Requirements, Rev. 3a. The Operations Manual contains general descriptions of all the process, safety and facility systems in the CVDF, a general CVD operations sequence, and has been developed for the SNFP Operations Organization and shall be updated, expanded, and revised in accordance with future design, construction and startup phases of themore » CVDF until the CVDF final ORR is approved.« less

DRD4 dopamine receptor allelic diversity in various primate species

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adamson, M.; Higley, D.; O`Brien, S.

The DRD4 dopamine receptor is uniquely characterized by a 48 bp repeating segment within the coding region, located in exon III. Different DRD4 alleles are produced by the presence of additional 48 bp repeats, each of which adds 16 amino acids to the length of the 3rd intracytoplasmic loop of the receptor. The DRD4 receptor is therefore an intriguing candidate gene for behaviors which are influenced by dopamine function. In several human populations, DRD4 alleles with 2-8 and 10 repeats have previously been identified, and the 4 and 7 repeat alleles are the most abundant. We have determined DRD4 genotypesmore » in the following nonhuman primate species: chimpanzee N=2, pygmy chimpanzee N=2, gorilla N=4, siamang N=2, Gelada baboon N=1, gibbon N=1, orangutan (Bornean and Sumatran) N=62, spider monkey N=4, owl monkey N=1, Colobus monkey N=1, Patas monkey N=1, ruffed lemur N=1, rhesus macaque N=8, and vervet monkey N=28. The degree of DRD4 polymorphism and which DRD4 alleles were present both showed considerable variation across primate species. In contrast to the human, rhesus macaque monkeys were monomorphic. The 4 and 7 repeat allels, highly abundant in the human, may not be present in certain other primates. For example, the four spider monkeys we studied showed the 7, 8 and 9 repeat length alleles and the only gibbon we analyzed was homozygous for the 9 repeat allele (thus far not observed in the human). Genotyping of other primate species and sequencing of the individual DRD4 repeat alleles in different species may help us determine the ancestral DRD4 repeat length and identify connections between DRD4 genotype and phenotype.« less

5' UTR polymorphism of dopamine receptor D1 (DRD1) associated with severity and temperament of alcoholism.

PubMed

Kim, Dai-Jin; Park, Byung Lae; Yoon, Sujung; Lee, Hae-Kook; Joe, Keun-Ho; Cheon, Young-Hoon; Gwon, Do-Hoon; Cho, Sung-Nam; Lee, Hye Won; NamGung, Suk; Shin, Hyoung Doo

2007-06-15

Multiple dopamine receptors in the dopaminergic system may be prime candidates for genetic influence on alcohol abuse and dependence due to their involvement in reward and reinforcing mechanisms. Genetic polymorphisms in dopamine receptor genes are believed to influence the development and/or severity of alcoholism. To examine the genetic effects of the Dopamine Receptor D1 (DRD) gene family (DRD1-DRD5) in the Korean population, 11 polymorphisms in the DRD gene family were genotyped and analyzed in 535 alcohol-dependent subjects and 273 population controls. Although none of the polymorphisms of DRD1-5 genes were found to be associated with the risk of alcoholism, one 5' UTR polymorphism in the DRD1 (DRD1-48A>G) gene was significantly associated with severity of alcohol-related problem, as measured by the Alcohol Use Disorders Identification Test (AUDIT) in a gene dose-dependent manner, i.e., 24.37 (+/-8.19) among patients with -48A/A genotype, 22.37 (+/-9.49) among those with -48A/G genotype, and 17.38 (+/-8.28) among those with -48G/G genotype (P=0.002). The genetic effects of DRD1-48A>G were further analyzed with other phenotypes among alcohol-dependent subjects. Interestingly, the DRD1-48A>A genotype was also found to be associated with novelty seeking (NC), harm avoidance (HA), and persistence (P) (P =0.01, 0.02, and 0.003, respectively). The information derived from this study could be valuable for understanding the genetic factors involved in alcoholic phenotypes and genetic distribution of the DRD gene family, and could facilitate further investigation in other ethnic groups.

Chronic ethanol exposure changes dopamine D2 receptor splicing during retinoic acid-induced differentiation of human SH-SY5Y cells.

PubMed

Wernicke, Catrin; Hellmann, Julian; Finckh, Ulrich; Rommelspacher, Hans

2010-01-01

There is evidence for ethanol-induced impairment of the dopaminergic system in the brain during development. The dopamine D2 receptor (DRD2) and the dopamine transporter (DAT) are decisively involved in dopaminergic signaling. Two splice variants of DRD2 are known, with the short one (DRD2s) representing the autoreceptor and the long one (DRD2l) the postsynaptic receptor. We searched for a model to investigate the impact of chronic ethanol exposure and withdrawal on the expression of these proteins during neuronal differentiation. RA-induced differentiation of human neuroblastoma SH-SY5Y cells seems to represent such a model. Our real-time RT-PCR, Western blot, and immunocytochemistry analyses of undifferentiated and RA-differentiated cells have demonstrated the enhanced expression of both splice variants of DRD2, with the short one being stronger enhanced than the long one under RA-treatment, and the DRD2 distribution on cell bodies and neurites under both conditions. In contrast, DAT was down-regulated by RA. The DAT is functional both in undifferentiated and RA-differentiated cells as demonstrated by [(3)H]dopamine uptake. Chronic ethanol exposure during differentiation for up to 4 weeks resulted in a delayed up-regulation of DRD2s. Ethanol withdrawal caused an increased expression of DRD2l and a normalization of DRD2s. Thus the DRD2s/DRD2l ratio was still disturbed. The dopamine level was increased by RA-differentiation compared to controls and was diminished under RA/ethanol treatment and ethanol withdrawal compared to RA-only treated cells. In conclusion, chronic ethanol exposure impairs differentiation-dependent adaptation of dopaminergic proteins, specifically of DRD2s. RA-differentiating SH-SY5Y cells are suited to study the impact of chronic ethanol exposure and withdrawal on expression of dopaminergic proteins during neuronal differentiation.

Association of Dopamine D2 Receptor Gene with Creative Ideation

ERIC Educational Resources Information Center

Yu, Qi; Zhang, Shun; Zhang, Jinghuan H.

2017-01-01

Although several studies suggest that dopamine D2 receptor (DRD2) gene may contribute to creativity, the relationship between DRD2 and creativity still needs to be further validated. To further test the relevance of DRD2 and creativity, this study explored the association between DRD2 and creative ideation in 483 unrelated healthy Chinese…

Dissociable Brain Signatures of Choice Conflict and Immediate Reward Preferences in Alcohol Use Disorders

PubMed Central

Amlung, Michael; Sweet, Lawrence H.; Acker, John; Brown, Courtney L.; MacKillop, James

2013-01-01

Impulsive delayed reward discounting (DRD) is an important behavioral process in alcohol use disorders (AUDs), reflecting incapacity to delay gratification. Recent work in neuroeconomics has begun to unravel the neural mechanisms supporting DRD, but applications of neuroeconomics in relation to AUDs have been limited. This study examined the neural mechanisms of DRD preferences in AUDs, with emphasis on dissociating activation patterns based on DRD choice type and level of cognitive conflict. Heavy drinking adult males with (n = 13) and without (n = 12) a diagnosis of an AUD completed a monetary DRD task during a functional magnetic resonance imaging scan. Participant responses were coded based on choice type (impulsive vs. restrained) and level of cognitive conflict (easy vs. hard). AUD+ participants exhibited significantly more impulsive DRD decision-making. Significant activation during DRD was found in several decision-making regions, including dorsolateral prefrontal cortex (DLPFC), insula, posterior parietal cortex (PPC), and posterior cingulate. An axis of cognitive conflict was also observed, with hard choices associated with anterior cingulate cortex and easy choices associated with activation in supplementary motor area. AUD+ individuals exhibited significant hyperactivity in regions associated with cognitive control (DLPFC) and prospective thought (PPC) and exhibited less task-related deactivation of areas associated with the brain's default network during DRD decisions. This study provides further clarification of the brain systems supporting DRD in general and in relation to AUDs. PMID:23231650

Dopamine-related genes and their relationships to monoamine metabolites in CSF.

PubMed

Jönsson, E; Sedvall, G; Brené, S; Gustavsson, J P; Geijer, T; Terenius, L; Crocq, M A; Lannfelt, L; Tylec, A; Sokoloff, P; Schwartz, J C; Wiesel, F A

1996-11-15

Monoamine metabolite (MM) levels in lumbar cerebrospinal fluid (CSF) are extensively used as indirect estimates of monoamine turnover in the brain. In this study we investigated genotypes for DNA polymorphisms in the D2 (DRD2), D3 (DRD3), and D4 (DRD4) dopamine receptor and tyrosine hydroxylase (TH) genes and their relationships to CSF MM in healthy volunteers (n = 66). Concentrations of homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) were corrected for back length, a confounding variable. Corrected MM levels were not related to age, gender, height, weight heredity, season or atmospheric pressure at sampling. Individuals with specific DRD2 and TH allele and genotype configurations significantly differed in HVA and MHPG concentrations. DRD3 homo- and heterozygotic genotypes had significantly different CSF 5-HIAA levels. DRD4 genotypes were not related to MM concentrations. The results suggest that specific DRD2, DRD3, and TH genotypes participate in the regulation of monoamine turnover in the central nervous system. Accordingly monoamine receptors and synthesizing enzyme genotypes appear to be variance factors influencing MM concentrations in CSF. The relationships found in this study support MM concentrations as markers for monoamine transmission in the human brain.

Characterization of Antibodies to Identify Cellular Expression of Dopamine Receptor 4.

PubMed

Deming, Janise D; Van Craenenbroeck, Kathleen; Eom, Yun Sung; Lee, Eun-Jin; Craft, Cheryl Mae

2016-01-01

The dopamine receptor D4 (DRD4) plays an important role in vision. In order to study the DRD4 expression in vivo, it is important to have antibodies that are specific for DRD4 for both immunoblot and immunohistochemical (IHC) applications. In this study, six antibodies raised against DRD4 peptides were tested in vitro, using transfected mammalian cells, and in vivo, using mouse retinas. Three Santa Cruz (SC) antibodies, D-16, N-20, and R-20, were successful in IHC of transfected DRD4; however, N-20 was the only one effective on immunoblot analysis in DRD4 transfected cells and IHC of mouse retinal sections, while R-20, 2B9, and Antibody Verify AAS63631C were non-specific or below detection.

Dissociable brain signatures of choice conflict and immediate reward preferences in alcohol use disorders.

PubMed

Amlung, Michael; Sweet, Lawrence H; Acker, John; Brown, Courtney L; MacKillop, James

2014-07-01

Impulsive delayed reward discounting (DRD) is an important behavioral process in alcohol use disorders (AUDs), reflecting incapacity to delay gratification. Recent work in neuroeconomics has begun to unravel the neural mechanisms supporting DRD, but applications of neuroeconomics in relation to AUDs have been limited. This study examined the neural mechanisms of DRD preferences in AUDs, with emphasis on dissociating activation patterns based on DRD choice type and level of cognitive conflict. Heavy drinking adult men with (n = 13) and without (n = 12) a diagnosis of an AUD completed a monetary DRD task during a functional magnetic resonance imaging scan. Participant responses were coded based on choice type (impulsive versus restrained) and level of cognitive conflict (easy versus hard). AUD+ participants exhibited significantly more impulsive DRD decision-making. Significant activation during DRD was found in several decision-making regions, including dorsolateral prefrontal cortex (DLPFC), insula, posterior parietal cortex (PPC), and posterior cingulate. An axis of cognitive conflict was also observed, with hard choices associated with anterior cingulate cortex and easy choices associated with activation in supplementary motor area. AUD+ individuals exhibited significant hyperactivity in regions associated with cognitive control (DLPFC) and prospective thought (PPC) and exhibited less task-related deactivation of areas associated with the brain's default network during DRD decisions. This study provides further clarification of the brain systems supporting DRD in general and in relation to AUDs. © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.

Clarifying the Relationship between Impulsive Delay Discounting and Nicotine Dependence

PubMed Central

Amlung, Michael; MacKillop, James

2014-01-01

Impulsive delayed reward discounting (DRD) has been linked to nicotine dependence, but with some inconsistency. This may be related to the considerable variability in the literature with regard to the DRD assessments used, particularly in the case of reward magnitudes assessed. In addition, previous studies have often not considered concurrent substance use when examining the relationship between DRD and nicotine dependence. The current study sought to further clarify the relationship between DRD and nicotine dependence by characterizing DRD across diverse reward magnitudes and incorporating other substance use. Daily smokers (N = 933) were assessed for DRD preferences across nine reward magnitudes (delayed reward range: $2.50–$850), comorbid substance use, and relevant demographic variables (age, education, income). A significant large effect size magnitude effect was found for DRD, reflecting steeper discounting for smaller delayed rewards, but significant correlations across magnitudes also suggested similar relative levels of discounting. Principal components analysis (PCA) was used to generate a single latent index of discounting across all magnitudes that accounted for 67% of the total variance. In both correlation and regression analyses, steeper composite DRD was significantly associated with nicotine dependence severity. This relationship remained statistically significant after incorporating demographic variables and alcohol and illicit drug use. These findings provide evidence of a specific link between impulsive DRD and nicotine dependence, and reveal that this association is robust across a broad range of monetary rewards. The study also demonstrates the utility of using PCA to generate latent indices of delay discounting across multiple magnitudes of delayed reward. PMID:24841186

Dopamine D2 receptor over-expression alters behavior and physiology in Drd2-EGFP mice

PubMed Central

Kramer, Paul F.; Christensen, Christine H.; Hazelwood, Lisa A.; Dobi, Alice; Bock, Roland; Sibley, David R.; Mateo, Yolanda; Alvarez, Veronica A.

2011-01-01

BAC transgenic mice expressing the fluorescent reporter protein EGFP under the control of the D1 and D2 dopamine receptor promoters (Drd1-EGFP and Drd2-EGFP) have been widely used to study striatal function and have contributed to our understanding of the physiological and pathological function of the basal ganglia. These tools were produced and promptly made available to address questions in a cell-specific manner that has transformed the way we frame hypotheses in neuroscience. However, these mice have not been fully characterized until now. We found that Drd2-EGFP mice display a ~40% increase in membrane expression of the dopamine D2 receptor (D2R) and a two-fold increase in D2R mRNA levels in the striatum when compared to wild-type and Drd1-EGFP mice D2R over-expression was accompanied by behavioral hypersensitivity to D2R-like agonists, as well as enhanced electrophysiological responses to D2R activation in midbrain dopaminergic neurons. DA transients evoked by stimulation in the nucleus accumbens showed slower clearance in Drd2-EGFP mice and cocaine actions on DA clearance were impaired in these mice. Thus, it was not surprising to find that Drd2-EGFP mice were hyperactive when exposed to a novel environment and locomotion was suppressed by acute cocaine administration. All together, this study demonstrates that Drd2-EGFP mice over-express D2R and have altered dopaminergic signaling that fundamentally differentiates them from wild-type and Drd1-EGFP mice. PMID:21209197

Effects of COMT, DRD2, BDNF, and APOE Genotypic Variation on Treatment Efficacy and Cognitive Side Effects of Electroconvulsive Therapy.

PubMed

Bousman, Chad A; Katalinic, Natalie; Martin, Donel M; Smith, Deidre J; Ingram, Anna; Dowling, Nathan; Ng, Chee; Loo, Colleen K

2015-06-01

The aim of this study was to explore the main and interaction effects of the COMT Val158Met, DRD2 C957T, BDNF Val66Met, and APOE polymorphisms on treatment efficacy and cognitive side effects of electroconvulsive therapy (ECT). A total of 117 adult inpatients with a diagnosis of major depressive disorder recruited from 3 hospitals were administered the Montgomery-Äsberg Depression Rating Scale and a cognitive battery assessing global cognition, anterograde memory, executive function, speed and concentration, as well as retrograde memory at baseline and after ECT treatment. DRD2 C957T heterozygotes had 3.7 (95% confidence interval, 1.13-12.25; P = 0.032) greater odds of remission compared with CC homozygotes. Among the men, COMT Val/Val carriers had greater depressive symptom reduction compared with Met/Met carriers (Montgomery-Äsberg Depression Rating Scale percentage of reduction, 76% vs 35%; P = 0.020) but not among the women (P = 0.903) after ECT. For cognitive outcomes, an interaction effect on anterograde memory was observed between the DRD2 and BDNF polymorphisms (P = 0.016), in which carriers of the DRD2 TT and BDNF Val/Val genotypes had significantly less decline in anterograde performance than those that carried the TC and Met-allele (P = 0.001) or CC and Met-allele (P = 0.003) genotypes. However, no results withstood correction for multiple comparisons. These observations provide preliminary evidence supporting an association between common functional genotypic variation and ECT efficacy as well as anterograde memory side effects after ECT. Validation of these findings is required before firm conclusions can be made and clinical utility can be assessed.

D4 dopamine-receptor (DRD4) alleles and novelty seeking in substance-dependent, personality-disorder, and control subjects.

PubMed Central

Gelernter, J; Kranzler, H; Coccaro, E; Siever, L; New, A; Mulgrew, C L

1997-01-01

Two reports have been published suggesting an association between the personality trait of novelty seeking and the DRD4*7R allele at the D4 dopamine-receptor locus (with heterozygotes or homozygotes for DRD4*7R having higher novelty seeking). We studied novelty seeking and four coding-sequence polymorphisms affecting protein structure in the D4 dopamine-receptor gene (DRD4) in a sample of 341 American subjects, of whom 224 are of primarily European ancestry and 117 are of primarily African ancestry. These subjects had diagnoses of substance dependence or personality disorder (PD) or were screened to exclude major psychiatric diagnosis. We found that, although the substance-dependent subjects had significantly higher novelty seeking than the control and PD subjects, they did not differ in DRD4*7R allele frequency. There was no association between any DRD4 polymorphism and novelty seeking in any population or diagnostic group, except for a significant association between the DRD4*7R allele and lower novelty seeking among European American females and African American substance abusers. The novelty seeking of subjects heterozygous for a null mutation did not differ from that of subjects with two functional alleles. We conclude that the most likely explanation of these results is that the DRD4 VNTR does not influence directly the trait of novelty seeking, in these samples. PMID:9345090

Dopamine receptor D4 promoter hypermethylation increases the risk of drug addiction.

PubMed

Ji, Huihui; Xu, Xuting; Liu, Guili; Liu, Huifen; Wang, Qinwen; Shen, Wenwen; Li, Longhui; Xie, Xiaohu; Hu, Haochang; Xu, Lei; Zhou, Wenhua; Duan, Shiwei

2018-02-01

Heroin and methylamphetamine (METH) are two addictive drugs that cause serious problems for society. Dopamine receptor D4 (DRD4), a key receptor in the dopaminergic system, may facilitate the development of drug addiction. The aim of the present study was to investigate the association between the promoter methylation level of DRD4 gene and drug addiction. Bisulfite pyrosequencing technology was used to measure the methylation levels of DRD4 promoter in 60 drug addicts and 52 matched controls. Significantly higher levels of DRD4 CpG1 and CpG4 methylation were detected in METH and heroin drug addicts compared with controls (P<0.05). Male METH addicts exhibited significantly higher DRD4 CpG1, CpG2 and CpG4 methylation levels compared with sex-matched controls (P<0.05). In heroin addicts, a positive correlation was observed between depression-dejection and DRD4 CpG5 methylation (r=0.537, P=0.039) whereas there was a negative correlation between drug usage frequency and CpG1 methylation (r=-0.632, P=0.011). In METH addicts, methylation levels were not significantly associated with depression-dejection and drug usage frequency. In addition, luciferase assays demonstrated that the target sequence of the DRD4 promoter upregulates gene expression. The results of the present study suggest that DNA methylation of DRD4 may be responsible for the pathophysiology of drug addiction.

Meta-analysis of six genes (BDNF, DRD1, DRD3, DRD4, GRIN2B and MAOA) involved in neuroplasticity and the risk for alcohol dependence.

PubMed

Forero, Diego A; López-León, Sandra; Shin, Hyoung Doo; Park, Byung Lae; Kim, Dai-Jin

2015-04-01

Alcohol-related problems have a large impact on human health, accounting for around 4% of deaths and 4.5% of disability-adjusted life-years around the world. Genetic factors could explain a significant fraction of the risk for alcohol dependence (AD). Recent meta-analyses have found significant pooled odds ratios (ORs) for variants in the ADH1B, ADH1C, DRD2 and HTR2A genes. In the present study, we carried out a meta-analysis of common variants in 6 candidate genes involved in neurotransmission and neuroplasticity: BDNF, DRD1, DRD3, DRD4, GRIN2B and MAOA. We carried out a systematic search for published association studies that analyzed the genes of interest. Relevant articles were retrieved and demographic and genetic data were extracted. Pooled ORs were calculated using a random-effects model using the Meta-Analyst program. Dominant, recessive and allelic models were tested and analyses were also stratified by ethnicity. Forty two published studies were included in the current meta-analysis: BDNF-rs6265 (nine studies), DRD1-rs4532 (four studies), DRD3-rs6280 (eleven studies), DRD4-VNTR (seven studies), GRIN2B-rs1806201 (three studies) and MAOA-uVNTR (eight studies). We did not find significant pooled ORs for any of the six genes, under different models and stratifying for ethnicity. In terms of the number of candidate genes included, this is one of the most comprehensive meta-analyses for genetics of AD. Pooled ORs did not support consistent associations with any of the six candidate genes tested. Future studies of novel genes of functional relevance and meta-analyses of quantitative endophenotypes could identify further susceptibility molecular factors for AD. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

DRD4 dopamine receptor genotype and CSF monoamine metabolites in Finnish alcoholics and controls

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adamson, M.D.; Dean, M.; Goldman, D.

1995-06-19

The DRD4 dopamine receptor is thus far unique among neurotransmitter receptors in having a highly polymorphic gene structure that has been reported to produce altered receptor functioning. These allelic variations are caused by a 48-bp segment in exon III of the coding region which may be repeated from 2-10 times. Varying the numbers of repeated segments changes the length, structure, and, possibly, the functional efficiency of the receptor, which makes this gene an intriguing candidate for variations in dopamine-related behaviors, such as alcoholism and drug abuse. Thus far, these DRD4 alleles have been investigated for association with schizophrenia, bipolar disorder,more » Parkinson`s disease, and chronic alcoholism, and all have been largely negative for a direct association. We evaluated the DRD4 genotype in 226 Finish adult males, 113 of whom were alcoholics, many of the early onset type with features of impulsivity and antisocial traits. Genotype frequencies were compared to 113 Finnish controls who were free of alcohol abuse, substance abuse, and major mental illness. In 70 alcoholics and 20 controls, we measured CSF homovanillic acid (HVA), the major metabolite of dopamine, and 5-hydroxyindoleacetic acid (5-HIAA). No association was found between a particular DRD4 dopamine receptor allele and alcoholism. CSF concentrations of the monoamine metabolites showed no significant difference among the DRD4 genotypes. This study of the DRD4 dopamine receptor in alcoholics is the first to be conducted in a clinically and ethnically homogeneous population and to relate the DRD4 genotype to CSF monoamine concentrations. The results indicate that there is no association of the DRD4 receptor with alcoholism. 52 refs., 3 figs., 1 tab.« less

Dopamine D4 receptor VNTR polymorphism associated with greater risk for substance abuse among adolescents with disruptive behavior disorders: Preliminary results.

PubMed

Mallard, Travis T; Doorley, James; Esposito-Smythers, Christianne L; McGeary, John E

2016-01-01

The variable number tandem repeats (VNTR) polymorphism of the dopamine D4 receptor gene (DRD4) has received considerable attention as a potential genetic contributor to addiction. However, is unclear whether the polymorphism is involved in developing general traits that lead to risky behavior or an intermediate phenotype more specific to substance use disorders. Association studies have produced equivocal results. To control for potential confounds, the present study examined whether the long variant of the DRD4 VNTR polymorphism (DRD4L) is associated with greater substance misuse in a homogenous clinical sample of youth with a disruptive behavior disorder (DBD). Fifty-one psychiatrically hospitalized adolescents (mean age = 14.86 years) with a DBD diagnosis were recruited as part of a larger study. Participants provided saliva samples for genotyping procedures after completing a diagnostic interview and an assessment battery. The odds of a substance use disorder diagnosis were significantly greater among DRD4L than DRD4S carriers (OR = 5.20, 95%CI:1.42-19.04, p = .01). Relative to DRD4S homozygotes, DRD4L carriers also reported greater marijuana use (t = -2.68, p = .01) and hard drug use (t = -2.26, p = .03). Although adolescents with DBDs are already at heightened risk for substance misuse, the present findings suggest that DRD4L further increases those odds. As differences persisted even among a psychiatrically homogenous sample of impulsive and risk-prone adolescents, the present findings suggest that DRD4L may be involved in the development of an intermediate phenotype specific to substance abuse (eg, cue-elicited craving). © American Academy of Addiction Psychiatry.

The association between dopamine receptor (DRD4) gene polymorphisms and second language learning style and behavioral variability in undergraduate students in Turkey.

PubMed

Maras Atabay, Meltem; Safi Oz, Zehra; Kurtman, Elvan

2014-08-01

The dopamine D4 receptor gene (DRD4) encodes a receptor for dopamine, a chemical messenger used in the brain. One variant of the DRD4 gene, the 7R allele, is believed to be associated with attention deficit hyperactivity disorder (ADHD). The aim of this study was to investigate the relationships between repeat polymorphisms in dopamine DRD4 and second language learning styles such as visual (seeing), tactile (touching), auditory (hearing), kinesthetic (moving) and group/individual learning styles, as well as the relationships among DRD4 gene polymorphisms and ADHD in undergraduate students. A total of 227 students between the ages of 17-21 years were evaluated using the Wender Utah rating scale and DSM-IV diagnostic criteria for ADHD. Additionally, Reid's perceptual learning style questionnaire for second language learning style was applied. In addition, these students were evaluated for social distress factors using the list of Threatening Events (TLE); having had no TLE, having had just one TLE or having had two or more TLEs within the previous 6 months before the interview. For DRD4 gene polymorphisms, DNA was extracted from whole blood using the standard phenol/chloroform method and genotyped using polymerase chain reaction. Second language learners with the DRD4.7+ repeats showed kinaesthetic and auditory learning styles, while students with DRD4.7-repeats showed visual, tactile and group learning, and also preferred the more visual learning styles [Formula: see text]. We also demonstrated that the DRD4 polymorphism significantly affected the risk effect conferred by an increasing level of exposure to TLE.

Religion priming differentially increases prosocial behavior among variants of the dopamine D4 receptor (DRD4) gene

PubMed Central

Kim, Heejung S.; Mojaverian, Taraneh; Kelley, Lauren D. S.; Park, In Young; Janušonis, Skirmantas

2013-01-01

Building on gene–environment interaction (G × E) research, this study examines how the dopamine D4 receptor (DRD4) gene interacts with a situational prime of religion to influence prosocial behavior. Some DRD4 variants tend to be more susceptible to environmental influences, whereas other variants are less susceptible. Thus, certain life environments may be associated with acts of prosociality for some DRD4 variants but not others. Given that religion can act as an environmental influence that increases prosocial behavior, environmental input in the form of religion priming may have G × E effects. Results showed that participants with DRD4 susceptibility variants were more prosocial when implicitly primed with religion than not primed with religion, whereas participants without DRD4 susceptibility variants were not impacted by priming. This research has implications for understanding why different people may behave prosocially for different reasons and also integrates G × E research with experimental psychology. PMID:22198971

Religion priming differentially increases prosocial behavior among variants of the dopamine D4 receptor (DRD4) gene.

PubMed

Sasaki, Joni Y; Kim, Heejung S; Mojaverian, Taraneh; Kelley, Lauren D S; Park, In Young; Janusonis, Skirmantas

2013-02-01

Building on gene-environment interaction (G × E) research, this study examines how the dopamine D4 receptor (DRD4) gene interacts with a situational prime of religion to influence prosocial behavior. Some DRD4 variants tend to be more susceptible to environmental influences, whereas other variants are less susceptible. Thus, certain life environments may be associated with acts of prosociality for some DRD4 variants but not others. Given that religion can act as an environmental influence that increases prosocial behavior, environmental input in the form of religion priming may have G × E effects. Results showed that participants with DRD4 susceptibility variants were more prosocial when implicitly primed with religion than not primed with religion, whereas participants without DRD4 susceptibility variants were not impacted by priming. This research has implications for understanding why different people may behave prosocially for different reasons and also integrates G × E research with experimental psychology.

Association of VNTR polymorphisms in DRD4, 5-HTT and DAT1 genes with obesity.

PubMed

Uzun, Mustafa; Saglar, Emel; Kucukyildirim, Sibel; Erdem, Beril; Unlu, Hande; Mergen, Hatice

2015-05-01

To investigate the association between VNTR polymorphisms of DRD4, DAT1 and 5-HTT genes and obesity. Peripheral blood samples of 234 obese (BMI ≥ 30) and 148 healthy individuals (BMI ≤ 25) were objected to PCR to detect the VNTR of the 2nd intron of 5-HTT, 3rd exon of DRD4 and 3'UTR of DAT1 genes. The association between obesity and genotype distributions of 5-HTT, DAT1 and DRD4 genes and between obesity and distributions of allele frequencies were tested by Chi Square (χ(2)) test and were not found statistically significant. BMI values for genotype of obese and morbidly obese (BMI > 40) individuals were analyzed by Kruskal-Wallis and not found statistically significant differences between BMI values for the most frequent genotypes of 5-HTT, DAT1 and DRD4 genes. As a conclusion, there was no association between 5-HTT, DAT1 and DRD4 genes VNTR polymorphisms and obesity.

DRD4 long allele carriers show heightened attention to high-priority items relative to low-priority items.

PubMed

Gorlick, Marissa A; Worthy, Darrell A; Knopik, Valerie S; McGeary, John E; Beevers, Christopher G; Maddox, W Todd

2015-03-01

Humans with seven or more repeats in exon III of the DRD4 gene (long DRD4 carriers) sometimes demonstrate impaired attention, as seen in attention-deficit hyperactivity disorder, and at other times demonstrate heightened attention, as seen in addictive behavior. Although the clinical effects of DRD4 are the focus of much work, this gene may not necessarily serve as a "risk" gene for attentional deficits, but as a plasticity gene where attention is heightened for priority items in the environment and impaired for minor items. Here we examine the role of DRD4 in two tasks that benefit from selective attention to high-priority information. We examine a category learning task where performance is supported by focusing on features and updating verbal rules. Here, selective attention to the most salient features is associated with good performance. In addition, we examine the Operation Span (OSPAN) task, a working memory capacity task that relies on selective attention to update and maintain items in memory while also performing a secondary task. Long DRD4 carriers show superior performance relative to short DRD4 homozygotes (six or less tandem repeats) in both the category learning and OSPAN tasks. These results suggest that DRD4 may serve as a "plasticity" gene where individuals with the long allele show heightened selective attention to high-priority items in the environment, which can be beneficial in the appropriate context.

[Knockdown of dopamine receptor D2 upregulates the expression of adiogenic genes in mouse primary mesencephalic neurons].

PubMed

Ding, Jiaqi; Chen, Xiaoli; Lin, Jiaji; Zhu, Junling; Li, Zhuyi

2018-01-01

Objective To study the effects of dopamine receptor D2 (DRD2) on the adipogenesis genes in mouse primary mesencephalic neurons. Methods The lentiviral vectors which expressed specific shRNA targeting DRD2 were constructed to decrease DRD2 expression in mouse primary mesencephalic neurons. High throughput sequencing (HTS) analysis was used to investigate gene expression changes between the DRD2 knock-down group and the negative control group. Real-time quantitative PCR (qRT-PCR) and Western blot analysis were applied to verify the differently expressed genes. Fatty acids were measured by fatty acid detection kit. Results DRD2 expression was effectively down-regulated in mouse primary mesencephalic neurons by lentiviral vectors. HTS revealed adipogenesis genes were significantly up-regulated after DRD2 down-regulation, mainly including delta(14)-sterol reductase, acetyl-coenzyme A synthetase, insulin-induced gene 1 protein and especially stearoyl-coenzyme A desaturase 1 (SCD1, 4-fold upregulated). The qRT-PCR and Western blot analysis verified that SCD1 was upregulated 2.6 folds and 2 folds respectively by lentiviral DRD2-shRNA vectors. Moreover, the SCD1-related free fatty acids were significantly more increased than the negative control group. Conclusion DRD2 in primary mesencephalic neurons had a significant regulative effect on the adipogenesis genes. The up-regulation of SCD1 can accelerate the conversion of saturated fatty acids to monounsaturated fatty acids and prevent the damage of lipid toxicity to cells.

DRD4 Long Allele Carriers Show Heightened Attention to High-Priority Items Relative to Low-Priority Items

PubMed Central

Gorlick, Marissa A.; Worthy, Darrell A.; Knopik, Valerie S.; McGeary, John E.; Beevers, Christopher G.; Maddox, W. Todd

2014-01-01

Humans with 7 or more repeats in exon III of the DRD4 gene (long DRD4 carriers) sometimes demonstrate impaired attention, as seen in ADHD, and at other times demonstrate heightened attention, as seen in addictive behavior. Though the clinical effects of DRD4 are the focus of much work, this gene may not necessarily serve as a ‘risk’ gene for attentional deficits, but as a plasticity gene where attention is heightened for priority items in the environment and impaired for minor items. Here we examine the role of DRD4 in two tasks that benefit from selective attention to high-priority information. We examine a category learning task where performance is supported by focusing on features and updating verbal rules. Here selective attention to the most salient features is associated with good performance. In addition, we examine the Operation Span Task (OSPAN), a working memory capacity task that relies on selective attention to update and maintain items in memory while also performing a secondary task. Long DRD4 carriers show superior performance relative to short DRD4 homozygotes (six or less tandem repeats) in both the category learning and OSPAN tasks. These results suggest that DRD4 may serve as a ‘plasticity’ gene where individuals with the long allele show heightened selective attention to high-priority items in the environment, which can be beneficial in the appropriate context. PMID:25244120

Upregulation of Cannabinoid Type 1 Receptors in Dopamine D2 Receptor Knockout Mice Is Reversed by Chronic Forced Ethanol Consumption

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thanos, P.K.; Wang, G.; Thanos, P.K.

2011-01-01

The anatomical proximity of the cannabinoid type 1 (CNR1/CB1R) and the dopamine D2 receptors (DRD2), their ability to form CB1R-DRD2 heteromers, their opposing roles in locomotion, and their involvement in ethanol's reinforcing and addictive properties prompted us to study the levels and distribution of CB1R after chronic ethanol intake, in the presence and absence of DRD2. We monitored the drinking patterns and locomotor activity of Drd2+/+ and Drd2-/- mice consuming either water or a 20% (v/v) ethanol solution (forced ethanol intake) for 6 months and used the selective CB1 receptor antagonist [{sup 3}H]SR141716A to quantify CB1R levels in different brainmore » regions with in vitro receptor autoradiography. We found that the lack of DRD2 leads to a marked upregulation (approximately 2-fold increase) of CB1R in the cerebral cortex, the caudate-putamen, and the nucleus accumbens, which was reversed by chronic ethanol intake. The results suggest that DRD2-mediated dopaminergic neurotransmission and chronic ethanol intake exert an inhibitory effect on cannabinoid receptor expression in cortical and striatal regions implicated in the reinforcing and addictive properties of ethanol.« less

Dopamine D2 gene expression interacts with environmental enrichment to impact lifespan and behavior.

PubMed

Thanos, Panayotis K; Hamilton, John; O'Rourke, Joseph R; Napoli, Anthony; Febo, Marcelo; Volkow, Nora D; Blum, Kenneth; Gold, Mark

2016-04-12

Aging produces cellular, molecular, and behavioral changes affecting many areas of the brain. The dopamine (DA) system is known to be vulnerable to the effects of aging, which regulate behavioral functions such as locomotor activity, body weight, and reward and cognition. In particular, age-related DA D2 receptor (D2R) changes have been of particular interest given its relationship with addiction and other rewarding behavioral properties. Male and female wild-type (Drd2 +/+), heterozygous (Drd2 +/-) and knockout (Drd2 -/-) mice were reared post-weaning in either an enriched environment (EE) or a deprived environment (DE). Over the course of their lifespan, body weight and locomotor activity was assessed. While an EE was generally found to be correlated with longer lifespan, these increases were only found in mice with normal or decreased expression of the D2 gene. Drd2 +/+ EE mice lived nearly 16% longer than their DE counterparts. Drd2 +/+ and Drd2 +/- EE mice lived 22% and 21% longer than Drd2 -/- EE mice, respectively. Moreover, both body weight and locomotor activity were moderated by environmental factors. In addition, EE mice show greater behavioral variability between genotypes compared to DE mice with respect to body weight and locomotor activity.

Diabetes-Related Distress, Depression and Distress-Depression among Adults with Type 2 Diabetes Mellitus in Malaysia.

PubMed

Chew, Boon-How; Vos, Rimke; Mohd-Sidik, Sherina; Rutten, Guy E H M

2016-01-01

Type 2 diabetes mellitus (T2DM) brings about an increasing psychosocial problem in adult patients. Prevalence data on and associated factors of diabetes related distress (DRD) and depression have been lacking in Asia. This study aimed to examine the prevalence of DRD and depression, and their associated factors in Asian adult T2DM patients. This study was conducted in three public health clinics measuring DRD (Diabetes Distress Scale, DDS), and depression (Patient Health Questionnaire, PHQ). Patients who were at least 30 years of age, had T2DM for more than one year, with regular follow-up and recent laboratory results (< 3 months) were consecutively recruited. Associations between DRD, depression and the combination DRD-depression with demographic and clinical characteristics were analysed using generalized linear models. From 752 invited people, 700 participated (mean age 56.9 years, 52.8% female, 52.9% Malay, 79.1% married). Prevalence of DRD and depression were 49.2% and 41.7%, respectively. Distress and depression were correlated, spearman's r = 0.50. Patients with higher DRD were younger (OR 0.995, 95% CI 0.996 to 0.991), Chinese (OR 1.2, 95% CI 1.04 to 1.29), attending Dengkil health clinic (OR 1.1, 95% CI 1.00 to 1.22) and had higher scores on the PHQ (OR 1.1, 95% CI 1.04 to 1.06). Depression was less likely in the unmarried compared to divorced/separately living and those attending Dengkil health clinic, but more likely in patients with microvascular complications (OR 1.4, 95% CI 1.06 to 1.73) and higher DDS (OR 1.03, 95% CI 1.02 to 1.03). For the combination of DRD and depression, unemployment (OR 4.7, 95% CI 1.02 to 21.20) had positive association, whereas those under medical care at the Salak health clinics (OR 0.28, 95% CI 0.12 to 0.63), and those with a blood pressure > 130/80 mmHg (OR 0.53, 95% CI 0.32 to 0.89) were less likely to experience both DRD and depression. DRD and depression were common and correlated in Asian adults with T2DM at primary care level. Socio-demographic more than clinical characteristics were related to DRD and depression.

Diabetes-Related Distress, Depression and Distress-Depression among Adults with Type 2 Diabetes Mellitus in Malaysia

PubMed Central

Chew, Boon-How; Vos, Rimke; Mohd-Sidik, Sherina; Rutten, Guy E. H. M.

2016-01-01

Type 2 diabetes mellitus (T2DM) brings about an increasing psychosocial problem in adult patients. Prevalence data on and associated factors of diabetes related distress (DRD) and depression have been lacking in Asia. This study aimed to examine the prevalence of DRD and depression, and their associated factors in Asian adult T2DM patients. This study was conducted in three public health clinics measuring DRD (Diabetes Distress Scale, DDS), and depression (Patient Health Questionnaire, PHQ). Patients who were at least 30 years of age, had T2DM for more than one year, with regular follow-up and recent laboratory results (< 3 months) were consecutively recruited. Associations between DRD, depression and the combination DRD-depression with demographic and clinical characteristics were analysed using generalized linear models. From 752 invited people, 700 participated (mean age 56.9 years, 52.8% female, 52.9% Malay, 79.1% married). Prevalence of DRD and depression were 49.2% and 41.7%, respectively. Distress and depression were correlated, spearman’s r = 0.50. Patients with higher DRD were younger (OR 0.995, 95% CI 0.996 to 0.991), Chinese (OR 1.2, 95% CI 1.04 to 1.29), attending Dengkil health clinic (OR 1.1, 95% CI 1.00 to 1.22) and had higher scores on the PHQ (OR 1.1, 95% CI 1.04 to 1.06). Depression was less likely in the unmarried compared to divorced/separately living and those attending Dengkil health clinic, but more likely in patients with microvascular complications (OR 1.4, 95% CI 1.06 to 1.73) and higher DDS (OR 1.03, 95% CI 1.02 to 1.03). For the combination of DRD and depression, unemployment (OR 4.7, 95% CI 1.02 to 21.20) had positive association, whereas those under medical care at the Salak health clinics (OR 0.28, 95% CI 0.12 to 0.63), and those with a blood pressure > 130/80 mmHg (OR 0.53, 95% CI 0.32 to 0.89) were less likely to experience both DRD and depression. DRD and depression were common and correlated in Asian adults with T2DM at primary care level. Socio-demographic more than clinical characteristics were related to DRD and depression. PMID:27002728

Delay discounting differences in brain activation, connectivity, and structure in individuals with addiction: a systematic review protocol.

PubMed

Owens, Max M; Amlung, Michael T; Beach, Steven R H; Sweet, Lawrence H; MacKillop, James

2017-07-11

Delayed reward discounting (DRD), the degree to which future rewards are discounted relative to immediate rewards, is used as an index of impulsive decision-making and has been associated with a number of problematic health behaviors. Given the robust behavioral association between DRD and addictive behavior, there is an expanding literature investigating the differences in the functional and structural correlates of DRD in the brain between addicted and healthy individuals. However, there has yet to be a systematic review which characterizes differences in regional brain activation, functional connectivity, and structure and places them in the larger context of the DRD literature. The objective of this systematic review is to summarize and critically appraise the existing literature examining differences between addicted and healthy individuals in the neural correlates of DRD using magnetic resonance imaging (MRI) or functional magnetic resonance imaging (fMRI). A systematic search strategy will be implemented that uses Boolean search terms in PubMed/MEDLINE and PsycINFO, as well as manual search methods, to identify the studies comprehensively. This review will include studies using MRI or fMRI in humans to directly compare brain activation, functional connectivity, or structure in relation to DRD between addicted and healthy individuals or continuously assess addiction severity in the context of DRD. Two independent reviewers will determine studies that meet the inclusion criteria for this review, extract data from included studies, and assess the quality of included studies using the Grading of Recommendations Assessment, Development and Evaluation framework. Then, narrative review will be used to explicate the differences in structural and functional correlates of DRD implicated by the literature and assess the strength of evidence for this conclusion. This review will provide a needed critical exegesis of the MRI studies that have been conducted investigating brain differences in addictive behavior in relation to healthy samples in the context of DRD. This will provide clarity on the elements of neural activation, connectivity, and structure that are most implicated in the differences in DRD seen in addicted individuals. PROSPERO CRD42017056857.

DRD2 and DRD4 in relation to regular alcohol and cannabis use among adolescents: does parenting modify the impact of genetic vulnerability? The TRAILS study.

PubMed

Creemers, H E; Harakeh, Z; Dick, D M; Meyers, J; Vollebergh, W A M; Ormel, J; Verhulst, F C; Huizink, A C

2011-05-01

The aims of the present study were to determine the direct effect of DRD2 and DRD4, as well as their interaction with parenting (i.e. rejection, overprotection and emotional warmth), on the development of regular alcohol and cannabis use in 1192 Dutch adolescents from the general population. Information was obtained by self-report questionnaires. Perceived rejection, overprotection and emotional warmth were assessed at age 10-12. Regular alcohol and cannabis use were determined at age 15-18 and defined as the consumption of alcohol on 10 or more occasions in the past four weeks, and the use of cannabis on 4 or more occasions in the past four weeks. Models were adjusted for age, sex, parental alcohol or cannabis use, and externalizing behavior. Carrying the A1 allele of the DRD2 TaqIA polymorphism, or the 7 repeat DRD4, was not directly related to regular alcohol or cannabis use. In addition, adolescent carriers of these genetic risk markers were not more susceptible to the influence of less optimal parenting. Main effects for parenting indicated that overprotection increased the risk of regular alcohol use, whereas the risk of cannabis use was enhanced by parental rejection and buffered by emotional warmth. Our findings do not support an association between DRD2/DRD4 and regular alcohol and cannabis use in adolescents. Given the substance-specific influences of rejection, overprotection and emotional warmth, these parenting factors might be promising candidates for prevention work. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Lack of association of DRD4 exon 3 VNTR genotype with reactivity to dynamic smoking cues in movies.

PubMed

Lochbuehler, Kirsten; Verhagen, Maaike; Munafò, Marcus R; Engels, Rutger C M E

2013-09-01

The objective of the present study was first to examine whether dynamic smoking cues in movies trigger craving, and second to explore whether the DRD4 48 bp variable number of tandem repeat (VNTR) exon 3 genotype modifies this relationship. Using an experimental design, daily adult smokers were exposed to a movie segment in which either several characters smoked, or the smoking was completely edited out. In a human laboratory, that reflected a naturalistic setting, 112 daily smokers (mean age=22.45; SD=4.15) watched an edited version of the movie Alfie (2007). Saliva samples were collected for DNA isolation. Craving was assessed at 4 times: before and after the movie, and in two advertisement breaks during the movie. The results did not indicate any evidence of a three-way interaction between movie condition, the DRD4 VNTR polymorphism and time and no evidence of a main effect of condition on craving. The results found evidence of a main effect of the DRD4 VNTR polymorphism on craving (p=.03), indicating that smokers carrying the DRD4 7-repeat allele showed higher levels of craving compared with smokers without the DRD4 7-repeat allele. Dynamic smoking cues in movies do not affect smokers' craving and this is not modified by DRD4 genotype. Smokers carrying the DRD4 7-repeat allele developed higher levels of craving in the context of watching a movie than non-carriers. Due to the small sample size, these results need to be treated with caution. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Genetic moderation of transactional relations between parenting practices and child self-regulation.

PubMed

Cho, Junhan; Kogan, Steven M; Brody, Gene H

2016-10-01

The present study addressed the ways in which parent and child dopamine D4 receptor (DRD4) genotypes jointly moderate the transactional relations between parenting practices and child self-regulation. African American children (N = 309) and their parents provided longitudinal data spanning child ages 11 to 15 years and a saliva sample from which variation at DRD4 was genotyped. Based on the differential susceptibility perspective, this study examined moderation effects of DRD4 status on (a) the extent to which parenting practices affect child self-regulation and (b) the extent to which child self-regulation, as an environmental influence on the parent, affects parenting behavior. Results indicated that responsive-supportive parenting interacted with children's DRD4 status to influence increases in child self-regulation. Also, child self-regulation interacted with parent's DRD4 status to predict changes in parenting practices. Both Gene × Environment effects conformed to a differential susceptibility model in which parents' and children's DRD4 genes operated to increase environmental sensitivity "for better and for worse." (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Genetic Moderation of Transactional Relations Between Parenting Practices and Child Self-Regulation

PubMed Central

Cho, Junhan; Kogan, Steven M.; Brody, Gene H.

2016-01-01

The present study addressed the ways in which parent and child dopamine D4 receptor (DRD4) genotypes jointly moderate the transactional relations between parenting practices and child self-regulation. African American children (N = 309) and their parents provided longitudinal data spanning child ages 11 to 15 years and a saliva sample from which variation at DRD4 was genotyped. Based on the differential susceptibility perspective, this study examined moderation effects of DRD4 status on (a) the extent to which parenting practices affect child self-regulation and (b) the extent to which child self-regulation, as an environmental influence on the parent, affects parenting behavior. Results indicated that responsive-supportive parenting interacted with children’s DRD4 status to influence increases in child self-regulation. Also, child self-regulation interacted with parent’s DRD4 status to predict changes in parenting practices. Both G × E effects conformed to a differential susceptibility model in which parents’ and children’s DRD4 genes operated to increase environmental sensitivity in a “for better and for worse” manner. PMID:27548745

The Association of DRD2 with Insight Problem Solving.

PubMed

Zhang, Shun; Zhang, Jinghuan

2016-01-01

Although the insight phenomenon has attracted great attention from psychologists, it is still largely unknown whether its variation in well-functioning human adults has a genetic basis. Several lines of evidence suggest that genes involved in dopamine (DA) transmission might be potential candidates. The present study explored for the first time the association of dopamine D2 receptor gene ( DRD2 ) with insight problem solving. Fifteen single-nucleotide polymorphisms (SNPs) covering DRD2 were genotyped in 425 unrelated healthy Chinese undergraduates, and were further tested for association with insight problem solving. Both single SNP and haplotype analysis revealed several associations of DRD2 SNPs and haplotypes with insight problem solving. In conclusion, the present study provides the first evidence for the involvement of DRD2 in insight problem solving, future studies are necessary to validate these findings.

The Association of DRD2 with Insight Problem Solving

PubMed Central

Zhang, Shun; Zhang, Jinghuan

2016-01-01

Although the insight phenomenon has attracted great attention from psychologists, it is still largely unknown whether its variation in well-functioning human adults has a genetic basis. Several lines of evidence suggest that genes involved in dopamine (DA) transmission might be potential candidates. The present study explored for the first time the association of dopamine D2 receptor gene (DRD2) with insight problem solving. Fifteen single-nucleotide polymorphisms (SNPs) covering DRD2 were genotyped in 425 unrelated healthy Chinese undergraduates, and were further tested for association with insight problem solving. Both single SNP and haplotype analysis revealed several associations of DRD2 SNPs and haplotypes with insight problem solving. In conclusion, the present study provides the first evidence for the involvement of DRD2 in insight problem solving, future studies are necessary to validate these findings. PMID:27933030

DRD4 genotype predicts longevity in mouse and human.

PubMed

Grady, Deborah L; Thanos, Panayotis K; Corrada, Maria M; Barnett, Jeffrey C; Ciobanu, Valentina; Shustarovich, Diana; Napoli, Anthony; Moyzis, Alexandra G; Grandy, David; Rubinstein, Marcelo; Wang, Gene-Jack; Kawas, Claudia H; Chen, Chuansheng; Dong, Qi; Wang, Eric; Volkow, Nora D; Moyzis, Robert K

2013-01-02

Longevity is influenced by genetic and environmental factors. The brain's dopamine system may be particularly relevant, since it modulates traits (e.g., sensitivity to reward, incentive motivation, sustained effort) that impact behavioral responses to the environment. In particular, the dopamine D4 receptor (DRD4) has been shown to moderate the impact of environments on behavior and health. We tested the hypothesis that the DRD4 gene influences longevity and that its impact is mediated through environmental effects. Surviving participants of a 30-year-old population-based health survey (N = 310; age range, 90-109 years; the 90+ Study) were genotyped/resequenced at the DRD4 gene and compared with a European ancestry-matched younger population (N = 2902; age range, 7-45 years). We found that the oldest-old population had a 66% increase in individuals carrying the DRD4 7R allele relative to the younger sample (p = 3.5 × 10(-9)), and that this genotype was strongly correlated with increased levels of physical activity. Consistent with these results, DRD4 knock-out mice, when compared with wild-type and heterozygous mice, displayed a 7-9.7% decrease in lifespan, reduced spontaneous locomotor activity, and no lifespan increase when reared in an enriched environment. These results support the hypothesis that DRD4 gene variants contribute to longevity in humans and in mice, and suggest that this effect is mediated by shaping behavioral responses to the environment.

Links between DRD4, Executive Attention, and Alphabetic Skills in a Nonclinical Sample

ERIC Educational Resources Information Center

Kegel, Cornelia A. T.; Bus, Adriana G.

2013-01-01

Background: The dopamine D4 receptor gene (DRD4) has been linked to attention deficit hyperactivity disorder (ADHD) and reading disorders. In this study, we examined whether diminished anticipatory dopamine cell firing--typical of the long variant of the DRD4 allele--is related to emergent and advanced alphabetic skills, and whether executive…

Association between DRD2, 5-HTTLPR, and ALDH2 genes and specific personality traits in alcohol- and opiate-dependent patients.

PubMed

Wang, Tzu-Yun; Lee, Sheng-Yu; Chen, Shiou-Lan; Huang, San-Yuan; Chang, Yun-Hsuan; Tzeng, Nian-Sheng; Wang, Chen-Lin; Hui Lee, I; Yeh, Tzung Lieh; Yang, Yen Kuang; Lu, Ru-Band

2013-08-01

The vulnerability of developing addictions is associated with genetic factors and personality traits. The predisposing genetic variants and personality traits may be common to all addictions or specific to a particular class of addiction. To investigate the relationship between genetic variances, personality traits, and their interactions in addiction are important. We recruited 175 opiate-dependent patients, 102 alcohol-dependent patients, and 111 healthy controls. All participants were diagnosed using DSM-IV criteria and assessed with Tridimensional Personality Questionnaire (TPQ). The dopamine D2 receptor (DRD2), 5-HTT-linked promoter region (5-HTTLPR), and aldehyde dehydrogenase 2 (ALDH2) genes were genotyped using PCR. The genotype frequency of the 5-HTTLPR and ALDH2 was significantly different between the patients and controls (P=0.013, P<0.001, respectively), and borderline significant (P=0.05) for DRD2 polymorphism. Both Novelty Seeking (NS) and Harm Avoidance (HA) scores were higher for patients (P<0.001). After stratification by candidate genes, addicts with ALDH2 *1/*1 interacting with the low-functional group of DRD2 and 5-HTTLPR genes have higher HA traits, whereas addicts with ALDH2 *1/*2 or *2/*2 and low-functional group of DRD2 and 5-HTTLPR genes have higher NS traits. We concluded that addicts, both alcohol- and opiate-dependent patients, have common genetic variants in DRD2 and 5-HTTLPR but specific for ALDH2. Higher NS and HA traits were found in both patient groups with the interaction with DRD2, 5-HTTLPR, and ALDH2 genes. The ALDH2 gene variants had different effect in the NS and HA dimension while the DRD2 and 5-HTTLPR genes did not. Copyright © 2013 Elsevier B.V. All rights reserved.

Interaction between DRD2 and lead exposure on the cortical thickness of the frontal lobe in youth with attention-deficit/hyperactivity disorder.

PubMed

Kim, Johanna Inhyang; Kim, Jae-Won; Lee, Jong-Min; Yun, Hyuk Jin; Sohn, Chul-Ho; Shin, Min-Sup; Kim, Bongseog; Chae, Jonghee; Roh, Jaewoo; Kim, Bung-Nyun

2018-03-02

The dopamine receptor D2 receptor (DRD2) gene and lead exposure are both thought to contribute to the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). ADHD is characterized by delay in brain maturation, most prominent in the prefrontal cortex (PFC). The D2 receptor is also mainly located in the PFC, and animal studies show that lead exposure affects the dopaminergic system of the frontal lobe, indicating an overlap in neural correlates of ADHD, DRD2, and lead exposure. We examined the interaction effects of DRD2 rs1800497 and lead exposure on the cortical thickness of the frontal lobe in patients with ADHD. A 1:1 age- and gender-matched sample of 75 participants with ADHD and 75 healthy participants was included in the analysis. The interaction effects of DRD2 and lead exposure on the cortical thickness of 12 regions of interest in the frontal lobe were examined by multivariable linear regression analyses. When we investigated the DRD2×lead effects in the ADHD and HC groups separately, significant DRD2×lead effects were found in the ADHD group, but not in the healthy control group in multiple ROIs of the frontal lobe. There was a significant negative correlation between the cortical thickness of the right superior frontal gyrus and inattention scores. The present findings demonstrated significant interaction effects of DRD2 and lead exposure on the cortical thickness of the frontal lobe in ADHD. Replication studies with larger sample sizes, using a prospective design, are warranted to confirm these findings. Copyright © 2017 Elsevier Inc. All rights reserved.

Relationship between genetic polymorphisms in the DRD5 gene and paranoid schizophrenia in northern Han Chinese.

PubMed

Zhao, Y; Ding, M; Pang, H; Xu, X M; Wang, B J

2014-03-12

Dopamine (DA) has been implicated in the pathophysiol-ogy of several psychiatric disorders, including schizophrenia. Thus, genes related to the dopaminergic (DAergic) system are good candidate genes for schizophrenia. One of receptors of the DA receptor system is dopa-mine receptor 5 (DRD5). Single nucleotide polymorphisms (SNPs) in the regulatory regions of DRD5 gene may affect gene expression, influence biosynthesis of DA and underlie various neuropsychiatric disorders re-lated to DA dysfunction. The present study explored the association of SNPs within the DRD5 gene with paranoid schizophrenia in Han Chinese. A total of 176 patients with schizophrenia and 206 healthy controls were genotyped for four DRD5 SNPs (rs77434921, rs2076907, rs6283, and rs1800762). Significant group differences were observed in the allele and genotype frequencies of rs77434921 and rs1800762 and in the frequen-cies of GC haplotypes corresponding to rs77434921-rs1800762. Our find-ings suggest that common genetic variations of DRD5 are likely to con-tribute to genetic susceptibility to paranoid schizophrenia in Han Chinese. Further studies in larger samples are needed to replicate this association.

Self-Reported Sexual Behavioral Interests and Polymorphisms in the Dopamine Receptor D4 (DRD4) Exon III VNTR in Heterosexual Young Adults.

PubMed

Halley, Andrew C; Boretsky, Melanie; Puts, David A; Shriver, Mark

2016-11-01

Polymorphisms in the dopamine D4 receptor (DRD4) have previously been shown to associate with a variety of human behavioral phenotypes, including ADHD pathology, alcohol and tobacco craving, financial risk-taking in males, and broader personality traits such as novelty seeking. Recent research has linked the presence of a 7-repeat (7R) allele in a 48-bp variable number of tandem repeats (VNTR) along exon III of DRD4 to age at first sexual intercourse, sexual desire, arousal and function, and infidelity and promiscuity. We hypothesized that carriers of longer DRD4 alleles may report interest in a wider variety of sexual behaviors and experiences than noncarriers. Participants completed a 37-item questionnaire measuring sexual interests as well as Cloninger's Temperament and Character Inventory, and were genotyped for the 48-bp VNTR on exon III of DRD4. Based on our final genotyped sample of female (n = 139) and male (n = 115) participants, we found that 7R carriers reported interest in a wider variety of sexual behaviors (r = 0.16) within a young adult heterosexual sample of European descent. To our knowledge, this is the first reported association between DRD4 exon III VNTR genotype and interest in a variety of sexual behaviors. We discuss these findings within the context of DRD4 research and broader trends in human evolutionary history.

Factors associated with diabetes-related distress over time among patients with T2DM in a tertiary hospital in Singapore.

PubMed

Tan, Maudrene L; Tan, Chuen S; Griva, Konstadina; Lee, Yung S; Lee, Jeannette; Tai, E S; Khoo, Eric Y; Wee, Hwee-Lin

2017-06-23

Persistent diabetes-related distress (DRD) is experienced by patients with Type 2 Diabetes Mellitus. Knowing factors associated with persistent DRD will aid clinicians in prioritising interventions efforts. A total of 216 patients were recruited from a tertiary hospital in Singapore, an Asian city state, and followed for 1.5 years (2011-2014). Data was collected by self-completed questionnaires assessing DRD (measured by the Problem Areas in Diabetes score) and other psychosocial aspects such as social support, presenteeism, depression, health-related quality of life (HRQoL) and excessive daytime sleepiness (EDS) at three time points. Clinical data (body-mass-index and glycated haemoglobin) was obtained from medical records. Change score was calculated for each clinical and psychosocial variable to capture changes in these variables from baseline. Generalized Linear Model with Generalized Estimating Equation method was used to assess whether baseline and change scores in clinical and psychosocial are associated with DRD over time. Complete data was available for 73 patients, with mean age 44 (SD 12.5) years and 67% males. Persistent DRD was experienced by 21% of the patients. In the final model, baseline HRQoL (OR = 0.56, p < 0.05) and change score of EDS (OR = 1.22, p < 0.05) was significantly associated with DRD over time. EDS might be a surrogate marker for persistent DRD and should be explored in larger samples of population to confirm the findings from this study.

DRD4 genotype predicts longevity in mouse and human

PubMed Central

Grady, Deborah L.; Thanos, Panayotis K.; Corrada, Maria M.; Barnett, Jeffrey C.; Ciobanu, Valentina; Shustarovich, Diana; Napoli, Anthony; Moyzis, Alexandra G.; Grandy, David; Rubinstein, Marcelo; Wang, Gene-Jack; H.Kawas, Claudia; Chen, Chuansheng; Dong, Qi; Wang, Eric; Volkow, Nora D.; Moyzis, Robert K.

2013-01-01

Longevity is influenced by genetic and environmental factors. The brain's dopamine system may be particularly relevant, since it modulates traits (e.g., sensitivity to reward, incentive motivation, sustained effort) that impact behavioral responses to the environment. In particular, the dopamine D4 receptor (DRD4) has been shown to moderate the impact of environments on behavior and health. We tested the hypothesis that the DRD4 gene influences longevity and that its impact is mediated through environmental effects. Surviving participants of a 30 year-old population-based health survey (N=310, age range 90–109; the 90+ Study) were genotyped/resequenced at the DRD4 gene, and compared to a European ancestry-matched younger population (N=2902, age range 7–45). We found that the oldest-old population had a 66% increase in individuals carrying the DRD4 7R allele relative to the younger sample (p=3.5 × 10−9), and that this genotype was strongly correlated with increased levels of physical activity. Consistent with these results, DRD4 knockout mice, when compared to wild-type and heterozygous mice, displayed a 7–9.7% decrease in lifespan, reduced spontaneous locomotor activity, and no lifespan increase when reared in an enriched environment. These results support the hypothesis that DRD4 gene variants contribute to longevity in humans and in mice, and suggest that this effect is mediated by shaping behavioral responses to the environment. PMID:23283341

Investigating the structural impact of S311C mutation in DRD2 receptor by molecular dynamics & docking studies.

PubMed

Podder, Avijit; Pandey, Deeksha; Latha, N

2016-04-01

Dopamine receptors (DR) are neuronal cell surface proteins that mediate the action of neurotransmitter dopamine in brain. Dopamine receptor D2 (DRD2) that belongs to G-protein coupled receptors (GPCR) family is a major therapeutic target for of various neurological and psychiatric disorders in human. The third inter cellular loop (ICL3) in DRD2 is essential for coupling G proteins and several signaling scaffold proteins. A mutation in ICL3 can interfere with this binding interface, thereby altering the DRD2 signaling. In this study we have examined the deleterious effect of serine to cysteine mutation at position 311 (S311C) in the ICL3 region that is implicated in diseases like schizophrenia and alcoholism. An in silico structure modeling approach was employed to determine the wild type (WT) and mutant S311C structures of DRD2, scaffold proteins - Gαi/o and NEB2. Protein-ligand docking protocol was exercised to predict the interactions of natural agonist dopamine with both the WT and mutant structures of DRD2. Besides, atomistic molecular dynamics (MD) simulations were performed to provide insights into essential dynamics of the systems-unbound and dopamine bound DRD2 (WT and mutant) and three independent simulations for Gαi, Gαo and NEB2 systems. To provide information on intra-molecular arrangement of the structures, a comprehensive residue interactions network of both dopamine bound WT and mutant DRD2 protein were studied. We also employed a protein-protein docking strategy to find the interactions of scaffold proteins - Gαi/o and NEB2 with both dopamine bound WT and mutant structures of DRD2. We observed a marginal effect of the mutation in dopamine binding mechanism on the trajectories analyzed. However, we noticed a significant structural alteration of the mutant receptor which affects Gαi/o and NEB2 binding that can be causal for malfunctioning in cAMP-dependent signaling and Ca(+) homeostasis in the brain dopaminergic system leading to neuropsychiatric disorders. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Association of dopamine gene variants, emotion dysregulation and ADHD in autism spectrum disorder.

PubMed

Gadow, Kenneth D; Pinsonneault, Julia K; Perlman, Greg; Sadee, Wolfgang

2014-07-01

The aim of the present study was to evaluate the association of dopaminergic gene variants with emotion dysregulation (EMD) and attention-deficit/hyperactivity disorder (ADHD) symptoms in children with autism spectrum disorder (ASD). Three dopamine transporter gene (SLC6A3/DAT1) polymorphisms (intron8 5/6 VNTR, 3'-UTR 9/10 VNTR, rs27072 in the 3'-UTR) and one dopamine D2 receptor gene (DRD2) variant (rs2283265) were selected for genotyping based on à priori evidence of regulatory activity or, in the case of DAT1 9/10 VNTR, commonly reported associations with ADHD. A sample of 110 children with ASD was assessed with a rigorously validated DSM-IV-referenced rating scale. Global EMD severity (parents' ratings) was associated with DAT1 intron8 (ηp(2)=.063) and rs2283265 (ηp(2)=.044). Findings for DAT1 intron8 were also significant for two EMD subscales, generalized anxiety (ηp(2)=.065) and depression (ηp(2)=.059), and for DRD2 rs2283265, depression (ηp(2)=.053). DRD2 rs2283265 was associated with teachers' global ratings of ADHD (ηp(2)=.052). DAT1 intron8 was associated with parent-rated hyperactivity (ηp(2)=.045) and both DAT1 9/10 VNTR (ηp(2)=.105) and DRD2 rs2283265 (ηp(2)=.069) were associated with teacher-rated inattention. These findings suggest that dopaminergic gene polymorphisms may modulate EMD and ADHD symptoms in children with ASD but require replication with larger independent samples. Copyright © 2014 Elsevier Ltd. All rights reserved.

Perinatal maternal alcohol consumption and methylation of the dopamine receptor DRD4 in the offspring: the Triple B study

PubMed Central

Fransquet, Peter D.; Hutchinson, Delyse; Olsson, Craig A.; Wilson, Judy; Allsop, Steve; Najman, Jake; Elliott, Elizabeth; Mattick, Richard P.; Saffery, Richard; Ryan, Joanne

2016-01-01

Maternal alcohol use during the perinatal period is a major public health issue, the higher ends of which are associated with foetal alcohol spectrum disorder and a range of adverse health outcomes in the progeny. The underlying molecular mechanisms remain largely unknown but may include the epigenetic disruption of gene activity during development. Alcohol directly activates the neurotransmitter dopamine, which plays an essential role in neurodevelopment. To investigate whether antenatal and early postnatal alcohol consumption were associated with differential dopamine receptor DRD4 promoter methylation in infants (n = 844). Data were drawn from the large population based Triple B pregnancy cohort study, with detailed information on maternal alcohol consumption in each trimester of pregnancy and early postpartum. DNA was extracted from infant buccal swabs collected at 8-weeks. DRD4 promoter DNA methylation was analysed by Sequenom MassARRAY. No strong evidence was found for an association between alcohol consumption during pregnancy and infant DRD4 methylation at 8-weeks postpartum. However, maternal alcohol consumption assessed contemporaneously at 8-weeks postpartum was associated with increased methylation at 13 of 19 CpG units examined (largest Δ + 3.20%, 95%Confidence Interval:1.66,4.75%, P = 0.0001 at CpG.6). This association was strongest in women who breastfeed, suggesting the possibility of a direct effect of alcohol exposure via breast milk. The findings of this study could influence public health guidelines around alcohol consumption for breastfeeding mothers; however, further research is required to confirm these novel findings. PMID:29492300

Delusional disorder: molecular genetic evidence for dopamine psychosis.

PubMed

Morimoto, Kiyoshi; Miyatake, Ryosuke; Nakamura, Mitsuo; Watanabe, Takemi; Hirao, Toru; Suwaki, Hiroshi

2002-06-01

Since delusional disorder is characterized by mono-symptomatic paranoid symptoms, it can be a good clinical model for investigating the dopaminergic mechanism responsible for paranoid symptoms. We examined neuroleptic responses, plasma homovanillic acid (pHVA) and genes of the dopamine receptor (DR) and its synthesizing enzyme (tyrosine hydroxylase: TH) in patients with delusional disorder and compared them with those of schizophrenic patients and healthy controls. (1) A relatively small dose of haloperidol was more effective for delusional disorder than for schizophrenia. (2) The pretreatment level of pHVA was higher in patients with persecution-type, but not in those with jealousy-type delusional disorder, compared with age- and sex-matched controls. This increased pHVA level was decreased eight weeks after successful haloperidol treatment. (3) The genotype frequency of the DRD2 gene Ser311Cys was significantly higher in patients with persecution-type delusional disorder (21%), compared with schizophrenic patients (6%) or controls (6%). (4) Patients homozygous for the DRD3 gene Ser9Ser had higher pretreatment levels of pHVA than those heterozygous for Ser9Gly. (v) A significant positive correlation was found between the polymorphic (TCAT)(n) repeat in the first intron of the TH gene and pretreatment levels of pHVA in delusional disorder. We suggest that delusional disorder, especially the persecution-type, includes a "dopamine psychosis," and that polymorphism of the DRD2, DRD3 and/or TH gene is part of the genetic basis underlying the hyperdopaminergic state that produces paranoid symptoms. Further studies on a large sample size are required.

Differential Susceptibility: The Genetic Moderation of Peer Pressure on Alcohol Use

PubMed Central

Cleveland, H. Harrington; Schlomer, Gabriel L.; Vandenbergh, David J.; Feinberg, Mark E.

2016-01-01

Although peer pressure can influence adolescents’ alcohol use, individual susceptibility to these pressures varies across individuals. The dopamine receptor D4 gene (DRD4) is a potential candidate gene that may influence adolescents’ susceptibility to their peer environment due to the role dopamine plays in reward sensation during social interaction. We hypothesized that DRD4 genotype status would moderate the impact of 7th-grade antisocial peer pressure on 12th-grade lifetime alcohol use (n = 414; 58.7 % female; 92.8 % White). The results revealed significant main effects for antisocial peer pressure, but no main effects for DRD4 genotype on lifetime alcohol use. Adolescent DRD4 genotype moderated the association between peer pressure and lifetime alcohol use. For individuals who carried at least one copy of the DRD4 7-repeat allele (7+), antisocial peer pressure was associated with increased lifetime alcohol use. These findings indicate that genetic sensitivity to peer pressure confers increased alcohol use in late adolescence. PMID:26307243

Differential Susceptibility: The Genetic Moderation of Peer Pressure on Alcohol Use.

PubMed

Griffin, Amanda M; Cleveland, H Harrington; Schlomer, Gabriel L; Vandenbergh, David J; Feinberg, Mark E

2015-10-01

Although peer pressure can influence adolescents' alcohol use, individual susceptibility to these pressures varies across individuals. The dopamine receptor D4 gene (DRD4) is a potential candidate gene that may influence adolescents' susceptibility to their peer environment due to the role dopamine plays in reward sensation during social interaction. We hypothesized that DRD4 genotype status would moderate the impact of 7th-grade antisocial peer pressure on 12th-grade lifetime alcohol use (n = 414; 58.7% female; 92.8% White). The results revealed significant main effects for antisocial peer pressure, but no main effects for DRD4 genotype on lifetime alcohol use. Adolescent DRD4 genotype moderated the association between peer pressure and lifetime alcohol use. For individuals who carried at least one copy of the DRD4 7-repeat allele (7+), antisocial peer pressure was associated with increased lifetime alcohol use. These findings indicate that genetic sensitivity to peer pressure confers increased alcohol use in late adolescence.

Role of LRRK2 in the regulation of dopamine receptor trafficking

PubMed Central

Sanna, Simona; Taymans, Jean Marc; Morari, Michele; Brugnoli, Alberto; Frassineti, Martina; Masala, Alessandra; Esposito, Sonia; Galioto, Manuela; Valle, Cristiana; Carri, Maria Teresa; Biosa, Alice; Greggio, Elisa; Crosio, Claudia

2017-01-01

Mutations in LRRK2 play a critical role in both familial and sporadic Parkinson’s disease (PD). Up to date, the role of LRRK2 in PD onset and progression remains largely unknown. However, experimental evidence highlights a critical role of LRRK2 in the control of vesicle trafficking that in turn may regulate different aspects of neuronal physiology. We have analyzed the role of LRRK2 in regulating dopamine receptor D1 (DRD1) and D2 (DRD2) trafficking. DRD1 and DRD2 are the most abundant dopamine receptors in the brain. They differ in structural, pharmacological and biochemical properties, as well as in localization and internalization mechanisms. Our results indicate that disease-associated mutant G2019S LRRK2 impairs DRD1 internalization, leading to an alteration in signal transduction. Moreover, the mutant forms of LRRK2 affect receptor turnover by decreasing the rate of DRD2 trafficking from the Golgi complex to the cell membrane. Collectively, our findings are consistent with the conclusion that LRRK2 influences the motility of neuronal vesicles and the neuronal receptor trafficking. These findings have important implications for the complex role that LRRK2 plays in neuronal physiology and the possible pathological mechanisms that may lead to neuronal death in PD. PMID:28582422

Polymorphisms in the dopamine D4 receptor gene (DRD4) contribute to individual differences in human sexual behavior: desire, arousal and sexual function.

PubMed

Ben Zion, I Z; Tessler, R; Cohen, L; Lerer, E; Raz, Y; Bachner-Melman, R; Gritsenko, I; Nemanov, L; Zohar, A H; Belmaker, R H; Benjamin, J; Ebstein, R P

2006-08-01

Although there is some evidence from twin studies that individual differences in sexual behavior are heritable, little is known about the specific molecular genetic design of human sexuality. Recently, a specific dopamine D4 receptor (DRD4) agonist was shown in rats to induce penile erection through a central mechanism. These findings prompted us to examine possible association between the well-characterized DRD4 gene and core phenotypes of human sexual behavior that included desire, arousal and function in a group of 148 nonclinical university students. We observed association between the exon 3 repeat region, and the C-521T and C-616G promoter region SNPs, with scores on scales that measure human sexual behavior. The single most common DRD4 5-locus haplotype (19%) was significantly associated with Desire, Function and Arousal scores. The current results are consistent with animal studies that show a role for dopamine and specifically the DRD4 receptor in sexual behavior and suggest that one pathway by which individual variation in human desire, arousal and function are mediated is based on allelic variants coding for differences in DRD4 receptor gene expression and protein concentrations in key brain areas.

Increased dopamine DRD4 receptor mRNA expression in lymphocytes of musicians and autistic individuals: bridging the music-autism connection.

PubMed

Emanuele, Enzo; Boso, Marianna; Cassola, Francesco; Broglia, Davide; Bonoldi, Ilaria; Mancini, Lara; Marini, Mara; Politi, Pierluigi

2010-01-01

People with autistic spectrum disorder (ASD) are affected by a long-life disabling condition, characterized by communication deficits, severe impairments in social functioning, and stereotyped behaviors. Although ASD individuals display several problems in interactions, it has been reported that they may show a peculiar interest in music. Previous studies have suggested a pivotal role for the dopaminergic system in the psychobiology of reward, including the pleasure of music. In the present study, we sought to investigate dopamine DRD3 and DRD4 receptor expression in peripheral blood lymphocytes of adult healthy musicians and age- and gender-matched patients with ASD against the background hypothesis that the dopaminergic system may contribute a biological cause to the reward dimensions of the musical experience in both healthy and autistic individuals. ANOVA showed significant differences in DRD4 mRNA expression between the groups (P = 0.008). Post-hoc analysis showed significant differences between the control group and both musicians (P < 0.05) and ASD individuals (P < 0.05). No differences were found for DRD3 mRNA expression between the groups. Our current results provide intriguing preliminary evidence for a possible molecular link between dopamine DRD4 receptor, music and autism, possibly via mechanisms involving the reward system and the appraisal of emotions.

Novelty-seeking DRD4 polymorphisms are associated with human migration distance out-of-Africa after controlling for neutral population gene structure.

PubMed

Matthews, Luke J; Butler, Paul M

2011-07-01

Numerous lines of evidence suggest that Homo sapiens evolved as a distinct species in Africa by 150,000 years before the present (BP) and began major migrations out-of-Africa ∼50,000 BP. By 20,000 BP, our species had effectively colonized the entire Old World, and by 12,000 BP H. sapiens had a global distribution. We propose that this rapid migration into new habitats selected for individuals with low reactivity to novel stressors. Certain dopamine receptor D4 (DRD4) polymorphisms are associated with low neuronal reactivity and increased exploratory behavior, novelty seeking, and risk taking, collectively considered novelty-seeking trait (NS). One previous report (Chen et al.: Evol Hum Behav 20 (1999) 309-324) demonstrated a correlation between migratory distance and the seven-repeat (7R) VNTR DRD4 allele at exon 3 for human populations. This study, however, failed to account for neutral genetic processes (drift and admixture) that might create such a correlation in the absence of natural selection. Furthermore, additional loci surrounding DRD4 are now recognized to influence NS. Herein we account for neutral genetic structure by modeling the nonindependence of neutral allele frequencies between human populations. We retest the DRD4 exon 3 alleles, and also test two other loci near DRD4 that are associated with NS. We conclude there is an association between migratory distance and DRD4 exon 3 2R and 7R alleles that cannot be accounted for by neutral genetic processes alone. Copyright © 2011 Wiley-Liss, Inc.

New functional activity of aripiprazole revealed: robust antagonism of D2 dopamine receptor-stimulated Gβγ signaling

PubMed Central

Brust, Tarsis F.; Hayes, Michael P.; Roman, David L.; Watts, Val J.

2014-01-01

The dopamine D2 receptor (DRD2) is a G protein-coupled receptor (GPCR) that is generally considered to be a primary target in the treatment of schizophrenia. First generation antipsychotic drugs (e.g. haloperidol) are antagonists of the DRD2, while second generation antipsychotic drugs (e.g. olanzapine) antagonize DRD2 and 5HT2A receptors. Notably, both these classes of drugs may cause side effects associated with D2 receptor antagonism (e.g. hyperprolactemia and extrapyramidal symptoms). The novel, “third generation” antipsychotic drug, aripiprazole is also used to treat schizophrenia, with the remarkable advantage that its tendency to cause extrapyramidal symptoms is minimal. Aripiprazole is considered a partial agonist of the DRD2, but it also has partial agonist/antagonist activity for other GPCRs. Further, aripiprazole has been reported to have a unique activity profile in functional assays with the DRD2. In the present study the molecular pharmacology of aripiprazole was further examined in HEK cell models stably expressing the DRD2 and specific isoforms of adenylyl cyclase to assess functional responses of Gα and Gβγ subunits. Additional studies examined the activity of aripiprazole in DRD2-mediated heterologous sensitization of adenylyl cyclase and cell-based dynamic mass redistribution (DMR). Aripiprazole displayed a unique functional profile for modulation of G proteins, being a partial agonist for Gαi/o and a robust antagonist for Gβγ signaling. Additionally, aripiprazole was a weak partial agonist for both heterologous sensitization and dynamic mass redistribution. PMID:25449598

Dopamine D4 Receptor Gene Associated with the Frontal-Striatal-Cerebellar Loop in Children with ADHD: A Resting-State fMRI Study.

PubMed

Qian, Andan; Wang, Xin; Liu, Huiru; Tao, Jiejie; Zhou, Jiejie; Ye, Qiong; Li, Jiance; Yang, Chuang; Cheng, Jingliang; Zhao, Ke; Wang, Meihao

2018-06-01

Attention deficit hyperactivity disorder (ADHD) is a common childhood neuropsychiatric disorder that has been linked to the dopaminergic system. This study aimed to investigate the effects of regulation of the dopamine D4 receptor (DRD4) on functional brain activity during the resting state in ADHD children using the methods of regional homogeneity (ReHo) and functional connectivity (FC). Resting-state functional magnetic resonance imaging data were analyzed in 49 children with ADHD. All participants were classified as either carriers of the DRD4 4-repeat/4-repeat (4R/4R) allele (n = 30) or the DRD4 2-repeat (2R) allele (n = 19). The results showed that participants with the DRD4 2R allele had decreased ReHo bilaterally in the posterior lobes of the cerebellum, while ReHo was increased in the left angular gyrus. Compared with participants carrying the DRD4 4R/4R allele, those with the DRD4 2R allele showed decreased FC to the left angular gyrus in the left striatum, right inferior frontal gyrus, and bilateral lobes of the cerebellum. The increased FC regions included the left superior frontal gyrus, medial frontal gyrus, and rectus gyrus. These data suggest that the DRD4 polymorphisms are associated with localized brain activity and specific functional connections, including abnormality in the frontal-striatal-cerebellar loop. Our study not only enhances the understanding of the correlation between the cerebellar lobes and ADHD, but also provides an imaging basis for explaining the neural mechanisms underlying ADHD in children.

Parental smoke exposure and the development of nicotine craving in adolescent novice smokers: the roles of DRD2, DRD4, and OPRM1 genotypes.

PubMed

Kleinjan, Marloes; Engels, Rutger C M E; DiFranza, Joseph R

2015-10-08

Among adolescent novice smokers, craving is often the first, and is the most reported, symptom of nicotine dependence. Until now, little has been known about the development of craving symptoms in novice smokers. The aim of this study was to identify specific genetic (i.e., DRD2 Taq1A, DRD4 48 bp VNTR, and OPRM1 A118G polymorphisms) and environmental mechanisms that underlie the emergence of both cue-induced and cognitive craving among adolescent novice smokers. A five-wave longitudinal, genetically-informed survey study was conducted with intervals of four months. The sample included 376 early adolescent smokers (12-13 years of age at baseline). Self-report questionnaires were completed regarding smoking behavior, observed parental smoking behavior, and both cue-induced and cognitive craving. Data were analyzed with a latent growth curve approach. For both cue-induced and cognitive craving, significant interaction effects were found for DRD2 Taq1A with parental smoke exposure. A1-allele carriers did not seem to be influenced by the environment with regard to craving development. Adolescents who are homozygous for the A2-allele and who are more exposed to parental smoking experience the highest levels of both types of craving over time. No significant interaction effects were found between parental smoke exposure and DRD4 48 bp VNTR or OPRM1 A118G. Previous studies identified DRD2 Taq1A A1-allele carriers as vulnerable to developing nicotine dependence. However, this study showed that parental smoking increased the chances of developing dependence more rapidly for early adolescents who are considered to be less sensitive to the rewarding effects of nicotine according to their DRD2 Taq1A genotype. It is thus especially important that these young people not be exposed to smoking in their social environment.

Commonly-occurring polymorphisms in the COMT, DRD1 and DRD2 genes influence different aspects of motor sequence learning in humans.

PubMed

Baetu, Irina; Burns, Nicholas R; Urry, Kristi; Barbante, Girolamo Giovanni; Pitcher, Julia B

2015-11-01

Performing sequences of movements is a ubiquitous skill that involves dopamine transmission. However, it is unclear which components of the dopamine system contribute to which aspects of motor sequence learning. Here we used a genetic approach to investigate the relationship between different components of the dopamine system and specific aspects of sequence learning in humans. In particular, we investigated variations in genes that code for the catechol-O-methyltransferase (COMT) enzyme, the dopamine transporter (DAT) and dopamine D1 and D2 receptors (DRD1 and DRD2). COMT and the DAT regulate dopamine availability in the prefrontal cortex and the striatum, respectively, two key regions recruited during learning, whereas dopamine D1 and D2 receptors are thought to be involved in long-term potentiation and depression, respectively. We show that polymorphisms in the COMT, DRD1 and DRD2 genes differentially affect behavioral performance on a sequence learning task in 161 Caucasian participants. The DRD1 polymorphism predicted the ability to learn new sequences, the DRD2 polymorphism predicted the ability to perform a previously learnt sequence after performing interfering random movements, whereas the COMT polymorphism predicted the ability to switch flexibly between two sequences. We used computer simulations to explore potential mechanisms underlying these effects, which revealed that the DRD1 and DRD2 effects are possibly related to neuroplasticity. Our prediction-error algorithm estimated faster rates of connection strengthening in genotype groups with presumably higher D1 receptor densities, and faster rates of connection weakening in genotype groups with presumably higher D2 receptor densities. Consistent with current dopamine theories, these simulations suggest that D1-mediated neuroplasticity contributes to learning to select appropriate actions, whereas D2-mediated neuroplasticity is involved in learning to inhibit incorrect action plans. However, the learning algorithm did not account for the COMT effect, suggesting that prefrontal dopamine availability might affect sequence switching via other, non-learning, mechanisms. These findings provide insight into the function of the dopamine system, which is relevant to the development of treatments for disorders such as Parkinson's disease. Our results suggest that treatments targeting dopamine D1 receptors may improve learning of novel sequences, whereas those targeting dopamine D2 receptors may improve the ability to initiate previously learned sequences of movements. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Positive effects of methylphenidate on hyperactivity are moderated by monoaminergic gene variants in children with autism spectrum disorders.

PubMed

McCracken, J T; Badashova, K K; Posey, D J; Aman, M G; Scahill, L; Tierney, E; Arnold, L E; Vitiello, B; Whelan, F; Chuang, S Z; Davies, M; Shah, B; McDougle, C J; Nurmi, E L

2014-06-01

Methylphenidate (MPH) reduces hyperactive-impulsive symptoms common in children with autism spectrum disorders (ASDs), however, response and tolerability varies widely. We hypothesized monoaminergic gene variants may moderate MPH effects in ASD, as in typically developing children with attention-deficit/hyperactivity disorder. Genotype data were available for 64 children with ASD and hyperactivity who were exposed to MPH during a 1-week safety/tolerability lead-in phase and 58 who went on to be randomized to placebo and three doses of MPH during a 4-week blinded, crossover study. Outcome measures included the Clinical Global Impression-Improvement (CGI-I) scale and the Aberrant Behavior Checklist (ABC-hyperactivity index). A total of 14 subjects discontinued the study because of MPH side effects. Subjects were genotyped for variants in DRD1-DRD5, ADRA2A, SLC6A3, SLC6A4, MAOA and MAOB, and COMT. Forty-nine percent of the sample met positive responder criteria. In this modest but relatively homogeneous sample, significant differences by DRD1 (P=0.006), ADRA2A (P<0.02), COMT (P<0.04), DRD3 (P<0.05), DRD4 (P<0.05), SLC6A3 (P<0.05) and SLC6A4 (P<0.05) genotypes were found for responders versus non-responders. Variants in DRD2 (P<0.001) and DRD3 (P<0.04) were associated with tolerability in the 14 subjects who discontinued the trial. For this first MPH pharmacogenetic study in children with ASD, multiple monoaminergic gene variants may help explain individual differences in MPH's efficacy and tolerability.

Molecular cloning, expression profile, polymorphism and the genetic effects of the dopamine D1 receptor gene on duck reproductive traits.

PubMed

Wang, Cui; Li, Shijun; Li, Chuang; Feng, Yanping; Peng, Xiuli; Gong, Yanzhang

2012-09-01

The dopamine D1 receptor (DRD1), a member of the dopamine receptor (DR) gene family, participates in the regulation of reproductive behaviors in birds. In this study, a 1,390 bp fragment covering the complete coding region (CDS) of duck DRD1 gene was obtained. The cDNA (GenBank: JQ346726) contains a 1,353 bp CDS and a 37 bp 3'- UTR including a TGA termination codon (nucleotides 1,354-1,356 bp). The duck DRD1 shares about 76-96 % nucleic acid identity and 82-98 % amino acid identity with their counterparts in other species. A phylogenetic tree based on amino acid sequences displays that duck DRD1 protein is closely related with those of chicken and zebra finch. The quantitative real-time PCR analysis indicates that the DRD1 mRNA is widely expressed in all examined tissues. Five single nucleotide polymorphisms (SNPs) (c.189A > T, c.507C > T, c.681C > T, c.765A > T, c.1044A > G) in the CDS of duck DRD1 gene were indentified, c.681C > T and c.765A > T were genotyped and analyzed in a two generations duck population by using of PCR-RFLP. Association analysis demonstrated that the c.681C > T genotypes were significantly associated with body weight at sexual maturity (when laying their first egg) (P < 0.01), egg production within 360 days (P < 0.05) and 420 days (P < 0.01); the c.765A > T genotypes were significantly associated with egg shape index and egg shell strength (P < 0.05). Those results suggest that the DRD1 gene may be a potential genetic marker to improve some reproductive traits in ducks.

Whole-Genome Sequencing for Optimized Patient Management

PubMed Central

Bainbridge, Matthew N.; Wiszniewski, Wojciech; Murdock, David R.; Friedman, Jennifer; Gonzaga-Jauregui, Claudia; Newsham, Irene; Reid, Jeffrey G.; Fink, John K.; Morgan, Margaret B.; Gingras, Marie-Claude; Muzny, Donna M.; Hoang, Linh D.; Yousaf, Shahed; Lupski, James R.; Gibbs, Richard A.

2012-01-01

Whole-genome sequencing of patient DNA can facilitate diagnosis of a disease, but its potential for guiding treatment has been under-realized. We interrogated the complete genome sequences of a 14-year-old fraternal twin pair diagnosed with dopa (3,4-dihydroxyphenylalanine)–responsive dystonia (DRD; Mendelian Inheritance in Man #128230). DRD is a genetically heterogeneous and clinically complex movement disorder that is usually treated with l-dopa, a precursor of the neurotransmitter dopamine. Whole-genome sequencing identified compound heterozygous mutations in the SPR gene encoding sepiapterin reductase. Disruption of SPR causes a decrease in tetrahydrobiopterin, a cofactor required for the hydroxylase enzymes that synthesize the neurotransmitters dopamine and serotonin. Supplementation of l-dopa therapy with 5-hydroxytryptophan, a serotonin precursor, resulted in clinical improvements in both twins. PMID:21677200

Ataxia telangiectasia presenting as dopa-responsive cervical dystonia

PubMed Central

Mohire, Mahavir D.; Schneider, Susanne A.; Stamelou, Maria; Wood, Nicholas W.; Bhatia, Kailash P.

2013-01-01

Objective: To identify the cause of cervical dopa-responsive dystonia (DRD) in a Muslim Indian family inherited in an apparently autosomal recessive fashion, as previously described in this journal. Methods: Previous testing for mutations in the genes known to cause DRD (GCH1, TH, and SPR) had been negative. Whole exome sequencing was performed on all 3 affected individuals for whom DNA was available to identify potentially pathogenic shared variants. Genotyping data obtained for all 3 affected individuals using the OmniExpress single nucleotide polymorphism chip (Illumina, San Diego, CA) were used to perform linkage analysis, autozygosity mapping, and copy number variation analysis. Sanger sequencing was used to confirm all variants. Results: After filtering of the variants, exome sequencing revealed 2 genes harboring potentially pathogenic compound heterozygous variants (ATM and LRRC16A). Of these, the variants in ATM segregated perfectly with the cervical DRD. Both mutations detected in ATM have been shown to be pathogenic, and α-fetoprotein, a marker of ataxia telangiectasia, was increased in all affected individuals. Conclusion: Biallelic mutations in ATM can cause DRD, and mutations in this gene should be considered in the differential diagnosis of unexplained DRD, particularly if the dystonia is cervical and if there is a recessive family history. ATM has previously been reported to cause isolated cervical dystonia, but never, to our knowledge, DRD. Individuals with dystonia related to ataxia telangiectasia may benefit from a trial of levodopa. PMID:23946315

Relations between three dopaminergic system genes, school attachment, and adolescent delinquency.

PubMed

Fine, Adam; Mahler, Alissa; Simmons, Cortney; Chen, Chuansheng; Moyzis, Robert; Cauffman, Elizabeth

2016-11-01

Both environmental factors and genetic variation, particularly in genes responsible for the dopaminergic system such as DRD4, DRD2, and DAT1 (SLC6A3), affect adolescent delinquency. The school context, despite its developmental importance, has been overlooked in gene-environment research. Using data from the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development (NICHD ECCYD), this study examined key interactions between school attachment and (a) each of the DRD4, DRD2, and DAT1 (SLC6A3) genotypes; and (b) a polygenic score. Results indicate that there is a main effect of school attachment, unlike genetic variation, on delinquency. Interestingly, there are important interactive effects of school attachment and dopaminergic genotypes on delinquency. Carriers of the DRD2-A1 allele were differentially affected by both positive and negative school environments, whereas DAT1-10R carriers fared the same as 9R homozygotes in poorer and moderate school environments, but fared disproportionately better in more positive environments. Contrary to expectations, youth without the DRD4-7R allele were particularly affected by the school environment. These findings contribute to the literature considering the roles of both context and genes in delinquency research, and inform our understanding of the individual-level traits that influence sensitivity to particular contexts. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Association study of DRD2 and MAOA genes with subtyped alcoholism comorbid with bipolar disorder in Han Chinese.

PubMed

Hu, Ming-Chuan; Lee, Sheng-Yu; Wang, Tzu-Yun; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chen, Shih-Heng; Chu, Chun-Hsien; Wang, Chen-Lin; Lee, I Hui; Yeh, Tzung Lieh; Yang, Yen Kuang; Lu, Ru-Band

2013-01-10

Several studies have hypothesized that genes involved in the dopamine system, including dopamine type-2 receptor (DRD2)-related TaqIA polymorphism and monoamine oxidase-A upstream variable number tandem repeat (uVNTR), may be associated with alcoholism. But their results were contradictory because of alcoholism's heterogeneity. Therefore, we examined whether the DRD2TaqIA and MAOA-uVNTR gene polymorphisms are susceptibility factors for alcoholism comorbid with bipolar disorder (ALC+BP) in Han Chinese in Taiwan. We recruited 101 Han Chinese men with comorbid alcoholism and bipolar disorder, and 328 healthy male controls from the community. Genotyping was done using PCR-RFLP. There were no significant differences in the genotypic frequencies of the DRD2TaqIA or the MAOA-uVNTR polymorphisms between the 2 groups. The MAOA-uVNTR 3-repeat had a significant protective effect on the ALC+BP (odds ratio=0.432, p=0.035) but not on the healthy controls. However, the interaction between the MAOA-uVNTR 3-repeat and DRD2 A1/A2 was a risk factor in the ALC+BP (odds ratio=3.451, p=0.018). We indicated the impact of the association between MAOA-uVNTR 3-repeat and DRD2 A1/A2 with ALC+BP. Copyright © 2012 Elsevier Inc. All rights reserved.

Lack of association between alcohol-dependence and D3 dopamine receptor gene in three independent samples

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gorwood, P.; Feingold, J.; Ades, J.

1995-12-18

Numerous studies on the involvement of dopamine receptors in the genetics of alcoholism focused on associations between a polymorphism of the D2 dopamine receptor (DRD2) gene and alcohol dependence. However, the results of these studies are conflicting. Another receptor, the D3 dopamine receptor (DRD3), may be of additional interest since it is specifically located in the limbic area, and in particular in the nucleus accumbens which plays a significant role in the reward process of addiction behavior. We thus tested the association in three independent samples of alcoholic patients, with different origins and various inclusion criteria. No difference in themore » DRD3 gene polymorphism emerged between controls and alcoholic patients, regardless of their origin, inclusion criteria, or presence or absence of the DRD2 TaqI A1-allele. Despite the fact that more information could have been considered and that association studies provide limited information, there is good evidence that this DRD3 polymorphism does not play a major role in the genetic component of alcoholism. 17 refs., 2 tabs.« less

DRD2/ANKK1 gene polymorphisms in forensic autopsies of methamphetamine intoxication fatalities.

PubMed

Matsusue, Aya; Ishikawa, Takaki; Ikeda, Tomoya; Tani, Naoto; Arima, Hisatomi; Waters, Brian; Hara, Kenji; Kashiwagi, Masayuki; Takayama, Mio; Ikematsu, Natsuki; Kubo, Shin-Ichi

2018-04-22

Dopamine D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) gene polymorphisms have been associated with responses to psychotropic drugs and addiction. We analyzed two DRD2/ANKK1 polymorphisms, Taq1A and -141C Ins/Del, in 37 fatal methamphetamine (MA) intoxication cases and 235 control cases in which MA and psychotropic drugs were not detected. The association among polymorphism, cause of death, and cerebrospinal fluid (CSF) dopamine concentration was evaluated. The Taq1A polymorphism distribution in the fatal MA intoxication cases differed from in the controls (P = 0.030) with a significantly high A1/A1 + A1/A2 genotype frequency. No significant associations were observed between -141C Ins/Del polymorphisms and MA intoxication cases or between DRD2/ANKK1 polymorphisms and CSF dopamine concentrations. Our findings suggest that the DRD2/ANKK1 Taq1A polymorphism is associated with susceptibility to fatal MA intoxication. Copyright © 2018 Elsevier B.V. All rights reserved.

Modulation by Cocaine of Dopamine Receptors through miRNA-133b in Zebrafish Embryos

PubMed Central

Barreto-Valer, Katherine; López-Bellido, Roger; Macho Sánchez-Simón, Fátima; Rodríguez, Raquel E.

2012-01-01

The use of cocaine during pregnancy can affect the mother and indirectly might alter the development of the embryo/foetus. Accordingly, in the present work our aim was to study in vivo (in zebrafish embryos) the effects of cocaine on the expression of dopamine receptors and on miR-133b. These embryos were exposed to cocaine hydrochloride (HCl) at 5 hours post-fertilization (hpf) and were then collected at 8, 16, 24, 48 and 72 hpf to study the expression of dopamine receptors, drd1, drd2a, drd2b and drd3, by quantitative real time PCR (qPCR) and in situ hybridization (ISH, only at 24 hpf). Our results indicate that cocaine alters the expression of the genes studied, depending on the stage of the developing embryo and the type of dopamine receptor. We found that cocaine reduced the expression of miR-133b at 24 and 48 hpf in the central nervous system (CNS) and at the periphery by qPCR and also that the spatial distribution of miR-133b was mainly seen in somites, a finding that suggests the involvement of miR-133b in the development of the skeletal muscle. In contrast, at the level of the CNS miR-133b had a weak and moderate expression at 24 and 48 hpf. We also analysed the interaction of miR-133b with the Pitx3 and Pitx3 target genes drd2a and drd2b, tyrosine hydroxylase (th) and dopamine transporter (dat) by microinjection of the Pitx3-3'UTR sequence. Microinjection of Pitx3-3'UTR affected the expression of pitx3, drd2a, drd2b, th and dat. In conclusion, in the present work we describe a possible mechanism to account for cocaine activity by controlling miR-133b transcription in zebrafish. Via miR-133b cocaine would modulate the expression of pitx3 and subsequently of dopamine receptors, dat and th. These results indicate that miRNAs can play an important role during embryogenesis and in drug addiction. PMID:23285158

Possible interaction between MAOA and DRD2 genes associated with antisocial alcoholism among Han Chinese men in Taiwan.

PubMed

Wang, Tso-Jen; Huang, San-Yuan; Lin, Wei-Wen; Lo, Hsin-Yi; Wu, Pei-Lin; Wang, Yu-Shan; Wu, Yi-Syuan; Ko, Huei-Chen; Shih, Jean-Chen; Lu, Ru-Band

2007-01-30

Both monoamine oxidase A (MAOA) and dopamine D(2) receptor (DRD2) genes have been considered as candidate genes for antisocial personality disorder with alcoholism (Antisocial ALC) [Parsian, A., 1999. Sequence analysis of exon 8 of MAO-A gene in alcoholics with antisocial personality and normal controls. Genomics. 45, 290-295.; Samochowiec, J., Lesch, K.P., Rottmann, M., Smolka, M., Syagailo, Y.V., Okladnova, O., Rommelspacher, H., Winterer, G., Schmidt, L.G., Sander, T., 1999. Association of a regulatory polymorphism in the promoter region of the monoamine oxidase A gene with antisocial alcoholism. Psychiatry. Res. 86, 67-72.; Schmidt, L.vG., Sander, T., Kuhn, S., Smolka, M., Rommelspacher, H., Samochowiec, J., Lesch, K.P., 2000. Different allele distribution of a regulatory MAO-A gene promotor polymorphism in antisocial and anxious-depressive alcoholics. J. Neural .Transm. 107, 681-689.]. However, the association between alcoholism and MAOA or DRD2 gene has not been universally accepted [Lee, J.F., Lu, R.B., Ko, H.C., Chang, F.M., Yin, S.J., Pakstis, A.J., Kidd, K.K., 1999. No association between DRD(2) locus and alcoholism after controlling the ADH and ALDH genotypes in Chinese Han population. Alcohol. Clin. Exp. Res. 23, 592-599.; Lu, R.B., Lin, W.W., Lee, J.F., Ko, H.C., Shih, J.C., 2003. Neither antisocial personality disorder nor antisocial alcoholism association with MAOA gene among Han Chinese males in Taiwan. Alcohol. Clin. Exp. Res. 27, 889-893.]. Since dopamine is metabolized to 3,4-dihydroxyphenyl-acetaldehyde (DOPAL) via monoamine oxidase (MAO) [Westerink, B.H., de Vries, J.B., 1985. On the origin of dopamine and its metabolite in predominantly noradrenergic innervated brain areas. Brain. Res. 330, 164-166.], the interaction between MAOA and DRD2 genes might be related to Antisocial ALC. The present study aimed to determine whether Antisocial ALC might be associated with the possible interactions of DRD2 gene with MAOA gene. Of the 231 Han Chinese subjects who were recruited for the study, 73 participants were diagnosed with Antisocial ALC and 158 subjects were diagnosed with antisocial personality disorder without alcoholism (Antisocial Non-ALC). The DRD2 TaqI A and MAOA-uVNTR (variable number of tandem repeat located upstream) polymorphisms were not found to be associated with Antisocial ALC. However, an association between DRD2 TaqI A polymorphisms and Antisocial ALC was shown only after stratification for the MAOA-uVNTR 4-repeat polymorphism. Additionally, after multiple logistic regressions, we found that, under stratification of MAOA-uVNTR 4-repeat polymorphism and in comparison with the DRD2 A1/A1 genotype as a reference group, the DRD2 A1/A2 genotype has a possible protective effect against alcoholism in individuals with antisocial personality disorder (ASPD). We concluded that the possible interactions between MAOA-uVNTR polymorphism and DRD2 TaqI A polymorphism might be related to Antisocial ALC among Han Chinese men in Taiwan.

Dopamine receptor gene d4 polymorphisms and early sexual onset: gender and environmental moderation in a sample of african-american youth.

PubMed

Kogan, Steven M; Lei, Man-Kit; Beach, Steven R H; Brody, Gene H; Windle, Michael; Lee, Sunbok; MacKillop, James; Chen, Yi-Fu

2014-08-01

Early sexual onset and its consequences disproportionately affect African-American youth, particularly male youth. The dopamine receptor D4 gene (DRD4) has been linked to sexual activity and other forms of appetitive behavior, particularly for male youth and in combination with environmental factors (gene × environment [G × E] effects). The differential susceptibility perspective suggests that DRD4 may exert this effect by amplifying the effects of both positive and negative environments. We hypothesized that DRD4 status would amplify the influence of both positive and negative neighborhood environments on early sexual onset among male, but not female, African-Americans. Hypotheses were tested with self-report, biospecimen, and census data from five prospective studies of male and female African-American youth in rural Georgia communities, N = 1,677. Early sexual onset was defined as intercourse before age 14. No significant G × E findings emerged for female youth. Male youth with a DRD4 long allele were more likely than those with two DRD4 short alleles to report early sexual onset in negative community environments and not to report early onset in positive community environments. Dopaminergic regulation of adolescent sexual behaviors may operate differently by gender. DRD4 operated as an environmental amplification rather than a vulnerability factor. Copyright © 2014 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

Ablation of D1 dopamine receptor-expressing cells generates mice with seizures, dystonia, hyperactivity, and impaired oral behavior

PubMed Central

Gantois, Ilse; Fang, Ke; Jiang, Luning; Babovic, Daniela; Lawrence, Andrew J.; Ferreri, Vincenzo; Teper, Yaroslav; Jupp, Bianca; Ziebell, Jenna; Morganti-Kossmann, Cristina M.; O'Brien, Terence J.; Nally, Rachel; Schütz, Günter; Waddington, John; Egan, Gary F.; Drago, John

2007-01-01

Huntington's disease is characterized by death of striatal projection neurons. We used a Cre/Lox transgenic approach to generate an animal model in which D1 dopamine receptor (Drd1a)+ cells are progressively ablated in the postnatal brain. Striatal Drd1a, substance P, and dynorphin expression is progressively lost, whereas D2 dopamine receptor (Drd2) and enkephalin expression is up-regulated. Magnetic resonance spectroscopic analysis demonstrated early elevation of the striatal choline/creatine ratio, a finding associated with extensive reactive striatal astrogliosis. Sequential MRI demonstrated a progressive reduction in striatal volume and secondary ventricular enlargement confirmed to be due to loss of striatal cells. Mutant mice had normal gait and rotarod performance but displayed hindlimb dystonia, locomotor hyperactivity, and handling-induced electrographically verified spontaneous seizures. Ethological assessment identified an increase in rearing and impairments in the oral behaviors of sifting and chewing. In line with the limbic seizure profile, cell loss, astrogliosis, microgliosis, and down-regulated dynorphin expression were seen in the hippocampal dentate gyrus. This study specifically implicates Drd1a+ cell loss with tail suspension hindlimb dystonia, hyperactivity, and abnormal oral function. The latter may relate to the speech and swallowing disturbances and the classic sign of tongue-protrusion motor impersistence observed in Huntington's disease. In addition, the findings of this study support the notion that Drd1a and Drd2 are segregated on striatal projection neurons. PMID:17360497

Delayed reward discounting and addictive behavior: a meta-analysis.

PubMed

MacKillop, James; Amlung, Michael T; Few, Lauren R; Ray, Lara A; Sweet, Lawrence H; Munafò, Marcus R

2011-08-01

Delayed reward discounting (DRD) is a behavioral economic index of impulsivity and numerous studies have examined DRD in relation to addictive behavior. To synthesize the findings across the literature, the current review is a meta-analysis of studies comparing DRD between criterion groups exhibiting addictive behavior and control groups. The meta-analysis sought to characterize the overall patterns of findings, systematic variability by sample and study type, and possible small study (publication) bias. Literature reviews identified 310 candidate articles from which 46 studies reporting 64 comparisons were identified (total N=56,013). From the total comparisons identified, a small magnitude effect was evident (d= .15; p< .00001) with very high heterogeneity of effect size. Based on systematic observed differences, large studies assessing DRD with a small number of self-report items were removed and an analysis of 57 comparisons (n=3,329) using equivalent methods and exhibiting acceptable heterogeneity revealed a medium magnitude effect (d= .58; p< .00001). Further analyses revealed significantly larger effect sizes for studies using clinical samples (d= .61) compared with studies using nonclinical samples (d=.45). Indices of small study bias among the various comparisons suggested varying levels of influence by unpublished findings, ranging from minimal to moderate. These results provide strong evidence of greater DRD in individuals exhibiting addictive behavior in general and particularly in individuals who meet criteria for an addictive disorder. Implications for the assessment of DRD and research priorities are discussed.

Delayed reward discounting and addictive behavior: a meta-analysis

PubMed Central

Amlung, Michael T.; Few, Lauren R.; Ray, Lara A.; Sweet, Lawrence H.; Munafò, Marcus R.

2011-01-01

Rationale Delayed reward discounting (DRD) is a behavioral economic index of impulsivity and numerous studies have examined DRD in relation to addictive behavior. To synthesize the findings across the literature, the current review is a meta-analysis of studies comparing DRD between criterion groups exhibiting addictive behavior and control groups. Objectives The meta-analysis sought to characterize the overall patterns of findings, systematic variability by sample and study type, and possible small study (publication) bias. Methods Literature reviews identified 310 candidate articles from which 46 studies reporting 64 comparisons were identified (total N=56,013). Results From the total comparisons identified, a small magnitude effect was evident (d=.15; p<.00001) with very high heterogeneity of effect size. Based on systematic observed differences, large studies assessing DRD with a small number of self-report items were removed and an analysis of 57 comparisons (n=3,329) using equivalent methods and exhibiting acceptable heterogeneity revealed a medium magnitude effect (d=.58; p<.00001). Further analyses revealed significantly larger effect sizes for studies using clinical samples (d=.61) compared with studies using nonclinical samples (d=.45). Indices of small study bias among the various comparisons suggested varying levels of influence by unpublished findings, ranging from minimal to moderate. Conclusions These results provide strong evidence of greater DRD in individuals exhibiting addictive behavior in general and particularly in individuals who meet criteria for an addictive disorder. Implications for the assessment of DRD and research priorities are discussed. PMID:21373791

Performance in the Wisconsin Card Sorting Test and the C957T polymorphism of the DRD2 gene in healthy volunteers.

PubMed

Rodriguez-Jimenez, R; Hoenicka, J; Jimenez-Arriero, M A; Ponce, G; Bagney, A; Aragues, M; Palomo, T

2006-01-01

Previous studies have associated a decreased striatal D2 dopamine receptor (DRD2) binding with impaired performance in cognitive tasks. In vivo studies have found a lower DRD2 binding associated with the CC genotype of the C957T single nucleotide polymorphism (SNP) of the DRD2 gene. The aim of this study was to investigate the relationship between executive functions and the C957T DRD2 SNP. We hypothesized that the CC genotype would be associated with a poorer executive functioning. Our sample consisted of 83 healthy volunteers (28 males and 55 females; mean age 25.2, SD 1.7 years). To assess executive functions, the Wisconsin Card Sorting Test was used, considering the variables perseverative errors, perseverative responses, and number of categories achieved. The genotype distribution was 13 CC, 41 CT, and 29 TT, satisfying Hardy-Weinberg equilibrium. Carriers of the CC genotype, compared with carriers of the CT/TT genotypes, achieved significantly fewer categories (5.00 vs. 5.81; p = 0.004), made a greater number of perseverative errors (13.46 vs. 8.39; p = 0.018), and had a greater number of perseverative responses (14.92 vs. 8.94; p = 0.014). Our results support the hypothesis that the C957T DRD2 SNP may influence cognitive performance through its repercussions on central dopaminergic function. 2006 S. Karger AG, Basel

Family-based association testing strongly implicates DRD2 as a risk gene for schizophrenia in Han Chinese from Taiwan

PubMed Central

Glatt, SJ; Faraone, SV; Lasky-Su, JA; Kanazawa, T; Hwu, H-G; Tsuang, MT

2009-01-01

The gene that codes for dopamine receptor D2 (DRD2 on chromosome 11q23) has long been a prime functional and positional candidate risk gene for schizophrenia. Collectively, prior case–control studies found a reliable effect of the Ser311Cys DRD2 polymorphism (rs1801028) on risk for schizophrenia, but few other polymorphisms in the gene had ever been evaluated and no adequately powered family-based association study has been performed to date. Our objective was to test 21 haplotype-tagging and all three known nonsynonymous single-nucleotide polymorphisms (SNPs) in DRD2 for association with schizophrenia in a family-based study of 2408 Han Chinese, including 1214 affected individuals from 616 families. We did not find a significant effect of rs1801028, but we did find significant evidence for association of schizophrenia with two multi-marker haplotypes spanning blocks of strong linkage disequilibrium (LD) and nine individual SNPs (Ps < 0.05). Importantly, two SNPs (rs1079727 and rs2283265) and both multi-marker haplotypes spanning entire LD blocks (including one that contained rs1801028) remained significant after correcting for multiple testing. These results further add to the body of data implicating DRD2 as a schizophrenia risk gene; however, a causal variant(s) in DRD2 remains to be elucidated by further fine mapping of the gene, with particular attention given to the area surrounding the third through fifth exons. PMID:18332877

Haplotype diversity and linkage disequilibrium at DRD2 locus--a study on four population groups of Andhra Pradesh, India.

PubMed

Saraswathy, Kallur Nava; Mukhopadhyay, Rupak; Shukla, Deepti; Kaur, Harpreet; Sachdeva, Mohinder Pal; Rao, A P; Saksena, Deepti; Kalla, Aloke Kumar

2009-02-01

Dopamine receptor D2 (DRD2) is expressed in the central nervous system and has a high affinity for many antipsychotic drugs. Besides several epidemiological investigations on association of DRD2 locus polymorphism(s) with neuropsychiatric problems and addictive behavior, a few polymorphisms in this locus have also been used to understand genomic diversity and population migratory histories globally. The present study attempts to understand the genomic diversity/affinity among four endogamous groups of Andhra Pradesh (India) against the backdrop of diversity studies from other parts of India and the rest of the world, with special reference to DRD2 locus. The four population groups from Adilabad District of Andhra Pradesh, namely, Brahmin (n=50), Nayakpod (n=49), Thoti (n=52), and Kolam (n=53), were included in the study. The DRD2 markers typed for the present study are three biallelic restriction fragments, that is, TaqI A (rs1800497), TaqI B (rs1079597), and TaqI D (rs1800498). Scoring of DRD2 haplotypes with respect to the three TaqI sites shows that five out of eight possible haplotypes are shared by the four populations. Ancestral haplotype B2D2A1 is most frequent among Thotis (0.359). The results of the present study indicate a differential gene flow into South India followed by certain important demographic events resulting in diversified peopling of India.

Epistatic interactions involving DRD2, DRD4, and COMT polymorphisms and risk of substance abuse in women with binge-purge eating disturbances.

PubMed

Steiger, Howard; Thaler, Lea; Gauvin, Lise; Joober, Ridha; Labbe, Aurelie; Israel, Mimi; Kucer, Audrey

2016-06-01

Substance abuse is common in individuals with bulimia-spectrum (binge-purge) eating disturbances, a co-occurrence that has been attributed to shared neurobiological substrates--notably alterations in dopaminergic activity. We examined the implications of variations of selected, dopamine-relevant polymorphisms (DRD2 Taq1A, DRD4 7R, and COMT) for risk of substance abuse in women with binge-purge eating syndromes. We genotyped 183 women (66.1% showing full-threshold BN and 33.9% showing sub-syndromic variants), and assessed lifetime presence of alcohol, cannabis, cocaine, and stimulant abuse or dependence using structured interviews. Tests for main and interaction effects of various allele combinations revealed that individuals who carried high function COMT and low-function DRD4 7R alleles (a combination expected to be associated with higher risk) did indeed show more lifetime substance abuse and, specifically, more cannabis abuse. Our findings suggest that a gene combination that, in theory, codes for low levels of dopaminergic neurotransmission coincides with sensitivity to substance abuse in a sample displaying binge-purge eating-disorder variants. Copyright © 2016 Elsevier Ltd. All rights reserved.

Ammonia Induces Autophagy through Dopamine Receptor D3 and MTOR

PubMed Central

Li, Zhiyuan; Ji, Xinmiao; Wang, Wenchao; Liu, Juanjuan; Liang, Xiaofei; Wu, Hong; Liu, Jing; Eggert, Ulrike S.; Liu, Qingsong

2016-01-01

Hyperammonemia is frequently seen in tumor microenvironments as well as in liver diseases where it can lead to severe brain damage or death. Ammonia induces autophagy, a mechanism that tumor cells may use to protect themselves from external stresses. However, how cells sense ammonia has been unclear. Here we show that culture medium alone containing Glutamine can generate milimolar of ammonia at 37 degrees in the absence of cells. In addition, we reveal that ammonia acts through the G protein-coupled receptor DRD3 (Dopamine receptor D3) to induce autophagy. At the same time, ammonia induces DRD3 degradation, which involves PIK3C3/VPS34-dependent pathways. Ammonia inhibits MTOR (mechanistic target of Rapamycin) activity and localization in cells, which is mediated by DRD3. Therefore, ammonia has dual roles in autophagy: one to induce autophagy through DRD3 and MTOR, the other to increase autophagosomal pH to inhibit autophagic flux. Our study not only adds a new sensing and output pathway for DRD3 that bridges ammonia sensing and autophagy induction, but also provides potential mechanisms for the clinical consequences of hyperammonemia in brain damage, neurodegenerative diseases and tumors. PMID:27077655

Epigenetic regulation of the DRD4 gene and dimensions of attention-deficit/hyperactivity disorder in children.

PubMed

Dadds, Mark R; Schollar-Root, Olivia; Lenroot, Rhoshel; Moul, Caroline; Hawes, David J

2016-10-01

Recent evidence suggests that epigenetic regulation of the DRD4 gene may characterise specific aspects of ADHD symptomology. We tested associations between ADHD symptoms and epigenetic changes to the DRD4 gene in DNA extracted from blood and saliva in N = 330 children referred for a variety of behavioural and emotional problems. ADHD was indexed using DSM diagnoses as well as mother, father, and teacher reports. Methylation levels were assayed for the island of 18 CpG sites in the DRD4 receptor gene. A nearby SNP, rs3758653, was also genotyped as it has previously been shown to influence methylation levels. There was high consistency of methylation levels across CpG sites and tissue sources, and higher methylation levels were associated with the major allele of SNP rs3758653. Higher methylation levels were associated with more severe ADHD independent of SNP status, tissue source, ethnicity, environmental adversity, and comorbid conduct problems. The association applied specifically to the cognitive/attentional, rather than hyperactivity problems that characterise ADHD. The results indicate that epigenetic regulation of the DRD4 gene in the form of increased methylation is associated with the cognitive/attentional deficits in ADHD.

Linking Gene, Brain, and Behavior

PubMed Central

Schmidt, Louis A.; Fox, Nathan A.; Perez-Edgar, Koraly; Hamer, Dean H.

2009-01-01

Gene-environment interactions involving exogenous environmental factors are known to shape behavior and personality development. Although gene-environment interactions involving endogenous environmental factors are hypothesized to play an equally important role, this conceptual approach has not been empirically applied in the study of early-developing temperament in humans. Here we report evidence for a gene-endoenvironment (i.e., resting frontal brain electroencephalogram, EEG, asymmetry) interaction in predicting child temperament. The DRD4 gene (long allele vs. short allele) moderated the relation between resting frontal EEG asymmetry (left vs. right) at 9 months and temperament at 48 months. Children who exhibited left frontal EEG asymmetry at 9 months and who possessed the DRD4 long allele were significantly more soothable at 48 months than other children. Among children with right frontal EEG asymmetry at 9 months, those with the DRD4 long allele had significantly more difficulties focusing and sustaining attention at 48 months than those with the DRD4 short allele. Resting frontal EEG asymmetry did not influence temperament in the absence of the DRD4 long allele. We discuss how the interaction of genetic and endoenvironment factors may confer risk and protection for different behavioral styles in children. PMID:19493320

Joint Analysis of the DRD5 Marker Concludes Association with Attention-Deficit/Hyperactivity Disorder Confined to the Predominantly Inattentive and Combined Subtypes

PubMed Central

Lowe, Naomi; Kirley, Aiveen; Hawi, Ziarih; Sham, Pak; Wickham, Harvey; Kratochvil, Christopher J.; Smith, Shelley D.; Lee, Saretta Y.; Levy, Florence; Kent, Lindsey; Middle, Fiona; Rohde, Luis A.; Roman, Tatiana; Tahir, Eda; Yazgan, Yanke; Asherson, Philip; Mill, Jonathan; Thapar, Anita; Payton, Antony; Todd, Richard D.; Stephens, Timothy; Ebstein, Richard P.; Manor, Iris; Barr, Cathy L.; Wigg, Karen G.; Sinke, Richard J.; Buitelaar, Jan K.; Smalley, Susan L.; Nelson, Stan F.; Biederman, Joseph; Faraone, Stephen V.; Gill, Michael

2004-01-01

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable, heterogeneous disorder of early onset, consisting of a triad of symptoms: inattention, hyperactivity, and impulsivity. The disorder has a significant genetic component, and theories of etiology include abnormalities in the dopaminergic system, with DRD4, DAT1, SNAP25, and DRD5 being implicated as major susceptibility genes. An initial report of association between ADHD and the common 148-bp allele of a microsatellite marker located 18.5 kb from the DRD5 gene has been followed by several studies showing nonsignificant trends toward association with the same allele. To establish the postulated association of the (CA)n repeat with ADHD, we collected genotypic information from 14 independent samples of probands and their parents, analyzed them individually and, in the absence of heterogeneity, analyzed them as a joint sample. The joint analysis showed association with the DRD5 locus (P=.00005; odds ratio 1.24; 95% confidence interval 1.12–1.38). This association appears to be confined to the predominantly inattentive and combined clinical subtypes. PMID:14732906

Season of Birth and Dopamine Receptor Gene Associations with Impulsivity, Sensation Seeking and Reproductive Behaviors

PubMed Central

Eisenberg, Dan T. A.; Campbell, Benjamin; MacKillop, James; Lum, J. Koji; Wilson, David S.

2007-01-01

Background Season of birth (SOB) has been associated with many physiological and psychological traits including novelty seeking and sensation seeking. Similar traits have been associated with genetic polymorphisms in the dopamine system. SOB and dopamine receptor genetic polymorphisms may independently and interactively influence similar behaviors through their common effects on the dopaminergic system. Methodology/Principal Findings Based on a sample of 195 subjects, we examined whether SOB was associated with impulsivity, sensation seeking and reproductive behaviors. Additionally we examined potential interactions of dopamine receptor genes with SOB for the same set of traits. Phenotypes were evaluated using the Sociosexual Orientation Inventory, the Barratt Impulsivity Scale, the Eysenck Impulsivity Questionnaire, the Sensation Seeking Scale, and the Delay Discounting Task. Subjects were also asked about their age at first sex as well as their desired age at the birth of their first child. The dopamine gene polymorphisms examined were Dopamine Receptor D2 (DRD2) TaqI A and D4 (DRD4) 48 bp VNTR. Primary analyses included factorial gender×SOB ANOVAs or binary logistic regression models for each dependent trait. Secondary analysis extended the factorial models by also including DRD2 and DRD4 genotypes as independent variables. Winter-born males were more sensation seeking than non-winter born males. In factorial models including both genotype and season of birth as variables, two previously unobserved effects were discovered: (1) a SOB×DRD4 interaction effect on venturesomeness and (2) a DRD2×DRD4 interaction effect on sensation seeking. Conclusion These results are consistent with past findings that SOB is related to sensation seeking. Additionally, these results provide tentative support for the hypothesis that SOB modifies the behavioral expression of dopaminergic genetic polymorphism. These findings suggest that SOB should be included in future studies of risky behaviors and behavioral genetic studies of the dopamine system. PMID:18030347

Diabetes-Related Distress Assessment among Type 2 Diabetes Patients.

PubMed

Aljuaid, Majed O; Almutairi, Abdulmajeed M; Assiri, Mohammed A; Almalki, Dhifallah M; Alswat, Khaled

2018-01-01

Diabetes is one of the most common chronic diseases; it is a debilitating and hard to live with. Diabetes-related distress (DRD) refers to the emotional and behavioral changes caused by diabetes. Our study aims to assess the prevalence of DRD among type 2 diabetes (T2D) patients using Diabetes Distress Scale-17 items (DDS-17) and its relation to complications and treatment modalities. A cross-sectional study of adult T2D patients with follow-up visits at the Diabetes and Endocrinology Center in Taif, Saudi Arabia, between January and July 2017. We excluded patients with other forms of diabetes, untreated hypothyroidism, and psychiatric illness. The total score of DDS-17 was calculated by summing the 17 items' results and then dividing the total by 17. If the total score was >2, then it was considered as clinically significant results (moderate distress), but if it is ≥3, then it is classified as a high distress. A total of 509 T2D patients with a mean age of 58 ± 14 years were included. The majority of participants were male, married, not college educated, and reported a sedentary lifestyle. We found 25% of the screened T2D patients have moderate to high DRD. Regarding the DRD components, emotional distress was the most prevalent followed by physician-related distress. HabA1c was significantly higher in those with high combined distress and high emotional distress compared to those with mild/moderate distress ( p = 0.015 and 0.030, resp.). Our study shows that DRD is a medically relevant issue that clinicians need to address. Despite observing a low prevalence of DRD compared to other studies, we found significant correlations between DRD scores and HabA1c, triglyceride levels, BMI, T2D duration, and interval between visits.

Interaction Between Functional Genetic Variation of DRD2 and Cannabis Use on Risk of Psychosis

PubMed Central

Colizzi, Marco; Iyegbe, Conrad; Powell, John; Ursini, Gianluca; Porcelli, Annamaria; Bonvino, Aurora; Taurisano, Paolo; Romano, Raffaella; Masellis, Rita; Blasi, Giuseppe; Morgan, Craig; Aitchison, Katherine; Mondelli, Valeria; Luzi, Sonija; Kolliakou, Anna; David, Anthony; Murray, Robin M.; Bertolino, Alessandro; Forti, Marta Di

2015-01-01

Both cannabis use and the dopamine receptor (DRD2) gene have been associated with schizophrenia, psychosis-like experiences, and cognition. However, there are no published data investigating whether genetically determined variation in DRD2 dopaminergic signaling might play a role in individual susceptibility to cannabis-associated psychosis. We genotyped (1) a case-control study of 272 patients with their first episode of psychosis and 234 controls, and also from (2) a sample of 252 healthy subjects, for functional variation in DRD2, rs1076560. Data on history of cannabis use were collected on all the studied subjects by administering the Cannabis Experience Questionnaire. In the healthy subjects’ sample, we also collected data on schizotypy and cognitive performance using the Schizotypal Personality Questionnaire and the N-back working memory task. In the case-control study, we found a significant interaction between the rs1076560 DRD2 genotype and cannabis use in influencing the likelihood of a psychotic disorder. Among cannabis users, carriers of the DRD2, rs1076560, T allele showed a 3-fold increased probability to suffer a psychotic disorder compared with GG carriers (OR = 3.07; 95% confidence interval [CI]: 1.22–7.63). Among daily users, T carrying subjects showed a 5-fold increase in the odds of psychosis compared to GG carriers (OR = 4.82; 95% CI: 1.39–16.71). Among the healthy subjects, T carrying cannabis users had increased schizotypy compared with T carrying cannabis-naïve subjects, GG cannabis users, and GG cannabis-naïve subjects (all P ≤ .025). T carrying cannabis users had reduced working memory accuracy compared with the other groups (all P ≤ .008). Thus, variation of the DRD2, rs1076560, genotype may modulate the psychosis-inducing effect of cannabis use. PMID:25829376

Interaction Between Functional Genetic Variation of DRD2 and Cannabis Use on Risk of Psychosis.

PubMed

Colizzi, Marco; Iyegbe, Conrad; Powell, John; Ursini, Gianluca; Porcelli, Annamaria; Bonvino, Aurora; Taurisano, Paolo; Romano, Raffaella; Masellis, Rita; Blasi, Giuseppe; Morgan, Craig; Aitchison, Katherine; Mondelli, Valeria; Luzi, Sonija; Kolliakou, Anna; David, Anthony; Murray, Robin M; Bertolino, Alessandro; Di Forti, Marta

2015-09-01

Both cannabis use and the dopamine receptor (DRD2) gene have been associated with schizophrenia, psychosis-like experiences, and cognition. However, there are no published data investigating whether genetically determined variation in DRD2 dopaminergic signaling might play a role in individual susceptibility to cannabis-associated psychosis. We genotyped (1) a case-control study of 272 patients with their first episode of psychosis and 234 controls, and also from (2) a sample of 252 healthy subjects, for functional variation in DRD2, rs1076560. Data on history of cannabis use were collected on all the studied subjects by administering the Cannabis Experience Questionnaire. In the healthy subjects' sample, we also collected data on schizotypy and cognitive performance using the Schizotypal Personality Questionnaire and the N-back working memory task. In the case-control study, we found a significant interaction between the rs1076560 DRD2 genotype and cannabis use in influencing the likelihood of a psychotic disorder. Among cannabis users, carriers of the DRD2, rs1076560, T allele showed a 3-fold increased probability to suffer a psychotic disorder compared with GG carriers (OR = 3.07; 95% confidence interval [CI]: 1.22-7.63). Among daily users, T carrying subjects showed a 5-fold increase in the odds of psychosis compared to GG carriers (OR = 4.82; 95% CI: 1.39-16.71). Among the healthy subjects, T carrying cannabis users had increased schizotypy compared with T carrying cannabis-naïve subjects, GG cannabis users, and GG cannabis-naïve subjects (all P ≤ .025). T carrying cannabis users had reduced working memory accuracy compared with the other groups (all P ≤ .008). Thus, variation of the DRD2, rs1076560, genotype may modulate the psychosis-inducing effect of cannabis use. © The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

GCH1 mutations are common in Serbian patients with dystonia-parkinsonism: Challenging previously reported prevalence rates of DOPA-responsive dystonia.

PubMed

Dobričić, Valerija; Tomić, Aleksandra; Branković, Vesna; Kresojević, Nikola; Janković, Milena; Westenberger, Ana; Rašić, Vedrana Milić; Klein, Christine; Novaković, Ivana; Svetel, Marina; Kostić, Vladimir S

2017-12-01

GTP cyclohydrolase 1-deficient DOPA-responsive dystonia, caused by autosomal dominant mutation in the gene coding for GTP cyclohydrolase 1, is a rare disorder with a reported prevalence of 0.5 per million. A correct diagnosis of DRD is crucial, given that this is an exquisitely treatable neurogenetic disorder. Although genetic testing is now widely available, we hypothesize that DRD is still underdiagnosed and its prevalence underestimated. Molecular genetic analysis of the GCH1 gene was performed in a representative cohort of 47 Serbian patients with clinical features of DRD and in their 16 available relatives. The DRD prevalence rate in Serbia was estimated based on population size, catchment area, and the centralized Serbian referral system for rare diseases. We identified 9 different GCH1 mutations in 23 individuals from 11 families, 5 of which are novel. Patients displayed a broad range of clinical phenotypes. The estimated prevalence of GCH1-related DOPA-responsive dystonia in Serbia was 2.96 per million individuals and there was no evidence for a common founder. Our data expand the genotypic spectrum of GCH1 and confirm the broad phenotypic spectrum of DRD in the Serbian population. The number of detected mutation carriers in this sample implies that the frequency of DRD in the Serbian population is considerably higher than expected based on published prevalence rates, suggesting that the prevalence of this treatable disease should be revisited also in other populations. Copyright © 2017 Elsevier Ltd. All rights reserved.

The dopamine-related polymorphisms BDNF, COMT, DRD2, DRD3, and DRD4 are not linked with changes in CSF dopamine levels and frequency of HIV infection.

PubMed

Horn, Anne; Scheller, C; du Plessis, S; Burger, R; Arendt, G; Joska, J; Sopper, S; Maschke, C M; Obermann, M; Husstedt, I W; Hain, J; Riederer, P; Koutsilieri, E

2017-04-01

We showed previously that higher levels in CSF dopamine in HIV patients are associated with the presence of the dopamine transporter (DAT) 10/10-repeat allele which was also detected more frequently in HIV-infected individuals compared to uninfected subjects. In the current study, we investigated further whether other genetic dopamine (DA)-related polymorphisms may be related with changes in CSF DA levels and frequency of HIV infection in HIV-infected subjects. Specifically, we studied genetic polymorphisms of brain-derived neurotrophic factor, catechol-O-methyltransferase, and dopamine receptors DRD2, DRD3, and DRD4 genetic polymorphisms in uninfected and HIV-infected people in two different ethnical groups, a German cohort (Caucasian, 72 individuals with HIV infection and 22 individuals without HIV infection) and a South African cohort (Xhosan, 54 individuals with HIV infection and 19 individuals without HIV infection). We correlated the polymorphisms with CSF DA levels, HIV dementia score, CD4 + T cell counts, and HIV viral load. None of the investigated DA-related polymorphisms was associated with altered CSF DA levels, CD4 + T cell count, viral load, and HIV dementia score. The respective allele frequencies were equally distributed between HIV-infected patients and controls. Our findings do not show any influence of the studied genetic polymorphisms on CSF DA levels and HIV infection. This is in contrast to what we found previously for the DAT 3'UTR VNTR and highlights the specific role of the DAT VNTR in HIV infection and disease.

Are infants differentially sensitive to parenting? Early maternal care, DRD4 genotype and externalizing behavior during adolescence.

PubMed

Nikitopoulos, Jörg; Zohsel, Katrin; Blomeyer, Dorothea; Buchmann, Arlette F; Schmid, Brigitte; Jennen-Steinmetz, Christine; Becker, Katja; Schmidt, Martin H; Esser, Günter; Brandeis, Daniel; Banaschewski, Tobias; Laucht, Manfred

2014-12-01

Insensitive and unresponsive caregiving during infancy has been linked to externalizing behavior problems during childhood and adolescence. The 7-repeat (7r) allele of the dopamine D4 receptor (DRD4) gene has meta-analytically been associated with a heightened susceptibility to adverse as well as supportive environments. In the present study, we examined long-term effects of early maternal care, DRD4 genotype and the interaction thereof on externalizing and internalizing psychopathology during adolescence. As part of an ongoing epidemiological cohort study, early maternal care was assessed at child's age 3 months during a nursing and playing situation. In a sample of 296 offspring, externalizing and internalizing symptoms were assessed using a psychiatric interview conducted at age 15 years. Parents additionally filled out a questionnaire on their children's psychopathic behaviors. Results indicated that adolescents with the DRD4 7r allele who experienced less responsive and stimulating early maternal care exhibited more symptoms of ADHD and CD/ODD as well as higher levels of psychopathic behavior. In accordance with the hypothesis of differential susceptibility, 7r allele carriers showed fewer ADHD symptoms and lower levels of psychopathic behavior when exposed to especially beneficial early caregiving. In contrast, individuals without the DRD4 7r allele proved to be insensitive to the effects of early maternal care. This study replicates earlier findings with regard to an interaction between DRD4 genotype and early caregiving on externalizing behavior problems in preschoolers. It is the first one to imply continuity of this effect until adolescence. Copyright © 2014 Elsevier Ltd. All rights reserved.

Post-TBI cognitive performance is moderated by variation within ANKK1 and DRD2 genes

PubMed Central

Failla, Michelle D.; Myrga, John M.; Ricker, Joseph H.; Dixon, C. Edward; Conley, Yvette P.; Wagner, Amy K.

2014-01-01

Objective As dopamine neurotransmission impacts cognition, we hypothesized variants in the linked dopamine D2 receptor (DRD2) and ankyrin repeat and kinase domain (ANKK1) genes might account for some individual variability in cognitive recovery post-TBI. Participants Prospective cohort of 108 survivors of severe TBI, recruited consecutively from a level 1 trauma center. Design We examined relationships between DRD2 genetic variation and functional recovery at 6 and 12 months post-TBI. Main Measures Cognitive performance was evaluated using 8 neuropsychological tests targeting different cognitive domains. An overall cognitive composite was developed based on normative data. We also assessed functional cognition, depression status, and global outcome. Subjects were genotyped for 6 DRD2 tagging single nucleotide polymorphisms and Taq1A within ANKK1. Results ANKK1 Taq1A heterozygotes performed better than homozygotes across several cognitive domains at both time-points post-injury. When adjusting for age, GCS, and education, the Taq1A (ANKK1) and rs6279 (DRD2) variants were associated with overall composite scores at 6 months post-TBI (p=0.0468, 0.0430, respectively). At 12 months, only Taq1A remained a significant genetic predictor of cognition (p=0.0128). Following multiple comparisons correction, there were no significant associations between examined genetic variants and functional cognition, depression status, and global outcome. Conclusion These data suggest genetic variation within DRD2 influences cognitive recovery post-TBI. Understanding genetic influences on dopaminergic systems post-TBI may impact current treatment paradigms. PMID:25931179

Season of birth, the dopamine D4 receptor gene and emotional eating in males and females. Evidence of a genetic plasticity factor?

PubMed

van Strien, Tatjana; Levitan, Robert D; Engels, Rutger C M E; Homberg, Judith R

2015-07-01

Emotional eating has a female preponderance and an understanding of possible genetic and environmental underpinnings is still in the early stages. The current study focuses on the possible role of the dopamine D4 receptor (DRD4) 'plasticity' gene in emotional eating and the possible moderator effects of sex and season of birth therein. We tested this in two samples (n = 93 and n = 586) of male and female Caucasian adults by genotyping DRD4 and assessing self-reported emotional eating. Participants were defined as high risk carriers if they had at least one long (7-repeat) allele, which confers hypo-function to DRD4. We also ran analyses that grouped 2- and 7-repeat carriers together. In the first sample there only was a moderator effect of sex. In the second sample there also was a 3 way interaction between season of birth, sex and genotype. In line with the idea that the Drd4 gene functions as a plasticity gene that affects the sensitivity to environmental influences, the moderator effect of sex was only found for the participants born in fall. Only in females the hypo-functional variants of DRD4 were associated with significantly higher degrees of emotional eating. Furthermore, the sex × genotype effects were somewhat stronger when the 2-repeat allele was grouped together with the 7-repeat allele. Our data suggest that DRD4 hypo-functional genetic variants are associated with emotional eating, only in females. Copyright © 2015 Elsevier Ltd. All rights reserved.

Dopamine DRD2/Cys311 is not associated with chronic schizophrenia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Crawford, F.; Hoyne, J.; Cai, Xingang

A mutation in the DRD2 receptor gene has been reported in association with schizophrenia in Japanese and Caucasian populations. The variation, Ser to Cys at codon 311, occurs in the third intracellular loop of the receptor and is therefore putatively functional. We report the results of screening US Caucasian schizophrenic and nonschizophrenic populations. We detected the occurrence of the DRD2 Cys311 variant in both schizophrenics and controls. Our data demonstrates no significant difference between the frequency of Cys311 in Caucasian schizophrenic and non-schizophrenic populations, indicating no association with schizophrenia. 8 refs., 1 fig., 1 tab.

The role of impulsivity traits and delayed reward discounting in dysregulated eating and drinking among heavy drinkers

PubMed Central

Stojek, Monika M.; Fischer, Sarah; Murphy, Cara M.; MacKillop, James

2016-01-01

Impulsivity is a multifaceted construct that has been linked to dysregulated eating and problematic alcohol use. The UPPS model identifies five personality-based impulsivity traits that have unique predictive utility: Negative Urgency, Perseverance, Premeditation, Sensation Seeking, and Positive Urgency. Delayed reward discounting (DRD) is an index of impulsive decision making characterized by preference for smaller immediate gains at the cost of larger delayed gains. In the current study, we sought to refine the influence of impulsive personality traits and DRD on disordered eating patterns and problematic drinking. One hundred and eight treatment-seeking heavy drinkers were assessed for UPPS impulsivity traits, DRD, disordered eating, alcohol use, and demographic information. With regard to disordered eating patterns, DRD predicted higher levels of Dietary Restraint and Weight and Shape Concerns. Negative Urgency predicted binge eating and Weight and Shape Concerns. Positive Urgency predicted Eating Concerns. Female sex predicted Eating, Weight, and Shape Concerns. When considering problematic alcohol use, only Negative Urgency and Sensation Seeking were predictive. This is the first study to examine both personality-based impulsivity and DRD in relation to pathological eating and drinking behavior. The results suggest the importance of disentangling the contributions of various impulsivity constructs on dysregulated eating. PMID:24816318

Gender-specific expression of the DRD4 gene on adolescent delinquency, anger and thrill seeking

PubMed Central

Chen, Chuansheng; Greenberger, Ellen; Ogunseitan, Oladele; Ding, Yuan-Chun

2011-01-01

The present study investigated gender differences in the associations between the DRD4 variable number tandem repeat (VNTR) polymorphism and adolescent delinquency, short temper and thrill seeking. We also explored whether the gender-specific expression of the DRD4 can be explained by gender differences in the exposure to psychosocial risks, such as poor parent–child relationship. Participants were 263 14- to 17-year olds (50% males) living in Russia. DNA was extracted from saliva samples and the VNTR DRD4 polymorphisms were genotyped using polymerase chain reaction. Participants reported on the extent of their delinquent behaviour, short temper, thrill seeking and exposure to psychosocial risk (i.e. poor parental monitoring of adolescent behaviour, exposure to violence and peer delinquency). Compared to individuals with the 4/4 genotype, males, but not females, with the 7-repeat allele (7R) had significantly higher delinquency, short temper and thrill seeking. This interaction effect, however, was completely explained by males’ higher exposure to psychosocial risk factors. When parental monitoring of youths’ activities and youth exposure to violence were included in the model, the 7R × gender interaction was no longer significant. Thus, social context plays an important role in explaining gender-specific phenotypic expression of the DRD4 gene. PMID:20203140

The role of impulsivity traits and delayed reward discounting in dysregulated eating and drinking among heavy drinkers.

PubMed

Stojek, Monika M; Fischer, Sarah; Murphy, Cara M; MacKillop, James

2014-09-01

Impulsivity is a multifaceted construct that has been linked to dysregulated eating and problematic alcohol use. The UPPS model identifies five personality-based impulsivity traits that have unique predictive utility: Negative Urgency, Perseverance, Premeditation, Sensation Seeking, and Positive Urgency. Delayed reward discounting (DRD) is an index of impulsive decision making characterized by preference for smaller immediate gains at the cost of larger delayed gains. In the current study, we sought to refine the influence of impulsive personality traits and DRD on disordered eating patterns and problematic drinking. One hundred and eight treatment-seeking heavy drinkers were assessed for UPPS impulsivity traits, DRD, disordered eating, alcohol use, and demographic information. With regard to disordered eating patterns, DRD predicted higher levels of Dietary Restraint and Weight and Shape Concerns. Negative Urgency predicted binge eating and Weight and Shape Concerns. Positive Urgency predicted Eating Concerns. Female sex predicted Eating, Weight, and Shape Concerns. When considering problematic alcohol use, only Negative Urgency and Sensation Seeking were predictive. This is the first study to examine both personality-based impulsivity and DRD in relation to pathological eating and drinking behavior. The results suggest the importance of disentangling the contributions of various impulsivity constructs on dysregulated eating. Copyright © 2014. Published by Elsevier Ltd.

The polymorphism of dopamine receptor D4 (DRD4) and dopamine transporter (DAT) genes in the men with antisocial behaviour and mixed martial arts fighters.

PubMed

Cherepkova, Elena V; Maksimov, Vladimir N; Kushnarev, Alexandr P; Shakhmatov, Igor I; Aftanas, Lyubomir I

2017-09-12

Variable-number tandem repeat (VNTR) polymorphisms of DRD4 and DAT genes were studied in the Russian and Chechen men convicted of crimes, and two control groups comprised of the MMA fighters and a sample of general population. A group of MMA fighters included only the subjects without history of antisocial behaviour. DNA was isolated by phenol-chloroform extraction from the blood. Genotyping VNTR polymorphisms of the DRD4 and DAT genes were performed by PCR on published methods. Among those convicted of felonies and most grave crimes, carriers of DRD4 long alleles are found more frequently, similarly to the cohort of MMA fighters (lacking criminal record in both paternal lines). The 9/9 DAT genotype carriers are more frequently encountered among the habitual offenders. A frequency of the combination of the DRD4 genotype 4/7 and DAT genotype 10/10 is clearly higher among the convicts of violent crimes and the MMA fighters. One can speculate the presence of a 'controlled aggression' without a predisposition to pathological violence in the MMA fighters. Our study supports the hypothesis of genetic predisposition to different variants of extreme behaviour mediated by genetic determinants involved in the functioning of neuromediator systems including those controlling dopamine pathways.

Striatal dopamine D2/3 receptor regulation by stress inoculation in squirrel monkeys.

PubMed

Lee, Alex G; Nechvatal, Jordan M; Shen, Bin; Buckmaster, Christine L; Levy, Michael J; Chin, Frederick T; Schatzberg, Alan F; Lyons, David M

2016-06-01

Intermittent mildly stressful situations provide opportunities to learn, practice, and improve coping in a process called stress inoculation. Stress inoculation also enhances cognitive control and response inhibition of impulsive motivated behavior. Cognitive control and motivation have been linked to striatal dopamine D2 and/or D3 receptors (DRD2/3) in rodents, monkeys, and humans. Here, we study squirrel monkeys randomized early in life to stress inoculation with or without maternal companionship and a no-stress control treatment condition. Striatal DRD2/3 availability in adulthood was measured in vivo by [ 11 C]raclopride binding using positron emission tomography (PET). DRD2/3 availability was greater in caudate and putamen compared to ventral striatum as reported in PET studies of humans and other non-human primates. DRD2/3 availability in ventral striatum was also consistently greater in stress inoculated squirrel monkeys compared to no-stress controls. Squirrel monkeys exposed to stress inoculation in the presence of their mother did not differ from squirrel monkeys exposed to stress inoculation without maternal companionship. Similar effects in different social contexts extend the generality of our findings and together suggest that stress inoculation increases striatal DRD2/3 availability as a correlate of cognitive control in squirrel monkeys.

Dopaminergic genetic variation moderates the effect of nicotine on cigarette reward.

PubMed

Harrell, Paul T; Lin, Hui-Yi; Park, Jong Y; Blank, Melissa D; Drobes, David J; Evans, David E

2016-01-01

Cigarette smoking is influenced by nicotine’s effects on dopaminergic activity in the mesocorticolimbic pathway. This activity appears to be moderated by genetic variation, specifically a variable number tandem repeat (VNTR) polymorphism in the third exon of the dopamine receptor gene (DRD4). We examined whether this polymorphism along with three DRD4 single-nucleotide polymorphisms (SNPs: rs936460, rs936461, and rs12280580) moderate the influence of nicotine on subjective responses to cigarettes. White, non-Hispanic smokers (n = 96, cigarettes/day ≥15) attended two double-blind, counterbalanced experimental sessions, each preceded by overnight smoking abstinence. Participants smoked four nicotine (8.9 mg) or placebo (1.0 mg) cigarettes per session, with each cigarette followed by completion of the modified Cigarette Evaluation Questionnaire (mCEQ). We examined the mCEQ composite score via 2 × 2 × 4 ANOVAs with genotype (major homozygotes versus minor carriers) as the between-subject factor and nicotine content and smoking bout as within-subject factors. Although DRD4 VNTR variation did not moderate overall nicotine response, there was a moderation of nicotine response over successive cigarettes. Smokers with fewer than seven repeats for the DRD4 VNTR reported markedly reduced craving, increased satisfaction, and a greater calming effect in response to earlier smoked nicotine cigarettes, whereas those with seven or more repeats did not. In addition, minor carriers for all three DRD4 SNPs displayed blunted overall response to nicotine. These findings provide support for DRD4 variation as an informative predictor of subjective responses to nicotine. We discuss how these data may lead to improved tailoring of smoking cessation pharmacotherapies.

DRD2/CHRNA5 Interaction on Prefrontal Biology and Physiology during Working Memory

PubMed Central

Fazio, Leonardo; D'Ambrosio, Enrico; Gelao, Barbara; Tomasicchio, Aldo; Selvaggi, Pierluigi; Taurisano, Paolo; Quarto, Tiziana; Masellis, Rita; Rampino, Antonio; Caforio, Grazia; Popolizio, Teresa; Blasi, Giuseppe; Sadee, Wolfgang; Bertolino, Alessandro

2014-01-01

Background Prefrontal behavior and activity in humans are heritable. Studies in animals demonstrate an interaction between dopamine D2 receptors and nicotinic acetylcholine receptors on prefrontal behavior but evidence in humans is weak. Therefore, we hypothesize that genetic variation regulating dopamine D2 and nicotinic acetylcholine receptor signaling impact prefrontal cortex activity and related cognition. To test this hypothesis in humans, we explored the interaction between functional genetic variants in the D2 receptor gene (DRD2, rs1076560) and in the nicotinic receptor α5 gene (CHRNA5, rs16969968) on both dorsolateral prefrontal cortex mediated behavior and physiology during working memory and on prefrontal gray matter volume. Methods A large sample of healthy subjects was compared for genotypic differences for DRD2 rs1076560 (G>T) and CHNRA5 rs16969968 (G>A) on prefrontal phenotypes, including cognitive performance at the N-Back task, prefrontal physiology with BOLD fMRI during performance of the 2-Back working memory task, and prefrontal morphometry with structural MRI. Results We found that DRD2 rs1076560 and CHNRA5 rs16969968 interact to modulate cognitive function, prefrontal physiology during working memory, and prefrontal gray matter volume. More specifically, CHRNA5-AA/DRD2-GT subjects had greater behavioral performance, more efficient prefrontal cortex activity at 2Back working memory task, and greater prefrontal gray matter volume than the other genotype groups. Conclusions The present data extend previous studies in animals and enhance our understanding of dopamine and acetylcholine signaling in the human prefrontal cortex, demonstrating interactions elicited by working memory that are modulated by genetic variants in DRD2 and CHRNA5. PMID:24819610

DRD2/CHRNA5 interaction on prefrontal biology and physiology during working memory.

PubMed

Di Giorgio, Annabella; Smith, Ryan M; Fazio, Leonardo; D'Ambrosio, Enrico; Gelao, Barbara; Tomasicchio, Aldo; Selvaggi, Pierluigi; Taurisano, Paolo; Quarto, Tiziana; Masellis, Rita; Rampino, Antonio; Caforio, Grazia; Popolizio, Teresa; Blasi, Giuseppe; Sadee, Wolfgang; Bertolino, Alessandro

2014-01-01

Prefrontal behavior and activity in humans are heritable. Studies in animals demonstrate an interaction between dopamine D2 receptors and nicotinic acetylcholine receptors on prefrontal behavior but evidence in humans is weak. Therefore, we hypothesize that genetic variation regulating dopamine D2 and nicotinic acetylcholine receptor signaling impact prefrontal cortex activity and related cognition. To test this hypothesis in humans, we explored the interaction between functional genetic variants in the D2 receptor gene (DRD2, rs1076560) and in the nicotinic receptor α5 gene (CHRNA5, rs16969968) on both dorsolateral prefrontal cortex mediated behavior and physiology during working memory and on prefrontal gray matter volume. A large sample of healthy subjects was compared for genotypic differences for DRD2 rs1076560 (G>T) and CHNRA5 rs16969968 (G>A) on prefrontal phenotypes, including cognitive performance at the N-Back task, prefrontal physiology with BOLD fMRI during performance of the 2-Back working memory task, and prefrontal morphometry with structural MRI. We found that DRD2 rs1076560 and CHNRA5 rs16969968 interact to modulate cognitive function, prefrontal physiology during working memory, and prefrontal gray matter volume. More specifically, CHRNA5-AA/DRD2-GT subjects had greater behavioral performance, more efficient prefrontal cortex activity at 2Back working memory task, and greater prefrontal gray matter volume than the other genotype groups. The present data extend previous studies in animals and enhance our understanding of dopamine and acetylcholine signaling in the human prefrontal cortex, demonstrating interactions elicited by working memory that are modulated by genetic variants in DRD2 and CHRNA5.

A DRD1 haplotype is associated with risk for autism spectrum disorders in male-only affected sib-pair families.

PubMed

Hettinger, Joe A; Liu, Xudong; Schwartz, Charles E; Michaelis, Ron C; Holden, Jeanette J A

2008-07-05

Individuals with autism spectrum disorders (ASDs) have impairments in executive function and social cognition, with males generally being more severely affected in these areas than females. Because the dopamine D1 receptor (encoded by DRD1) is integral to the neural circuitry mediating these processes, we examined the DRD1 gene for its role in susceptibility to ASDs by performing single marker and haplotype case-control comparisons, family-based association tests, and genotype-phenotype assessments (quantitative transmission disequilibrium tests: QTDT) using three DRD1 polymorphisms, rs265981C/T, rs4532A/G, and rs686T/C. Our previous findings suggested that the dopaminergic system may be more integrally involved in families with affected males only than in other families. We therefore restricted our study to families with two or more affected males (N = 112). There was over-transmission of rs265981-C and rs4532-A in these families (P = 0.040, P = 0.038), with haplotype TDT analysis showing over-transmission of the C-A-T haplotype (P = 0.022) from mothers to affected sons (P = 0.013). In addition, haplotype case-control comparisons revealed an increase of this putative risk haplotype in affected individuals relative to a comparison group (P = 0.004). QTDT analyses showed associations of the rs265981-C, rs4532-A, rs686-T alleles, and the C-A-T haplotype with more severe problems in social interaction, greater difficulties with nonverbal communication and increased stereotypies compared to individuals with other haplotypes. Preferential haplotype transmission of markers at the DRD1 locus and an increased frequency of a specific haplotype support the DRD1 gene as a risk gene for core symptoms of ASD in families having only affected males. Copyright 2008 Wiley-Liss, Inc.

Age and DRD4 Genotype Moderate Associations Between Stimulant Treatment History and Cortex Structure in Attention-Deficit/Hyperactivity Disorder.

PubMed

Schweren, Lizanne J S; Hartman, Catharina A; Heslenfeld, Dirk J; Groenman, Annabeth P; Franke, Barbara; Oosterlaan, Jaap; Buitelaar, Jan K; Hoekstra, Pieter J

2016-10-01

Attention-deficit/hyperactivity disorder (ADHD) has been associated with dopaminergic imbalance and subtle volume decreases in the brain. Stimulants acutely enhance dopaminergic neurotransmission. Long-term effects of prolonged manipulation of the dopaminergic system on brain structure remain poorly understood; they could be beneficial or unfavorable and could be moderated by common genetic variants and/or age. In a large observational ADHD cohort study (N = 316), the effects of cumulative stimulant treatment, genotype (for DAT1 haplotype and DRD4 variants), and treatment-by-genotype interactions on striatal, frontal, and hippocampal volumes and their interactions with age were evaluated. No main effects of treatment were found. Associations between treatment and bilateral frontal and left hippocampal volume depended on DRD4 genotype and age. At a younger age and lower treatment levels, but not at a younger age and higher treatment levels, carriers of the DRD4 7R allele showed decreased frontal cortex volumes. At an older age, carriers and non-carriers showed smaller frontal volumes irrespective of treatment history. Left hippocampal volume was similar to that in controls at average treatment levels and increased with treatment only in carriers of the DRD4 risk allele and at a younger age. No interaction effects were found in the striatum. Carriers of the DRD4 risk allele at a younger age might be sensitive to cortical remodeling after stimulant treatment. The cross-sectional nature of this study warrants cautious interpretation of age effects. The present findings, although of small effect size, might ultimately contribute to optimal care for individuals with ADHD. Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Negative perceived paternal parenting is associated with dopamine D2 receptor exon 8 and GABA(A) alpha 6 receptor variants: an explorative study.

PubMed

Lucht, Michael; Barnow, Sven; Schroeder, Winnie; Grabe, Hans Joergen; Finckh, Ulrich; John, Ulrich; Freyberger, Harald J; Herrmann, Falko H

2006-03-05

Twin studies suggest a genetic influence upon perceived parenting. The D(2) dopaminergic receptor is involved in the modulation of social behaviors, and might influence parenting and its perception. A polymorphism (E8) in exon 8 of the D(2) receptor gene (DRD2) has been previously associated with alcoholism-related phenotypes. Similarly, the Pro385Ser variant of GABRA6, the polymorphic gene for GABA(A) receptor alpha6 subunit, has been associated with alcohol- and depression-related traits; and rat pups maintained a more immature GABAR phenotype after brief separation distress. The relationships among DRD2 (E8) and GABRA6 (Pro385Ser) polymorphisms, and perceived parenting were studied here. The association of DRD2 (E8) and GABRA6 (Pro385Ser) genotypes and perceived parental rearing behavior (short-EMBU; questionnaire concerning own memories concerning upbringing) were determined in 207 unrelated adults using multivariate analysis of variance. Temperaments (Temperament and Character Inventory; TCI) were included as covariates. Probands with DRD2 (E8) A/A genotype showed higher scores for father rejection (P = 0.011), parents overprotection (P = 0.021), and father overprotection (P = 0.016) in the total group. An interaction between DRD2 and GABRA6 genotypes on father rejection (P = 0.010) and parents rejection (P = 0.030) was also observed. Further analyses showed that these associations were restricted to the female subgroup only; however, secondary gender-specific analyses were not corrected for multiple testing. Our findings support a role for DRD2 (E8) and GABRA6 (Pro385Ser) in perceived parenting. (c) 2006 Wiley-Liss, Inc.

Advancing the dual reciprocating drill design for efficient planetary subsurface exploration

NASA Astrophysics Data System (ADS)

Pitcher, Craig

Accessing the subsurface of planetary bodies with drilling systems is vital for furthering our understanding of the solar system and in the search for life and volatiles. The extremely stringent mass and sizing mission constraints have led to the examination of novel low-mass drilling techniques. One such system is the Dual-Reciprocating Drill (DRD), inspired by the ovipositor of the sirex noctilio, which uses the reciprocation of two halves lined with backwards-facing teeth to engage with and grip the surrounding substrate. For the DRD to become a viable alternative technique, further work is required to expand its testing, improve its efficiency and evolve it from the current proof-of-concept to a system prototype. To do this, three areas of research were identified. This involved examining how the drill head design affects the drilling depth, exploring the effects of ice content in regolith on its properties and drilling performance, and determining the benefits of additional controlled lateral motions in an integrated actuation mechanism. The tests performed in this research revealed that the cross-sectional area of the drill head was by far the most significant geometrical parameter with regards to drilling performance, while the teeth shape had a negligible effect. An ice content of 5 +/- 1% in the regolith corresponded to an increase in drilling time and a clear change in the regolith's physical properties. Finally, it was demonstrated that the addition of lateral motions allowed the drill to achieve greater depths. This work has advanced both the understanding and design of the DRD considerably. It has continued the exploration of the geometrical and substrate parameters that affect drilling performance and provided the first characterisation of the properties of an icy lunar polar simulant. The construction and testing of the complex motion internal actuation mechanism has both evolved the DRD design and opened a new avenue through which the system can be further optimised.

Interaction of DRD4 Methylation and Phthalate Metabolites Affects Continuous Performance Test Performance in ADHD.

PubMed

Kim, Johanna Inhyang; Kim, Jae-Won; Shin, Inkyung; Kim, Bung-Nyun

2018-05-01

We investigated the interaction effect between the methylation of dopamine receptor D4 (DRD4) and phthalate exposure in ADHD on continuous performance test (CPT) variables. Urine concentrations of mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-n-butyl phthalate (MBP) were tested. The methylation status was analyzed for CpG sites of DRD4. Multivariable linear regression models were applied to investigate the interaction effects of methylation and phthalate levels. There was a significant interaction effect of the methylation of CpG26 and CpG28 with the MEHHP level on omission errors in ADHD patients, but not in controls. The post hoc analysis revealed a significant correlation between the MEHHP concentration and omission errors in the methylated group, but not in the unmethylated group. The interaction between the methylation status of CpG sites of DRD4, particularly CpG26 and CpG28, and phthalate metabolite levels affects the attention level in ADHD patients.

Association study between the dopamine D4 receptor gene and schizophrenia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Petronis, A.; Macciardi, F.; Athanassiades, A.

The dopamine D4 receptor is of major interest in schizophrenia research due to its high affinity for the atypical neuroleptic clozapine and a high degree of variability in the receptor gene (DRD4). Although several genetic linkage analyses performed on schizophrenia multiplex families from different regions of the world have either excluded or failed to prove that DRD4 is a major genetic factor for the development of schizophrenia, analyses for moderate predisposing effects are still of significant interest. We performed a study examining differences in allele frequencies of 4 different DRD4 polymorphisms in schizophrenia patients and age, sex, and ethnic originmore » matched controls. None of these 4 polymorphisms showed evidence for genetic association with schizophrenia, although a trend towards excess of the allele with 7 repeats in the (48){sub n} bp exon III polymorphism was observed. Complexities in the DRD4 genetic investigation and further analytic approaches are discussed. 18 refs., 2 tabs.« less

Everyday Discrimination, Diabetes-Related Distress, and Depressive Symptoms Among African Americans and Latinos with Diabetes

PubMed Central

Valerio, Melissa A.; Kieffer, Edith; Sinco, Brandy; Rosland, Ann-Marie; Hawkins, Jaclynn; Espitia, Nicolaus; Palmisano, Gloria; Spencer, Michael

2013-01-01

It is not known how discrimination might affect diabetes-related distress (DRD), an important correlate of diabetes outcomes. We examined correlates of discrimination and the influence of discrimination on DRD and depressive symptoms (DS) for African Americans and Latinos with type 2 diabetes. We analyzed survey data (n = 157) collected at enrollment into a diabetes management intervention. Using multiple linear regression, we examined correlates of discrimination and the association between discrimination and DRD and DS. Discrimination was significantly associated with higher DRD for Latinos (b 1.58, 95 % CI 1.08, 2.31, p < 0.05), but not significant for African Americans (b 0.96, 95 % CI 0.59, 1.57). Discrimination was marginally significantly associated with more DS for Latinos (b 1.43, 95 % CI 0.97, 2.12, p < 0.10), but not significant for African Americans (b 1.21, 95 % CI 0.87, 1.70). These findings suggest the need to address stressors unique to racial/ethnic minorities to improve diabetes-related outcomes. PMID:23689972

The dopamine D4 receptor gene (DRD4) moderates cultural difference in independent versus interdependent social orientation.

PubMed

Kitayama, Shinobu; King, Anthony; Yoon, Carolyn; Tompson, Steve; Huff, Sarah; Liberzon, Israel

2014-06-01

Prior research suggests that cultural groups vary on an overarching dimension of independent versus interdependent social orientation, with European Americans being more independent, or less interdependent, than Asians. Drawing on recent evidence suggesting that the dopamine D4 receptor gene (DRD4) plays a role in modulating cultural learning, we predicted that carriers of DRD4 polymorphisms linked to increased dopamine signaling (7- or 2-repeat alleles) would show higher levels of culturally dominant social orientations, compared with noncarriers. European Americans and Asian-born Asians (total N = 398) reported their social orientation on multiple scales. They were also genotyped for DRD4. As in earlier work, European Americans were more independent, and Asian-born Asians more interdependent. This cultural difference was significantly more pronounced for carriers of the 7- or 2-repeat alleles than for noncarriers. Indeed, no cultural difference was apparent among the noncarriers. Implications for potential coevolution of genes and culture are discussed. © The Author(s) 2014.

Effects of Interaction Between DRD4 Methylation and Prenatal Maternal Stress on Methylphenidate-Induced Changes in Continuous Performance Test Performance in Youth with Attention-Deficit/Hyperactivity Disorder.

PubMed

Kim, Johanna Inhyang; Kim, Jae-Won; Shin, Inkyung; Kim, Bung-Nyun

2018-06-15

Environmental factors may interact with genetic factors via the epigenetic process, and this interaction can contribute to inter-individual variability in the treatment response. The purpose of this study was to investigate the interaction effects between dopamine receptor D4 (DRD4) methylation and prenatal maternal stress on the methylphenidate (MPH) response of youth with attention-deficit/hyperactivity disorder (ADHD). This study was an 8-week open-label trial of MPH that included 74 ADHD youth. We investigated the associations between MPH treatment response, which was defined as a score ≤2 on the Clinical Global Impressions-Improvement (CGI-I) scale, and the methylation of 28 cytosine-guanine dinucleotide (CpG) sites of DRD4. Additionally, the interaction effects between DRD4 methylation and prenatal maternal stress on changes in Continuous Performance Test (CPT) scores after MPH treatment were investigated. Although there were no significant sites that showed significant association with treatment response, there was a significant interaction effect of the methylation of CpG7 and prenatal maternal stress on changes in omission errors of the CPT following treatment (p = 0.0001). The present findings indicate that the interaction between methylation of CpG7 of DRD4 and prenatal maternal stress may be predictive of the treatment response to MPH in youth with ADHD.

Relations between Three Dopaminergic System Genes, School Attachment, and Adolescent Delinquency

ERIC Educational Resources Information Center

Fine, Adam; Mahler, Alissa; Simmons, Cortney; Chen, Chuansheng; Moyzis, Robert; Cauffman, Elizabeth

2016-01-01

Both environmental factors and genetic variation, particularly in genes responsible for the dopaminergic system such as "DRD4," "DRD2," and "DAT1" ("SLC6A3"), affect adolescent delinquency. The school context, despite its developmental importance, has been overlooked in gene-environment research. Using data…

Parenting and Child "DRD4" Genotype Interact to Predict Children's Early Emerging Effortful Control

ERIC Educational Resources Information Center

Smith, Heather J.; Sheikh, Haroon I.; Dyson, Margaret W.; Olino, Thomas M.; Laptook, Rebecca S.; Durbin, C. Emily; Hayden, Elizabeth P.; Singh, Shiva M.; Klein, Daniel N.

2012-01-01

Effortful control (EC), or the trait-like capacity to regulate dominant responses, has important implications for children's development. Although genetic factors and parenting likely influence EC, few studies have examined whether they interact to predict its development. This study examined whether the "DRD4" exon III variable number tandem…

Conjugal Transfer of R-Plasmid R1drd-19 in Escherichia coli Below 22°C

PubMed Central

Singleton, Paul; Anson, Avril E.

1981-01-01

The conjugal transfer of R-plasmids is known to occur at temperatures above 22°C. We found that R1drd-19 is transferable below 22°C, and we discuss this finding in the context of plasmid transfer in environmental waters. PMID:7032420

Three Dopaminergic Polymorphisms Are Associated with Academic Achievement in Middle and High School

ERIC Educational Resources Information Center

Beaver, Kevin M.; Vaughn, Michael G.; Wright, John Paul; DeLisi, Matt; Howard, Matthew O.

2010-01-01

Although academic achievement is a heritable construct, to date research has yet to explore its molecular genetic underpinnings. Drawing on data from the National Longitudinal Study of Adolescent Health, the current longitudinal study investigated the associations between polymorphisms in three dopaminergic genes (DAT1, DRD2, and DRD4) and…

Association and family studies of DRD2 gene polymorphisms in alcohol dependence syndrome.

PubMed

Małecka, Iwona; Jasiewicz, Andrzej; Suchanecka, Aleksandra; Samochowiec, Jerzy; Grzywacz, Anna

2014-11-06

The human dopamine receptor 2 gene DRD2 plays a central role in susceptibility to Alcohol Dependence Syndrome (ADS). The aim of this study was to evaluate 3 single nucleotide polymorphisms: D2 (rs1076560), Tag1D (rs1800498), Tag1B (rs1079597) located in dopamine receptor 2 DRD2 gene and its role in alcohol dependence. DNA was provided from alcohol dependent (AD) patients (n=171) and healthy control subjects (n=160) all of Polish descent. The history of alcoholism was obtained using the Polish version of the SSAGA (Semi-Structured Assessment for the Genetics of Alcoholism). We conducted case-control association study and transmission disequilibrium test (TDT). Samples were genotyped using real-time PCR method. We did not confirm the association between studied polymorphisms and alcohol dependence syndrome. TDT reveled an adequate transmission of both alleles in the group of alcohol families. The lack of association of studied polymorphisms and ADS does not preclude its participation in the pathogenesis. Further research is needed to determine the actual contribution of DRD2 gene in the pathogenesis of alcoholism.

The DRD4 exon 3 VNTR polymorphism and addiction-related phenotypes: a review

PubMed Central

McGeary, John

2009-01-01

In addition to the large literatures on associations of the DRD4 VNTR polymorphism with ADHD and personality traits, there is an emerging literature linking this variant to addiction and addiction-related phenotypes. When only diagnosis-based studies are considered, an inconsistent picture emerges raising doubts as to the relevance of this polymorphism to addiction. However the use of multiple levels of analysis in examining the importance of this polymorphism has raised the possibility of an urge-related “intermediate phenotype” that puts one at risk for developing addiction but may not be found in all persons with an addiction diagnosis. From cellular assays through neuroimaging and behavioral phenotypes, these studies highlight the power of the “intermediate phenotype” approach and suggest a possible explanation of the mixed findings when diagnosis is used as the phenotype. Strengths and weaknesses of alternative DRD4 VNTR genotype grouping strategies are discussed. In sum, converging evidence across multiple methodologies supports the possibility of a robust relationship between the DRD4 exon 3 VNTR polymorphism and urge for addictive substances. PMID:19336242

Genetic association between the dopamine D1-receptor gene and paranoid schizophrenia in a northern Han Chinese population.

PubMed

Yao, Jun; Ding, Mei; Xing, Jiaxin; Xuan, Jinfeng; Pang, Hao; Pan, Yuqing; Wang, Baojie

2014-01-01

Dysregulation of dopaminergic neurotransmission at the D1 receptor in the prefrontal cortex has been implicated in the pathogenesis of schizophrenia. Genetic polymorphisms of the dopamine D1-receptor gene have a plausible role in modulating the risk of schizophrenia. To determine the role of DRD1 genetic polymorphisms as a risk factor for schizophrenia, we undertook a case-control study to look for an association between the DRD1 gene and schizophrenia. We genotyped eleven single-nucleotide polymorphisms within the DRD1 gene by deoxyribonucleic acid sequencing involving 173 paranoid schizophrenia patients and 213 unrelated healthy individuals. Statistical analysis was performed to identify the difference of genotype, allele, or haplotype distribution between cases and controls. A significantly lower risk of paranoid schizophrenia was associated with the AG + GG genotype of rs5326 and the AG + GG genotype of rs4532 compared to the AA genotype and the AA genotype, respectively. Distribution of haplotypes was no different between controls and paranoid schizophrenia patients. In the males, the genotype distribution of rs5326 was statistically different between cases and controls. In the females, the genotype distribution of rs4532 was statistically different between cases and controls. However, the aforementioned statistical significances were lost after Bonferroni correction. It is unlikely that DRD1 accounts for a substantial proportion of the genetic risk for schizophrenia. As an important dopaminergic gene, DRD1 may contribute to schizophrenia by interacting with other genes, and further relevant studies are warranted.

Central dopamine D2 receptors regulate growth-hormone-dependent body growth and pheromone signaling to conspecific males.

PubMed

Noaín, Daniela; Pérez-Millán, M Inés; Bello, Estefanía P; Luque, Guillermina M; Casas Cordero, Rodrigo; Gelman, Diego M; Peper, Marcela; Tornadu, Isabel García; Low, Malcolm J; Becú-Villalobos, Damasia; Rubinstein, Marcelo

2013-03-27

Competition between adult males for limited resources such as food and receptive females is shaped by the male pattern of pituitary growth hormone (GH) secretion that determines body size and the production of urinary pheromones involved in male-to-male aggression. In the brain, dopamine (DA) provides incentive salience to stimuli that predict the availability of food and sexual partners. Although the importance of the GH axis and central DA neurotransmission in social dominance and fitness is clearly appreciated, the two systems have always been studied unconnectedly. Here we conducted a cell-specific genetic dissection study in conditional mutant mice that selectively lack DA D2 receptors (D2R) from pituitary lactotropes (lacDrd2KO) or neurons (neuroDrd2KO). Whereas lacDrd2KO mice developed a normal GH axis, neuroDrd2KO mice displayed fewer somatotropes; reduced hypothalamic Ghrh expression, pituitary GH content, and serum IGF-I levels; and exhibited reduced body size and weight. As a consequence of a GH axis deficit, neuroDrd2KO adult males excreted low levels of major urinary proteins and their urine failed to promote aggression and territorial behavior in control male challengers, in contrast to the urine taken from control adult males. These findings reveal that central D2Rs mediate a neuroendocrine-exocrine cascade that controls the maturation of the GH axis and downstream signals that are critical for fitness, social dominance, and competition between adult males.

The DRD2 Taq1A A1 Allele May Magnify the Risk of Alzheimer's in Aging African-Americans.

PubMed

Blum, Kenneth; Badgaiyan, Rajendra D; Dunston, Georgia M; Baron, David; Modestino, Edward J; McLaughlin, Thomas; Steinberg, Bruce; Gold, Mark S; Gondré-Lewis, Marjorie C

2017-09-30

Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys cognitive skills and the ability to perform the simplest tasks. More than 5 million Americans are afflicted with Alzheimer's; a disorder which ranks third, just behind heart disease and cancer, as a cause of death for older people. With no real cure and in spite of enormous efforts worldwide, the disease remains a mystery in terms of treatment. Importantly, African-Americans are two times as likely as Whites to develop late-onset Alzheimer's disease and less likely to receive timely diagnosis and treatment. Dopamine function is linked to normal cognition and memory and carriers of the DRD2 Taq1A A1 allele have significant loss of D2 receptor density in the brain. Recent research has shown that A1 carriers have worse memory performance during long-term memory (LTM) updating, compared to non-carriers or A2-carriers. A1carriers also show less blood oxygen level-dependent (BOLD) activation in the left caudate nucleus which is important for LTM updating. This latter effect was only seen in older adults, suggesting magnification of genetic effects on brain functioning in the elderly. Moreover, the frequency of the A1 allele is 0.40 in African-Americans, with an approximate prevalence of the DRD2 A1 allele in 50% of an African-American subset of individuals. This is higher than what is found in a non-screened American population (≤ 28%) for reward deficiency syndrome (RDS) behaviors. Based on DRD2 known genetic polymorphisms, we hypothesize that the DRD2 Taq1A A1 allele magnifies the risk of Alzheimer's in aging African-Americans. Research linking this high risk for Alzheimer's in the African-American population, with DRD2/ANKK1-TaqIA polymorphism and neurocognitive deficits related to LTM, could pave the way for novel, targeted pro-dopamine homeostatic treatment.

Variation at the DRD4 locus is associated with wariness and local site selection in urban black swans.

PubMed

van Dongen, Wouter F D; Robinson, Randall W; Weston, Michael A; Mulder, Raoul A; Guay, Patrick-Jean

2015-12-11

Interactions between wildlife and humans are increasing. Urban animals are often less wary of humans than their non-urban counterparts, which could be explained by habituation, adaptation or local site selection. Under local site selection, individuals that are less tolerant of humans are less likely to settle in urban areas. However, there is little evidence for such temperament-based site selection, and even less is known about its underlying genetic basis. We tested whether site selection in urban and non-urban habitats by black swans (Cygnus atratus) was associated with polymorphisms in two genes linked to fear in animals, the dopamine receptor D4 (DRD4) and serotonin transporter (SERT) genes. Wariness in swans was highly repeatable between disturbance events (repeatability = 0.61) and non-urban swans initiated escape from humans earlier than urban swans. We found no inter-individual variation in the SERT gene, but identified five DRD4 genotypes and an association between DRD4 genotype and wariness. Individuals possessing the most common DRD4 genotype were less wary than individuals possessing rarer genotypes. As predicted by the local site selection hypothesis, genotypes associated with wary behaviour were over three times more frequent at the non-urban site. This resulted in moderate population differentiation at DRD4 (FST = 0.080), despite the sites being separated by only 30 km, a short distance for this highly-mobile species. Low population differentiation at neutrally-selected microsatellite loci and the likely occasional migration of swans between the populations reduces the likelihood of local site adaptations. Our results suggest that wariness in swans is partly genetically-determined and that wary swans settle in less-disturbed areas. More generally, our findings suggest that site-specific management strategies may be necessary that consider the temperament of local animals.

Diabetes-Related Distress and Depressive Symptoms Are Not Merely Negative over a 3-Year Period in Malaysian Adults with Type 2 Diabetes Mellitus Receiving Regular Primary Diabetes Care

PubMed Central

Chew, Boon-How; Vos, Rimke C.; Stellato, Rebecca K.; Rutten, Guy E. H. M.

2017-01-01

For people with type 2 diabetes mellitus (T2DM) the daily maintenance of physical and psychological health is challenging. However, the interrelatedness of these two health domains, and of diabetes-related distress (DRD) and depressive symptoms, in the Asian population is still poorly understood. DRD and depressive symptoms have important but distinct influences on diabetes self-care and disease control. Furthermore, the question of whether changes in DRD or depressive symptoms follow a more or less natural course or depend on disease and therapy-related factors is yet to be answered. The aim of this study was to identify the factors influencing changes in DRD or depressive symptoms, at a 3-year follow-up point, in Malaysian adults with T2DM who received regular primary diabetes care. Baseline data included age, sex, ethnicity, marital status, educational level, employment status, health-related quality of life (WHOQOL-BREF), insulin use, diabetes-related complications and HbA1c. DRD was assessed both at baseline and after 3 years using a 17-item Diabetes Distress Scale (DDS-17), while depressive symptoms were assessed using the Patient Health Questionnaire (PHQ-9). Linear mixed models were used to examine the relationship between baseline variables and change scores in DDS-17 and PHQ-9. Almost half (336) of 700 participants completed both measurements. At follow-up, their mean (SD) age and diabetes duration were 60.6 (10.1) years and 9.8 (5.9) years, respectively, and 54.8% were women. More symptoms of depression at baseline was the only significant and independent predictor of improved DRD at 3 years (adjusted β = −0.06, p = 0.002). Similarly, worse DRD at baseline was the only significant and independent predictor of fewer depressive symptoms 3 years later (adjusted β = −0.98, p = 0.005). Thus, more “negative feelings” at baseline could be a manifestation of initial coping behaviors or a facilitator of a better psychological coaching by physicians or nurses that might be beneficial in the long term. We therefore conclude that initial negative feelings should not be seen as a necessarily adverse factor in diabetes care. PMID:29089913

From Evidence to Policy: The Scottish National Naloxone Programme

ERIC Educational Resources Information Center

McAuley, Andrew; Best, David; Taylor, Avril; Hunter, Carole; Robertson, Roy

2012-01-01

Drug-related death (DRD) is a major public health problem globally, with rates in Scotland higher than any other UK region and among the highest in Europe. One of the most important public health interventions to emerge aimed at tackling rising DRD rates is the distribution of naloxone, the opioid antagonist, for peer administration. The Scottish…

Familial Clustering and DRD4 Effects on Electroencephalogram Measures in Multiplex Families with Attention Deficit/Hyperactivity Disorder

ERIC Educational Resources Information Center

Loo, Sandra K.; Hale, T. Sigi; Hanada, Grant; Macion, James; Shrestha, Anshu; McGough, James J.; McCracken, James T.; Nelson, Stanley; Smalley, Susan L.

2010-01-01

Objective: The current study tests electroencephalogram (EEG) measures as a potential endophenotype for attention deficit/hyperactivity disorder (ADHD) by examining sibling and parent-offspring similarity, familial clustering with the disorder, and association with the dopamine receptor D4 (DRD4) candidate gene. Method: The sample consists of 531…

Dopaminergic Polymorphisms and Educational Achievement: Results from a Longitudinal Sample of Americans

ERIC Educational Resources Information Center

Beaver, Kevin M.; Wright, John Paul; DeLisi, Matt; Vaughn, Michael G.

2012-01-01

Although educational attainment has been found to be moderately heritable, research has yet to explore candidate genes for it. Drawing on data from the National Longitudinal Study of Adolescent Health, in the current study, we examined the association between polymorphisms in three dopaminergic genes (DAT1, DRD2, and DRD4), a dopamine index, and…

Monoamine oxidase-A polymorphisms might modify the association between the dopamine D2 receptor gene and alcohol dependence.

PubMed

Huang, San-Yuan; Lin, Wei-Wen; Wan, Fang-Jung; Chang, Ai-Ju; Ko, Huei-Chen; Wang, Tso-Jen; Wu, Pei-Lin; Lu, Ru-Band

2007-05-01

Low monoamine oxidase (MAO) activity and the neurotransmitter dopamine are 2 important factors in the development of alcohol dependence. MAO is an important enzyme associated with the metabolism of biogenic amines. Therefore, the present study investigates whether the association between the dopamine D2 receptor (DRD2) gene and alcoholism is affected by different polymorphisms of the MAO type A (MAOA) gene. A total of 427 Han Chinese men in Taiwan (201 control subjects and 226 with alcoholism) were recruited for the study. Of the subjects with alcoholism, 108 had pure alcohol dependence (ALC) and 118 had both alcohol dependence and anxiety, depression or both (ANX/DEP ALC). All subjects were assessed with the Chinese Version of the Modified Schedule of Affective Disorders and Schizophrenia-Lifetime. Alcohol dependence, anxiety and major depressive disorders were diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria. The genetic variant of the DRD2 gene was only associated with the ANX/DEP ALC phenotype, and the genetic variant of the MAOA gene was associated with pure ALC. Subjects carrying the MAOA 3-repeat allele and genotype A1/A1 of the DRD2 were 3.48 times (95% confidence interval = 1.47-8.25) more likely to be ANX/DEP ALC than the subjects carrying the MAOA 3-repeat allele and DRD2 A2/A2 genotype. The MAOA gene may modify the association between the DRD2 gene and ANX/DEP ALC phenotype.

The Effect of Chronic Antipsychotic Drug on Hypothalamic Expression of Neural Nitric Oxide Synthase and Dopamine D2 Receptor in the Male Rat

PubMed Central

Zhang, Zhi Jun; Li, Lei; Reynolds, Gavin P.

2012-01-01

Antipsychotic-induced sexual dysfunction is a common and serious clinical side effect. It has been demonstrated that both neuronal nitric oxide (nNOS) and dopamine D2 receptor (DRD2) in the medial preoptic area (MPOA) and the paraventricular nucleus (PVN) of the hypothalamus have important roles in the regulation of sexual behaviour. We investigated the influences of 21 days’ antipsychotic drug administration on expression of nNOS and DRD2 in the rat hypothalamus. Haloperidol (0.5 mg/kg/day i.p.) significantly decreased nNOS integrated optical density in a sub-nucleus of the MPOA, medial preoptic nucleus (MPN), and decreased the nNOS integrated optical density and cell density in another sub-nucleus of the MPOA, anterodorsal preoptic nucleus (ADP). Risperidone (0.25 mg/kg) inhibited the nNOS integrated optical density in the ADP. nNOS mRNA and protein in the MPOA but not the PVN was also significantly decreased by haloperidol. Haloperidol and risperidone increased DRD2 mRNA and protein expression in both the MPOA and the PVN. Quetiapine (20 mg/kg/day i.p.) did not influence the expression of nNOS and DRD2 in either the MPOA or the PVN. These findings indicate that hypothalamic nNOS and DRD2 are affected to different extents by chronic administration of risperidone and haloperidol, but are unaffected by quetiapine. These central effects might play a role in sexual dysfunction induced by certain antipsychotic drugs. PMID:22514604

Genetic variations in the dopamine system and facial expression recognition in healthy chinese college students.

PubMed

Zhu, Bi; Chen, Chuansheng; Moyzis, Robert K; Dong, Qi; Chen, Chunhui; He, Qinghua; Stern, Hal S; Li, He; Li, Jin; Li, Jun; Lessard, Jared; Lin, Chongde

2012-01-01

This study investigated the relation between genetic variations in the dopamine system and facial expression recognition. A sample of Chinese college students (n = 478) was given a facial expression recognition task. Subjects were genotyped for 98 loci [96 single-nucleotide polymorphisms (SNPs) and 2 variable number tandem repeats] in 16 genes involved in the dopamine neurotransmitter system, including its 4 subsystems: synthesis (TH, DDC, and DBH), degradation/transport (COMT,MAOA,MAOB, and SLC6A3), receptors (DRD1,DRD2,DRD3,DRD4, and DRD5), and modulation (NTS,NTSR1,NTSR2, and NLN). To quantify the total contributions of the dopamine system to emotion recognition, we used a series of multiple regression models. Permutation analyses were performed to assess the posterior probabilities of obtaining such results. Among the 78 loci that were included in the final analyses (after excluding 12 SNPs that were in high linkage disequilibrium and 8 that were not in Hardy-Weinberg equilibrium), 1 (for fear), 3 (for sadness), 5 (for anger), 13 (for surprise), and 15 (for disgust) loci exhibited main effects on the recognition of facial expressions. Genetic variations in the dopamine system accounted for 3% for fear, 6% for sadness, 7% for anger, 10% for surprise, and 18% for disgust, with the latter surviving a stringent permutation test. Genetic variations in the dopamine system (especially the dopamine synthesis and modulation subsystems) made significant contributions to individual differences in the recognition of disgust faces. Copyright © 2012 S. Karger AG, Basel.

D{sub 2} dopamine receptor gene and behavioral characteristics in nicotine dependence

DOE Office of Scientific and Technical Information (OSTI.GOV)

Noble, E.P.; Fitch, R.J.; Syndulko, K.

1994-09-01

The D{sub 2} dopamine receptor (DRD2) A1 allele has been recently associated with nicotine dependence. In the present study, TaqI A alleles (the minor A1 and the major A2 allele) of the DRD2 were determined in medically-ill subjects. The sample was composed of 41 non-smokers (N), 69 ex-smokers (X) and 63 active smokers (A). The relationships of DRD2 alleles to personality (Eysenick`s Addictive Personality [AP]), depression and nicotine dependence (Fagerstroem) scores were ascertained. A significant (P = 0.002) group effect prevailed in the AP scores, with the A group having the highest scores. Moreover, a significant (P = 0.025) allelemore » by group interaction was found, with A1 allelic subjects in group A showing the highest AP scores. Significant group effects were also found in both the depression (P = 0.0004) and the nicotine dependence (P = 0.0003) scores, with the A group again showing the highest scores. However, in contrast to the AP scores, no significant allele by group interaction was found either in the depression or the nicotine dependence scores. In conclusion, the present findings suggest a role for the DRD2 gene in personality of smokers. However, relationship of the DRD2 gene to the degree of depression or nicotine dependence was not found. The data indicate the importance of using behavioral and genetic variables in dissecting the complex set of variables associated with the smoking habit, and thus in achieving a better understanding of the biobehavioral bases of this addiction.« less

Genetically determined interaction between the dopamine transporter and the D2 receptor on prefronto-striatal activity and volume in humans.

PubMed

Bertolino, Alessandro; Fazio, Leonardo; Di Giorgio, Annabella; Blasi, Giuseppe; Romano, Raffaella; Taurisano, Paolo; Caforio, Grazia; Sinibaldi, Lorenzo; Ursini, Gianluca; Popolizio, Teresa; Tirotta, Emanuele; Papp, Audrey; Dallapiccola, Bruno; Borrelli, Emiliana; Sadee, Wolfgang

2009-01-28

Dopamine modulation of neuronal activity during memory tasks identifies a nonlinear inverted-U shaped function. Both the dopamine transporter (DAT) and dopamine D(2) receptors (encoded by DRD(2)) critically regulate dopamine signaling in the striatum and in prefrontal cortex during memory. Moreover, in vitro studies have demonstrated that DAT and D(2) proteins reciprocally regulate each other presynaptically. Therefore, we have evaluated the genetic interaction between a DRD(2) polymorphism (rs1076560) causing reduced presynaptic D(2) receptor expression and the DAT 3'-VNTR variant (affecting DAT expression) in a large sample of healthy subjects undergoing blood oxygenation level-dependent (BOLD)-functional magnetic resonance imaging (MRI) during memory tasks and structural MRI. Results indicated a significant DRD(2)/DAT interaction in prefrontal cortex and striatum BOLD activity during both working memory and encoding of recognition memory. The differential effect on BOLD activity of the DAT variant was mostly manifest in the context of the DRD(2) allele associated with lower presynaptic expression. Similar results were also evident for gray matter volume in caudate. These interactions describe a nonlinear relationship between compound genotypes and brain activity or gray matter volume. Complementary data from striatal protein extracts from wild-type and D(2) knock-out animals (D2R(-/-)) indicate that DAT and D(2) proteins interact in vivo. Together, our results demonstrate that the interaction between genetic variants in DRD(2) and DAT critically modulates the nonlinear relationship between dopamine and neuronal activity during memory processing.

Linkage disequilibria at the D[sub 2] dopamine receptor locus (DRD2) in alcoholics and controls

DOE Office of Scientific and Technical Information (OSTI.GOV)

Suarez, B.K.; Parsian, A.; Hampe, C.L.

1994-01-01

Because of its central role in the neuromodulation of appetitive behaviors, the D[sub 2] dopamine receptor gene (DRD2) has received considerable scrutiny as a possible candidate that may affect susceptibility to addictive behaviors--especially alcoholism. Association studies that compare the frequencies of anonymous restriction fragment length polymorphisms (RFLPs) in alcoholics and controls have yielded equivocal results, suggesting that any role played by this receptor will account for only part of the variation. Since these RFLPs are not located in coding regions, the hypothesis has been advanced that the association seen in some studies results from linkage disequilibrium between these markers andmore » one or more functional DRD2 alleles that affect susceptibility. To test this hypothesis, the authors have assayed four DRD2 RFLPs that span coding regions as well as a 3[prime] flanking RFLP in an expanded sample of 88 unrelated Caucasian alcoholics and 89 unrelated race-matched controls. No significant difference for any RFLP frequency between these samples was observed, although for one marker (phD2-244), the alcoholic sample showed a significant departure from the Hardy-Weinberg equilibrium. The pattern of pairwise composite disequilibrium coefficients is broadly similar in the two samples, although when the five-marker haplotype frequencies are compared, a significant difference is revealed. This difference appears to be due to greater linkage disequilibrium of the control sample. These results do not support the involvement of the DRD2 region in the etiology of alcoholism. 64 refs., 2 figs., 6 tabs.« less

Dopamine risk and paternal ADHD symptomatology associated with ADHD symptoms in four and a half-year-old boys.

PubMed

Auerbach, Judith G; Atzaba-Poria, Naama; Berger, Andrea; Landau, Rivka; Arbelle, Shoshana; Raz, Yael; Ebstein, Richard

2010-08-01

This study examined the influence of allelic variation in two dopamine genes, the dopamine receptor D4 (DRD4) gene and the dopamine transporter D1 (DAT1) gene, and paternal attention-deficit hyperactivity disorder (ADHD) symptomatology on the level of ADHD symptoms in 96 four and a half-year-old boys. DNA was collected by means of a buccal swab and genotyped for DRD4 and DAT1. Mothers completed the Dupaul ADHD checklist on their sons. ADHD symptomatology ratings for fathers were based on a summed father self-reported and spouse-reported symptoms (Conners Adult ADHD Rating Scale). There were main effects for DAT1 and father symptomatology for the child Total ADHD and Hyperactivity-Impulsivity scores. The main effects for DRD4 were limited to the child Hyperactivity-Impulsivity scores. Child Inattentive scores were influenced only by father symptomatology. Interaction effects between DAT1 and DRD4 and between DAT1 and the father ADHD risk group were found for child Hyperactivity-Impulsivity scores. Boys with the highest level of symptomatology were those with the 10/10 DAT1 genotype and the DRD4-7 genotype or fathers with high symptomatology. The findings of this study indicate that the risk for ADHD, particularly hyperactivity-impulsivity, is exacerbated in the presence of dopamine risk genes and paternal ADHD symptomatology. This study adds to the growing literature on the efficacy of including multiple genetic and environmental risk factors in studies related to the development of psychopathology.

Aberrant mesolimbic dopamine-opiate interaction in obesity.

PubMed

Tuominen, Lauri; Tuulari, Jetro; Karlsson, Henry; Hirvonen, Jussi; Helin, Semi; Salminen, Paulina; Parkkola, Riitta; Hietala, Jarmo; Nuutila, Pirjo; Nummenmaa, Lauri

2015-11-15

Dopamine and opioid neurotransmitter systems share many functions such as regulation of reward and pleasure. μ-Opioid receptors (MOR) modulate the mesolimbic dopamine system in ventral tegmental area and striatum, key areas implicated in reward. We hypothesized that dopamine and opioid receptor availabilities correlate in vivo and that this correlation is altered in obesity, a disease with altered reward processing. Twenty lean females (mean BMI 22) and 25 non-binge eating morbidly obese females (mean BMI 41) underwent two positron emission tomography scans with [(11)C]carfentanil and [(11)C]raclopride to measure the MOR and dopamine D2 receptor (DRD2) availability, respectively. In lean subjects, the MOR and DRD2 availabilities were positively associated in the ventral striatum (r=0.62, p=0.003) and dorsal caudate nucleus (r=0.62, p=0.004). Moreover, DRD2 availability in the ventral striatum was associated with MOR availability in other regions of the reward circuitry, particularly in the ventral tegmental area. In morbidly obese subjects, this receptor interaction was significantly weaker in ventral striatum but unaltered in the caudate nucleus. Finally, the association between DRD2 availability in the ventral striatum and MOR availability in the ventral tegmental area was abolished in the morbidly obese. The study demonstrates a link between DRD2 and MOR availabilities in living human brain. This interaction is selectively disrupted in mesolimbic dopamine system in morbid obesity. We propose that interaction between the dopamine and opioid systems is a prerequisite for normal reward processing and that disrupted cross-talk may underlie altered reward processing in obesity. Copyright © 2015 Elsevier Inc. All rights reserved.

Association between the DRD2 A1 allele and response to methadone and buprenorphine maintenance treatments.

PubMed

Barratt, Daniel T; Coller, Janet K; Somogyi, Andrew A

2006-06-05

The TaqI A polymorphism (A(1)) of the dopamine D(2) receptor gene (DRD2), although not a specific predictor of opioid dependence, has been strongly associated with high levels of prior heroin use and poor treatment outcomes among methadone maintenance patients. The aims of this study were to confirm these findings via a retrospective analysis of A(1) allele frequency in methadone (n = 46) and buprenorphine (n = 25) patients, and non-opioid-dependent controls (n = 95). Subjects were genotyped at the DRD2 TaqI A locus using PCR amplification followed by TaqI restriction enzyme digestion and gel electrophoresis. For methadone and buprenorphine subjects, heroin use (prior to treatment), treatment outcomes, and withdrawal occurrence were determined from comprehensive case notes. No significant differences in A(1) allele frequency (%) were observed between: methadone (19.6%), buprenorphine (18.0%), and control (17.9%) groups (P > 0.7); successful and poor treatment outcome groups, methadone: 20.0% and 19.2%, respectively (P = 1.0); buprenorphine: 18.4% and 20.0%, respectively (P = 1.0). Also, there were no significant relationships between TaqI A genotype and prior heroin use (P = 0.47). However, among the successful methadone subjects, significantly fewer A(1) allele carriers experienced withdrawal than non-A(1) carriers (P = 0.04). In conclusion, the DRD2 genotype effects did not affect opioid maintenance treatment outcomes. This suggests the need for a further prospective investigation into the role of the DRD2 A(1) allele in heroin use and response to maintenance pharmacotherapies for opioid dependence.

Impact of DRD2/ANKK1 and COMT Polymorphisms on Attention and Cognitive Functions in Schizophrenia.

PubMed

Nkam, Irene; Ramoz, Nicolas; Breton, Florence; Mallet, Jasmina; Gorwood, Philip; Dubertret, Caroline

2017-01-01

Cognitive deficits such as poor selective attention and executive functions decline have been reported in patients with schizophrenia. Many studies have emphasized the role of dopamine in regulating cognitive functions in the general population as well as in schizophrenia. However, the relationship between cognitive processes, schizophrenia and dopaminergic candidate genes is an original approach given interesting results. The purpose of the current exploratory study was to examine the interaction of dopaminergic genes (coding for dopamine receptor D2, DRD2, and for Catecholamine-O-Methyl-Transferase, COMT) with the diagnostic of schizophrenia in (i) the executive control of attention, (ii) selective attention, and (iii) executive functions. We recruited 52 patients with schizophrenia and 53 healthy controls who performed the Stroop Color-Word Test, the Attention Network Test and the Wisconsin Card Sorting test. Four single nucleotide polymorphisms (SNPs) in the DRD2 gene (rs6275, rs6277, rs2242592 and rs1800497) and two SNPs in the COMT gene (rs4680 and rs165599) have been genotyped. Patients with schizophrenia performed significantly worse than controls in all cognitive performance, taking into account demographic variables. A significant gene by disease interaction was found for the Stroop interference (p = 0.002) for rs6275 of the DRD2 gene. The COMT Val/Val genotype and schizophrenia were associated with increased number of perseverative errors (p = 0.01). In our study, the DRD2 gene is involved in attention while the COMT gene is implicated in executive functions in patients with schizophrenia.

The Dopamine Receptor D4 Gene ("DRD4") Moderates Family Environmental Effects on ADHD

ERIC Educational Resources Information Center

Martel, Michelle M.; Nikolas, Molly; Jernigan, Katherine; Friderici, Karen; Waldman, Irwin; Nigg, Joel T.

2011-01-01

Attention-Deficit/Hyperactivity Disorder (ADHD) is a prime candidate for exploration of gene-by-environment interaction (i.e., G x E), particularly in relation to dopamine system genes, due to strong evidence that dopamine systems are dysregulated in the disorder. Using a G x E design, we examined whether the "DRD4" promoter 120-bp tandem repeat…

Dopamine D4 receptor gene and religious affiliation correlate with dictator game altruism in males and not females: evidence for gender-sensitive gene × culture interaction.

PubMed

Jiang, Yushi; Bachner-Melman, Rachel; Chew, Soo Hong; Ebstein, Richard P

2015-01-01

On a large sample of 2288 Han Chinese undergraduates, we investigated how religion and DRD4 are related to human altruistic giving behavior as measured with the Andreoni-Miller Dictator Game. This game enables us to clearly specify (non-)selfishness, efficiency, and fairness motives for sharing. Participants were further classified into religious categories (Christian, Buddhist-Tao, and No Religion) based on self-reports, and genotyped for the dopamine D4 receptor (DRD4) gene exon III VNTR. Our analysis revealed a significant interaction between religion and DRD4 correlated with giving behavior solely among males: Whereas no significant association between religion and sharing decisions was observed in the majority 4R/4R genotype group, a significant difference in giving behavior between Christian and non-Christian males was seen in the non-4R/4R group, with Christian men being overall more altruistic (less selfish and fairer) than non-Christian men. These results support the vantage sensitivity hypothesis regarding DRD4 that the non-4R/4R "susceptibility" genotype is more responsive to a positive environment provided by some religions.

Dopamine D4 receptor gene and religious affiliation correlate with dictator game altruism in males and not females: evidence for gender-sensitive gene × culture interaction

PubMed Central

Jiang, Yushi; Bachner-Melman, Rachel; Chew, Soo Hong; Ebstein, Richard P.

2015-01-01

On a large sample of 2288 Han Chinese undergraduates, we investigated how religion and DRD4 are related to human altruistic giving behavior as measured with the Andreoni-Miller Dictator Game. This game enables us to clearly specify (non-)selfishness, efficiency, and fairness motives for sharing. Participants were further classified into religious categories (Christian, Buddhist-Tao, and No Religion) based on self-reports, and genotyped for the dopamine D4 receptor (DRD4) gene exon III VNTR. Our analysis revealed a significant interaction between religion and DRD4 correlated with giving behavior solely among males: Whereas no significant association between religion and sharing decisions was observed in the majority 4R/4R genotype group, a significant difference in giving behavior between Christian and non-Christian males was seen in the non-4R/4R group, with Christian men being overall more altruistic (less selfish and fairer) than non-Christian men. These results support the vantage sensitivity hypothesis regarding DRD4 that the non-4R/4R “susceptibility” genotype is more responsive to a positive environment provided by some religions. PMID:26441510

Disentangling the relative effects of bushmeat availability on human nutrition in central Africa.

PubMed

Fa, John E; Olivero, Jesús; Real, Raimundo; Farfán, Miguel A; Márquez, Ana L; Vargas, J Mario; Ziegler, Stefan; Wegmann, Martin; Brown, David; Margetts, Barrie; Nasi, Robert

2015-02-02

We studied links between human malnutrition and wild meat availability within the Rainforest Biotic Zone in central Africa. We distinguished two distinct hunted mammalian diversity distributions, one in the rainforest areas (Deep Rainforest Diversity, DRD) containing taxa of lower hunting sustainability, the other in the northern rainforest-savanna mosaic, with species of greater hunting potential (Marginal Rainforest Diversity, MRD). Wild meat availability, assessed by standing crop mammalian biomass, was greater in MRD than in DRD areas. Predicted bushmeat extraction was also higher in MRD areas. Despite this, stunting of children, a measure of human malnutrition, was greater in MRD areas. Structural equation modeling identified that, in MRD areas, mammal diversity fell away from urban areas, but proximity to these positively influenced higher stunting incidence. In DRD areas, remoteness and distance from dense human settlements and infrastructures explained lower stunting levels. Moreover, stunting was higher away from protected areas. Our results suggest that in MRD areas, forest wildlife rational use for better human nutrition is possible. By contrast, the relatively low human populations in DRD areas currently offer abundant opportunities for the continued protection of more vulnerable mammals and allow dietary needs of local populations to be met.

Disentangling the relative effects of bushmeat availability on human nutrition in central Africa

NASA Astrophysics Data System (ADS)

Fa, John E.; Olivero, Jesús; Real, Raimundo; Farfán, Miguel A.; Márquez, Ana L.; Vargas, J. Mario; Ziegler, Stefan; Wegmann, Martin; Brown, David; Margetts, Barrie; Nasi, Robert

2015-02-01

We studied links between human malnutrition and wild meat availability within the Rainforest Biotic Zone in central Africa. We distinguished two distinct hunted mammalian diversity distributions, one in the rainforest areas (Deep Rainforest Diversity, DRD) containing taxa of lower hunting sustainability, the other in the northern rainforest-savanna mosaic, with species of greater hunting potential (Marginal Rainforest Diversity, MRD). Wild meat availability, assessed by standing crop mammalian biomass, was greater in MRD than in DRD areas. Predicted bushmeat extraction was also higher in MRD areas. Despite this, stunting of children, a measure of human malnutrition, was greater in MRD areas. Structural equation modeling identified that, in MRD areas, mammal diversity fell away from urban areas, but proximity to these positively influenced higher stunting incidence. In DRD areas, remoteness and distance from dense human settlements and infrastructures explained lower stunting levels. Moreover, stunting was higher away from protected areas. Our results suggest that in MRD areas, forest wildlife rational use for better human nutrition is possible. By contrast, the relatively low human populations in DRD areas currently offer abundant opportunities for the continued protection of more vulnerable mammals and allow dietary needs of local populations to be met.

Population-based case-control study of DRD2 gene polymorphisms and alcoholism.

PubMed

Bhaskar, L V K S; Thangaraj, K; Non, A L; Singh, Lalji; Rao, V R

2010-10-01

Several independent lines of evidence for genetic contributions to vulnerability to alcoholism exist. Dopamine is thought to play a major role in the mechanism of reward and reinforcement in response to alcohol. D2 dopamine receptor (DRD2) gene has been among the stronger candidate genes implicated in alcoholism. In this study, alcohol use was assessed in 196 randomly selected Kota individuals of Nilgiri Hills, South India. Six DRD2 SNPs were assessed in 81 individuals with alcoholism and 151 controls to evaluate the association between single nucleotide polymorphisms (SNPs) and alcoholism. Of the three models (dominant, recessive, and additive) tested for association between alcoholism and DRD2 SNPs, only the additive model shows association for three loci (rs1116313, TaqID, and rs2734835). Of six studied polymorphisms, five are in strong linkage disequilibrium forming onesingle haplotype block. Though the global haplotype analysis with these five SNPs was not significant, haplotype analysis using all six SNPs yielded a global P value of .033, even after adjusting for age. These findings support the importance of dopamine receptor gene polymorphisms in alcoholism. Further studies to replicate these findings in different populations are needed to confirm these results.

The Dopamine D2 Receptor Gene, Perceived Parental Support, and Adolescent Loneliness: Longitudinal Evidence for Gene-Environment Interactions

ERIC Educational Resources Information Center

van Roekel, Eeske; Goossens, Luc; Scholte, Ron H. J.; Engels, Rutger C. M. E.; Verhagen, Maaike

2011-01-01

Background: Loneliness is a common problem in adolescence. Earlier research focused on genes within the serotonin and oxytocin systems, but no studies have examined the role of dopamine-related genes in loneliness. In the present study, we focused on the dopamine D2 receptor gene (DRD2). Methods: Associations among the DRD2, sex, parental support,…

Moderator Effects of Working Memory on the Stability of ADHD Symptoms by Dopamine Receptor Gene Polymorphisms during Development

ERIC Educational Resources Information Center

Trampush, Joey W.; Jacobs, Michelle M.; Hurd, Yasmin L.; Newcorn, Jeffrey H.; Halperin, Jeffrey M.

2014-01-01

We tested the hypothesis that dopamine D1 and D2 receptor gene (DRD1 and DRD2, respectively) polymorphisms and the development of working memory skills can interact to influence symptom change over 10 years in children with attention-deficit/hyperactivity disorder (ADHD). Specifically, we examined whether improvements in working memory maintenance…

A DRD4 Gene by Maternal Sensitivity Interaction Predicts Risk for Overweight or Obesity in Two Independent Cohorts of Preschool Children

ERIC Educational Resources Information Center

Levitan, Robert D.; Jansen, Pauline; Wendland, Barbara; Tiemeier, Henning; Jaddoe, Vincent W.; Silveira, Patricia P.; Kennedy, James L.; Atkinson, Leslie; Fleming, Alison; Sokolowski, Marla; Gaudreau, Helene; Steiner, Meir; Dubé, Laurette; Hamilton, Jill; Moss, Ellen; Wazana, Ashley; Meaney, Michael

2017-01-01

Background: Recent evidence suggests that early exposure to low maternal sensitivity is a risk factor for obesity in children and adolescents. A separate line of study shows that the seven-repeat (7R) allele of the dopamine-4 receptor gene (DRD4) increases susceptibility to environmental factors including maternal sensitivity. The current study…

Gene-Environment Contributions to the Development of Infant Vagal Reactivity: The Interaction of Dopamine and Maternal Sensitivity

ERIC Educational Resources Information Center

Propper, Cathi; Moore, Ginger A.; Mills-Koonce, W. Roger; Halpern, Carolyn Tucker; Hill-Soderlund, Ashley L.; Calkins, Susan D.; Carbone, Mary Anna; Cox, Martha

2008-01-01

This study investigated dopamine receptor genes ("DRD2" and "DRD4") and maternal sensitivity as predictors of infant respiratory sinus arrhythmia (RSA) and RSA reactivity, purported indices of vagal tone and vagal regulation, in a challenge task at 3, 6, and 12 months in 173 infant-mother dyads. Hierarchical linear modeling (HLM) revealed that at…

Dopaminergic, Serotonergic, and Oxytonergic Candidate Genes Associated with Infant Attachment Security and Disorganization? In Search of Main and Interaction Effects

ERIC Educational Resources Information Center

Luijk, Maartje P. C. M.; Roisman, Glenn I.; Haltigan, John D.; Tiemeier, Henning; Booth-LaForce, Cathryn; van IJzendoorn, Marinus H.; Belsky, Jay; Uitterlinden, Andre G.; Jaddoe, Vincent W. V.; Hofman, Albert; Verhulst, Frank C.; Tharner, Anne; Bakermans-Kranenburg, Marian J.

2011-01-01

Background and methods: In two birth cohort studies with genetic, sensitive parenting, and attachment data of more than 1,000 infants in total, we tested main and interaction effects of candidate genes involved in the dopamine, serotonin, and oxytocin systems ("DRD4", "DRD2", "COMT", "5-HTT", "OXTR") on attachment security and disorganization.…

Argument within a Scientific Debate: The Case of the DRD2 A1 Allele as a Gene for Alcoholism.

ERIC Educational Resources Information Center

Wastyn, Ronald O.; Wastyn, M. Linda

1997-01-01

Investigates how opposing parties advanced arguments to the scientific community about the validity of DRD2 A1 allele as a gene causing alcoholism. Demonstrates to what extent scientists debate each other in journals by advancing opposing viewpoints with rigor and insight. Reveals what it means when scientists label a discovery in terms of finding…

Use of micro-positron emission tomography with (18)F-fallypride to measure the levels of dopamine receptor-D2 and (18)F-FDG as molecular imaging tracer in the pituitary glands and prolactinomas of Fischer-344 rats.

PubMed

Li, Ping; Gui, Songbai; Cao, Lei; Gao, Hua; Bai, Jiwei; Li, Chuzhong; Zhang, Yazhuo

2016-01-01

Dopamine receptor-D2 (DRD2) is the most important drug target in prolactinoma. The aim of this current study was to investigate the role of using micro-positron emission tomography (micro-PET) with (18)F-fallypride and (18)F-fluorodeoxyglucose ((18)F-FDG) as molecular imaging tracer in the pituitary glands and prolactinomas of Fischer-344 (F344) rats and detect the difference of the levels of DRD2 in the pituitary glands and prolactinomas of F344 rat prolactinoma models. Female F344 rat prolactinoma models were established by subcutaneous administration of 15 mg 17β-estradiol for 8 weeks. The growth of tumors was monitored by the small-animal magnetic resonance imaging and micro-PET. A series of molecular biological experiments were also performed 4 and 6 weeks after pump implantation. The micro-PET molecular imaging with (18)F-fallypride revealed a decreased expression of DRD2 in F344 rat prolactinoma models, but the micro-PET molecular imaging with (18)F-FDG presented an increased uptake in the prolactinoma compared with the pituitary gland. A decreasing trend of levels of DRD2 in F344 rat prolactinoma models was also detected by molecular biological experiments. From this, we can conclude that micro-PET with (18)F-fallypride and (18)F-FDG can be used to assess tumorigenesis of the prolactinomas in vivo and molecular imaging detection of DRD2 level in prolactinoma may be an indication of treatment effect in the animal experiment.

Real-time assessment of alcohol craving and naltrexone treatment responsiveness in a randomized clinical trial.

PubMed

Miranda, Robert; Treloar Padovano, Hayley; Gray, Joshua C; Wemm, Stephanie E; Blanchard, Alexander

2018-08-01

This secondary data analysis examined whether and how the dopamine receptor D 4 gene (DRD4) influenced naltrexone treatment responsiveness in a randomized clinical trial. We leveraged intensive experience sampling methods to test the hypothesis that craving recorded at drinking and non-drinking moments would mediate naltrexone effects on the likelihood of heavy drinking, but only among carriers of the DRD4 long (DRD4-L) allele. Participants (M age =29.8years, SD=12.1) were non-treatment seeking heavy drinkers (n=104, 54.8% female, 61.5% alcohol dependent) randomized to 3weeks of daily naltrexone (50mg) or placebo. During these 3weeks, participants used handheld electronic devices to complete real-time reports of alcohol use and craving multiple times per day in their natural environments. This approach afforded intensive repeated assessment of focal variables and provided in-the-moment data to test whether craving when not drinking or early in drinking episodes explained naltrexone effects on drinking. Moderated-mediation multilevel structural equation models showed that craving during non-drinking moments mediated the treatment effect of naltrexone on heavy drinking but only among carriers of the DRD4-L allele. The same pattern of associations was not shown when evaluating craving while participants were consuming alcoholic beverages. Findings provide the first in vivo evidence that, among carriers of the DRD4-L allele, naltrexone blunts craving in real-world settings, and this effect in turn reduces the likelihood of heavy drinking. This work highlights the utility of EMA methods for elucidating how treatments work and further demonstrates the importance of genetic factors for understanding individual differences in pharmacotherapy responsiveness. Copyright © 2018 Elsevier Ltd. All rights reserved.

Linguistic Grammar Learning and DRD2-TAQ-IA Polymorphism

PubMed Central

Wong, Patrick C. M.; Ettlinger, Marc; Zheng, Jing

2013-01-01

As research into the neurobiology of language has focused primarily on the systems level, fewer studies have examined the link between molecular genetics and normal variations in language functions. Because the ability to learn a language varies in adults and our genetic codes also vary, research linking the two provides a unique window into the molecular neurobiology of language. We consider a candidate association between the dopamine receptor D2 gene (DRD2) and linguistic grammar learning. DRD2-TAQ-IA polymorphism (rs1800497) is associated with dopamine receptor D2 distribution and dopamine impact in the human striatum, such that A1 allele carriers show reduction in D2 receptor binding relative to carriers who are homozygous for the A2 allele. The individual differences in grammatical rule learning that are particularly prevalent in adulthood are also associated with striatal function and its role in domain-general procedural memory. Therefore, we reasoned that procedurally-based grammar learning could be associated with DRD2-TAQ-IA polymorphism. Here, English-speaking adults learned artificial concatenative and analogical grammars, which have been respectively associated with procedural and declarative memory. Language learning capabilities were tested while learners’ neural hemodynamic responses were simultaneously measured by fMRI. Behavioral learning and brain activation data were subsequently compared with the learners’ DRD2 (rs1800497) genotype. Learners who were homozygous for the A2 allele were better at concatenative (but not analogical) grammar learning and had higher striatal responses relative to those who have at least one A1 allele. These results provide preliminary evidence for the neurogenetic basis of normal variations in linguistic grammar learning and its link to domain-general functions. PMID:23741438

Cannabis use by women during pregnancy does not influence infant DNA methylation of the dopamine receptor DRD4.

PubMed

Fransquet, Peter D; Hutchinson, Delyse; Olsson, Craig A; Allsop, Steve; Elliott, Elizabeth J; Burns, Lucinda; Mattick, Richard; Saffery, Richard; Ryan, Joanne

2017-11-01

Maternal cannabis use in pregnancy is linked with long-term adverse behavioral outcomes in offspring. Epigenetic processes established in utero that affect dopaminergic (reward) signaling may mediate risks. Associations between cannabis use and offspring DNA methylation have not been investigated; however, maternal tobacco smoking in pregnancy is associated with distinct patterns of DNA methylation at birth and beyond. To determine whether maternal cannabis use is associated with methylation of the dopamine receptor gene DRD4 promoter in infants. Mothers in the Triple B study provided detailed information on drug use in each trimester of pregnancy. Buccal swabs were collected from neonates at 8 weeks (n = 804, 51.7% male, and 48.3% female). DRD4 promoter DNA methylation was measured using SEQUENOM MassARRAY. Fifty-seven of the women in the study reported drug use during pregnancy, of whom 44 used cannabis. Of 19 cytosine-phosphate-guanine dinucleotides (CpG) units tested in DRD4, gestational cannabis use was associated with offspring methylation at 1 CpG unit in multivariate models (β + 1.48, CI: 0.02 to 2.93, and p = 0.047). At another site there was weak evidence that both cannabis and other drug use were independently associated with increased methylation, while the association with tobacco was in the reverse direction (cannabis use β + 0.67, CI: -0.12 to 1.46, and p = 0.09; other drug use β + 1.11, CI: 0.17 to 2.05, and p = 0.02; tobacco use β -0.41, CI: -0.85 to 0.03, and p = 0.07). None of the associations would remain significant after correction for multiple testing. There is no strong evidence that maternal cannabis use in pregnancy is associated with offspring DRD4 methylation.

A preliminary study: novelty seeking, frontal executive function, and dopamine receptor (D2) TaqI A gene polymorphism in patients with methamphetamine dependence.

PubMed

Han, Doug Hyun; Yoon, Sujung J; Sung, Young Hoon; Lee, Young Sik; Kee, Baik Seok; Lyoo, In Kyoon; Renshaw, Perry F; Cho, Soo Churl

2008-01-01

Dopamine receptor polymorphisms have been associated with specific patterns of novelty seeking (NS) temperamental nature and frontal executive function. In addition, carriers of dopamine receptor type 2 (DRD2)-TaqI A1 have been hypothesized to be potentially vulnerable to addictive behaviors. In the present study, the association between dopamine D2 polymorphisms, NS, and frontal executive function was studied. Thirty-seven methamphetamine (MA)-dependent subjects and 40 healthy comparison subjects participated in the current study. The severity of addiction, NS temperament, and frontal executive functions were measured using the Addiction Severity Index, the NS subscale in the Temperament and Character Inventory, and the Wisconsin Card Sorting Test, respectively. All subjects were genotyped with regard to DRD2-TaqI polymorphisms. The prevalence of DRD2-TaqI A1 allele polymorphisms was greater in the MA-abuser group than in the comparison group. Patients with MA dependence also had higher NS characteristics and high scores in total trials, errors, and perseverative errors of the Wisconsin Card Sorting Test than comparison subjects. Within patients with MA dependence, the subgroup of DRD2-TaqI A1 carrier had greater NS scores relative to those without, whereas there was only a trend level of lower frontal executive function in the first subgroup. In the present study, the MA-dependent patients with DRD2-TaqI A1 allele had significantly greater NS scores and lower frontal executive function with a trend level than those without. These preliminary results suggest that MA-dependent patients may have the possibility of genetic and biogenic vulnerability to MA.

Combined epigenetic and intraspecific variation of the DRD4 and SERT genes influence novelty seeking behavior in great tit Parus major

PubMed Central

Riyahi, Sepand; Sánchez-Delgado, Marta; Calafell, Francesc; Monk, David; Senar, Juan Carlos

2015-01-01

DNA methylation is one of the main epigenetic mechanisms that can regulate gene expression and is an important means for creating phenotypic variation. In the present study, we performed methylation profiling of 2 candidate genes for personality traits, namely DRD4 and SERT, in the great tit Parus major to ascertain whether personality traits and behavior within different habitats have evolved with the aid of epigenetic variation. We applied bisulphite PCR and strand-specific sequencing to determine the methylation profile of the CpG dinucleotides in the DRD4 and SERT promoters and also in the CpG island overlapping DRD4 exon 3. Furthermore, we performed pyrosequencing to quantify the total methylation levels at each CpG location. Our results indicated that methylation was ∼1–4% higher in urban than in forest birds, for all loci and tissues analyzed, suggesting that this epigenetic modification is influenced by environmental conditions. Screening of genomic DNA sequence revealed that the SERT promoter is CpG poor region. The methylation at a single CpG dinucleotide located 288 bp from the transcription start site was related to exploration score in urban birds. In addition, the genotypes of the SERT polymorphism SNP234 located within the minimal promoter were significantly correlated with novelty seeking behavior in captivity, with the allele increasing this behavior being more frequent in urban birds. As a conclusion, it seems that both genetic and methylation variability of the SERT gene have an important role in shaping personality traits in great tits, whereas genetic and methylation variation at the DRD4 gene is not strongly involved in behavior and personality traits. PMID:25933062

Tyrosine hydroxylase and dopamine D4 receptor allelic distribution in Scandinavian chronic alcoholics.

PubMed

Geijer, T; Jönsson, E; Neiman, J; Persson, M L; Brené, S; Gyllander, A; Sedvall, G; Rydberg, U; Wasserman, D; Terenius, L

1997-02-01

Associations of polymorphic genetic markers at the tyrosine hydroxylase (TH) and dopamine D4 receptor (DRD4) loci were examined in Scandinavian chronic alcoholics (n = 72) and control subjects (n = 67). Patients were divided into subgroups with regard to the presence of parental alcoholism and age of onset. Neither the TH nor the DRD4 allele distributions were significantly different when alcoholic samples were compared with control subjects. However, a tendency to high prevalence for 1 of the 5 TH alleles assayed (TH-K3) was observed in a subsample of 44 alcoholics characterized by late onset when compared with control subjects (27.3% vs. 10.6%, p = 0.041). Results suggest that no major influence on alcoholism is exerted through genes associated with the DRD4 or TH allelic markers examined.

Brief Report: The Dopamine-3-Receptor Gene ("DRD3") Is Associated with Specific Repetitive Behavior in Autism Spectrum Disorder (ASD)

ERIC Educational Resources Information Center

Staal, Wouter G.; de Krom, Mariken; de Jonge, Maretha V.

2012-01-01

Recently the "DRD3" gene has been associated with ASD in two independent samples. Follow up analysis of the risk allele of the SNP rs167771 in 91 subjects revealed a significant association with a specific type of repetitive behavior: the factor "insistence on sameness" (IS) derived from the Autism Diagnostic Interview. This risk allele was…

Genome-wide association study of aggressive behaviour in chicken.

PubMed

Li, Zhenhui; Zheng, Ming; Abdalla, Bahareldin Ali; Zhang, Zhe; Xu, Zhenqiang; Ye, Qiao; Xu, Haiping; Luo, Wei; Nie, Qinghua; Zhang, Xiquan

2016-08-03

In the poultry industry, aggressive behaviour is a large animal welfare issue all over the world. To date, little is known about the underlying genetics of the aggressive behaviour. Here, we performed a genome-wide association study (GWAS) to explore the genetic mechanism associated with aggressive behaviour in chickens. The GWAS results showed that a total of 33 SNPs were associated with aggressive behaviour traits (P < 4.6E-6). rs312463697 on chromosome 4 was significantly associated with aggression (P = 2.10905E-07), and it was in the intron region of the sortilin-related VPS10 domain containing receptor 2 (SORCS2) gene. In addition, biological function analysis of the nearest 26 genes around the significant SNPs was performed with Ingenuity Pathway Analysis. An interaction network contained 17 genes was obtained and SORCS2 was involved in this network, interacted with nerve growth factor (NGF), nerve growth factor receptor (NGFR), dopa decarboxylase (L-dopa) and dopamine. After knockdown of SORCS2, the mRNA levels of NGF, L-dopa and dopamine receptor genes DRD1, DRD2, DRD3 and DRD4 were significantly decreased (P < 0.05). In summary, our data indicated that SORCS2 might play an important role in chicken aggressive behaviour through the regulation of dopaminergic pathways and NGF.

Motor Impulsivity in Parkinson Disease: Associations with COMT and DRD2 polymorphisms

PubMed Central

Ziegler, David A.; Ashourian, Paymon; Wonderlick, Julien S.; Sarokhan, Alison K.; Prelec, Drazen; Scherzer, Clemens R.; Corkin, Suzanne

2017-01-01

Parkinson disease (PD) is an age-related degenerative disease of the brain, characterized by motor, cognitive, and psychiatric symptoms. Neurologists and neuroscientists now understand that several symptoms of the disease, including hallucinations and impulse control behaviors, stem from the dopaminergic medications used to control the motor aspects of PD. Converging evidence from animals and humans suggests that individual differences in the genes that affect the dopamine system influence the response of PD patients to dopaminergic medication. In this study, we tested the hypothesis that patients taking dopamine replacement therapy who carry candidate alleles that increase dopamine signaling exhibit greater amounts of motor impulsivity. We examined the relation between inhibitory ability (measured by the Stop Signal Task) and polymorphisms of COMT Val158Met and DRD2 C957T in patients with idiopathic PD. On the Stop Signal Task, carriers of COMT Val/Met and Met/Met genotypes were more impulsive than Val/Val carriers, but we did not find a link between DRD2 polymorphisms and inhibitory ability. These results support the hypothesis that the Met allele of COMT confers an increased risk for behavioral impulsivity in PD patients, whereas DRD2 polymorphisms appear to be less important in determining whether PD patients exhibit a dopamine overdose in the form of motor impulsivity. PMID:24749760

Interaction between DRD2 variation and sound environment on mood and emotion-related brain activity.

PubMed

Quarto, T; Fasano, M C; Taurisano, P; Fazio, L; Antonucci, L A; Gelao, B; Romano, R; Mancini, M; Porcelli, A; Masellis, R; Pallesen, K J; Bertolino, A; Blasi, G; Brattico, E

2017-01-26

Sounds, like music and noise, are capable of reliably affecting individuals' mood and emotions. However, these effects are highly variable across individuals. A putative source of variability is genetic background. Here we explored the interaction between a functional polymorphism of the dopamine D2 receptor gene (DRD2 rs1076560, G>T, previously associated with the relative expression of D2S/L isoforms) and sound environment on mood and emotion-related brain activity. Thirty-eight healthy subjects were genotyped for DRD2 rs1076560 (G/G=26; G/T=12) and underwent functional magnetic resonance imaging (fMRI) during performance of an implicit emotion-processing task while listening to music or noise. Individual variation in mood induction was assessed before and after the task. Results showed mood improvement after music exposure in DRD2GG subjects and mood deterioration after noise exposure in GT subjects. Moreover, the music, as opposed to noise environment, decreased the striatal activity of GT subjects as well as the prefrontal activity of GG subjects while processing emotional faces. These findings suggest that genetic variability of dopamine receptors affects sound environment modulations of mood and emotion processing. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Genome-Wide Supported Risk Variants in MIR137, CACNA1C, CSMD1, DRD2, and GRM3 Contribute to Schizophrenia Susceptibility in Pakistani Population.

PubMed

Fatima, Ambrin; Farooq, Muhammad; Abdullah, Uzma; Tariq, Muhammad; Mustafa, Tanveer; Iqbal, Muhammad; Tommerup, Niels; Mahmood Baig, Shahid

2017-09-01

Schizophrenia is a chronic neuropsychiatric disease afflicting around 1.1% of the population worldwide. Recently, MIR137 , CACNA1C , CSMD1 , DRD2 , and GRM3 have been reported as the most robustly emerging candidates involved in the etiology of schizophrenia. In this case control study, we performed an association analysis of rs1625579 ( MIR137 ), rs1006737, rs4765905 ( CACNA1C ), rs10503253 ( CSMD1 ), rs1076560 ( DRD2 ), rs12704290, rs6465084, and rs148754219 ( GRM3 ) in Pakistani population. Schizophrenia was diagnosed on the basis of the Diagnostic and Statistical Manual of Mental Disorders 4th ed (DSM-IV). Detailed clinical information, family history of all patients and healthy controls were collected. RFLP based case control association study was performed in a Pakistani cohort of 508 schizophrenia patients and 300 healthy control subjects. Alleles and genotype frequencies were calculated using SPSS. A significant difference in the genotype and allele frequencies for rs4765905, rs1076560 and rs6465084 were found between the patients and controls (p=0.000). This study provides substantial evidence supporting the role of CACNA1C , GRM3 and DRD2 as schizophrenia susceptibility genes in Pakistani population.

Structural signatures of DRD4 mutants revealed using molecular dynamics simulations: Implications for drug targeting.

PubMed

Jatana, Nidhi; Thukral, Lipi; Latha, N

2016-01-01

Human Dopamine Receptor D4 (DRD4) orchestrates several neurological functions and represents a target for many psychological disorders. Here, we examined two rare variants in DRD4; V194G and R237L, which elicit functional alterations leading to disruption of ligand binding and G protein coupling, respectively. Using atomistic molecular dynamics (MD) simulations, we provide in-depth analysis to reveal structural signatures of wild and mutant complexes with their bound agonist and antagonist ligands. We constructed intra-protein network graphs to discriminate the global conformational changes induced by mutations. The simulations also allowed us to elucidate the local side-chain dynamical variations in ligand-bound mutant receptors. The data suggest that the mutation in transmembrane V (V194G) drastically disrupts the organization of ligand binding site and causes disorder in the native helical arrangement. Interestingly, the R237L mutation leads to significant rewiring of side-chain contacts in the intracellular loop 3 (site of mutation) and also affects the distant transmembrane topology. Additionally, these mutations lead to compact ICL3 region compared to the wild type, indicating that the receptor would be inaccessible for G protein coupling. Our findings thus reveal unreported structural determinants of the mutated DRD4 receptor and provide a robust framework for design of effective novel drugs.

No Association between Personality and Candidate Gene Polymorphisms in a Wild Bird Population

PubMed Central

Durieux, Gillian; Burke, Terry; Dugdale, Hannah L.

2015-01-01

Consistency of between-individual differences in behaviour or personality is a phenomenon in populations that can have ecological consequences and evolutionary potential. One way that behaviour can evolve is to have a genetic basis. Identifying the molecular genetic basis of personality could therefore provide insight into how and why such variation is maintained, particularly in natural populations. Previously identified candidate genes for personality in birds include the dopamine receptor D4 (DRD4), and serotonin transporter (SERT). Studies of wild bird populations have shown that exploratory and bold behaviours are associated with polymorphisms in both DRD4 and SERT. Here we tested for polymorphisms in DRD4 and SERT in the Seychelles warbler (Acrocephalus sechellensis) population on Cousin Island, Seychelles, and then investigated correlations between personality and polymorphisms in these genes. We found no genetic variation in DRD4, but identified four polymorphisms in SERT that clustered into five haplotypes. There was no correlation between bold or exploratory behaviours and SERT polymorphisms/haplotypes. The null result was not due to lack of power, and indicates that there was no association between these behaviours and variation in the candidate genes tested in this population. These null findings provide important data to facilitate representative future meta-analyses on candidate personality genes. PMID:26473495

Steep Delay Discounting and Addictive Behavior: A Meta-Analysis of Continuous Associations

PubMed Central

Amlung, Michael; Vedelago, Lana; Acker, John; Balodis, Iris; MacKillop, James

2016-01-01

Aims To synthesize continuous associations between delayed reward discounting (DRD) and both addiction severity and quantity-frequency (QF); to examine moderators of these relationships; and to investigate publication bias. Methods Meta-analysis of published studies examining continuous associations between DRD and addictive behaviors. Published, peer-reviewed studies on addictive behaviors (alcohol, tobacco, cannabis, stimulants, opiates, and gambling) were identified via PubMed, MEDLINE, and PsycInfo. Studies were restricted to DRD measures of monetary gains. Random effects meta-analysis was conducted using Pearson’s r as the effect size. Publication bias was evaluated using fail-safe N, Begg-Mazumdar and Egger’s tests, meta-regression of publication year and effect size, and imputation of missing studies. Results The primary meta-analysis revealed a small magnitude effect size that was highly significant (r = 0.14, p < 10−14). Significantly larger effect sizes were observed for studies examining severity compared with QF (p = 0.01), but not between the type of addictive behavior (p = 0.30) or DRD assessment (p = 0.90). Indices of publication bias suggested a modest impact of unpublished findings. Conclusions Delayed reward discounting is robustly associated with continuous measures of addiction severity and quantity-frequency. This relation is generally robust across type of addictive behavior and delayed reward discounting assessment modality. PMID:27450931

Autosomal-dominant GTPCH1-deficient DRD: clinical characteristics and long-term outcome of 34 patients.

PubMed

Trender-Gerhard, I; Sweeney, M G; Schwingenschuh, P; Mir, P; Edwards, M J; Gerhard, A; Polke, J M; Hanna, M G; Davis, M B; Wood, N W; Bhatia, K P

2009-08-01

An autosomal dominantly inherited defect in the GCH1 gene that encodes guanosine triphosphate cyclohydrolase 1 (GTPCH1) is the most common cause of dopa-responsive dystonia (DRD). A classic phenotype of young-onset lower-limb dystonia, diurnal fluctuations and excellent response to levodopa has been well recognised in association with GCH1 mutations, and rare atypical presentations have been reported. However, a number of clinical issues remain unresolved including phenotypic variability, long-term response to levodopa and associated non-motor symptoms, and there are limited data on long-term follow-up of genetically proven cases. A detailed clinical evaluation of 34 patients (19 women, 15 men), with confirmed mutations in the GCH1 gene, is presented. The classic phenotype was most frequent (n = 23), with female predominance (F:M = 16:7), and early onset (mean 4.5 years) with involvement of legs. However, a surprisingly large number of patients developed craniocervical dystonia, with spasmodic dysphonia being the predominant symptom in two subjects. A subset of patients, mainly men, presented with either a young-onset (mean 6.8 years) mild DRD variant not requiring treatment (n = 4), or with an adult-onset (mean 37 years) Parkinson disease-like phenotype (n = 4). Two siblings were severely affected with early hypotonia and delay in motor development, associated with compound heterozygous GCH1 gene mutations. The study also describes a number of supplementary features including restless-legs-like symptoms, influence of female sex hormones, predominance of tremor or parkinsonism in adult-onset cases, initial reverse reaction to levodopa, recurrent episodes of depressive disorder and specific levodopa-resistant symptoms (writer's cramp, dysphonia, truncal dystonia). Levodopa was used effectively and safely in 20 pregnancies, and did not cause any fetal abnormalities.

The interplay of birth weight, dopamine receptor D4 gene (DRD4), and early maternal care in the prediction of disorganized attachment at 36 months of age.

PubMed

Wazana, Ashley; Moss, Ellen; Jolicoeur-Martineau, Alexis; Graffi, Justin; Tsabari, Gal; Lecompte, Vanessa; Pascuzzo, Katherine; Babineau, Vanessa; Gordon-Green, Cathryn; Mileva, Viara; Atkinson, Leslie; Minde, Klaus; Bouvette-Turcot, André Anne; Sassi, Roberto; St-André, Martin; Carrey, Normand; Matthews, Stephen; Sokolowski, Marla; Lydon, John; Gaudreau, Helene; Steiner, Meir; Kennedy, James L; Fleming, Alison; Levitan, Robert; Meaney, Michael J

2015-11-01

Disorganized attachment is an important early risk factor for socioemotional problems throughout childhood and into adulthood. Prevailing models of the etiology of disorganized attachment emphasize the role of highly dysfunctional parenting, to the exclusion of complex models examining the interplay of child and parental factors. Decades of research have established that extreme child birth weight may have long-term effects on developmental processes. These effects are typically negative, but this is not always the case. Recent studies have also identified the dopamine D4 receptor (DRD4) as a moderator of childrearing effects on the development of disorganized attachment. However, there are inconsistent findings concerning which variant of the polymorphism (seven-repeat long-form allele or non-seven-repeat short-form allele) is most likely to interact with caregiving in predicting disorganized versus organized attachment. In this study, we examined possible two- and three-way interactions and child DRD4 polymorphisms and birth weight and maternal caregiving at age 6 months in longitudinally predicting attachment disorganization at 36 months. Our sample is from the Maternal Adversity, Vulnerability and Neurodevelopment project, a sample of 650 mother-child dyads. Birth weight was cross-referenced with normative data to calculate birth weight percentile. Infant DRD4 was obtained with buccal swabs and categorized according to the presence of the putative allele seven repeat. Macroanalytic and microanalytic measures of maternal behavior were extracted from a videotaped session of 20 min of nonfeeding interaction followed by a 10-min divided attention maternal task at 6 months. Attachment was assessed at 36 months using the Strange Situation procedure, and categorized into disorganized attachment and others. The results indicated that a main effect for DRD4 and a two-way interaction of birth weight and 6-month maternal attention (frequency of maternal looking away behavior) and sensitivity predicted disorganized attachment in robust logistic regression models adjusted for social demographic covariates. Specifically, children in the midrange of birth weight were more likely to develop a disorganized attachment when exposed to less attentive maternal care. However, the association reversed with extreme birth weight (low and high). The DRD4 seven-repeat allele was associated with less disorganized attachment (protective), while non-seven-repeat children were more likely to be classified as disorganized attachment. The implications for understanding inconsistencies in the literature about which DRD4 genotype is the risk direction are also considered. Suggestions for intervention with families with infants at different levels of biological risk and caregiving risk are also discussed.

The dopamine D2 receptor gene and depressive and anxious symptoms in childhood: associations and evidence for gene–environment correlation and gene–environment interaction

PubMed Central

Hayden, Elizabeth P.; Klein, Daniel N.; Dougherty, Lea R.; Olino, Thomas M.; Laptook, Rebecca S.; Dyson, Margaret W.; Bufferd, Sara J.; Durbin, C. Emily; Sheikh, Haroon I.; Singh, Shiva M.

2012-01-01

Objectives Research implicates the A1 allele of the dopamine D2 receptor gene (DRD2) Taq1A polymorphism in the development of depression and anxiety. Furthermore, recent papers suggest that children with A1 allele of this gene may receive less positive parenting, and that the effects of this gene on child symptoms may be moderated by parenting. We sought to replicate and extend these findings using behavioral measures in a nonclinical sample of young children. Methods In a sample of 473 preschool-aged children and their mothers, structured clinical interview measures and maternal reports of child symptoms were collected, and standardized observations of parent–child interactions were conducted. Results An association was detected between the DRD2 A1 allele and symptoms of depression and anxiety indexed using interview and parent report methods. As found in previous reports, children with the DRD2 A1 allele received less supportive parenting and displayed higher levels of negative emotionality during parent–child interactions. Tests of mediation and moderation were conducted. Conclusion We found associations between the DRD2 A1 allele and early-emerging anxious and depressive symptoms in a community sample of preschool-aged children, and evidence of a gene–environment correlation and moderation of the main effect of child genotype on child symptoms by parenting. PMID:20526230

Snf2 family gene distribution in higher plant genomes reveals DRD1 expansion and diversification in the tomato genome.

PubMed

Bargsten, Joachim W; Folta, Adam; Mlynárová, Ludmila; Nap, Jan-Peter

2013-01-01

As part of large protein complexes, Snf2 family ATPases are responsible for energy supply during chromatin remodeling, but the precise mechanism of action of many of these proteins is largely unknown. They influence many processes in plants, such as the response to environmental stress. This analysis is the first comprehensive study of Snf2 family ATPases in plants. We here present a comparative analysis of 1159 candidate plant Snf2 genes in 33 complete and annotated plant genomes, including two green algae. The number of Snf2 ATPases shows considerable variation across plant genomes (17-63 genes). The DRD1, Rad5/16 and Snf2 subfamily members occur most often. Detailed analysis of the plant-specific DRD1 subfamily in related plant genomes shows the occurrence of a complex series of evolutionary events. Notably tomato carries unexpected gene expansions of DRD1 gene members. Most of these genes are expressed in tomato, although at low levels and with distinct tissue or organ specificity. In contrast, the Snf2 subfamily genes tend to be expressed constitutively in tomato. The results underpin and extend the Snf2 subfamily classification, which could help to determine the various functional roles of Snf2 ATPases and to target environmental stress tolerance and yield in future breeding.

Association of genetic variations in the serotonin and dopamine systems with aggressive behavior in the Chinese adolescent population: Single- and multiple-risk genetic variants.

PubMed

Chang, Hongjuan; Yan, Qiuge; Tang, Lina; Huang, Juan; Ma, Yuqiao; Ye, Xiaozhou; Wu, Chunxia; Wu, Linguo; Yu, Yizhen

2018-01-01

Genetic predisposition is an important factor leading to aggressive behavior. However, the relationship between genetic polymorphisms and aggressive behavior has not been elucidated. We identified candidate genes located in the dopaminergic and serotonin system (DRD3, DRD4, and FEV) that had been previously reported to be associated with aggressive behavior. We investigated 14 tag single-nucleotide polymorphisms (SNPs) using a multi-analytic strategy combining logistic regression (LR) and classification and regression tree (CART) to explore higher-order interactions between these SNPs and aggressive behavior in 318 patients and 558 controls. Both LR and CART analyses suggested that the rs16859448 polymorphism is the strongest individual factor associated with aggressive behavior risk. In CART analysis, individuals carrying the combined genotypes of rs16859448TT/GT-rs11246228CT/TT-rs3773679TT had the highest risk, while rs16859448GG-rs2134655CT had the lowest risk (OR = 5.25, 95% CI: 2.53-10.86). This study adds to the growing evidence on the association of single- and multiple-risk variants in DRD3, DRD4, and FEV with aggressive behavior in Chinese adolescents. However, the aggressive behavior scale used to diagnose aggression in this study did not account for comorbid conditions; therefore, further studies are needed to confirm our observations. Copyright © 2017 Elsevier B.V. All rights reserved.

Steep delay discounting and addictive behavior: a meta-analysis of continuous associations.

PubMed

Amlung, Michael; Vedelago, Lana; Acker, John; Balodis, Iris; MacKillop, James

2017-01-01

To synthesize continuous associations between delayed reward discounting (DRD) and both addiction severity and quantity-frequency (QF); to examine moderators of these relationships; and to investigate publication bias. Meta-analysis of published studies examining continuous associations between DRD and addictive behaviors. Published, peer-reviewed studies on addictive behaviors (alcohol, tobacco, cannabis, stimulants, opiates and gambling) were identified via PubMed, MEDLINE and PsycInfo. Studies were restricted to DRD measures of monetary gains. Random-effects meta-analysis was conducted using Pearson's r as the effect size. Publication bias was evaluated using fail-safe N, Begg-Mazumdar and Egger's tests, meta-regression of publication year and effect size and imputation of missing studies. The primary meta-analysis revealed a small magnitude effect size that was highly significant (r = 0.14, P < 10 -14 ). Significantly larger effect sizes were observed for studies examining severity compared with QF (P = 0.01), but not between the type of addictive behavior (P = 0.30) or DRD assessment (P = 0.90). Indices of publication bias suggested a modest impact of unpublished findings. Delayed reward discounting is associated robustly with continuous measures of addiction severity and quantity-frequency. This relation is generally robust across type of addictive behavior and delayed reward discounting assessment modality. © 2016 Society for the Study of Addiction.

Dopaminergic Variants in Siblings at High Risk for Autism: Associations With Initiating Joint Attention

PubMed Central

Gangi, Devon N.; Messinger, Daniel S.; Martin, Eden R.; Cuccaro, Michael L.

2016-01-01

Younger siblings of children with autism spectrum disorder (ASD; high-risk siblings) exhibit lower levels of initiating joint attention (IJA; sharing an object or experience with a social partner through gaze and/or gesture) than low-risk siblings of children without ASD. However, high-risk siblings also exhibit substantial variability in this domain. The neurotransmitter dopamine is linked to brain areas associated with reward, motivation, and attention, and common dopaminergic variants have been associated with attention difficulties. We examined whether these common dopaminergic variants, DRD4 and DRD2, explain variability in IJA in high-risk (n = 55) and low-risk (n = 38) siblings. IJA was assessed in the first year during a semi-structured interaction with an examiner. DRD4 and DRD2 genotypes were coded according to associated dopaminergic functioning to create a gene score, with higher scores indicating more genotypes associated with less efficient dopaminergic functioning. Higher dopamine gene scores (indicative of less efficient dopaminergic functioning) were associated with lower levels of IJA in the first year for high-risk siblings, while the opposite pattern emerged in low-risk siblings. Findings suggest differential susceptibility—IJA was differentially associated with dopaminergic functioning depending on familial ASD risk. Understanding genes linked to ASD-relevant behaviors in high-risk siblings will aid in early identification of children at greatest risk for difficulties in these behavioral domains, facilitating targeted prevention and intervention. PMID:26990357

The role of attachment styles in regulating the effects of dopamine on the behavior of salespersons

PubMed Central

Verbeke, Willem; Bagozzi, Richard P.; van den Berg, Wouter E.

2014-01-01

Two classic strategic orientations have been found to pervade the behavior of modern salespersons: a sales orientation (SO) where salespersons use deception or guile to get customers to buy even if they do not need a product, and a customer orientation (CO) where salespersons first attempt to discover the customer's needs and adjust their product and selling approach to meet those needs. Study 1 replicates recent research and finds that the Taq A1 variant of the DRD2 gene is not related to either sales or CO, whereas the 7-repeat variant of the DRD4 gene is related to CO but not SO. Study 2 investigates gene × phenotype explanations of orientation of salespersons, drawing upon recent research in molecular genetics and biological/psychological attachment theory. The findings show that attachment style regulates the effects of DRD2 on CO, such that greater avoidant attachment styles lead to higher CO for persons with the A2/A2 variant but neither the A1/A2 nor A1/A1 variants. Likewise, attachment style regulates the effects of DRD4 on CO, such that greater avoidant attachment styles lead to higher CO for persons with the 7-repeat variant but not other variants. No effects were found on a SO, and secure and anxious attachment styles did not function as moderators. PMID:24550811

Dopamine D4 receptor polymorphism modulates cue-elicited heroin craving in Chinese.

PubMed

Shao, Chunhong; Li, Yifeng; Jiang, Kaida; Zhang, Dandan; Xu, Yifeng; Lin, Ling; Wang, Qiuying; Zhao, Min; Jin, Li

2006-06-01

Subjective craving, which contributes to the continuation of drug use in active abuser and the occurrence of relapse in detoxified abusers, is considered to be a central phenomenon in addiction. Dopamine pathway has been implicated in the mechanism underlying the cue-elicited craving for a variety of addictive substances. The objective of this study was to test the hypothesis that heroin addicts carrying D4 dopamine receptor gene (DRD4) variable number tandem repeat (VNTR) long type allele would have higher craving after exposure to a heroin-related cue. Craving was induced by a series of exposure to neutral and heroin-related cue and were assessed in a cohort of Chinese heroin abusers (n=420) recruited from the Voluntary Drug Dependence Treatment Center at Shanghai. Significantly stronger cue-elicited heroin craving was found in individuals carrying DRD4 VNTR long type allele than the non-carriers (F=31.040, p<0.001). As for baseline craving and mean change in craving responding to neutral stimuli, no significance was found (1.06+/-0.34 vs 1.07+/-0.36, F=0.067, p=0.797 and 0.42+/-0.34 vs 0.45+/-0.37, F=0.277, p=0.599, respectively). The results of our study suggest that DRD4 VNTR polymorphism contributes to cue-elicited craving in heroin dependence, indicating DRD4 VNTR represents one of potential genetic risk factors for cue-induced craving.

Association between a promoter dopamine D2 receptor gene variant and the personality trait detachment.

PubMed

Jönsson, Erik G; Cichon, Sven; Gustavsson, J Petter; Grünhage, Frank; Forslund, Kaj; Mattila-Evenden, Marja; Rylander, Gunnar; Asberg, Marie; Farde, Lars; Propping, Peter; Nöthen, Markus M

2003-04-01

Personality traits have shown considerable heritable components. Striatal dopamine D(2) receptor density, as determined by positron-emission tomography, has been associated with detached personality, as assessed by the Karolinska Scales of Personality. A putative functional promoter polymorphism in the dopamine D(2) receptor gene (DRD2), -141C ins/del, has been associated with dopamine D(2) receptor density. In this study healthy subjects (n = 235) who filled in at least one of several personality questionnaires (Karolinska Scales of Personality, Swedish Universities Scales of Personality, Health-relevant Five-factor Personality Inventory, and Temperament and Character Inventory) were analyzed with regard to the DRD2 -141C ins/del variant. There was an association (p =.001) between the DRD2 -141C ins/del variant and Karolinska Scales of Personality Detachment scale, indicating higher scores in subjects with the -141C del variant. There were also associations between the DRD2 -141C ins/del variant and a number of Karolinska Scales of Personality and Swedish Universities Scales of Personality Neuroticism-related scales, but of these only Swedish Universities Scales of Personality Lack of Assertiveness scale (p =.001) survived correction for multiple testing. These results add further support for the involvement of dopamine D(2) receptor in certain personality traits. The results should be treated with caution until replicated.

Polymorphisms in HTR2A and DRD4 Predispose to Smoking and Smoking Quantity.

PubMed

Pérez-Rubio, Gloria; Ramírez-Venegas, Alejandra; Noé Díaz, Valeri; García Gómez, Leonor; Elvira Fabián, Karina; García Carmona, Salvador; López-Flores, Luis A; Ambrocio-Ortiz, Enrique; Contreras Romero, Rocío; Alcantar-Ayala, Noé; Sansores, Raúl H; Falfán-Valencia, Ramcés

2017-01-01

Genes encoding the receptors involved in the dopaminergic and serotonergic pathways are potential candidates in the mechanisms of nicotine addiction. To identify genetic variants in the promoter regions and exons of the DRD4 and HTR2A genes associated with tobacco smoking and the degree of nicotine addiction in Mexican mestizos. The study included 438 non-smokers (NS) and 1,157 current smokers, ranked based on their consumption of cigarettes per day (cpd): 574 heavy smokers (HS, >20 cpd) and 583 light smokers (LS, 1-10 cpd). Genotyping was performed for 4 and 8 single nucleotide polymorphisms (SNPs) in the DRD4 and HTR2A genes, respectively. The C allele of rs1800955 in DRD4 was found to be associated with cigarette smoking in the HS vs. NS and LS vs. NS comparisons (p = 2.34E-03 and p = 1.13E-03, respectively); the association was maintained in the homozygous CC genotype (p = 5.00E-04 and p = 2.00E-04, respectively). The T allele of rs6313 in HTR2A was significantly associated with cigarette smoking and a greater degree of nicotine addiction (p = 4.77E-03, OR = 1.55); the association was maintained in the homozygous genotype (TT) (p = 4.90E-03, OR = 1.96). The A allele of rs6313 was associated with cigarette smoking in the HS vs. NS comparison (p = 1.53E-02, OR = 1.36); the risk was nearly doubled in the homozygous AA genotype (p = 1.30E-03, OR = 1.83) compared with the heterozygous GA genotype (OR = 1.38). Among Mexican mestizos, the C allele of rs1800955 in the DRD4 gene and the A allele of rs6311 in the HTR2A gene are associated with cigarette smoking, whereas the T allele of rs6313 in HTR2A is associated with cigarette smoking and the degree of nicotine addiction.

Behavioral and Neural Manifestations of Reward Memory in Carriers of Low-Expressing versus High-Expressing Genetic Variants of the Dopamine D2 Receptor

PubMed Central

Richter, Anni; Barman, Adriana; Wüstenberg, Torsten; Soch, Joram; Schanze, Denny; Deibele, Anna; Behnisch, Gusalija; Assmann, Anne; Klein, Marieke; Zenker, Martin; Seidenbecher, Constanze; Schott, Björn H.

2017-01-01

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. PMID:28507526

Cannabis use by women during pregnancy does not influence infant DNA methylation of the dopamine receptor DRD4

PubMed Central

Fransquet, Peter D.; Hutchinson, Delyse; Olsson, Craig A.; Allsop, Steve; Elliott, Elizabeth J.; Burns, Lucinda; Mattick, Richard; Saffery, Richard; Ryan, Joanne

2017-01-01

ABSTRACT Background: Maternal cannabis use in pregnancy is linked with long-term adverse behavioral outcomes in offspring. Epigenetic processes established in utero that affect dopaminergic (reward) signaling may mediate risks. Associations between cannabis use and offspring DNA methylation have not been investigated; however, maternal tobacco smoking in pregnancy is associated with distinct patterns of DNA methylation at birth and beyond. Objectives: To determine whether maternal cannabis use is associated with methylation of the dopamine receptor gene DRD4 promoter in infants. Methods: Mothers in the Triple B study provided detailed information on drug use in each trimester of pregnancy. Buccal swabs were collected from neonates at 8 weeks (n = 804, 51.7% male, and 48.3% female). DRD4 promoter DNA methylation was measured using SEQUENOM MassARRAY. Results: Fifty-seven of the women in the study reported drug use during pregnancy, of whom 44 used cannabis. Of 19 cytosine-phosphate-guanine dinucleotides (CpG) units tested in DRD4, gestational cannabis use was associated with offspring methylation at 1 CpG unit in multivariate models (β + 1.48, CI: 0.02 to 2.93, and p = 0.047). At another site there was weak evidence that both cannabis and other drug use were independently associated with increased methylation, while the association with tobacco was in the reverse direction (cannabis use β + 0.67, CI: −0.12 to 1.46, and p = 0.09; other drug use β + 1.11, CI: 0.17 to 2.05, and p = 0.02; tobacco use β −0.41, CI: −0.85 to 0.03, and p = 0.07). None of the associations would remain significant after correction for multiple testing. Conclusion: There is no strong evidence that maternal cannabis use in pregnancy is associated with offspring DRD4 methylation. PMID:28448718

Polymorphisms in dopaminergic system genes; association with criminal behavior and self-reported aggression in violent prison inmates from Pakistan.

PubMed

Qadeer, Muhammad Imran; Amar, Ali; Mann, J John; Hasnain, Shahida

2017-01-01

Genetic factors contribute to antisocial and criminal behavior. Dopamine transporter DAT-1 (SLC6A3) and DRD2 gene for the dopamine-2 receptor are dopaminergic system genes that regulate dopamine reuptake and signaling, and may be part of the pathogenesis of psychiatric disorders including antisocial behaviors and traits. No previous studies have analyzed DAT-1 and DRD2 polymorphisms in convicted murderers, particularly from Indian subcontinent. In this study we investigated the association of 40 bp VNTR polymorphism of DAT-1 and Taq1 variant of DRD2 gene (rs1800479) with criminal behavior and self-reported aggression in 729 subjects, including 370 men in Pakistani prisons convicted of first degree murder(s) and 359 control men without any history of violence or criminal tendency. The 9R allele of DAT-1 VNTR polymorphism was more prevalent in convicted murderers compared with control samples, for either one or two risk alleles (OR = 1.49 and 3.99 respectively, P = 0.003). This potential association of DAT-1 9R allele polymorphism with murderer phenotype was confirmed assuming different genetic models of inheritance. However, no genetic association was found for DRD2 Taq1 polymorphism. In addition, a combined haplotype (9R-A2) of DAT-1 and DRD2 genes was associated with this murderer phenotype. Further, 9R allele of DAT-1 was also associated with response to verbal abuse and parental marital complications, but not with other measures pertinent to self-reported aggression. These results suggest that 9R allele, which may influence levels of intra-synaptic dopamine in the brain, may contribute to criminal tendency in this sample of violent murderers of Pakistani origin. Future studies are needed to replicate this finding in other populations of murderers and see if this finding extends to other forms of violence and lesser degrees of aggression.

Polymorphisms in dopaminergic system genes; association with criminal behavior and self-reported aggression in violent prison inmates from Pakistan

PubMed Central

Qadeer, Muhammad Imran; Amar, Ali; Mann, J. John; Hasnain, Shahida

2017-01-01

Genetic factors contribute to antisocial and criminal behavior. Dopamine transporter DAT-1 (SLC6A3) and DRD2 gene for the dopamine-2 receptor are dopaminergic system genes that regulate dopamine reuptake and signaling, and may be part of the pathogenesis of psychiatric disorders including antisocial behaviors and traits. No previous studies have analyzed DAT-1 and DRD2 polymorphisms in convicted murderers, particularly from Indian subcontinent. In this study we investigated the association of 40 bp VNTR polymorphism of DAT-1 and Taq1 variant of DRD2 gene (rs1800479) with criminal behavior and self-reported aggression in 729 subjects, including 370 men in Pakistani prisons convicted of first degree murder(s) and 359 control men without any history of violence or criminal tendency. The 9R allele of DAT-1 VNTR polymorphism was more prevalent in convicted murderers compared with control samples, for either one or two risk alleles (OR = 1.49 and 3.99 respectively, P = 0.003). This potential association of DAT-1 9R allele polymorphism with murderer phenotype was confirmed assuming different genetic models of inheritance. However, no genetic association was found for DRD2 Taq1 polymorphism. In addition, a combined haplotype (9R-A2) of DAT-1 and DRD2 genes was associated with this murderer phenotype. Further, 9R allele of DAT-1 was also associated with response to verbal abuse and parental marital complications, but not with other measures pertinent to self-reported aggression. These results suggest that 9R allele, which may influence levels of intra-synaptic dopamine in the brain, may contribute to criminal tendency in this sample of violent murderers of Pakistani origin. Future studies are needed to replicate this finding in other populations of murderers and see if this finding extends to other forms of violence and lesser degrees of aggression. PMID:28582390

The interactions among organophosphate pesticide exposure, oxidative stress, and genetic polymorphisms of dopamine receptor D4 increase the risk of attention deficit/hyperactivity disorder in children.

PubMed

Chang, Chia-Huang; Yu, Ching-Jung; Du, Jung-Chieh; Chiou, Hsien-Chih; Chen, Hsin-Chang; Yang, Winnie; Chung, Ming-Yi; Chen, Ying-Sheue; Hwang, Betau; Mao, I-Fang; Chen, Mei-Lien

2018-01-01

The aim of this study was to clarify the association between organophosphate pesticides (OPs) and attention-deficit/hyperactivity disorder (ADHD) related to oxidative stress and genetic polymorphisms. This case-control study enrolled 93 children with ADHD and 112 control children in north Taiwan. Six dialkyl phosphate (DAP) metabolites of OPs and oxidative stress biomarkers were analyzed. Polymorphisms of the dopamine receptor D4 gene (DRD4) were identified. Children with ADHD had significantly higher dimethylphosphate (DMP, 236.69nmol/g cre. vs. 186.84nmol/g cre., p value = 0.01) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA, 28.95µg/g cre. vs. 16.55µg/g cre., p value<0.01) concentrations than control children. Children who carried DRD4 GA/AA genotypes (rs752306) were less likely than those who carried the DRD4 GG genotype to have ADHD (odds ratio [OR]: 0.45, 95% CI: 0.24-0.84). The estimated value of the AP (attributable proportion due to interaction) was 0.59 (95% CI: 0.13-1.05), indicating that 59% of ADHD cases in DMP-exposed children with the DRD4 GG genotype were due to the gene-environment interaction. After adjustment for other covariates, children who carried the DRD4 GG genotype, had been exposed to high DMP levels (more than the median), and had high HNE-MA levels had a significantly increased risk for developing ADHD (OR = 11.74, 95% CI: 2.12-65.04). This study indicated a gene-environment interaction in the risk of ADHD in children. The association between DMP and ADHD in children might relate to the mechanism of lipid peroxidation. Dose-response relationships and the combined effects of OPs, oxidative stress, and genetic polymorphism on ADHD should not be neglected. Copyright © 2017 Elsevier Inc. All rights reserved.

Enhancing the gene-environment interaction framework through a quasi-experimental research design: evidence from differential responses to September 11.

PubMed

Fletcher, Jason M

2014-01-01

This article uses a gene-environment interaction framework to examine the differential responses to an objective external stressor based on genetic variation in the production of depressive symptoms. This article advances the literature by utilizing a quasi-experimental environmental exposure design, as well as a regression discontinuity design, to control for seasonal trends, which limit the potential for gene-environment correlation and allow stronger causal claims. Replications are attempted for two prominent genes (5-HTT and MAOA), and three additional genes are explored (DRD2, DRD4, and DAT1). This article provides evidence of a main effect of 9/11 on reports of feelings of sadness and fails to replicate a common finding of interaction using 5-HTT but does show support for interaction with MAOA in men. It also provides new evidence that variation in the DRD4 gene modifies an individual's response to the exposure, with individuals with no 7-repeats found to have a muted response.

Approach for a Clinically Useful Comprehensive Classification of Vascular and Neural Aspects of Diabetic Retinal Disease

PubMed Central

Abramoff, Michael D.; Fort, Patrice E.; Han, Ian C.; Jayasundera, K. Thiran; Sohn, Elliott H.; Gardner, Thomas W.

2018-01-01

The Early Treatment Diabetic Retinopathy Study (ETDRS) and other standardized classification schemes have laid a foundation for tremendous advances in the understanding and management of diabetic retinopathy (DR). However, technological advances in optics and image analysis, especially optical coherence tomography (OCT), OCT angiography (OCTa), and ultra-widefield imaging, as well as new discoveries in diabetic retinal neuropathy (DRN), are exposing the limitations of ETDRS and other classification systems to completely characterize retinal changes in diabetes, which we term diabetic retinal disease (DRD). While it may be most straightforward to add axes to existing classification schemes, as diabetic macular edema (DME) was added as an axis to earlier DR classifications, doing so may make these classifications increasingly complicated and thus clinically intractable. Therefore, we propose future research efforts to develop a new, comprehensive, and clinically useful classification system that will identify multimodal biomarkers to reflect the complex pathophysiology of DRD and accelerate the development of therapies to prevent vision-threatening DRD. PMID:29372250

Approach for a Clinically Useful Comprehensive Classification of Vascular and Neural Aspects of Diabetic Retinal Disease.

PubMed

Abramoff, Michael D; Fort, Patrice E; Han, Ian C; Jayasundera, K Thiran; Sohn, Elliott H; Gardner, Thomas W

2018-01-01

The Early Treatment Diabetic Retinopathy Study (ETDRS) and other standardized classification schemes have laid a foundation for tremendous advances in the understanding and management of diabetic retinopathy (DR). However, technological advances in optics and image analysis, especially optical coherence tomography (OCT), OCT angiography (OCTa), and ultra-widefield imaging, as well as new discoveries in diabetic retinal neuropathy (DRN), are exposing the limitations of ETDRS and other classification systems to completely characterize retinal changes in diabetes, which we term diabetic retinal disease (DRD). While it may be most straightforward to add axes to existing classification schemes, as diabetic macular edema (DME) was added as an axis to earlier DR classifications, doing so may make these classifications increasingly complicated and thus clinically intractable. Therefore, we propose future research efforts to develop a new, comprehensive, and clinically useful classification system that will identify multimodal biomarkers to reflect the complex pathophysiology of DRD and accelerate the development of therapies to prevent vision-threatening DRD.

Molecular imaging genetics of methylphenidate response in ADHD and substance use comorbidity.

PubMed

Szobot, Claudia M; Roman, Tatiana; Hutz, Mara H; Genro, Júlia P; Shih, Ming Chi; Hoexter, Marcelo Q; Júnior, Neivo; Pechansky, Flávio; Bressan, Rodrigo A; Rohde, Luis A P

2011-02-01

Attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs) are highly comorbid and may share a genetic vulnerability. Methylphenidate (MPH), a dopamine transporter (DAT) blocker, is an effective drug for most ADHD patients. Although dopamine D4 receptor (DRD4) and dopamine transporter (DAT1) genes have a role in both disorders, little is known about how these genes influence brain response to MPH in individuals with ADHD/SUDs. The goal of this study was to evaluate whether ADHD risk alleles at DRD4 and DAT1 genes could predict the change in striatal DAT occupancy after treatment with MPH in adolescents with ADHD/SUDs. Seventeen adolescents with ADHD/SUDs underwent a SPECT scan with [Tc(99m) ]TRODAT-1 at baseline and after three weeks on MPH. Caudate and putamen DAT binding potential was calculated. Comparisons on DAT changes were made according to the subjects' genotype. The combination of both DRD4 7-repeat allele (7R) and homozygosity for the DAT1 10-repeat allele (10/10) was significantly associated with a reduced DAT change after MPH treatment in right and left caudate and putamen, even adjusting the results for potential confounders (P ≤ 0.02; R² from 0.50 to 0.56). In patients with ADHD/SUDs, combined DRD4 7R and DAT1 10/10 could index MPH reduced DAT occupancy. This might be important for clinical trials, in terms of better understanding individual variability in treatment response. Copyright © 2010 Wiley-Liss, Inc.

DRD2 genotype predicts prefrontal activity during working memory after stimulation of D2 receptors with bromocriptine.

PubMed

Gelao, Barbara; Fazio, Leonardo; Selvaggi, Pierluigi; Di Giorgio, Annabella; Taurisano, Paolo; Quarto, Tiziana; Romano, Raffaella; Porcelli, Annamaria; Mancini, Marina; Masellis, Rita; Ursini, Gianluca; De Simeis, Giuseppe; Caforio, Grazia; Ferranti, Laura; Lo Bianco, Luciana; Rampino, Antonio; Todarello, Orlando; Popolizio, Teresa; Blasi, Giuseppe; Bertolino, Alessandro

2014-06-01

Pharmacological stimulation of D2 receptors modulates prefrontal neural activity associated with working memory (WM) processing. The T allele of a functional single-nucleotide polymorphism (SNP) within DRD2 (rs1076560 G > T) predicts reduced relative expression of the D2S receptor isoform and less efficient neural cortical responses during WM tasks. We used functional MRI to test the hypothesis that DRD2 rs1076560 genotype interacts with pharmacological stimulation of D2 receptors with bromocriptine on prefrontal responses during different loads of a spatial WM task (N-Back). Fifty-three healthy subjects (38 GG and 15 GT) underwent two 3-T functional MRI scans while performing the 1-, 2- and 3-Back versions of the N-Back WM task. Before the imaging sessions, either bromocriptine or placebo was administered to all subjects in a counterbalanced order. A factorial repeated-measures ANOVA within SPM8 (p < 0.05, family-wise error corrected) was used. On bromocriptine, GG subjects had reduced prefrontal activity at 3-Back together with a significant decrement in performance, compared with placebo. On the other hand, GT subjects had lower activity for the same level of performance at 1-Back but a trend for reduced behavioral performance in the face of unchanged activity at 2-Back. These results indicate that bromocriptine stimulation modulates prefrontal activity in terms of disengagement or of efficiency depending on DRD2 genotype and working memory load.

The dopamine receptor D4 gene and familial loading interact with perceived parenting in predicting externalizing behavior problems in early adolescence: the TRacking Adolescents' Individual Lives Survey (TRAILS).

PubMed

Marsman, Rianne; Oldehinkel, Albertine J; Ormel, Johan; Buitelaar, Jan K

2013-08-30

Although externalizing behavior problems show in general a high stability over time, the course of externalizing behavior problems may vary from individual to individual. Our main goal was to investigate the predictive role of parenting on externalizing behavior problems. In addition, we investigated the potential moderating role of gender and genetic risk (operationalized as familial loading of externalizing behavior problems (FLE), and presence or absence of the dopamine receptor D4 (DRD4) 7-repeat and 4-repeat allele, respectively). Perceived parenting (rejection, emotional warmth, and overprotection) and FLE were assessed in a population-based sample of 1768 10- to 12-year-old adolescents. Externalizing behavior problems were assessed at the same age and 212 years later by parent report (CBCL) and self-report (YSR). DNA was extracted from blood samples. Parental emotional warmth predicted lower, and parental overprotection and rejection predicted higher levels of externalizing behavior problems. Whereas none of the parenting factors interacted with gender and the DRD4 7-repeat allele, we did find interaction effects with FLE and the DRD4 4-repeat allele. That is, the predictive effect of parental rejection was only observed in adolescents from low FLE families and the predictive effect of parental overprotection was stronger in adolescents not carrying the DRD4 4-repeat allele. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Polymorphic variants of neurotransmitter receptor genes may affect sexual function in aging males: data from the HALS study.

PubMed

Jóźków, Paweł; Słowińska-Lisowska, Małgorzata; Łaczmański, Łukasz; Mędraś, Marek

2013-01-01

Human behavior is influenced by a number of brain neurotransmitters. Central dopamine, serotonin and melanocortin systems have special importance for male sexual function. We searched for associations between male aging symptoms and polymorphic sites of serotonin (5-HTR1B), melanocortin (MC4R) and dopamine (DRD2, DRD4) receptors. In a population-based sample, genotyping of 5-HTR1B (polymorphism: G861C), MC4R (polymorphisms: C-2745T, Val103Ile), DRD2 (polymorphism: C313T) and DRD4 (polymorphism: 48-bp VNTR) was performed in 387 healthy men. The Aging Males' Symptoms (AMS) scale was used to evaluate specific ailments of aging men. We analyzed answers to questions from the AMS scale. Five points of the questionnaire addressed sexual symptoms of the aging male: feeling of passing one's peak, decrease in beard growth, decrease in ability/frequency to perform sexually, decrease in the number of morning erections, and decrease in sexual desire/libido (lacking pleasure in sex, lacking desire for sexual intercourse). Relations between reported symptoms and variants of the polymorphic sites of the studied genes were assessed. After adjusting for confounding factors (education, arterial hypertension, physical activity, weight, waist circumference) an association between the sexual dimension of AMS and genetic variants of 5-HTR1B G861C (p = 0.04) was observed. Variability of neurotransmitter receptor genes may be associated with sexual symptoms of aging in men. Copyright © 2013 S. Karger AG, Basel.

Prediction of striatal D2 receptor binding by DRD2/ANKK1 TaqIA allele status

PubMed Central

Eisenstein, Sarah A.; Bogdan, Ryan; Love-Gregory, Latisha; Corral-Frías, Nadia S.; Koller, Jonathan M.; Black, Kevin J.; Moerlein, Stephen M.; Perlmutter, Joel S.; Barch, Deanna M.; Hershey, Tamara

2016-01-01

In humans, the A1 (T) allele of the dopamine (DA) D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) TaqIA (rs1800497) single nucleotide polymorphism has been associated with reduced striatal DA D2/D3 receptor (D2/D3R) availability. However, radioligands used to estimate D2/D3R are displaceable by endogenous DA and are non-selective for D2R, leaving the relationship between TaqIA genotype and D2R specific binding uncertain. Using the positron emission tomography (PET) radioligand, (N‐[11C]methyl)benperidol ([11C]NMB), which is highly selective for D2R over D3R and is not displaceable by endogenous DA, the current study examined whether DRD2/ANKK1 TaqIA genotype predicts D2R specific binding in 2 independent samples. Sample 1 (n = 39) was composed of obese and non-obese adults; sample 2 (n = 18) was composed of healthy controls, unmedicated individuals with schizophrenia, and siblings of individuals with schizophrenia. Across both samples, A1 allele carriers (A1+) had 5-12% less striatal D2R specific binding relative to individuals homozygous for the A2 allele (A1−), regardless of body mass index or diagnostic group. This reduction is comparable to previous PET studies of D2/D3R availability (10-14%). The pooled effect size for the difference in total striatal D2R binding between A1+ and A1− was large (0.84). In summary, in line with studies using displaceable D2/D3R radioligands, our results indicate that DRD2/ANKK1 TaqIA allele status predicts striatal D2R specific binding as measured by D2R-selective [11C]NMB. These findings support the hypothesis that DRD2/ANKK1 TaqIA allele status may modify D2R, perhaps conferring risk for certain disease states. GRAPHICAL ABSTRACT We investigated the difference in striatal dopamine D2 receptor binding, as measured by PET with (N-[11C]methyl)benperidol ([11C]NMB), between A1 allele carriers (A1+) and individuals homozygous for the A2 allele (A1−) of the DRD2/ANKK1 TaqIA single nucleotide polymorphism. In Study 1, A1+ had 5-12% less striatal [11C]NMB binding than A1−. PMID:27241797

Occurrence of the Cys311 DRD2 variant in a pedigree multiply affected with panic disorder

DOE Office of Scientific and Technical Information (OSTI.GOV)

Crawford, F.; Hoyne, J.; Diaz, P.

1995-08-14

Following the detection of the rare DRD2 codon 311 variant (Ser{yields}Cys) in an affected member from a large, multiply affected panic disorder family, we investigated the occurrence of this variant in other family members. The variant occurred in both affected and unaffected individuals. Further screening in panic disorder sib pairs unrelated to this family failed to detect the Cys311 variant. Our data suggests that this variant has no pathogenic role in panic disorder. 18 refs., 1 fig.

Do dopaminergic gene polymorphisms affect mesolimbic reward activation of music listening response? Therapeutic impact on Reward Deficiency Syndrome (RDS).

PubMed

Blum, Kenneth; Chen, Thomas J H; Chen, Amanda L H; Madigan, Margaret; Downs, B William; Waite, Roger L; Braverman, Eric R; Kerner, Mallory; Bowirrat, Abdalla; Giordano, John; Henshaw, Harry; Gold, Mark S

2010-03-01

Using fMRI, Menon and Levitin [9] clearly found for the first time that listening to music strongly modulates activity in a network of mesolimbic structures involved in reward processing including the nucleus accumbens (NAc) and the ventral tegmental area (VTA), as well as the hypothalamus, and insula, which are thought to be involved in regulating autonomic and physiological responses to rewarding and emotional stimuli. Importantly, responses in the NAc and VTA were strongly correlated pointing to an association between dopamine release and NAc response to music. Listing to pleasant music induced a strong response and significant activation of the VTA-mediated interaction of the NAc with the hypothalamus, insula, and orbitofrontal cortex. Blum et al. [10] provided the first evidence that the dopamine D2 receptor gene (DRD2) Taq 1 A1 allele significantly associated with severe alcoholism whereby the author's suggested that they found the first "reward gene" located in the mesolimbic system. The enhanced functional and effective connectivity between brain regions mediating reward, autonomic, and cognitive processing provides insight into understanding why listening to music is one of the most rewarding and pleasurable human experiences. However, little is known about why some people have a more or less powerful mesolimbic experience when they are listening to music. It is well-known that music may induce an endorphinergic response that is blocked by naloxone, a known opioid antagonist (Goldstein [19]). Opioid transmission in the NAc is associated with dopamine release in the VTA. Moreover, dopamine release in the VTA is linked to polymorphisms of the DRD2 gene and even attention-deficit hyperactivity disorder (ADHD), whereby carriers of the DRD2 A1 allele show a reduced NAc release of dopamine (DA). Thus it is conjectured that similar mechanisms in terms of adequate dopamine release and subsequent activation of reward circuitry by listening to music might also be affected by an individual's D2 density in the VTA mediated interaction of the NAc. It is therefore hypothesized that carriers of DRD2 A1 allele may respond significantly differently to carriers of the DRD2 A2 genotype. In this regard, carriers of the D2 A1 allele have a blunted response to glucose and monetary rewards. In contrast powerful D2 agonists like bromocryptine show a heightened activation of the reward circuitry only in DRD2 A1 allele carriers. If music causes a powerful activation in spite of the DRD2 A1 allele due to a strong DA neuronal release which subsequently impinges on existing D2 receptors, then it is reasonable to assume that music is a strong indirect D2 agonist (by virtue of DA neuronal release in the NAc) and may have important therapeutic applicability in Reward Deficiency Syndrome (RDS) related behaviors including Substance Use Disorder (SUD). Ross et al. [18] found that music therapy appears to be a novel motivational tool in a severely impaired inpatient sample of patients with co-occurring mental illness and addiction. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

Polymorphisms in HTR2A and DRD4 Predispose to Smoking and Smoking Quantity

PubMed Central

Pérez-Rubio, Gloria; Ramírez-Venegas, Alejandra; Noé Díaz, Valeri; García Gómez, Leonor; Elvira Fabián, Karina; García Carmona, Salvador; López-Flores, Luis A.; Ambrocio-Ortiz, Enrique; Contreras Romero, Rocío; Alcantar-Ayala, Noé; Sansores, Raúl H.

2017-01-01

Background Genes encoding the receptors involved in the dopaminergic and serotonergic pathways are potential candidates in the mechanisms of nicotine addiction. Aims To identify genetic variants in the promoter regions and exons of the DRD4 and HTR2A genes associated with tobacco smoking and the degree of nicotine addiction in Mexican mestizos. Methods The study included 438 non-smokers (NS) and 1,157 current smokers, ranked based on their consumption of cigarettes per day (cpd): 574 heavy smokers (HS, >20 cpd) and 583 light smokers (LS, 1–10 cpd). Genotyping was performed for 4 and 8 single nucleotide polymorphisms (SNPs) in the DRD4 and HTR2A genes, respectively. Results The C allele of rs1800955 in DRD4 was found to be associated with cigarette smoking in the HS vs. NS and LS vs. NS comparisons (p = 2.34E-03 and p = 1.13E-03, respectively); the association was maintained in the homozygous CC genotype (p = 5.00E-04 and p = 2.00E-04, respectively). The T allele of rs6313 in HTR2A was significantly associated with cigarette smoking and a greater degree of nicotine addiction (p = 4.77E-03, OR = 1.55); the association was maintained in the homozygous genotype (TT) (p = 4.90E-03, OR = 1.96). The A allele of rs6313 was associated with cigarette smoking in the HS vs. NS comparison (p = 1.53E-02, OR = 1.36); the risk was nearly doubled in the homozygous AA genotype (p = 1.30E-03, OR = 1.83) compared with the heterozygous GA genotype (OR = 1.38). Conclusions Among Mexican mestizos, the C allele of rs1800955 in the DRD4 gene and the A allele of rs6311 in the HTR2A gene are associated with cigarette smoking, whereas the T allele of rs6313 in HTR2A is associated with cigarette smoking and the degree of nicotine addiction. PMID:28103253

Impact of implementation of a novel antimicrobial stewardship tool on antibiotic use in nursing homes: a prospective cluster randomized control pilot study.

PubMed

Fleet, Elizabeth; Gopal Rao, G; Patel, Bharat; Cookson, Barry; Charlett, Andre; Bowman, Clive; Davey, Peter

2014-08-01

To evaluate the impact of 'Resident Antimicrobial Management Plan' (RAMP), a novel antimicrobial stewardship tool on systemic antibiotic use for treatment of infection in nursing homes (NHs). A pilot cluster randomized control study was conducted in 30 NHs in London. Pre-intervention, we collected point prevalence data on antimicrobial use on three occasions and total antimicrobial consumption for a 12 week period. Post-intervention data were collected in the same manner and included assessment of compliance with RAMP in the intervention group (IG). The number of residents included was 1628 pre-intervention [825 IG/803 control group (CG)] and 1610 post-intervention (838 IG/772 CG). The corresponding pre- and post-intervention point prevalence of systemic antibiotic prescribing for treatment of infection was 6.46% and 6.52% in the IG [estimated prevalence ratio: 1.01 (95% CI: 0.81-1.25), P = 0.94] compared with 5.27% and 5.83%, respectively, in the CG [estimated prevalence ratio: 1.11 (95% CI: 0.87-1.41), P = 0.4]. Total antibiotic consumption was 69.78 defined daily doses/1000 residents/day (DRD) pre-intervention and 66.53 DRD post-intervention in the IG compared with 49.68 and 51.92 DRD, respectively, in the CG. There was a significant decrease of 4.9% (3.25 DRD) in the IG (95% CI: 1.0%-8.6%) (P = 0.02) compared with a significant increase of 5.1% (2.24 DRD) in the CG (95% CI: 0.2%-10.2%) (P = 0.04). Main indications for antibiotics were lower respiratory tract infections (34.1%), urinary tract infections (28.5%) and skin/soft tissue infections (25.1%). This pilot study demonstrated that use of RAMP was associated with a statistically significant decrease in total antibiotic consumption and has the potential to be an important antimicrobial stewardship tool for NHs. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Ondansetron and sertraline may interact with 5-HTTLPR and DRD4 polymorphisms to reduce drinking in non-treatment seeking alcohol dependent women: exploratory findings

PubMed Central

Kenna, George A.; Zywiak, William H.; Swift, Robert M.; McGeary, John E.; Clifford, James S.; Shoaff, Jessica R.; Fricchione, Samuel; Brickley, Michael; Beaucage, Kayla; Haass-Koffler, Carolina L.; Leggio, Lorenzo

2014-01-01

The purpose of this exploratory study was to examine the interaction of 5-HTTLPR and DRD4 exon III polymorphisms with gender in non-treatment seeking alcohol dependent (AD) individuals while alternately taking ondansetron and sertraline. Evidence suggests that alcohol dependence may be influenced by a genetic interaction that may be gender specific with temporal changes making pharmacological treatment with serotonergic drugs complex. The main trial was a within-subject double-blind placebo-controlled human laboratory study with 77 non-treatment-seeking AD individuals randomized (55 completed, 49 complete data) to receive 200mg/day of sertraline or 0.5mg/day of ondansetron for 3-weeks followed by an alcohol self-administration experiment (ASAE), then placebo for three weeks followed by a second ASAE, then receive the alternate drug, in a counterbalanced order, for three weeks followed by a third ASAE. Results for men were not significant. Women with the LL 5-HTTLPR genotype receiving ondansetron and SS/SL 5-HTTLPR genotypes receiving sertraline (matched), drank significantly fewer drinks per drinking day (DDD) during the 7-days prior to the first and third ASAEs than women receiving the mismatched medication (i.e. sertraline to LL and ondansetron to SS/SL). In a three-way interaction, 5-HTTLPR alleles by DRD4 alleles by medications, women with the LL genotype who received ondansetron and had DRD4 ≥7 exon III repeats drank significantly fewer DDD as did SS/SL women who received sertraline but conversely had DRD4 <7-repeats in the 7-day period leading up to the first and third ASAEs. Consistent with these data was a significant reduction of milliliters consumed ad lib during these same ASAEs. These exploratory findings add possible support to gender and genetic differences among AD individuals in response to serotonergic pharmacotherapies. Future trials should be powerful enough to take into account that endophenotypes and a targeting of serotonergic interactions may be essential to successfully treat alcohol dependence. PMID:25212749

Injecting drug users in Scotland, 2006: Listing, number, demography, and opiate-related death-rates.

PubMed

King, Ruth; Bird, Sheila M; Overstall, Antony; Hay, Gordon; Hutchinson, Sharon J

2013-06-01

Using Bayesian capture-recapture analysis, we estimated the number of current injecting drug users (IDUs) in Scotland in 2006 from the cross-counts of 5670 IDUs listed on four data-sources: social enquiry reports (901 IDUs listed), hospital records (953), drug treatment agencies (3504), and recent Hepatitis C virus (HCV) diagnoses (827 listed as IDU-risk). Further, we accessed exact numbers of opiate-related drugs-related deaths (DRDs) in 2006 and 2007 to improve estimation of Scotland's DRD rates per 100 current IDUs. Using all four data-sources, and model-averaging of standard hierarchical log-linear models to allow for pairwise interactions between data-sources and/or demographic classifications, Scotland had an estimated 31700 IDUs in 2006 (95% credible interval: 24900-38700); but 25000 IDUs (95% CI: 20700-35000) by excluding recent HCV diagnoses whose IDU-risk can refer to past injecting. Only in the younger age-group (15-34 years) were Scotland's opiate-related DRD rates significantly lower for females than males. Older males' opiate-related DRD rate was 1.9 (1.24-2.40) per 100 current IDUs without or 1.3 (0.94-1.64) with inclusion of recent HCV diagnoses. If, indeed, Scotland had only 25000 current IDUs in 2006, with only 8200 of them aged 35+ years, the opiate-related DRD rate is higher among this older age group than has been appreciated hitherto. There is counter-balancing good news for the public health: the hitherto sharp increase in older current IDUs had stalled by 2006.

Dopaminergic variants in siblings at high risk for autism: Associations with initiating joint attention.

PubMed

Gangi, Devon N; Messinger, Daniel S; Martin, Eden R; Cuccaro, Michael L

2016-11-01

Younger siblings of children with autism spectrum disorder (ASD; high-risk siblings) exhibit lower levels of initiating joint attention (IJA; sharing an object or experience with a social partner through gaze and/or gesture) than low-risk siblings of children without ASD. However, high-risk siblings also exhibit substantial variability in this domain. The neurotransmitter dopamine is linked to brain areas associated with reward, motivation, and attention, and common dopaminergic variants have been associated with attention difficulties. We examined whether these common dopaminergic variants, DRD4 and DRD2, explain variability in IJA in high-risk (n = 55) and low-risk (n = 38) siblings. IJA was assessed in the first year during a semi-structured interaction with an examiner. DRD4 and DRD2 genotypes were coded according to associated dopaminergic functioning to create a gene score, with higher scores indicating more genotypes associated with less efficient dopaminergic functioning. Higher dopamine gene scores (indicative of less efficient dopaminergic functioning) were associated with lower levels of IJA in the first year for high-risk siblings, while the opposite pattern emerged in low-risk siblings. Findings suggest differential susceptibility-IJA was differentially associated with dopaminergic functioning depending on familial ASD risk. Understanding genes linked to ASD-relevant behaviors in high-risk siblings will aid in early identification of children at greatest risk for difficulties in these behavioral domains, facilitating targeted prevention and intervention. Autism Res 2016, 9: 1142-1150. © 2016 International Society for Autism Research, Wiley Periodicals, Inc. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Variation in Mothers’ Arginine Vasopressin Receptor 1a and Dopamine Receptor D4 Genes Predict Maternal Sensitivity via Social Cognition

PubMed Central

Leerkes, Esther M.; Su, Jinni; Calkins, Susan; Henrich, Vincent C.; Smolen, Andrew

2016-01-01

We examined the extent to which the arginine vasopressin receptor 1a (AVPR1a) and dopamine receptor d4 (DRD4) were related to sensitive maternal behavior directly or indirectly via maternal social cognition. Participants were 207 (105 European American, 102 African American) mothers and their children (52% female). Sensitive maternal behavior was rated and aggregated across a series of tasks when infants were 6 months, 1 year, and 2 years old. At 6 months, mothers were interviewed about their empathy, attributions about infant behavior, and beliefs about crying to assess their parenting-related social cognition. Mothers with long alleles for AVPR1a and DRD4 engaged in more mother-oriented social cognition (i.e., negative attributions and beliefs about their infants’ crying), β = .13, p < .05 and β = .16, p < .05, respectively, which in turn predicted less sensitive maternal behavior, β = −.23, p < .01. Both indirect effects were statistically significant independent of one another and covariates; 95% CI [−.22, −.03] and β = −.03 for AVPR; 95% CI [−.20, −.03] and β = −.04 for DRD4. There were no significant direct effects of AVPR1a or DRD4 on maternal sensitivity, β = .02, ns and β = −.10, ns, respectively. The results did not vary for African American and European American mothers (Δχ2 = 18.76, Δdf = 16, p = .28). Results support the view that one mechanism by which maternal genes are associated with parental behavior is via social cognition. PMID:27581946

Acute D3 Antagonist GSK598809 Selectively Enhances Neural Response During Monetary Reward Anticipation in Drug and Alcohol Dependence

PubMed Central

Murphy, Anna; Nestor, Liam J; McGonigle, John; Paterson, Louise; Boyapati, Venkataramana; Ersche, Karen D; Flechais, Remy; Kuchibatla, Shankar; Metastasio, Antonio; Orban, Csaba; Passetti, Filippo; Reed, Laurence; Smith, Dana; Suckling, John; Taylor, Eleanor; Robbins, Trevor W; Lingford-Hughes, Anne; Nutt, David J; Deakin, John FW; Elliott, Rebecca

2017-01-01

Evidence suggests that disturbances in neurobiological mechanisms of reward and inhibitory control maintain addiction and provoke relapse during abstinence. Abnormalities within the dopamine system may contribute to these disturbances and pharmacologically targeting the D3 dopamine receptor (DRD3) is therefore of significant clinical interest. We used functional magnetic resonance imaging to investigate the acute effects of the DRD3 antagonist GSK598809 on anticipatory reward processing, using the monetary incentive delay task (MIDT), and response inhibition using the Go/No-Go task (GNGT). A double-blind, placebo-controlled, crossover design approach was used in abstinent alcohol dependent, abstinent poly-drug dependent and healthy control volunteers. For the MIDT, there was evidence of blunted ventral striatal response to reward in the poly-drug-dependent group under placebo. GSK598809 normalized ventral striatal reward response and enhanced response in the DRD3-rich regions of the ventral pallidum and substantia nigra. Exploratory investigations suggested that the effects of GSK598809 were mainly driven by those with primary dependence on alcohol but not on opiates. Taken together, these findings suggest that GSK598809 may remediate reward deficits in substance dependence. For the GNGT, enhanced response in the inferior frontal cortex of the poly-drug group was found. However, there were no effects of GSK598809 on the neural network underlying response inhibition nor were there any behavioral drug effects on response inhibition. GSK598809 modulated the neural network underlying reward anticipation but not response inhibition, suggesting that DRD3 antagonists may restore reward deficits in addiction. PMID:28042871

Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions.

PubMed

Correia, C T; Almeida, J P; Santos, P E; Sequeira, A F; Marques, C E; Miguel, T S; Abreu, R L; Oliveira, G G; Vicente, A M

2010-10-01

Little has been reported on the factors, genetic or other, that underlie the variability in individual response, particularly for autism. In this study we simultaneously explored the effects of multiple candidate genes on clinical improvement and occurrence of adverse drug reactions, in 45 autistic patients who received monotherapy with risperidone up to 1 year. Candidate genes involved in the pharmacokinetics (CYP2D6 and ABCB1) and pharmacodynamics (HTR2A, HTR2C, DRD2, DRD3, HTR6) of the drug, and the brain-derived neurotrophic factor (BDNF) gene, were analysed. Using the generalized estimating equation method these genes were tested for association with drug efficacy, assessed with the Autism Treatment Evaluation Checklist, and with safety and tolerability measures, such as prolactin levels, body mass index (BMI), waist circumference and neurological adverse effects, including extrapyramidal movements. Our results confirm that risperidone therapy was very effective in reducing some autism symptoms and caused few serious adverse effects. After adjusting for confounding factors, the HTR2A c.-1438G>A, DRD3 Ser9Gly, HTR2C c.995G>A and ABCB1 1236C>T polymorphisms were predictors for clinical improvement with risperidone therapy. The HTR2A c.-1438G>A, HTR2C c.68G>C (p.C33S), HTR6 c.7154-2542C>T and BDNF c.196G>A (p.V66M) polymorphisms influenced prolactin elevation. HTR2C c.68G>C and CYP2D6 polymorphisms were associated with risperidone-induced increase in BMI or waist circumference. We thus identified for the first time several genes implicated in risperidone efficacy and safety in autism patients. Although association results require replication, given the small sample size, the study makes a preliminary contribution to the personalized therapy of risperidone in autism.

DRD4 and DAT1 in ADHD: Functional neurobiology to pharmacogenetics

PubMed Central

Turic, Darko; Swanson, James; Sonuga-Barke, Edmund

2010-01-01

Attention deficit/hyperactivity disorder (ADHD) is a common and potentially very impairing neuropsychiatric disorder of childhood. Statistical genetic studies of twins have shown ADHD to be highly heritable, with the combination of genes and gene by environment interactions accounting for around 80% of phenotypic variance. The initial molecular genetic studies where candidates were selected because of the efficacy of dopaminergic compounds in the treatment of ADHD were remarkably successful and provided strong evidence for the role of DRD4 and DAT1 variants in the pathogenesis of ADHD. However, the recent application of non-candidate gene strategies (eg, genome-wide association scans) has failed to identify additional genes with substantial genetic main effects, and the effects for DRD4 and DAT1 have not been replicated. This is the usual pattern observed for most other physical and mental disorders evaluated with current state-of-the-art methods. In this paper we discuss future strategies for genetic studies in ADHD, highlighting both the pitfalls and possible solutions relating to candidate gene studies, genome-wide studies, defining the phenotype, and statistical approaches. PMID:23226043

Association between the dopamine D4 receptor gene exon III variable number of tandem repeats and political attitudes in female Han Chinese

PubMed Central

Ebstein, Richard P.; Monakhov, Mikhail V.; Lu, Yunfeng; Jiang, Yushi; Lai, Poh San; Chew, Soo Hong

2015-01-01

Twin and family studies suggest that political attitudes are partially determined by an individual's genotype. The dopamine D4 receptor gene (DRD4) exon III repeat region that has been extensively studied in connection with human behaviour, is a plausible candidate to contribute to individual differences in political attitudes. A first United States study provisionally identified this gene with political attitude along a liberal–conservative axis albeit contingent upon number of friends. In a large sample of 1771 Han Chinese university students in Singapore, we observed a significant main effect of association between the DRD4 exon III variable number of tandem repeats and political attitude. Subjects with two copies of the 4-repeat allele (4R/4R) were significantly more conservative. Our results provided evidence for a role of the DRD4 gene variants in contributing to individual differences in political attitude particularly in females and more generally suggested that associations between individual genes, and neurochemical pathways, contributing to traits relevant to the social sciences can be provisionally identified. PMID:26246555

Behavioral Abnormalities and Circuit Defects in the Basal Ganglia of a Mouse Model of 16p11.2 Deletion Syndrome

PubMed Central

Portmann, Thomas; Ellegood, Jacob; Dolen, Gul; Bader, Patrick L.; Grueter, Brad A.; Goold, Carleton; Fisher, Elaine; Clifford, Katherine; Rengarajan, Pavitra; Kalikhman, David; Loureiro, Darren; Saw, Nay L.; Zhengqui, Zhou; Miller, Michael A.; Lerch, Jason P.; Henkelman, Mark; Shamloo, Mehrdad; Malenka, Robert C.; Crawley, Jacqueline N.; Dolmetsch, Ricardo E.

2014-01-01

Summary A deletion on human chromosome 16p11.2 is associated with autism spectrum disorders. We deleted the syntenic region on mouse chromosome 7F3. MRI and high-throughput single-cell transcriptomics revealed anatomical and cellular abnormalities, particularly in cortex and striatum of juvenile mutant mice (16p11+/−). We found elevated numbers of striatal medium spiny neurons (MSNs) expressing the dopamine D2 receptor (Drd2+) and fewer dopamine-sensitive (Drd1+) neurons in deep layers of cortex. Electrophysiological recordings of Drd2+ MSN revealed synaptic defects, suggesting abnormal basal ganglia circuitry function in 16p11+/− mice. This is further supported by behavioral experiments showing hyperactivity, circling, and deficits in movement control. Strikingly, 16p11+/− mice showed a complete lack of habituation reminiscent of what is observed in some autistic individuals. Our findings unveil a fundamental role of genes affected by the 16p11.2 deletion in establishing the basal ganglia circuitry and provide insights in the pathophysiology of autism. PMID:24794428

Association between the dopamine D4 receptor gene exon III variable number of tandem repeats and political attitudes in female Han Chinese.

PubMed

Ebstein, Richard P; Monakhov, Mikhail V; Lu, Yunfeng; Jiang, Yushi; Lai, Poh San; Chew, Soo Hong

2015-08-22

Twin and family studies suggest that political attitudes are partially determined by an individual's genotype. The dopamine D4 receptor gene (DRD4) exon III repeat region that has been extensively studied in connection with human behaviour, is a plausible candidate to contribute to individual differences in political attitudes. A first United States study provisionally identified this gene with political attitude along a liberal-conservative axis albeit contingent upon number of friends. In a large sample of 1771 Han Chinese university students in Singapore, we observed a significant main effect of association between the DRD4 exon III variable number of tandem repeats and political attitude. Subjects with two copies of the 4-repeat allele (4R/4R) were significantly more conservative. Our results provided evidence for a role of the DRD4 gene variants in contributing to individual differences in political attitude particularly in females and more generally suggested that associations between individual genes, and neurochemical pathways, contributing to traits relevant to the social sciences can be provisionally identified. © 2015 The Author(s).

The Great Recession, genetic sensitivity, and maternal harsh parenting

PubMed Central

Lee, Dohoon; Brooks-Gunn, Jeanne; McLanahan, Sara S.; Notterman, Daniel; Garfinkel, Irwin

2013-01-01

Using data from the Fragile Families and Child Wellbeing Study, this study examined the effects of the Great Recession on maternal harsh parenting. We found that changes in macroeconomic conditions, rather than current conditions, affected harsh parenting, that declines in macroeconomic conditions had a stronger impact on harsh parenting than improvements in conditions, and that mothers’ responses to adverse economic conditions were moderated by the DRD2 Taq1A genotype. We found no evidence of a moderating effect for two other, less well-studied SNPs from the DRD4 and DAT1 genes. PMID:23918380

No association between the TaqI A1 RFLP of the D2 receptor gene and alcoholism in a Mexican population

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cruz-Fuentes, C.; Carmarena, B.; Eroza, V.

1994-09-01

The suggested association of the A1 allele of the D2 dopamine receptor (DRD2) human gene with alcoholism was studied by comparing the DRD2/TaqI genotypes of 36 healthy controls and 38 individuals who met the DSM-III-R diagnostic criteria for alcohol dependence. All subjects were unrelated, with parents and grandparents of Mexican origin. The alcoholics in our sample suffered one of the following conditions: delirium tremens (16.6%), alcohol hallucinosis (56.6%) or uncomplicated alcohol withdrawal (26.4%). Eight-eight percent of the controls carried the A1 allele. The frequency of the DRD2 A1 allele in the Mexican urban sample (pA1 = 0.61) was 2 tomore » 3-fold higher than reported in Caucasian populations from the USA and Europe, but similar to the allele frequencies found in defined Amerindian populations. There were not significant differences in the prevalence or allele frequency between alcoholics (pA1 = 0.64) and controls, regardless if the alcoholics were subtyped accordingly to severity, age of onset or positive family history. Alcoholics had higher scores than controls in the neuroticism (N) and psychoticism (P) subscales on the Eysenck personality test: alcoholics P = 6.2 {+-} 2.9, N = 16.0 {+-} 4.2 vs. controls P = 2.5 {+-} 2.3, N = 5.7 {+-} 5.1; p<0.001 and p<0.001, respectively. However, no relationship between personality traits and genotypes was found. Our results do not support a consistent association between the TaqI A1 RFLP for the DRD2 gene and alcoholism.« less

Polymorphisms in the dopamine receptor 2 gene region influence improvements during working memory training in children and adolescents.

PubMed

Söderqvist, Stina; Matsson, Hans; Peyrard-Janvid, Myriam; Kere, Juha; Klingberg, Torkel

2014-01-01

Studying the effects of cognitive training can lead to finding better treatments, but it can also be a tool for investigating factors important for brain plasticity and acquisition of cognitive skills. In this study, we investigated how single-nucleotide polymorphisms (SNPs) and ratings of intrinsic motivation were associated to interindividual differences in improvement during working memory training. The study included 256 children aged 7-19 years who were genotyped for 13 SNPs within or near eight candidate genes previously implicated in learning: COMT, SLC6A3 (DAT1), DRD4, DRD2, PPP1R1B (DARPP32), MAOA, LMX1A, and BDNF. Ratings on the intrinsic motivation inventory were also available for 156 of these children. All participants performed at least 20 sessions of working memory training, and performance during the training was logged and used as the outcome variable. We found that two SNPs, rs1800497 and rs2283265, located near and within the dopamine receptor 2 (DRD2) gene, respectively, were significantly associated with improvements during training (p < .003 and p < .0004, respectively). Scores from a questionnaire regarding intrinsic motivation did not correlate with training outcome. However, we observed both the main effect of genotype at those two loci as well as the interaction between genotypes and ratings of intrinsic motivation (perceived competence). Both SNPs have previously been shown to affect DRD2 receptor density primarily in the BG. Our results suggest that genetic variation is accounting for some interindividual differences in how children acquire cognitive skills and that part of this effect is also seen on intrinsic motivation. Moreover, they suggest that dopamine D2 transmission in the BG is a key factor for cognitive plasticity.

Reward-seeking and discrimination deficits displayed by hypodopaminergic mice are prevented in mice lacking dopamine D4 receptors.

PubMed

Nemirovsky, Sergio I; Avale, M Elena; Brunner, Daniela; Rubinstein, Marcelo

2009-11-01

The dopamine D4 receptor (D4R) is predominantly expressed in the prefrontal cortex, a brain area that integrates motor, rewarding, and cognitive information. Because participation of D4Rs in executive learning is largely unknown, we challenged D4R knockout mice (Drd4(-/-)) and their wild-type (WT) littermates, neonatally treated with 6-hydroxydopamine (6-OHDA; icv) or vehicle in two operant learning paradigms. A continuous reinforcement task, in which one food-pellet was delivered after every lever press, showed that 6-OHDA-treated mice (hypodopaminergic) WT mice pressed the reinforcing lever at much lower rates than normodopaminergic WT mice. In contrast, Drd4(-/-) mice displayed increased lever pressing rates, regardless of their dopamine content. In another study, mice were trained to solve an operant two-choice task in which a first showing lever was coupled to the delivery of one food pellet only after a second lever emerged. Interval between presentation of both levers was initially 12 s and progressively shortened to 6, 2, and finally 0.5 s. Normodopaminergic WT mice obtained a pellet reward in more than 75% of the trials at 12, 6, and 2 s, whereas hypodopaminergic WT mice were severely impaired to select the reward-paired lever. Absence of D4Rs was not detrimental in this task. Moreover, hypodopaminergic Drd4(-/-) mice were as efficient as their normodopaminergic Drd4(-/-) siblings in selecting the reward-paired lever. In summary, hypodopaminergic mice exhibit severe impairments to retrieve rewards in two operant positive reinforcement tasks, but these deleterious effects are totally prevented in the absence of functional D4Rs.

Expression and function of dopamine receptors in the developing medial frontal cortex and striatum of the rat

PubMed Central

Sillivan, Stephanie E.; Konradi, Christine

2011-01-01

The timeline of dopamine (DA) system maturation and the signaling properties of dopamine receptors (DRs) during rat brain development are not fully characterized. We used in situ hybridization and quantitative PCR to map DR mRNA transcripts in the medial frontal cortex (mFC) and striatum (STR) of the rat from embryonic day (E) 15 to E21. The developmental trajectory of DR mRNAs revealed distinct patterns of DA receptors 1 and 2 (DRD1, DRD2) in these brain regions. Whereas the mFC had a steeper increase in DRD1 mRNA, the STR had a steeper increase in DRD2 mRNA. Both DR mRNAs were expressed at a higher level in the STR compared to the mFC. To identify the functional properties of DRs during embryonic development, the phosphorylation states of cyclic AMP response element binding protein (CREB), extracellular signal-regulated kinase 1/2 (ERK1/2), and glycogen synthase kinase 3 beta (GSK3β) were examined after DR stimulation in primary neuronal cultures obtained from E15 and E18 embryos and cultured for 3 days to ensure a stable baseline level. DR-mediated signaling cascades were functional in E15 cultures in both brain regions. Because DA fibers do not reach the mFC by E15, and DA was not present in cultures, these data indicate that DRs can become functional in the absence of DA innervation. Since activation of DR signal transduction pathways can affect network organization of the developing brain, maternal exposure to drugs that affect DR activity may be liable to interfere with fetal brain development. PMID:22015925

DRD4 Genotype and the Developmental Link of Peer Social Preference with Conduct Problems and Prosocial Behavior Across Ages 9-12 Years.

PubMed

Buil, J Marieke; Koot, Hans M; Olthof, Tjeert; Nelson, Kelly A; van Lier, Pol A C

2015-07-01

The peer environment is among the most important factors for children's behavioral development. However, not all children are equally influenced by their peers, which is potentially due to their genetic make-up. The dopamine receptor D4 gene (DRD4) is a potential candidate gene that may influence children's susceptibility to the peer environment. In the present study, we explored whether variations in the DRD4 gene moderated the association between children's social standing in the peer group (i.e., social preference among classmates) with subsequent conduct problems and prosocial behavior among 405 (51% females) elementary school children followed annually throughout early adolescence (ages 9-12 years). The behavioral development of children with and without the DRD4 7-repeat allele was compared. The results indicated that children who had higher positive social preference scores (i.e., who were more liked relative to disliked by their peers) showed less conduct problem development in subsequent years relative to children who had lower positive social preference scores. In contrast, children who had more negative preference scores (i.e., who were more disliked relative to liked among peers) showed more conduct problem development in subsequent years, relative to children who had less negative preference scores. However, these effects only occurred when children had a 7-repeat allele. For children who did not have a 7-repeat allele, the level of social preference was not associated with subsequent conduct problems. No evidence for gene-environment interaction effects for prosocial behavior was found. The implications for our understanding of conduct problem development and its prevention are discussed.

Food cravings, food addiction, and a dopamine-resistant (DRD2 A1) receptor polymorphism in Asian American college students.

PubMed

Yeh, Joanna; Trang, Amy; Henning, Susanne M; Wilhalme, Holly; Carpenter, Catherine; Heber, David; Li, Zhaoping

2016-01-01

In an era where obesity remains an important public health concern, food addiction has emerged as a possible contributor to obesity. The DRD2 gene is the most studied polymorphism. The aim of this study was to investigate a relationship between food addiction questionnaires, body composition measurements, and a dopamine- resistant receptor polymorphism (DRD2 A1) among Asian Americans. A total of 84 Asian American college students were recruited. Participants underwent body composition measurement via bioelectrical impedance, answered questionnaires (Food Craving Inventory and Power of Food Scale), and had blood drawn for genotyping (PCR). There was no difference in body composition (BMI, percent body fat) between the A1 (A1A1 or A1A2) and A2 (A2A2) groups. There were statistically significant differences in food cravings of carbohydrates and fast food on the Food Craving Inventory between the A1 and A2 groups (p=0.03), but not for sugar or fat. Among Asian college females, there was also a difference on the Power of Food questionnaire (p=0.04), which was not seen among men. 13 out of 55 women also had >30% body fat at a BMI of 21.4 to 28.5 kg/m2. Greater carbohydrate and fast food craving was associated with the DRD2 A1 versus A2 allele among Asian Americans. Further studies examining the ability of dopamine agonists to affect food craving and to reduce body fat in Asian American are warranted. More studies in food addiction among obese Asian Americans are needed with careful definition of obesity, specifically for Asian women.

Interaction of childhood urbanicity and variation in dopamine genes alters adult prefrontal function as measured by functional magnetic resonance imaging (fMRI).

PubMed

Reed, Jessica L; D'Ambrosio, Enrico; Marenco, Stefano; Ursini, Gianluca; Zheutlin, Amanda B; Blasi, Giuseppe; Spencer, Barbara E; Romano, Raffaella; Hochheiser, Jesse; Reifman, Ann; Sturm, Justin; Berman, Karen F; Bertolino, Alessandro; Weinberger, Daniel R; Callicott, Joseph H

2018-01-01

Brain phenotypes showing environmental influence may help clarify unexplained associations between urban exposure and psychiatric risk. Heritable prefrontal fMRI activation during working memory (WM) is such a phenotype. We hypothesized that urban upbringing (childhood urbanicity) would alter this phenotype and interact with dopamine genes that regulate prefrontal function during WM. Further, dopamine has been hypothesized to mediate urban-associated factors like social stress. WM-related prefrontal function was tested for main effects of urbanicity, main effects of three dopamine genes-catechol-O-methyltransferase (COMT), dopamine receptor D1 (DRD1), and dopamine receptor D2 (DRD2)-and, importantly, dopamine gene-by-urbanicity interactions. For COMT, three independent human samples were recruited (total n = 487). We also studied 253 subjects genotyped for DRD1 and DRD2. 3T fMRI activation during the N-back WM task was the dependent variable, while childhood urbanicity, dopamine genotype, and urbanicity-dopamine interactions were independent variables. Main effects of dopamine genes and of urbanicity were found. Individuals raised in an urban environment showed altered prefrontal activation relative to those raised in rural or town settings. For each gene, dopamine genotype-by-urbanicity interactions were shown in prefrontal cortex-COMT replicated twice in two independent samples. An urban childhood upbringing altered prefrontal function and interacted with each gene to alter genotype-phenotype relationships. Gene-environment interactions between multiple dopamine genes and urban upbringing suggest that neural effects of developmental environmental exposure could mediate, at least partially, increased risk for psychiatric illness in urban environments via dopamine genes expressed into adulthood.

Prefronto-striatal physiology is associated with schizotypy and is modulated by a functional variant of DRD2.

PubMed

Taurisano, Paolo; Romano, Raffaella; Mancini, Marina; Giorgio, Annabella Di; Antonucci, Linda A; Fazio, Leonardo; Rampino, Antonio; Quarto, Tiziana; Gelao, Barbara; Porcelli, Annamaria; Papazacharias, Apostolos; Ursini, Gianluca; Caforio, Grazia; Masellis, Rita; Niccoli-Asabella, Artor; Todarello, Orlando; Popolizio, Teresa; Rubini, Giuseppe; Blasi, Giuseppe; Bertolino, Alessandro

2014-01-01

"Schizotypy" is a latent organization of personality related to the genetic risk for schizophrenia. Some evidence suggests that schizophrenia and schizotypy share some biological features, including a link to dopaminergic D2 receptor signaling. A polymorphism in the D2 gene (DRD2 rs1076560, guanine > thymine (G > T)) has been associated with the D2 short/long isoform expression ratio, as well as striatal dopamine signaling and prefrontal cortical activity during different cognitive operations, which are measures that are altered in patients with schizophrenia. Our aim is to determine the association of schizotypy scores with the DRD2 rs1076560 genotype in healthy individuals and their interaction with prefrontal activity during attention and D2 striatal signaling. A total of 83 healthy subjects were genotyped for DRD2 rs1076560 and completed the Schizotypal Personality Questionnaire (SPQ). Twenty-six participants underwent SPECT with [(123)I]IBZM D2 receptor radiotracer, while 68 performed an attentional control task during fMRI. We found that rs1076560 GT subjects had greater SPQ scores than GG individuals. Moreover, the interaction between schizotypy and the GT genotype predicted prefrontal activity and related attentional behavior, as well as striatal binding of IBZM. No interaction was found in GG individuals. These results suggest that rs1076560 GT healthy individuals are prone to higher levels of schizotypy, and that the interaction between rs1076560 and schizotypy scores modulates phenotypes related to the pathophysiology of schizophrenia, such as prefrontal activity and striatal dopamine signaling. These results provide systems-level qualitative evidence for mapping the construct of schizotypy in healthy individuals onto the schizophrenia continuum.

Functional variation of the dopamine D2 receptor gene is associated with emotional control as well as brain activity and connectivity during emotion processing in humans

PubMed Central

Blasi, Giuseppe; Bianco, Luciana Lo; Taurisano, Paolo; Gelao, Barbara; Romano, Raffaella; Fazio, Leonardo; Papazacharias, Apostolos; Di Giorgio, Annabella; Caforio, Grazia; Rampino, Antonio; Masellis, Rita; Papp, Audrey; Ursini, Gianluca; Sinibaldi, Lorenzo; Popolizio, Teresa; Sadee, Wolfgang; Bertolino, Alessandro

2010-01-01

Personality traits related to emotion processing are, at least in part, heritable and genetically determined. Dopamine D2 receptor signaling is involved in modulation of emotional behavior and activity of associated brain regions such as the amygdala and the prefrontal cortex. An intronic single nucleotide polymorphism within the D2 receptor gene (DRD2, rs1076560, guanine>thymine - G>T) shifts splicing of the two protein isoforms (D2 short, D2S, mainly presynaptic, and D2 long, D2L) and has been associated with modulation of memory performance and brain activity. Here, our aim was to investigate the association of DRD2 rs1076560 genotype with personality traits of emotional stability and with brain physiology during processing of emotionally relevant stimuli. DRD2 genotype and Big Five Questionnaire scores were evaluated in 134 healthy subjects demonstrating that GG subjects have reduced ‘emotion control’ compared with GT subjects. fMRI in a sample of 24 individuals indicated greater amygdala activity during implicit processing and greater dorsolateral prefrontal cortex (DLPFC) response during explicit processing of facial emotional stimuli in GG subjects compared with GT. Other results also demonstrate an interaction between DRD2 genotype and facial emotional expression on functional connectivity of both amygdala and dorsolateral prefrontal regions with overlapping medial prefrontal areas. Moreover, rs1076560 genotype is associated with differential relationships between amygdala/DLPFC functional connectivity and emotion control scores. These results suggest that genetically determined D2 signaling may explain part of personality traits related to emotion processing and individual variability in specific brain responses to emotionally relevant inputs. PMID:19940176

Functional variation of the dopamine D2 receptor gene is associated with emotional control as well as brain activity and connectivity during emotion processing in humans.

PubMed

Blasi, Giuseppe; Lo Bianco, Luciana; Taurisano, Paolo; Gelao, Barbara; Romano, Raffaella; Fazio, Leonardo; Papazacharias, Apostolos; Di Giorgio, Annabella; Caforio, Grazia; Rampino, Antonio; Masellis, Rita; Papp, Audrey; Ursini, Gianluca; Sinibaldi, Lorenzo; Popolizio, Teresa; Sadee, Wolfgang; Bertolino, Alessandro

2009-11-25

Personality traits related to emotion processing are, at least in part, heritable and genetically determined. Dopamine D(2) receptor signaling is involved in modulation of emotional behavior and activity of associated brain regions such as the amygdala and the prefrontal cortex. An intronic single nucleotide polymorphism within the D(2) receptor gene (DRD2) (rs1076560, guanine > thymine or G > T) shifts splicing of the two protein isoforms (D(2) short, mainly presynaptic, and D(2) long) and has been associated with modulation of memory performance and brain activity. Here, our aim was to investigate the association of DRD2 rs1076560 genotype with personality traits of emotional stability and with brain physiology during processing of emotionally relevant stimuli. DRD2 genotype and Big Five Questionnaire scores were evaluated in 134 healthy subjects demonstrating that GG subjects have reduced "emotion control" compared with GT subjects. Functional magnetic resonance imaging in a sample of 24 individuals indicated greater amygdala activity during implicit processing and greater dorsolateral prefrontal cortex (DLPFC) response during explicit processing of facial emotional stimuli in GG subjects compared with GT. Other results also demonstrate an interaction between DRD2 genotype and facial emotional expression on functional connectivity of both amygdala and dorsolateral prefrontal regions with overlapping medial prefrontal areas. Moreover, rs1076560 genotype is associated with differential relationships between amygdala/DLPFC functional connectivity and emotion control scores. These results suggest that genetically determined D(2) signaling may explain part of personality traits related to emotion processing and individual variability in specific brain responses to emotionally relevant inputs.

Prefronto-striatal physiology is associated with schizotypy and is modulated by a functional variant of DRD2

PubMed Central

Taurisano, Paolo; Romano, Raffaella; Mancini, Marina; Giorgio, Annabella Di; Antonucci, Linda A.; Fazio, Leonardo; Rampino, Antonio; Quarto, Tiziana; Gelao, Barbara; Porcelli, Annamaria; Papazacharias, Apostolos; Ursini, Gianluca; Caforio, Grazia; Masellis, Rita; Niccoli-Asabella, Artor; Todarello, Orlando; Popolizio, Teresa; Rubini, Giuseppe; Blasi, Giuseppe; Bertolino, Alessandro

2014-01-01

“Schizotypy” is a latent organization of personality related to the genetic risk for schizophrenia. Some evidence suggests that schizophrenia and schizotypy share some biological features, including a link to dopaminergic D2 receptor signaling. A polymorphism in the D2 gene (DRD2 rs1076560, guanine > thymine (G > T)) has been associated with the D2 short/long isoform expression ratio, as well as striatal dopamine signaling and prefrontal cortical activity during different cognitive operations, which are measures that are altered in patients with schizophrenia. Our aim is to determine the association of schizotypy scores with the DRD2 rs1076560 genotype in healthy individuals and their interaction with prefrontal activity during attention and D2 striatal signaling. A total of 83 healthy subjects were genotyped for DRD2 rs1076560 and completed the Schizotypal Personality Questionnaire (SPQ). Twenty-six participants underwent SPECT with [123I]IBZM D2 receptor radiotracer, while 68 performed an attentional control task during fMRI. We found that rs1076560 GT subjects had greater SPQ scores than GG individuals. Moreover, the interaction between schizotypy and the GT genotype predicted prefrontal activity and related attentional behavior, as well as striatal binding of IBZM. No interaction was found in GG individuals. These results suggest that rs1076560 GT healthy individuals are prone to higher levels of schizotypy, and that the interaction between rs1076560 and schizotypy scores modulates phenotypes related to the pathophysiology of schizophrenia, such as prefrontal activity and striatal dopamine signaling. These results provide systems-level qualitative evidence for mapping the construct of schizotypy in healthy individuals onto the schizophrenia continuum. PMID:25071490

Polymorphisms of the mu-opioid receptor and dopamine D4 receptor genes and subjective responses to alcohol in the natural environment.

PubMed

Ray, Lara A; Miranda, Robert; Tidey, Jennifer W; McGeary, John E; MacKillop, James; Gwaltney, Chad J; Rohsenow, Damaris J; Swift, Robert M; Monti, Peter M

2010-02-01

Polymorphisms of the mu-opioid receptor (OPRM1) and dopamine D4 receptor (DRD4) genes are associated with subjective responses to alcohol and urge to drink under laboratory conditions. This study examined these associations in the natural environment using ecological momentary assessment. Participants were non-treatment-seeking heavy drinkers (n = 112, 52% female, 61% alcohol dependent) who enrolled in a study of naltrexone effects on craving and drinking in the natural environment. Data were culled from 5 consecutive days of drinking reports prior to medication randomization. Analyses revealed that, after drinking, carriers of the Asp40 allele of the OPRM1 gene reported higher overall levels of vigor and lower levels negative mood, as compared to homozygotes for the Asn40 variant. Carriers of the long allele (i.e., >or=7 tandem repeats) of the DRD4 endorsed greater urge to drink than homozygotes for the short allele. Effects of OPRM1 and DRD4 variable-number-of-tandem-repeats genotypes appear to be alcohol dose-dependent. Specifically, carriers of the DRD4-L allele reported slight decreases in urge to drink at higher levels of estimated blood alcohol concentration (eBAC), and Asp40 carriers reported decreases in vigor and increases in negative mood as eBAC rose, as compared to carriers of the major allele for each gene. Self-reported vigor and urge to drink were positively associated with alcohol consumption within the same drinking episode. This study extends findings on subjective intoxication, urge to drink, and their genetic bases from controlled laboratory to naturalistic settings.

Interaction between ALDH2*1*1 and DRD2/ANKK1 TaqI A1A1 genes may be associated with antisocial personality disorder not co-morbid with alcoholism.

PubMed

Lu, Ru-Band; Lee, Jia-Fu; Huang, San-Yuan; Lee, Sheng-Yu; Chang, Yun-Hsuan; Kuo, Po-Hsiu; Chen, Shiou-Lan; Chen, Shih-Heng; Chu, Chun-Hsien; Lin, Wei-Wen; Wu, Pei-Lin; Ko, Huei-Chen

2012-09-01

Previous studies on acetaldehyde dehydrogenase 2 (ALDH2) focused on drinking behavior or alcoholism because the ALDH2*2 allele protects against the risk of developing alcoholism. The mechanism provides that the ALDH2 gene's protective effect is also involved in dopamine metabolism. The interaction of the ALDH2 gene with neurotransmitters, such as dopamine, is suggested to be related to alcoholism. Because alcoholism is often co-morbid with antisocial personality disorder (ASPD), previous association studies on antisocial alcoholism cannot differentiate whether those genes relate to ASPD with alcoholism or ASPD only. This study examined the influence of the interaction effect of the ALDH2*1*1, *1*2 or *2*2 polymorphisms with the dopamine 2 receptor (DRD2) Taq I polymorphism on ASPD. Our 541 Han Chinese male participants were classified into three groups: antisocial alcoholism (ASPD co-morbid with alcohol dependence, antisocial ALC; n = 133), ASPD without alcoholism (ASPD not co-morbid with alcohol dependence, antisocial non-ALC; n = 164) and community controls (healthy volunteers from the community; n = 244). Compared with healthy controls, individuals with the DRD2 A1/A1 and the ALDH2*1/*1 genotypes were at a 5.39 times greater risk for antisocial non-ALC than were those with other genotypes. Our results suggest that the DRD2/ANKK1 and ALDH2 genes interacted in the antisocial non-ALC group; a connection neglected in previous studies caused by not separating antisocial ALC from ASPD. Our study made this distinction and showed that these two genes may be associated ASPD without co-morbid alcoholism. © 2010 The Authors, Addiction Biology © 2010 Society for the Study of Addiction.

Variation in the dopamine D2 receptor gene plays a key role in human pain and its modulation by transcranial magnetic stimulation.

PubMed

Jääskeläinen, Satu K; Lindholm, Pauliina; Valmunen, Tanja; Pesonen, Ullamari; Taiminen, Tero; Virtanen, Arja; Lamusuo, Salla; Forssell, Heli; Hagelberg, Nora; Hietala, Jarmo; Pertovaara, Antti

2014-10-01

We tested whether variation of the dopamine D2 receptor (DRD2) gene contributes to individual differences in thermal pain sensitivity and analgesic efficacy of repetitive transcranial magnetic stimulation (rTMS) in healthy subjects (n=29) or susceptibility to neuropathic pain in patients with neurophysiologically confirmed diagnosis (n=16). Thermal sensitivity of healthy subjects was assessed before and after navigated rTMS provided to the S1/M1 cortex. All subjects were genotyped for the DRD2 gene 957C>T and catechol-O-methyltransferase (COMT) protein Val158Met polymorphisms. In healthy subjects, 957C>T influenced both innocuous and noxious thermal detection thresholds that were lowest in 957TT homozygotes (P values from .0277 to .0462). rTMS to S1 cortex had analgesic effect only in 957TT homozygote genotype (P=.0086). In patients, prevalence of 957TT homozygote genotype was higher than in a healthy Finnish population (50% vs 27%; P=.0191). Patients with 957TT genotype reported more severe pain than patients with other genotypes (P=.0351). COMT Val158Met polymorphism was not independently associated with the studied variables. Genetic regulation of DRD2 function by 957C>T polymorphism thus seems to influence thermal and pain sensitivity, its modulation by rTMS, and susceptibility to neuropathic pain. This indicates a central role for the dopamine system and DRD2 in pain and analgesia. This may have clinical implications regarding individualized selection of patients for rTMS treatment and assessment of risks for neuropathic pain. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

COMT and DRD2/ANKK-1 gene-gene interaction account for resetting of gamma neural oscillations to auditory stimulus-driven attention.

PubMed

Garcia-Garcia, Manuel; Via, Marc; Zarnowiec, Katarzyna; SanMiguel, Iria; Escera, Carles; Clemente, Immaculada C

2017-01-01

Attention capture by potentially relevant environmental stimuli is critical for human survival, yet it varies considerably among individuals. A large series of studies has suggested that attention capture may depend on the cognitive balance between maintenance and manipulation of mental representations and the flexible switch between goal-directed representations and potentially relevant stimuli outside the focus of attention; a balance that seems modulated by a prefrontostriatal dopamine pathway. Here, we examined inter-individual differences in the cognitive control of attention through studying the effects of two single nucleotide polymorphisms regulating dopamine at the prefrontal cortex and the striatum (i.e., COMTMet108/158Val and ANKK1/DRD2TaqIA) on stimulus-driven attention capture. Healthy adult participants (N = 40) were assigned to different groups according to the combination of the polymorphisms COMTMet108/158Val and ANKK1/DRD2TaqIA, and were instructed to perform on a well-established distraction protocol. Performance in individuals with a balance between prefrontal dopamine display and striatal receptor density was slowed down by the occurrence of unexpected distracting events, while those with a rather unbalanced dopamine activity were able maintain task performance with no time delay, yet at the expense of a slightly lower accuracy. This advantage, associated to their distinct genetic profiles, was paralleled by an electrophysiological mechanism of phase-resetting of gamma neural oscillation to the novel, distracting events. Taken together, the current results suggest that the epistatic interaction between COMTVal108/158Met and ANKK1/DRD2 TaqIa genetic polymorphisms lies at the basis of stimulus-driven attention capture.

Genetic determinants of financial risk taking.

PubMed

Kuhnen, Camelia M; Chiao, Joan Y

2009-01-01

Individuals vary in their willingness to take financial risks. Here we show that variants of two genes that regulate dopamine and serotonin neurotransmission and have been previously linked to emotional behavior, anxiety and addiction (5-HTTLPR and DRD4) are significant determinants of risk taking in investment decisions. We find that the 5-HTTLPR s/s allele carriers take 28% less risk than those carrying the s/l or l/l alleles of the gene. DRD4 7-repeat allele carriers take 25% more risk than individuals without the 7-repeat allele. These findings contribute to the emerging literature on the genetic determinants of economic behavior.

A common variant in DRD3 receptor is associated with autism spectrum disorder.

PubMed

de Krom, Mariken; Staal, Wouter G; Ophoff, Roel A; Hendriks, Judith; Buitelaar, Jan; Franke, Barbara; de Jonge, Maretha V; Bolton, Patrick; Collier, David; Curran, Sarah; van Engeland, Herman; van Ree, Jan M

2009-04-01

The presence of specific and common genetic etiologies for autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD) was investigated for 132 candidate genes in a two-stage design-association study. 1,536 single nucleotide polymorphisms (SNPs) covering these candidate genes were tested in ASD (n = 144) and ADHD (n = 110) patients and control subjects (n = 404) from The Netherlands. A second stage was performed with those SNPs from Stage I reaching a significance threshold for association of p < .01 in an independent sample of ASD patients (n = 128) and controls (n = 124) from the United Kingdom and a Dutch ADHD (n = 150) and control (n = 149) sample. No shared association was found between ASD and ADHD. However, in the first and second ASD samples and in a joint statistical analysis, a significant association between SNP rs167771 located in the DRD3 gene was found (joint analysis uncorrected: p = 3.11 x 10(-6); corrected for multiple testing and potential stratification: p = .00162). The DRD3 gene is related to stereotyped behavior, liability to side effects of antipsychotic medication, and movement disorders and may therefore have important clinical implications for ASD.

Systematic screening for mutations in the 5{prime}-regulatory region of the human dopamine D{sub 1} receptor (DRD1) gene in patients with schizophrenia and bipolar affective disorder

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cichon, S.; Noethen, M.M.; Stoeber, G.

1996-07-26

A possible dysregulation of dopaminergic neurotransmission has been implicated in a variety of neuropsychiatric diseases. In the present study we systematically searched for the presence of mutations in the 5{prime}-flanking region of the dopamine D{sub 1} receptor (DRD1) gene. This region has previously been shown to contain a functional promoter. We investigated 119 unrelated individuals (including 36 schizophrenic patients, 38 bipolar affective patients, and 45 healthy controls) using single-strand conformation analysis (SSCA). Eleven overlapping PCR fragments covered 2,189 bp of DNA sequence. We identified six single base substitutions: -2218T/C, -2102C/A, -2030T/C, -1992G/A, -1251G/C, and -800T/C. None of the mutations wasmore » found to be located in regions which have important influence on the level of transcriptional activity. Allele frequencies were similar in patients and controls, indicating that genetic variation in the 5{prime}-regulatory region of the DRD1 gene is unlikely to play a frequent, major role in the genetic predisposition to either schizophrenia or bipolar affective disorder. 31 refs., 3 tabs.« less

Self-esteem in remitted patients with mood disorders is not associated with the dopamine receptor D4 and the serotonin transporter genes.

PubMed

Serretti, A; Macciardi, F; Di Bella, D; Catalano, M; Smeraldi, E

1998-08-17

Disturbances of the dopaminergic and serotoninergic neurotransmitter systems have been implicated in the pathogenesis of depressive symptoms. Associations have been reported between markers of the two neurotransmitter systems and the presence of illness or severity of depressive episodes, but no attention has been focused on the periods of remission. The present report focuses on a possible association of self-esteem in remitted mood disorder patients with the functional polymorphism located in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) and the dopamine receptor D4 (DRD4). Inpatients (N=162) affected by bipolar (n=103) and unipolar (n=59) disorder (DSM III-R) were assessed by the Self-Esteem Scale (SES, Rosenberg, 1965) and were typed for DRD4 and 5-HTTLPR (n=58 subjects) variants at the third exon using polymerase chain reaction (PCR) techniques. Neither DRD4 nor 5-HTTLPR variants were associated with SES scores, and consideration of possible stratification effects such as sex and psychiatric diagnosis did not reveal any association either. The serotonin transporter and dopamine receptor D4 genes do not, therefore, influence self-esteem in remitted mood disorder subjects.

Preliminary evidence for an association between a dopamine D3 receptor gene variant and obsessive-compulsive personality disorder in patients with major depression.

PubMed

Light, Katrina J; Joyce, Peter R; Luty, Suzanne E; Mulder, Roger T; Frampton, Christropher M A; Joyce, Laura R M; Miller, Allison L; Kennedy, Martin A

2006-06-05

We have previously reported that the Ser9Gly dopamine D3 receptor (DRD3) polymorphism was associated with increased rates of obsessive-compulsive personality disorder (OCPD) symptomology. We tested the replicability of this association within a further two independent groups of individuals with a history of depression, from a clinical sample (n = 149) and a family study (n = 213). The data from the replication samples and the original sample, within which the association was found, were compiled within a meta-analysis. Although the independent samples did not replicate the original finding, the meta-analysis elucidated significant evidence supporting the association. An individual with Gly/Gly genotype is 2.4 (P = 0.017) times more likely to be diagnosed with OCPD. Male gender was also found to be a significant predictor of OCPD diagnosis (OR = 2.82, P = 0.001). An exploration of an association of DRD3 with Axis I anxiety disorder diagnoses and Temperament and Character Inventory (TCI) traits, in particular persistence, revealed no support for an association. We conclude that DRD3 may contribute to the development of OCPD.

Functional Polymorphisms in Dopaminergic Genes Modulate Neurobehavioral and Neurophysiological Consequences of Sleep Deprivation.

PubMed

Holst, Sebastian C; Müller, Thomas; Valomon, Amandine; Seebauer, Britta; Berger, Wolfgang; Landolt, Hans-Peter

2017-04-10

Sleep deprivation impairs cognitive performance and reliably alters brain activation in wakefulness and sleep. Nevertheless, the molecular regulators of prolonged wakefulness remain poorly understood. Evidence from genetic, behavioral, pharmacologic and imaging studies suggest that dopaminergic signaling contributes to the behavioral and electroencephalographic (EEG) consequences of sleep loss, although direct human evidence thereof is missing. We tested whether dopamine neurotransmission regulate sustained attention and evolution of EEG power during prolonged wakefulness. Here, we studied the effects of functional genetic variation in the dopamine transporter (DAT1) and the dopamine D 2 receptor (DRD2) genes, on psychomotor performance and standardized waking EEG oscillations during 40 hours of wakefulness in 64 to 82 healthy volunteers. Sleep deprivation consistently enhanced sleepiness, lapses of attention and the theta-to-alpha power ratio (TAR) in the waking EEG. Importantly, DAT1 and DRD2 genotypes distinctly modulated sleep loss-induced changes in subjective sleepiness, PVT lapses and TAR, according to inverted U-shaped relationships. Together, the data suggest that genetically determined differences in DAT1 and DRD2 expression modulate functional consequences of sleep deprivation, supporting the hypothesis that striato-thalamo-cortical dopaminergic pathways modulate the neurobehavioral and neurophysiological consequences of sleep loss in humans.

Transgenic mice reveal unexpected diversity of On-Off direction selective retinal ganglion cell subtypes and brain structures involved in motion processing

PubMed Central

Rivlin-Etzion, Michal; Zhou, Kaili; Wei, Wei; Elstrott, Justin; Nguyen, Phong L.; Barres, Ben; Huberman, Andrew D.; Feller, Marla B.

2011-01-01

On-Off direction selective retinal ganglion cells (DSGCs) encode the axis of visual motion. They respond strongly to an object moving in a preferred direction and weakly to an object moving in the opposite, ‘null’, direction. Historically, On-Off DSGCs were classified into 4 subtypes according to their directional preference (anterior, posterior, superior or inferior). Here, we compare two genetically identified populations of On-Off DSGCs: DRD4-DSGCs and TRHR-DSGCs. We find that although both populations are tuned for posterior motion, they can be distinguished by a variety of physiological and anatomical criteria. First, the directional tuning of TRHR-DSGCs is broader than that of DRD4-DSGCs. Second, whereas both populations project similarly to the dorsal lateral geniculate nucleus, they project differently to the ventral lateral geniculate nucleus and the superior colliculus. Moreover, TRHR-DSGCs, but not DRD4-DSGCs, also project to the zona incerta, a thalamic area not previously known to receive direction-tuned visual information. Our findings reveal unexpected diversity among mouse On-Off DSGC subtypes that uniquely process and convey image motion to the brain. PMID:21677160

The interaction of reward genes with environmental factors in contribution to alcoholism in mexican americans.

PubMed

Du, Yanlei; Wan, Yu-Jui Yvonne

2009-12-01

Alcoholism is a polygenic disorder resulting from reward deficiency; polymorphisms in reward genes including serotonin transporter (5-HTT)-linked polymorphic region (5-HTTLPR), A118G in opioid receptor mu1 (OPRM1), and -141C Insertion/Deletion (Ins/Del) in dopamine receptor D2 (DRD2) as well as environmental factors (education and marital status) might affect the risk of alcoholism. Objective of the current study was to examine the main and interacting effect of these 3 polymorphisms and 2 environmental factors in contribution to alcoholism in Mexican Americans. Genotyping of 5-HTTLPR, OPRM1 A118G, and DRD2-141C Ins/Del was performed in 365 alcoholics and 338 nonalcoholic controls of Mexican Americans who were gender- and age-matched. Alcoholics were stratified according to tertiles of MAXDRINKS, which denotes the largest number of drinks consumed in one 24-hour period. Data analysis was done in the entire data set and in each alcoholic stratum. Multinomial logistic regression was conducted to explore the main effect of 3 polymorphisms and 2 environmental factors (education and marital status); classification tree, generalized multifactor dimensionality reduction (GMDR) analysis, and polymorphism interaction analysis version 2.0 (PIA 2) program were used to study factor interaction. Main effect of education, OPRM1, and DRD2 was detected in alcoholic stratum of moderate and/or largest MAXDRINKS with education < or =12 years, OPRM1 118 A/A, and DRD2 -141C Ins/Ins being risk factors. Classification tree analysis, GMDR analysis, and PIA 2 program all supported education*OPRM1 interaction in alcoholics of largest MAXDRINKS with education < or =12 years coupled with OPRM1 A/A being a high risk factor; dendrogram showed synergistic interaction between these 2 factors; dosage-effect response was also observed for education*OPRM1 interaction. No definite effect of marital status and 5-HTTLPR in pathogenesis of alcoholism was observed. Our results suggest main effect of education background, OPRM1 A118G, and DRD2 -141C Ins/Del as well as education*OPRM1 interaction in contribution to moderate and/or severe alcoholism in Mexican Americans. Functional relevance of these findings still needs to be explored.

Genetics of tardive dyskinesia: Promising leads and ways forward.

PubMed

Zai, Clement C; Maes, Miriam S; Tiwari, Arun K; Zai, Gwyneth C; Remington, Gary; Kennedy, James L

2018-06-15

Tardive dyskinesia (TD) is a potentially irreversible and often debilitating movement disorder secondary to chronic use of dopamine receptor blocking medications. Genetic factors have been implicated in the etiology of TD. We therefore have reviewed the most promising genes associated with TD, including DRD2, DRD3, VMAT2, HSPG2, HTR2A, HTR2C, and SOD2. In addition, we present evidence supporting a role for these genes from preclinical models of TD. The current understanding of the etiogenesis of TD is discussed in the light of the recent approvals of valbenazine and deutetrabenazine, VMAT2 inhibitors, for treating TD. Copyright © 2018 Elsevier B.V. All rights reserved.

The interaction between the DRD4 VNTR polymorphism and perceived peer drinking norms in adolescent alcohol use and misuse

PubMed Central

Park, Aesoon; Kim, Jueun; Zaso, Michelle J.; Glatt, Stephen J.; Sher, Kenneth J.; Scott-Sheldon, Lori A. J.; Eckert, Tanya L.; Vanable, Peter A.; Carey, Kate B.; Ewart, Craig K.; Carey, Michael P.

2015-01-01

Peer drinking norms are arguably one of the strongest correlates of adolescent drinking. Prospective studies indicate that adolescents tend to select peers based on drinking (peer-selection) and their peers’ drinking is associated with changes in adolescent drinking over time (peer socialization). The present study investigated whether the peer selection and socialization processes in adolescent drinking differed as a function of the DRD4 VNTR genotype in two independent prospective datasets. The first sample was 174 high school students drawn from a 2-wave 6-month prospective study. The second sample was 237 college students drawn from a 3-wave annual prospective study. Multigroup cross-lagged panel analyses of the high school student sample indicated stronger socialization via peer drinking norms among carriers, whereas analyses of the college student sample indicated stronger drinking-based peer selection in the junior year among carriers, compared to non-carriers. Although replication and meta-analytic synthesis are needed, these findings suggest in part genetically determined peer-selection (carriers of the DRD4 7-repeat allele tend to associate with peers who have more favorable attitudes toward drinking and greater alcohol use) and peer socialization (carriers’ subsequent drinking behaviors are more strongly associated with their peer drinking norms) may differ across adolescent developmental stages. PMID:26902782

Acute effects of cocaine and cannabis on reversal learning as a function of COMT and DRD2 genotype.

PubMed

Spronk, Desirée B; Van der Schaaf, Marieke E; Cools, Roshan; De Bruijn, Ellen R A; Franke, Barbara; van Wel, Janelle H P; Ramaekers, Johannes G; Verkes, Robbert J

2016-01-01

Long-term cannabis and cocaine use has been associated with impairments in reversal learning. However, how acute cannabis and cocaine administration affect reversal learning in humans is not known. In this study, we aimed to establish the acute effects of administration of cannabis and cocaine on valence-dependent reversal learning as a function of DRD2 Taq1A (rs1800497) and COMT Val108/158Met (rs4680) genotype. A double-blind placebo-controlled randomized 3-way crossover design was used. Sixty-one regular poly-drug users completed a deterministic reversal learning task under the influence of cocaine, cannabis, and placebo that enabled assessment of both reward- and punishment-based reversal learning. Proportion correct on the reversal learning task was increased by cocaine, but decreased by cannabis. Effects of cocaine depended on the DRD2 genotype, as increases in proportion correct were seen only in the A1 carriers, and not in the A2/A2 homozygotes. COMT genotype did not modulate drug-induced effects on reversal learning. These data indicate that acute administration of cannabis and cocaine has opposite effects on reversal learning. The effects of cocaine, but not cannabis, depend on interindividual genetic differences in the dopamine D2 receptor gene.

DRD4 Polymorphism Moderates the Effect of Alcohol Consumption on Social Bonding

PubMed Central

Creswell, Kasey G.; Sayette, Michael A.; Manuck, Stephen B.; Ferrell, Robert E.; Hill, Shirley Y.; Dimoff, John D.

2012-01-01

Development of interpersonal relationships is a fundamental human motivation, and behaviors facilitating social bonding are prized. Some individuals experience enhanced reward from alcohol in social contexts and may be at heightened risk for developing and maintaining problematic drinking. We employed a 3 (group beverage condition) ×2 (genotype) design (N = 422) to test the moderating influence of the dopamine D4 receptor gene (DRD4 VNTR) polymorphism on the effects of alcohol on social bonding. A significant gene x environment interaction showed that carriers of at least one copy of the 7-repeat allele reported higher social bonding in the alcohol, relative to placebo or control conditions, whereas alcohol did not affect ratings of 7-absent allele carriers. Carriers of the 7-repeat allele were especially sensitive to alcohol's effects on social bonding. These data converge with other recent gene-environment interaction findings implicating the DRD4 polymorphism in the development of alcohol use disorders, and results suggest a specific pathway by which social factors may increase risk for problematic drinking among 7-repeat carriers. More generally, our findings highlight the potential utility of employing transdisciplinary methods that integrate genetic methodologies, social psychology, and addiction theory to improve theories of alcohol use and abuse. PMID:22347363

Human dopamine receptor nanovesicles for gate-potential modulators in high-performance field-effect transistor biosensors

NASA Astrophysics Data System (ADS)

Park, Seon Joo; Song, Hyun Seok; Kwon, Oh Seok; Chung, Ji Hyun; Lee, Seung Hwan; An, Ji Hyun; Ahn, Sae Ryun; Lee, Ji Eun; Yoon, Hyeonseok; Park, Tai Hyun; Jang, Jyongsik

2014-03-01

The development of molecular detection that allows rapid responses with high sensitivity and selectivity remains challenging. Herein, we demonstrate the strategy of novel bio-nanotechnology to successfully fabricate high-performance dopamine (DA) biosensor using DA Receptor-containing uniform-particle-shaped Nanovesicles-immobilized Carboxylated poly(3,4-ethylenedioxythiophene) (CPEDOT) NTs (DRNCNs). DA molecules are commonly associated with serious diseases, such as Parkinson's and Alzheimer's diseases. For the first time, nanovesicles containing a human DA receptor D1 (hDRD1) were successfully constructed from HEK-293 cells, stably expressing hDRD1. The nanovesicles containing hDRD1 as gate-potential modulator on the conducting polymer (CP) nanomaterial transistors provided high-performance responses to DA molecule owing to their uniform, monodispersive morphologies and outstanding discrimination ability. Specifically, the DRNCNs were integrated into a liquid-ion gated field-effect transistor (FET) system via immobilization and attachment processes, leading to high sensitivity and excellent selectivity toward DA in liquid state. Unprecedentedly, the minimum detectable level (MDL) from the field-induced DA responses was as low as 10 pM in real- time, which is 10 times more sensitive than that of previously reported CP based-DA biosensors. Moreover, the FET-type DRNCN biosensor had a rapid response time (<1 s) and showed excellent selectivity in human serum.

Oxytocin receptor gene (OXTR) in relation to loneliness in adolescence: interactions with sex, parental support, and DRD2 and 5-HTTLPR genotypes.

PubMed

van Roekel, Eeske; Verhagen, Maaike; Engels, Rutger C M E; Goossens, Luc; Scholte, Ron H J

2013-10-01

Recent research has shown that loneliness, a common problem in adolescence, may have a genetic basis. The evidence, though, was limited mostly to serotonin-related and dopamine-related genes. In the present study, we focused on the oxytocin receptor gene (OXTR). Associations were examined in a longitudinal study spanning five annual waves (N=307). The relations between OXTR and loneliness were examined, as well as interactions between OXTR and sex, parental support, 5-HTTLPR genotype, and DRD2 genotype. Using Latent Growth Curve Modeling, the OXTR genotype was not directly related to loneliness. An OXTR×sex interaction was found. Girls showed a steeper decline in loneliness when they had an A allele compared with girls who were homozygous for the G allele. In addition, a gene-gene interaction or epistasis was observed. Both boys and girls who had at least one A1 allele for the DRD2 gene and also had the GG genotype for the OXTR gene showed stable levels of loneliness over time. The present study is the first to show that the GG genotype for the OXTR gene is linked to the development of loneliness in adolescence and that this association is moderated by participants' sex and their genotype for a dopamine-related gene.

DRD4 polymorphism moderates the effect of alcohol consumption on social bonding.

PubMed

Creswell, Kasey G; Sayette, Michael A; Manuck, Stephen B; Ferrell, Robert E; Hill, Shirley Y; Dimoff, John D

2012-01-01

Development of interpersonal relationships is a fundamental human motivation, and behaviors facilitating social bonding are prized. Some individuals experience enhanced reward from alcohol in social contexts and may be at heightened risk for developing and maintaining problematic drinking. We employed a 3 (group beverage condition) ×2 (genotype) design (N = 422) to test the moderating influence of the dopamine D4 receptor gene (DRD4 VNTR) polymorphism on the effects of alcohol on social bonding. A significant gene x environment interaction showed that carriers of at least one copy of the 7-repeat allele reported higher social bonding in the alcohol, relative to placebo or control conditions, whereas alcohol did not affect ratings of 7-absent allele carriers. Carriers of the 7-repeat allele were especially sensitive to alcohol's effects on social bonding. These data converge with other recent gene-environment interaction findings implicating the DRD4 polymorphism in the development of alcohol use disorders, and results suggest a specific pathway by which social factors may increase risk for problematic drinking among 7-repeat carriers. More generally, our findings highlight the potential utility of employing transdisciplinary methods that integrate genetic methodologies, social psychology, and addiction theory to improve theories of alcohol use and abuse.

Drug-related death following release from prison: a brief review of the literature with recommendations for practice.

PubMed

Leach, D; Oliver, P

2011-12-01

Mortality from drug-related death is a significant contributor to the loss of life of young people in the UK. Despite attention, the high death rate from this cause continues to persist. One of the most frequently cited factors involved in drug-related death (DRD) is release from prison. This review aims to examine the published literature with a view to quantifying the risk associated with recent prison release and identifying risk factors and prevention strategies. Most deaths following release from prison are caused by overdose, usually from opioid use. The risk of death is greatest within the first week of release but, when compared with the general population, continues to be elevated for several weeks. Relative risk estimates suggest that those released from prison are up to 40 times more likely to die than similar individuals from the general population. Other than gender and an association with poor mental health, there is little in the way of robust risk factors for post-release death that could be identified from the literature. In-prison pharmacological maintenance treatment with methadone and buprenorphine has been shown to reduce the rate of heroin use, in the period immediately following release, in a small number of randomised controlled trials. It is widely recognised that continuity of care, of any form, is critical in avoiding DRDs. For problem drug users, packages of education, including information on the associated risks, treatments, and recognition of DRD after release from prison, are seen as a basic minimum requirement of the prison services. However, special protocols may be required for those drug-using prisoners who have a possibility of being released at short notice.

Dopamine D3 receptor Ser9Gly variant is associated with impulse control disorders in Parkinson's disease patients.

PubMed

Krishnamoorthy, Soumya; Rajan, Roopa; Banerjee, Moinak; Kumar, Hardeep; Sarma, Gangadhara; Krishnan, Syam; Sarma, Sankara; Kishore, Asha

2016-09-01

Impulse control disorders (ICD) are reported to occur at variable frequencies in different ethnic groups. Genetic vulnerability is suspected to underlie the individual risk for ICD. We investigated whether the allelic variants of dopamine (DRD3), glutamate (GRIN2B) and serotonin (HTR2A) receptors are linked to ICD in Indian Parkinson's disease (PD) patients. We conducted a prospective, case-control study which included PD patients (70 with ICD, 100 without ICD categorized after direct psychiatric interview of patient and caregiver) and 285 healthy controls. Single nucleotide polymorphism (SNP) variants of DRD3 p.S9G (rs6280), GRIN2B c.2664C>T (rs1806201) and HTR2A c.102T>C (rs6313) were genotyped. Multivariate regression analysis revealed that DRD3 p.Ser9Gly (rs6280) heterozygous variant CT (OR = 2.22, 95% CI: 1.03-4.86, p = 0.041), higher daily Levodopa equivalent doses (LED) of drugs (for 100 mg LED, OR = 1.14, 95% CI: 1.01-1.29, p = 0.041), current dopamine agonist but not Levodopa use (OR = 2.16, 95% CI: 1.03-4.55, p = 0.042) and age of onset of motor symptoms under 50 years (OR 2.09, 95% CI: 1.05-4.18, p = 0.035) were independently associated with ICD. DRD3 p.Ser9Gly (rs6280) CT genotype is associated with ICD in Indian PD patients and this association is novel. Enhanced D3 receptor affinity due to gain-of-function conferred by the glycine residues could impair reward-risk assessment in the mesolimbic system and contribute to development of impulsive behaviour, in carriers of this genotype. Copyright © 2016. Published by Elsevier Ltd.

The impact of common dopamine D2 receptor gene polymorphisms on D2/3 receptor availability: C957T as a key determinant in putamen and ventral striatum.

PubMed

Smith, C T; Dang, L C; Buckholtz, J W; Tetreault, A M; Cowan, R L; Kessler, R M; Zald, D H

2017-04-11

Dopamine function is broadly implicated in multiple neuropsychiatric conditions believed to have a genetic basis. Although a few positron emission tomography (PET) studies have investigated the impact of single-nucleotide polymorphisms (SNPs) in the dopamine D2 receptor gene (DRD2) on D2/3 receptor availability (binding potential, BP ND ), these studies have often been limited by small sample size. Furthermore, the most commonly studied SNP in D2/3 BP ND (Taq1A) is not located in the DRD2 gene itself, suggesting that its linkage with other DRD2 SNPs may explain previous PET findings. Here, in the largest PET genetic study to date (n=84), we tested for effects of the C957T and -141C Ins/Del SNPs (located within DRD2) as well as Taq1A on BP ND of the high-affinity D2 receptor tracer 18 F-Fallypride. In a whole-brain voxelwise analysis, we found a positive linear effect of C957T T allele status on striatal BP ND bilaterally. The multilocus genetic scores containing C957T and one or both of the other SNPs produced qualitatively similar striatal results to C957T alone. The number of C957T T alleles predicted BP ND in anatomically defined putamen and ventral striatum (but not caudate) regions of interest, suggesting some regional specificity of effects in the striatum. By contrast, no significant effects arose in cortical regions. Taken together, our data support the critical role of C957T in striatal D2/3 receptor availability. This work has implications for a number of psychiatric conditions in which dopamine signaling and variation in C957T status have been implicated, including schizophrenia and substance use disorders.

D2 receptor genotype and striatal dopamine signaling predict motor cortical activity and behavior in humans.

PubMed

Fazio, Leonardo; Blasi, Giuseppe; Taurisano, Paolo; Papazacharias, Apostolos; Romano, Raffaella; Gelao, Barbara; Ursini, Gianluca; Quarto, Tiziana; Lo Bianco, Luciana; Di Giorgio, Annabella; Mancini, Marina; Popolizio, Teresa; Rubini, Giuseppe; Bertolino, Alessandro

2011-02-14

Pre-synaptic D2 receptors regulate striatal dopamine release and DAT activity, key factors for modulation of motor pathways. A functional SNP of DRD2 (rs1076560 G>T) is associated with alternative splicing such that the relative expression of D2S (mainly pre-synaptic) vs. D2L (mainly post-synaptic) receptor isoforms is decreased in subjects with the T allele with a putative increase of striatal dopamine levels. To evaluate how DRD2 genotype and striatal dopamine signaling predict motor cortical activity and behavior in humans, we have investigated the association of rs1076560 with BOLD fMRI activity during a motor task. To further evaluate the relationship of this circuitry with dopamine signaling, we also explored the correlation between genotype based differences in motor brain activity and pre-synaptic striatal DAT binding measured with [(123)I] FP-CIT SPECT. Fifty healthy subjects, genotyped for DRD2 rs1076560 were studied with BOLD-fMRI at 3T while performing a visually paced motor task with their right hand; eleven of these subjects also underwent [(123)I]FP-CIT SPECT. SPM5 random-effects models were used for statistical analyses. Subjects carrying the T allele had greater BOLD responses in left basal ganglia, thalamus, supplementary motor area, and primary motor cortex, whose activity was also negatively correlated with reaction time at the task. Moreover, left striatal DAT binding and activity of left supplementary motor area were negatively correlated. The present results suggest that DRD2 genetic variation was associated with focusing of responses in the whole motor network, in which activity of predictable nodes was correlated with reaction time and with striatal pre-synaptic dopamine signaling. Our results in humans may help shed light on genetic risk for neurobiological mechanisms involved in the pathophysiology of disorders with dysregulation of striatal dopamine like Parkinson's disease. Copyright © 2010 Elsevier Inc. All rights reserved.

Genetically determined measures of striatal D2 signaling predict prefrontal activity during working memory performance.

PubMed

Bertolino, Alessandro; Taurisano, Paolo; Pisciotta, Nicola Marco; Blasi, Giuseppe; Fazio, Leonardo; Romano, Raffaella; Gelao, Barbara; Lo Bianco, Luciana; Lozupone, Madia; Di Giorgio, Annabella; Caforio, Grazia; Sambataro, Fabio; Niccoli-Asabella, Artor; Papp, Audrey; Ursini, Gianluca; Sinibaldi, Lorenzo; Popolizio, Teresa; Sadee, Wolfgang; Rubini, Giuseppe

2010-02-22

Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known. Thirty-seven healthy subjects were genotyped for rs1076560 (G>T) and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors) and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors), as well as BOLD fMRI during N-Back working memory. Subjects carrying the T allele (previously associated with reduced D2S expression) had striatal reductions of [123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers) and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT. Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic-cortical pathway.

Genetically Determined Measures of Striatal D2 Signaling Predict Prefrontal Activity during Working Memory Performance

PubMed Central

Bertolino, Alessandro; Taurisano, Paolo; Pisciotta, Nicola Marco; Blasi, Giuseppe; Fazio, Leonardo; Romano, Raffaella; Gelao, Barbara; Bianco, Luciana Lo; Lozupone, Madia; Di Giorgio, Annabella; Caforio, Grazia; Sambataro, Fabio; Niccoli-Asabella, Artor; Papp, Audrey; Ursini, Gianluca; Sinibaldi, Lorenzo; Popolizio, Teresa; Sadee, Wolfgang; Rubini, Giuseppe

2010-01-01

Background Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known. Methods Thirty-seven healthy subjects were genotyped for rs1076560 (G>T) and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors) and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors), as well as BOLD fMRI during N-Back working memory. Results Subjects carrying the T allele (previously associated with reduced D2S expression) had striatal reductions of [123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers) and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT. Conclusions Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic-cortical pathway. PMID:20179754

Genetic deletion of GPR52 enhances the locomotor-stimulating effect of an adenosine A2A receptor antagonist in mice: A potential role of GPR52 in the function of striatopallidal neurons.

PubMed

Nishiyama, Keiji; Suzuki, Hirobumi; Maruyama, Minoru; Yoshihara, Tomoki; Ohta, Hiroyuki

2017-09-01

G protein-coupled receptor 52 (GPR52) is largely co-expressed with dopamine D 2 receptor (DRD2) in the striatum and nucleus accumbens, and this expression pattern is similar to that of adenosine A 2A receptor (ADORA2A). GPR52 has been proposed as a therapeutic target for positive symptoms of schizophrenia, based on observations from pharmacological and transgenic mouse studies. However, the physiological role of GPR52 in dopaminergic functions in the basal ganglia remains unclear. Here, we used GPR52 knockout (KO) mice to examine the role of GPR52 in dopamine receptor-mediated and ADORA2A-mediated locomotor activity and dopamine receptor signaling. High expression of GPR52 protein in the striatum, nucleus accumbens, and lateral globus pallidus of wild type (WT) littermates was confirmed by immunohistochemical analysis. GPR52 KO and WT mice exhibited almost identical locomotor responses to the dopamine releaser methamphetamine and the N-methyl-d-aspartate antagonist MK-801. In contrast, the locomotor response to the ADORA2A antagonist istradefylline was significantly augmented in GPR52 KO mice compared to WT mice. Gene expression analysis revealed that striatal expression of DRD2, but not of dopamine D 1 receptor and ADORA2A, was significantly decreased in GPR52 KO mice. Moreover, a significant reduction in the mRNA expression of enkephalin, a marker of the activity of striatopallidal neurons, was observed in the striatum of GPR52 KO mice, suggesting that GPR52 deletion could enhance DRD2 signaling. Taken together, these results imply the physiological relevance of GPR52 in modulating the function of striatopallidal neurons, possibly by interaction of GPR52 with ADORA2A and DRD2. Copyright © 2017 Elsevier B.V. All rights reserved.

Serotonergic systems in the balance: CRHR1 and CRHR2 differentially control stress-induced serotonin synthesis.

PubMed

Donner, Nina C; Siebler, Philip H; Johnson, Danté T; Villarreal, Marcos D; Mani, Sofia; Matti, Allison J; Lowry, Christopher A

2016-01-01

Anxiety and affective disorders are often associated with hypercortisolism and dysfunctional serotonergic systems, including increased expression of TPH2, the gene encoding the rate-limiting enzyme of neuronal serotonin synthesis. We previously reported that chronic glucocorticoid exposure is anxiogenic and increases rat Tph2 mRNA expression, but it was still unclear if this also translates to increased TPH2 protein levels and in vivo activity of the enzyme. Here, we found that adult male rats treated with corticosterone (CORT, 100 μg/ml) via the drinking water for 21 days indeed show increased TPH2 protein expression in the dorsal and ventral part of the dorsal raphe nucleus (DRD, DRV) during the light phase, abolishing the enzyme's diurnal rhythm. In a second study, we systemically blocked the conversion of 5-hydroxytryptophan (5-HTP) to serotonin immediately before rats treated with CORT or vehicle were either exposed to 30 min acoustic startle stress or home cage control conditions. This allowed us to measure 5-HTP accumulation as a direct readout of basal versus stress-induced in vivo TPH2 activity. As expected, basal TPH2 activity was elevated in the DRD, DRV and MnR of CORT-treated rats. In response to stress, a multitude of serotonergic systems reacted with increased TPH2 activity, but the stress-, anxiety-, and learned helplessness-related dorsal and caudal DR (DRD/DRC) displayed stress-induced increases in TPH2 activity only after chronic CORT-treatment. To address the mechanisms underlying this region-specific CORT-dependent sensitization, we stereotaxically implanted CORT-treated rats with cannulae targeting the DR, and pharmacologically blocked either corticotropin-releasing hormone receptor type 1 (CRHR1) or type 2 (CRHR2) 10 min prior to acoustic startle stress. CRHR2 blockade prevented stress-induced increases of TPH2 activity within the DRD/DRC, while blockade of CRHR1 potentiated stress-induced TPH2 activity in the entire DR. Stress-induced TPH2 activity in the DRD/DRC furthermore predicted TPH2 activity in the amygdala and in the caudal pontine reticular nucleus (PnC), while serotonin synthesis in the PnC was strongly correlated with the maximum startle response. Our data demonstrate that chronically elevated glucocorticoids sensitize stress- and anxiety-related serotonergic systems, and for the first time reveal competing roles of CRHR1 and CRHR2 on stress-induced in vivo serotonin synthesis. Copyright © 2015 Elsevier Ltd. All rights reserved.

Serotonergic systems in the balance: CRHR1 and CRHR2 differentially control stress-induced serotonin synthesis

PubMed Central

Donner, Nina C.; Siebler, Philip H.; Johnson, Danté T.; Villarreal, Marcos D.; Mani, Sofia; Matti, Allison J.; Lowry, Christopher A.

2015-01-01

Anxiety and affective disorders are often associated with hypercortisolism and dysfunctional serotonergic systems, including increased expression of TPH2, the gene encoding the rate-limiting enzyme of neuronal serotonin synthesis. We previously reported that chronic glucocorticoid exposure is anxiogenic and increases rat Tph2 mRNA expression, but it was still unclear if this also translates to increased TPH2 protein levels and in vivo activity of the enzyme. Here, we found that adult male rats treated with corticosterone (CORT, 100 μg/ml) via the drinking water for 21 days indeed show increased TPH2 protein expression in the dorsal and ventral part of the dorsal raphe nucleus (DRD, DRV) during the light phase, abolishing the enzyme’s diurnal rhythm. In a second study, we systemically blocked the conversion of 5-hydroxytryptophan (5-HTP) to serotonin immediately before rats treated with CORT or vehicle were either exposed to 30 min acoustic startle stress or home cage control conditions. This allowed us to measure 5-HTP accumulation as a direct readout of basal versus stress-induced in vivo TPH2 activity. As expected, basal TPH2 activity was elevated in the DRD, DRV and MnR of CORT-treated rats. In response to stress, a multitude of serotonergic systems reacted with increased TPH2 activity, but the stress-, anxiety-, and learned helplessness-related dorsal and caudal DR (DRD/DRC) displayed stress-induced increases in TPH2 activity only after chronic CORT-treatment. To address the mechanisms underlying this region-specific CORT-dependent sensitization, we stereotaxically implanted CORT-treated rats with cannulae targeting the DR, and pharmacologically blocked either corticotropin-releasing hormone receptor type 1 (CRHR1) or type 2 (CRHR2) 10 min prior to acoustic startle stress. CRHR2 blockade prevented stress-induced increases of TPH2 activity within the DRD/DRC, while blockade of CRHR1 potentiated stress-induced TPH2 activity in the entire DR. Stress-induced TPH2 activity in the DRD/DRC furthermore predicted TPH2 activity in the amygdala and in the caudal pontine reticular nucleus (PnC), while serotonin synthesis in the PnC was strongly correlated with the maximum startle response. Our data demonstrate that chronically elevated glucocorticoids sensitize stress- and anxiety-related serotonergic systems, and for the first time reveal competing roles of CRHR1 and CRHR2 on stress-induced in vivo serotonin synthesis. PMID:26454419

Association between dopamine and somatostatin receptor expression and pharmacological response to somatostatin analogues in acromegaly.

PubMed

Venegas-Moreno, Eva; Vazquez-Borrego, Mari C; Dios, Elena; Gros-Herguido, Noelia; Flores-Martinez, Alvaro; Rivero-Cortés, Esther; Madrazo-Atutxa, Ainara; Japón, Miguel A; Luque, Raúl M; Castaño, Justo P; Cano, David A; Soto-Moreno, Alfonso

2018-03-01

Acromegaly is a hormonal disorder resulting from excessive growth hormone (GH) secretion frequently produced by pituitary adenomas and consequent increase in insulin-like growth factor 1 (IGF-I). Elevated GH and IGF-I levels result in a wide range of somatic, cardiovascular, endocrine, metabolic and gastrointestinal morbidities. Somatostatin analogues (SSAs) form the basis of medical therapy for acromegaly and are currently used as first-line treatment or as second-line therapy in patients undergoing unsuccessful surgery. However, a considerable percentage of patients do not respond to SSAs treatment. Somatostatin receptors (SSTR1-5) and dopamine receptors (DRD1-5) subtypes play critical roles in the regulation of hormone secretion. These receptors are considered important pharmacological targets to inhibit hormone oversecretion. It has been proposed that decreased expression of SSTRs may be associated with poor response to SSAs. Here, we systematically examine SSTRs and DRDs expression in human somatotroph adenomas by quantitative PCR. We observed an association between the response to SSAs treatment and DRD4, DRD5, SSTR1 and SSTR2 expression. We also examined SSTR expression by immunohistochemistry and found that the immunohistochemical detection of SSTR2 in particular might be a good predictor of response to SSAs. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Hypothesizing dopaminergic genetic antecedents in schizophrenia and substance seeking behavior.

PubMed

Blum, Kenneth; Oscar-Berman, Marlene; Badgaiyan, Rajendra D; Palomo, Tomas; Gold, Mark S

2014-05-01

The dopamine system has been implicated in both substance use disorder (SUD) and schizophrenia. A recent meta-analysis suggests that A1 allele of the DRD2 gene imposes genetic risk for SUD, especially alcoholism and has been implicated in Reward Deficiency Syndrome (RDS). We hypothesize that dopamine D2 receptor (DRD2) gene Taq1 A2 allele is associated with a subtype of non-SUD schizophrenics and as such may act as a putative protective agent against the development of addiction to alcohol or other drugs of abuse. Schizophrenics with SUD may be carriers of the DRD2 Taq1 A1 allele, and/or other RDS reward polymorphisms and have hypodopaminergic reward function. One plausible mechanism for alcohol seeking in schizophrenics with SUD, based on previous research, may be a deficiency of gamma type endorphins that has been linked to schizophrenic type psychosis. We also propose that alcohol seeking behavior in schizophrenics, may serve as a physiological self-healing process linked to the increased function of the gamma endorphins, thereby reducing abnormal dopaminergic activity at the nucleus accumbens (NAc). These hypotheses warrant further investigation and cautious interpretation. We, therefore, encourage research involving neuroimaging, genome wide association studies (GWAS), and epigenetic investigation into the relationship between neurogenetics and systems biology to unravel the role of dopamine in psychiatric illness and SUD. Copyright © 2014 Elsevier Ltd. All rights reserved.

Hypothesizing Dopaminergic Genetic Antecedents in Schizophrenia and Substance Seeking Behavior

PubMed Central

Blum, Kenneth; Oscar-Berman, Marlene; Badgaiyan, Rajendra; Palomo, Tomas; Gold, Mark S.

2014-01-01

The dopamine system has been implicated in both substance use disorder (SUD) and schizophrenia. A recent meta- analysis suggests that A1 allele of the DRD2 gene imposes genetic risk for SUD, especially alcoholism and has been implicated in Reward Deficiency Syndrome (RDS). We hypothesize that dopamine D2 receptor (DRD2) gene Taq1 A2 allele is associated with a subtype of non- SUD schizophrenics and as such may act as a putative protective agent against the development of addiction to alcohol or other drugs of abuse. Schizophrenics with SUD may be carriers of the DRD2 Taq1 A1 allele, and/or other RDS reward polymorphisms and have hypodopaminergic reward function. One plausible mechanism for alcohol seeking in schizophrenics with SUD, based on previous research, may be a deficiency of gamma type endorphins that has been linked to schizophrenic type psychosis.. We also propose that alcohol seeking behavior in schizophrenics, may serve as a physiological self-healing process linked to the increased function of the gamma endorphins, thereby reducing abnormal dopaminergic activity at the nucleus accumbens (NAc). These hypotheses warrant further investigation and cautious interpretation. We, therefore, encourage research involving neuroimaging, genome wide association studies (GWAS), and epigenetic investigation into the relationship between neurogenetics and systems biology to unravel the role of dopamine in psychiatric illness and SUD. PMID:24636783

Genetic variants of neurotransmitter-related genes and miRNAs in Egyptian autistic patients.

PubMed

Salem, Ahmed M; Ismail, Samira; Zarouk, Waheba A; Abdul Baky, Olwya; Sayed, Ahmed A; Abd El-Hamid, Sawsan; Salem, Sohair

2013-01-01

Autism is a neurodevelopmental disorder with indisputable evidence for a genetic component. This work studied the association of autism with genetic variations in neurotransmitter-related genes, including MAOA uVNTR, MAOB rs1799836, and DRD2 TaqI A in 53 autistic patients and 30 healthy individuals. The study also analyzed sequence variations of miR-431 and miR-21. MAOA uVNTR was genotyped by PCR, MAOB and DRD2 polymorphisms were analyzed by PCR-based RFLP, and miR-431 and miR-21 were sequenced. Low expressing allele of MAOA uVNTR was frequently higher in female patients compared to that in controls (OR = 2.25). MAOB G allele frequency was more significantly increased in autistic patients than in controls (P < 0.001 for both males and females). DRD2 A1+ genotype increased autism risk (OR = 5.1). Severity of autism tends to be slightly affected by MAOA/B genotype. Plasma MAOB activity was significantly reduced in G than in A allele carrying males. There was no significant difference in patients and maternal plasma MAOA/B activity compared to controls. Neither mutations nor SNPs in miR-431 and miR-21 were found among studied patients. This study threw light on some neurotransmitter-related genes suggesting their potential role in Autism pathogenesis that warrants further studies and much consideration.

New Repeat Polymorphism in the AKT1 Gene Predicts Striatal Dopamine D2/D3 Receptor Availability and Stimulant-Induced Dopamine Release in the Healthy Human Brain.

PubMed

Shumay, Elena; Wiers, Corinde E; Shokri-Kojori, Ehsan; Kim, Sung Won; Hodgkinson, Colin A; Sun, Hui; Tomasi, Dardo; Wong, Christopher T; Weinberger, Daniel R; Wang, Gene-Jack; Fowler, Joanna S; Volkow, Nora D

2017-05-10

The role of the protein kinase Akt1 in dopamine neurotransmission is well recognized and has been implicated in schizophrenia and psychosis. However, the extent to which variants in the AKT1 gene influence dopamine neurotransmission is not well understood. Here we investigated the effect of a newly characterized variant number tandem repeat (VNTR) polymorphism in AKT1 [major alleles: L- (eight repeats) and H- (nine repeats)] on striatal dopamine D2/D3 receptor (DRD2) availability and on dopamine release in healthy volunteers. We used PET and [ 11 C]raclopride to assess baseline DRD2 availability in 91 participants. In 54 of these participants, we also measured intravenous methylphenidate-induced dopamine release to measure dopamine release. Dopamine release was quantified as the difference in specific binding of [ 11 C]raclopride (nondisplaceable binding potential) between baseline values and values following methylphenidate injection. There was an effect of AKT1 genotype on DRD2 availability at baseline for the caudate ( F (2,90) = 8.2, p = 0.001) and putamen ( F (2,90) = 6.6, p = 0.002), but not the ventral striatum ( p = 0.3). For the caudate and putamen, LL showed higher DRD2 availability than HH; HL were in between. There was also a significant effect of AKT1 genotype on dopamine increases in the ventral striatum ( F (2,53) = 5.3, p = 0.009), with increases being stronger in HH > HL > LL. However, no dopamine increases were observed in the caudate ( p = 0.1) or putamen ( p = 0.8) following methylphenidate injection. Our results provide evidence that the AKT1 gene modulates both striatal DRD2 availability and dopamine release in the human brain, which could account for its association with schizophrenia and psychosis. The clinical relevance of the newly characterized AKT1 VNTR merits investigation. SIGNIFICANCE STATEMENT The AKT1 gene has been implicated in schizophrenia and psychosis. This association is likely to reflect modulation of dopamine signaling by Akt1 kinase since striatal dopamine hyperstimulation is associated with psychosis and schizophrenia. Here, using PET with [ 11 C]raclopride, we identified in the AKT1 gene a new variable number tandem repeat (VNTR) marker associated with baseline striatal dopamine D2/D3 receptor availability and with methylphenidate-induced striatal dopamine increases in healthy volunteers. Our results confirm the involvement of the AKT1 gene in modulating striatal dopamine signaling in the human brain. Future studies are needed to assess the association of this new VNTR AKT1 variant in schizophrenia and drug-induced psychoses. Copyright © 2017 the authors 0270-6474/17/374983-10$15.00/0.

A study of chromosome 4p markers and dopamine D5 receptor gene in schizophrenia and bipolar disorder.

PubMed

Asherson, P; Mant, R; Williams, N; Cardno, A; Jones, L; Murphy, K; Collier, D A; Nanko, S; Craddock, N; Morris, S; Muir, W; Blackwood, B; McGuffin, P; Owen, M J

1998-07-01

There are several lines of evidence which suggest that chromosome 4p may contain a major susceptibility locus for the functional psychoses. We previously reported a family (family 50) with cases of schizophrenia and schizoaffective disorder which gave maximum lod scores of 1.96 and 1.84 respectively with the markers D4S403 and a microsatellite near to DRD5 (DRD5-M). More recently Blackwood and co-workers described a family segregating bipolar and unipolar affective disorders which gives a maximum lod score of 4.1 with the marker D4S394, which lies 10 cM from D4S403. They obtained a combined maximum lod of 3.3 in their total sample of 12 bipolar families and found significant evidence of heterogeneity (chi 2 = 18.8, df = 2, P = 0.00008). Here we report the results of a linkage study of chromosome 4p markers in a sample of 24 multiply affected families with schizophrenia and related disorders. We obtained an overall maximum lod of 1.12 with D4S403 under both dominant and recessive modes of transmission, with no statistical support for heterogeneity within our sample. Examination of family by family data shows that only family 50 appears to show linkage at this locus. However, a discrepancy exists since our study examined families fulfilling criteria for a linkage study of schizophrenia while Blackwood et al examined families included in a genetic linkage study of bipolar disorder. This may be explained by the clinical features displayed by members of family 50, which show that all the affected members have some affective symptoms. It is therefore possible that a broad phenotype including unipolar depression, bipolar disorder, schizoaffective disorder and schizophrenia when accompanied by significant affective symptoms can result from mutations within a gene in this region. The dopamine D5 receptor gene lies within the region identified by the linkage studies and is therefore a major candidate for the putative disease gene. In family 50 we have looked for mutations of DRD5 by sequence analysis of the coding region and single stranded conformational polymorphism (SSCP) analysis of the promoter. SSCP analysis of the coding and promoter regions have also been carried out in unrelated cases of DSM-IIIR schizophrenia. Finally association studies of the (TC)n repeat in the promoter and schizophrenia, and DRD5-M and bipolar disorder were performed. These studies provided no further evidence supporting the possibility that mutations in DRD5 give rise to the linkage findings or are acting as susceptibility loci in schizophrenia or bipolar disorder.

Genetic variants and early cigarette smoking and nicotine dependence phenotypes in adolescents.

PubMed

O'Loughlin, Jennifer; Sylvestre, Marie-Pierre; Labbe, Aurélie; Low, Nancy C; Roy-Gagnon, Marie-Hélène; Dugas, Erika N; Karp, Igor; Engert, James C

2014-01-01

While the heritability of cigarette smoking and nicotine dependence (ND) is well-documented, the contribution of specific genetic variants to specific phenotypes has not been closely examined. The objectives of this study were to test the associations between 321 tagging single-nucleotide polymorphisms (SNPs) that capture common genetic variation in 24 genes, and early smoking and ND phenotypes in novice adolescent smokers, and to assess if genetic predictors differ across these phenotypes. In a prospective study of 1294 adolescents aged 12-13 years recruited from ten Montreal-area secondary schools, 544 participants who had smoked at least once during the 7-8 year follow-up provided DNA. 321 single-nucleotide polymorphisms (SNPs) in 24 candidate genes were tested for an association with number of cigarettes smoked in the past 3 months, and with five ND phenotypes (a modified version of the Fagerstrom Tolerance Questionnaire, the ICD-10 and three clusters of ND symptoms representing withdrawal symptoms, use of nicotine for self-medication, and a general ND/craving symptom indicator). The pattern of SNP-gene associations differed across phenotypes. Sixteen SNPs in seven genes (ANKK1, CHRNA7, DDC, DRD2, COMT, OPRM1, SLC6A3 (also known as DAT1)) were associated with at least one phenotype with a p-value <0.01 using linear mixed models. After permutation and FDR adjustment, none of the associations remained statistically significant, although the p-values for the association between rs557748 in OPRM1 and the ND/craving and self-medication phenotypes were both 0.076. Because the genetic predictors differ, specific cigarette smoking and ND phenotypes should be distinguished in genetic studies in adolescents. Fifteen of the 16 top-ranked SNPs identified in this study were from loci involved in dopaminergic pathways (ANKK1/DRD2, DDC, COMT, OPRM1, and SLC6A3). Dopaminergic pathways may be salient during early smoking and the development of ND.

Dopamine D2 receptor gene polymorphisms and externalizing behaviors in children and adolescents.

PubMed

Della Torre, Osmar Henrique; Paes, Lúcia Arisaka; Henriques, Taciane Barbosa; de Mello, Maricilda Palandi; Celeri, Eloisa Helena Rubello Valler; Dalgalarrondo, Paulo; Guerra-Júnior, Gil; Santos-Júnior, Amilton Dos

2018-05-02

Dopamine is involved in several cerebral physiological processes, and single nucleotide polymorphisms (SNP) in the dopamine D2 receptor gene (DRD2) have been associated with numerous neurological and mental disorders, including those involving alterations in cognitive and emotional processes. The aim of this study was to evaluate the association between the SNPs c.957C > T (rs6277) and c.-585A > G (rs1799978) in the DRD2 gene and behavioral characteristics of children and adolescents based on an inventory of the Child Behavior Checklist (CBCL). Children and adolescents between 8 and 20 years old who were clinically followed-up were genotyped for the SNPs c.957C > T and c.-585A > G, and related to data of the CBCL/6-18 scale assessment performed with the help of caregivers. The chi-squared test was used to assess the differences in the frequencies of the C and T alleles in the polymorphism c.957C > T and of the A and G alleles in the polymorphism c.-585A > G with respect to the grouped CBCL scores at a significance level of 5%. Multiple logistic regression models were performed, to control whether sex and/or ethnicity could influence the results. Eighty-five patients were assessed overall, and the presence of the T allele (C/T and T/T) of DRD2 c.957C > T polymorphism was found to be significantly associated with the occurrence of defiant and oppositional problems and with attention and hyperactivity problems. There were no associations detected with polymorphism DRD2 c.-585A > G polymorphism. Both SNPs were in Hardy-Weinberg-equilibrium. Although the findings of this study are preliminary, due to its small number of participants, the presence of T allele (C/T, T/T) in c.957C > T SNP was associated with difficulty in impulse control, self-control of emotions, and conduct adjustment, which can contribute to improving the identification of mental and behavioral phenotypes associated with gene expression.

Role of Dorsomedial Striatum Neuronal Ensembles in Incubation of Methamphetamine Craving after Voluntary Abstinence

PubMed Central

Venniro, Marco; Zhang, Michelle; Bossert, Jennifer M.; Warren, Brandon L.; Hope, Bruce T.

2017-01-01

We recently developed a rat model of incubation of methamphetamine craving after choice-based voluntary abstinence. Here, we studied the role of dorsolateral striatum (DLS) and dorsomedial striatum (DMS) in this incubation. We trained rats to self-administer palatable food pellets (6 d, 6 h/d) and methamphetamine (12 d, 6 h/d). We then assessed relapse to methamphetamine seeking under extinction conditions after 1 and 21 abstinence days. Between tests, the rats underwent voluntary abstinence (using a discrete choice procedure between methamphetamine and food; 20 trials/d) for 19 d. We used in situ hybridization to measure the colabeling of the activity marker Fos with Drd1 and Drd2 in DMS and DLS after the tests. Based on the in situ hybridization colabeling results, we tested the causal role of DMS D1 and D2 family receptors, and DMS neuronal ensembles in “incubated” methamphetamine seeking, using selective dopamine receptor antagonists (SCH39166 or raclopride) and the Daun02 chemogenetic inactivation procedure, respectively. Methamphetamine seeking was higher after 21 d of voluntary abstinence than after 1 d (incubation of methamphetamine craving). The incubated response was associated with increased Fos expression in DMS but not in DLS; Fos was colabeled with both Drd1 and Drd2. DMS injections of SCH39166 or raclopride selectively decreased methamphetamine seeking after 21 abstinence days. In Fos-lacZ transgenic rats, selective inactivation of relapse test-activated Fos neurons in DMS on abstinence day 18 decreased incubated methamphetamine seeking on day 21. Results demonstrate a role of DMS dopamine D1 and D2 receptors in the incubation of methamphetamine craving after voluntary abstinence and that DMS neuronal ensembles mediate this incubation. SIGNIFICANCE STATEMENT In human addicts, abstinence is often self-imposed and relapse can be triggered by exposure to drug-associated cues that induce drug craving. We recently developed a rat model of incubation of methamphetamine craving after choice-based voluntary abstinence. Here, we used classical pharmacology, in situ hybridization, immunohistochemistry, and the Daun02 inactivation procedure to demonstrate a critical role of dorsomedial striatum neuronal ensembles in this new form of incubation of drug craving. PMID:28123032

Generational Association Studies of Dopaminergic Genes in Reward Deficiency Syndrome (RDS) Subjects: Selecting Appropriate Phenotypes for Reward Dependence Behaviors

PubMed Central

Blum, Kenneth; Chen, Amanda L. C.; Oscar-Berman, Marlene; Chen, Thomas J. H.; Lubar, Joel; White, Nancy; Lubar, Judith; Bowirrat, Abdalla; Braverman, Eric; Schoolfield, John; Waite, Roger L.; Downs, Bernard W.; Madigan, Margaret; Comings, David E.; Davis, Caroline; Kerner, Mallory M.; Knopf, Jennifer; Palomo, Tomas; Giordano, John J.; Morse, Siobhan A.; Fornari, Frank; Barh, Debmalya; Femino, John; Bailey, John A.

2011-01-01

Abnormal behaviors involving dopaminergic gene polymorphisms often reflect an insufficiency of usual feelings of satisfaction, or Reward Deficiency Syndrome (RDS). RDS results from a dysfunction in the “brain reward cascade,” a complex interaction among neurotransmitters (primarily dopaminergic and opioidergic). Individuals with a family history of alcoholism or other addictions may be born with a deficiency in the ability to produce or use these neurotransmitters. Exposure to prolonged periods of stress and alcohol or other substances also can lead to a corruption of the brain reward cascade function. We evaluated the potential association of four variants of dopaminergic candidate genes in RDS (dopamine D1 receptor gene [DRD1]; dopamine D2 receptor gene [DRD2]; dopamine transporter gene [DAT1]; dopamine beta-hydroxylase gene [DBH]). Methodology: We genotyped an experimental group of 55 subjects derived from up to five generations of two independent multiple-affected families compared to rigorously screened control subjects (e.g., N = 30 super controls for DRD2 gene polymorphisms). Data related to RDS behaviors were collected on these subjects plus 13 deceased family members. Results: Among the genotyped family members, the DRD2 Taq1 and the DAT1 10/10 alleles were significantly (at least p < 0.015) more often found in the RDS families vs. controls. The TaqA1 allele occurred in 100% of Family A individuals (N = 32) and 47.8% of Family B subjects (11 of 23). No significant differences were found between the experimental and control positive rates for the other variants. Conclusions: Although our sample size was limited, and linkage analysis is necessary, the results support the putative role of dopaminergic polymorphisms in RDS behaviors. This study shows the importance of a nonspecific RDS phenotype and informs an understanding of how evaluating single subset behaviors of RDS may lead to spurious results. Utilization of a nonspecific “reward” phenotype may be a paradigm shift in future association and linkage studies involving dopaminergic polymorphisms and other neurotransmitter gene candidates. PMID:22408582

Genetic Correlates of Spirituality/Religion and Depression: A Study in Offspring and Grandchildren at High and Low Familial Risk for Depression

PubMed Central

Anderson, Micheline R.; Miller, Lisa; Wickramaratne, Priya; Svob, Connie; Odgerel, Zagaa; Zhao, Ruixin; Weissman, Myrna M.

2017-01-01

Rationale Possible genetic correlates of spirituality and depression have been identified in community samples. We investigate some of the previously identified candidates in a sample of families at both high and low-risk for depression. Method Offspring and grandchildren of individuals at high and low-risk for depression, participating in a multi-wave thirty-year longitudinal study, were assessed for seven SNPS drawn from four single gene candidates associated with systems implicated in both depression and spirituality: Serotonin (5-HT1B and 5-HT2A), Dopamine (DRD2), Oxytocin (OT) and Monoamine Vesicular Transporter (VMAT1). Results Dopamine (DRD2) Serotonin (5-HT1B), their Transporter (VMAT1) and Oxytocin (OXTR) were positively associated with a high level of importance of spirituality or religion (S/R) in the group at low familial risk for depression. DRD2 minor allele was associated with both lifetime major depressive disorder (MDD) and spirituality in the low-risk group for depression. No SNPs were related to S/R in the group at high familial risk for depression. OXTR was associated with lifetime MDD in the full sample. Conclusion Genes for dopamine, serotonin, their vesicular transporter, and oxytocin may be associated with S/R in people at low familial risk for depression. Genes for dopamine may be associated both with S/R and increased risk for depression in people at low-risk for depression, suggesting a common pathway or physiology to mild to moderate depression. MDD is associated with oxytocin across risk groups. In the high-risk group, phenotypic expression of S/R may be suppressed. Implications The shared association of DRD2 by S/R and depression, generally found to be inversely related, calls for further research on their common physiological pathways, and the phenotypic expression of these pathways based upon use and environment. Prevention for offspring at high familial risk for depression might include support for the development of child spirituality. PMID:29057276

Pharmacogenetic evaluation to assess breakthrough psychosis with aripiprazole long-acting injection: a case report.

PubMed

Eum, Seenae; Schneiderhan, Mark E; Brown, Jacob T; Lee, Adam M; Bishop, Jeffrey R

2017-07-03

Given the complex nature of symptom presentation and medication regimens, psychiatric clinics may benefit from additional tools to personalize treatments. Utilizing pharmacogenetic information may be helpful in assessing unique responses to therapy. We report herein a case of wearing-off phenomena during treatment with aripiprazole long-acting injectable (LAI) and a proof of concept strategy of how pharmacogenetic information may be used to assess possible genetic factors and also hypothesize potential mechanisms for further study. A 51-year-old African American male with schizoaffective disorder was referred to a psychiatric clinic for medication management. After unsuccessful trials of multiple antipsychotics, oral aripiprazole was initiated (up to 30 mg/day) and transitioned to aripiprazole LAI with symptom improvement. At a high dose of aripiprazole LAI (400 mg Q3wks), the patient experienced breakthrough symptoms approximately 3 days prior to his next injection. Various considerations were examined to explain his atypical dose requirements, including but not limited to pharmacogenetic influences. Pharmacogenetic testing ruled out genetic influences on drug metabolism but noted a -141C Del variant in the dopamine-D2 receptor (DRD2) gene associated in prior studies of poor-response to antipsychotics. At this time, a new formulation, aripiprazole lauroxil, was explored due to its availability in higher dose options. Transition to the new formulation (882 mg Q4wks) greatly improved and stabilized the patient's symptoms with no breakthrough psychosis. Comparable daily dose equivalents were achieved with two different formulations due to the Q3wks vs Q4wks dosing strategies, although the two agents have some differences in pharmacokinetic profiles. We report a case of a patient experiencing wearing-off symptoms with aripiprazole LAI who benefited from switching to aripiprazole lauroxil. Pharmacogenetic testing revealed normal activity for relevant metabolism pathways but a DRD2 -141C variant that may influence brain D2 expression and antipsychotic responsiveness. The clinical utility of DRD2 information and what to do with genotyping results has not been previously addressed, despite availability on clinical test panels. Our case report suggests further investigations of altered dosing strategies and receptor genotype sensitivities to pharmacokinetic factors may be helpful in understanding symptom re-emergence observed in some patients taking LAI antipsychotics.

Associations between dopamine and serotonin genes and job satisfaction: preliminary evidence from the Add Health Study.

PubMed

Song, Zhaoli; Li, Wendong; Arvey, Richard D

2011-11-01

Previous behavioral genetic studies have found that job satisfaction is partially heritable. We went a step further to examine particular genetic markers that may be associated with job satisfaction. Using an oversample from the National Adolescent Longitudinal Study (Add Health Study), we found 2 genetic markers, dopamine receptor gene DRD4 VNTR and serotonin transporter gene 5-HTTLPR, to be weakly but significantly associated with job satisfaction. Furthermore, we found study participants' level of pay to mediate the DRD4 and job satisfaction relationship. However, we found no evidence that self-esteem mediated the relationships between these 2 genes and job satisfaction. The study represents an initial effort to introduce a molecular genetics approach to the fields of organizational psychology and organizational behavior. (c) 2011 APA, all rights reserved.

Population differentiation and behavioural association of the two 'personality' genes DRD4 and SERT in dunnocks (Prunella modularis).

PubMed

Holtmann, B; Grosser, S; Lagisz, M; Johnson, S L; Santos, E S A; Lara, C E; Robertson, B C; Nakagawa, S

2016-02-01

Quantifying the variation in behaviour-related genes within and between populations provides insight into how evolutionary processes shape consistent behavioural traits (i.e. personality). Deliberate introductions of non-native species offer opportunities to investigate how such genes differ between native and introduced populations and how polymorphisms in the genes are related to variation in behaviour. Here, we compared the genetic variation of the two 'personality' genes, DRD4 and SERT, between a native (United Kingdom, UK) and an introduced (New Zealand, NZ) population of dunnocks, Prunella modularis. The NZ population showed a significantly lower number of single nucleotide polymorphisms (SNPs) compared to the UK population. Standardized F'st estimates of the personality genes and neutral microsatellites indicate that selection (anthropogenic and natural) probably occurred during and post the introduction event. Notably, the largest genetic differentiation was found in the intronic regions of the genes. In the NZ population, we also examined the association between polymorphisms in DRD4 and SERT and two highly repeatable behavioural traits: flight-initiation distance and mating status (promiscuous females and cobreeding males). We found 38 significant associations (for different allele effect models) between the two behavioural traits and the studied genes. Further, 22 of the tested associations showed antagonistic allele effects for males and females. Our findings illustrate how introduction events and accompanying ecological changes could influence the genetic diversity of behaviour-related genes. © 2015 John Wiley & Sons Ltd.

A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma.

PubMed

Arrillaga-Romany, Isabel; Chi, Andrew S; Allen, Joshua E; Oster, Wolfgang; Wen, Patrick Y; Batchelor, Tracy T

2017-10-03

ONC201 is an oral, small molecule selective antagonist of the G protein-coupled receptor DRD2 that causes p53-independent apoptosis in tumor cells via integrated stress response activation and Akt/ERK inactivation. We performed a Phase II study that enrolled 17 patients with recurrent, bevacizumab-naïve, IDH1/2 WT glioblastoma who received 625mg ONC201 every three weeks. Median OS was 41.6 weeks with OS6 of 71% and OS9 of 53%. Seven of 17 patients are alive. PFS6 was 11.8% with two patients remaining on study who continue to receive ONC201 for >12 months. One of these patients had a durable objective response with a secondary glioblastoma possessing a H3.3 K27M mutation, exhibiting regression by 85% in one lesion and 76% in the second lesion. The second patient who continues to receive ONC201 for >12 months remains disease-free after enrolling on this trial following a re-resection. No drug-related SAEs or treatment discontinuation due to toxicity occurred. Plasma PK at 2 hours post-dose was 2.6 ug/mL, serum prolactin induction was observed as a surrogate marker of target engagement, and DRD2 was expressed in all evaluated archival tumor specimens. In summary, ONC201 is well tolerated and may have single agent activity in recurrent glioblastoma patients.

A variant in ANKK1 modulates acute subjective effects of cocaine: a preliminary study

PubMed Central

Spellicy, Catherine J.; Harding, Mark J.; Hamon, Sara C.; Mahoney, James J.; Reyes, Jennifer A.; Kosten, Thomas R.; Newton, Thomas F.; De La Garza, Richard; Nielsen, David A.

2014-01-01

This study aimed to evaluate whether functional variants in the ankyrin repeat and kinase domain-containing 1 gene (ANKK1) and/or the dopamine receptor D2 gene (DRD2) modulate the subjective effects (reward or non-reward response to a stimulus) produced by cocaine administration. Cocaine-dependent participants (N = 47) were administered 40 mg of cocaine or placebo at time 0, and a subjective effects questionnaire (visual analog scale) was administered 15 minutes prior to cocaine administration, and at 5, 10,15, and 20 minutes following administration. The influence of polymorphisms in the ANKK1 and DRD2 genes on subjective experience of cocaine in the laboratory was tested. Participants with a T allele of ANKK1 rs1800497 experienced greater subjective ‘high’ (p = 0.00006), ‘any drug effect’ (p = 0.0003), and ‘like’ (p = 0.0004) relative to the CC genotype group. Although the variant in the DRD2 gene was shown to be associated with subjective effects, LD analysis revealed this association was driven by the ANKK1 rs1800497 variant. A participant’s ANKK1 genotype may identify individuals who are likely to experience greater positive subjective effects following cocaine exposure, including greater ‘high’ and ‘like’, and these individuals may have increased vulnerability to continue using cocaine or they may be at greater risk to relapse during periods of abstinence. However, these results are preliminary and replication is necessary to confirm these findings. PMID:24528631

A meta-analysis of data associating DRD4 gene polymorphisms with schizophrenia.

PubMed

Xu, Feng-Ling; Wu, Xue; Zhang, Jing-Jing; Wang, Bao-Jie; Yao, Jun

2018-01-01

To explore the association between DRD4 polymorphisms and schizophrenia risk, a meta-analysis was carried out with 41 case-control articles. Specifically, we included 28 articles (5,735 cases and 5,278 controls) that pertained to the 48 bp variable number tandem repeat (VNTR) polymorphism, nine articles (1,517 cases and 1,746 controls) that corresponded to the 12 bp tandem repeat (TR), six articles (1,912 cases and 1,836 controls) that addressed the 120 bp TR, 10 articles (2,927 cases and 2,938 controls) that entailed the -521 C>T polymorphism, six articles (1,735 cases and 1,724 controls) that pertained to the -616 C>G polymorphism, and four articles (1,191 cases and 1,215 controls) that involved the -376 C>T polymorphism. Pooled analysis, subgroup analysis, and sensitivity analysis were performed, and the data were visualized by means of forest and funnel plots. Results of pooled analysis indicated that the -521 CC variant ( P z =0.009, odds ratio [OR] =1.218, 95% confidence interval [CI] =1.050-1.413) and genotype L/L (ie, long allele) of the 120 bp TR were risk factors of schizophrenia ( P z =0.004, OR =1.275, 95% CI =1.081-1.504). The 48 bp VNTR, the 12 bp TR, the -616 C>G polymorphism, and the -376 C>T polymorphism were not associated with schizophrenia. Additional research is warranted to explore the association between polymorphisms of DRD4 and schizophrenia risk.

Associations between dopamine D4 receptor gene variation with both infidelity and sexual promiscuity.

PubMed

Garcia, Justin R; MacKillop, James; Aller, Edward L; Merriwether, Ann M; Wilson, David Sloan; Lum, J Koji

2010-11-30

Human sexual behavior is highly variable both within and between populations. While sex-related characteristics and sexual behavior are central to evolutionary theory (sexual selection), little is known about the genetic bases of individual variation in sexual behavior. The variable number tandem repeats (VNTR) polymorphism in exon III of the human dopamine D4 receptor gene (DRD4) has been correlated with an array of behavioral phenotypes and may be predicatively responsible for variation in motivating some sexual behaviors, particularly promiscuity and infidelity. We administered an anonymous survey on personal history of sexual behavior and intimate relationships to 181 young adults. We also collected buccal wash samples and genotyped the DRD4 VNTR. Here we show that individuals with at least one 7-repeat allele (7R+) report a greater categorical rate of promiscuous sexual behavior (i.e., having ever had a "one-night stand") and report a more than 50% increase in instances of sexual infidelity. DRD4 VNTR genotype varies considerably within and among populations and has been subject to relatively recent, local selective pressures. Individual differences in sexual behavior are likely partially mediated by individual genetic variation in genes coding for motivation and reward in the brain. Conceptualizing these findings in terms of r/K selection theory suggests a mechanism for selective pressure for and against the 7R+ genotype that may explain the considerable global allelic variation for this polymorphism.

Associations between Dopamine D4 Receptor Gene Variation with Both Infidelity and Sexual Promiscuity

PubMed Central

Garcia, Justin R.; MacKillop, James; Aller, Edward L.; Merriwether, Ann M.; Wilson, David Sloan; Lum, J. Koji

2010-01-01

Background Human sexual behavior is highly variable both within and between populations. While sex-related characteristics and sexual behavior are central to evolutionary theory (sexual selection), little is known about the genetic bases of individual variation in sexual behavior. The variable number tandem repeats (VNTR) polymorphism in exon III of the human dopamine D4 receptor gene (DRD4) has been correlated with an array of behavioral phenotypes and may be predicatively responsible for variation in motivating some sexual behaviors, particularly promiscuity and infidelity. Methodology/Principal Findings We administered an anonymous survey on personal history of sexual behavior and intimate relationships to 181 young adults. We also collected buccal wash samples and genotyped the DRD4 VNTR. Here we show that individuals with at least one 7-repeat allele (7R+) report a greater categorical rate of promiscuous sexual behavior (i.e., having ever had a “one-night stand”) and report a more than 50% increase in instances of sexual infidelity. Conclusions/Significance DRD4 VNTR genotype varies considerably within and among populations and has been subject to relatively recent, local selective pressures. Individual differences in sexual behavior are likely partially mediated by individual genetic variation in genes coding for motivation and reward in the brain. Conceptualizing these findings in terms of r/K selection theory suggests a mechanism for selective pressure for and against the 7R+ genotype that may explain the considerable global allelic variation for this polymorphism. PMID:21152404

Association between the dopamine D3 receptor gene locus (DRD3) and unipolar affective disorder.

PubMed

Dikeos, D G; Papadimitriou, G N; Avramopoulos, D; Karadima, G; Daskalopoulou, E G; Souery, D; Mendlewicz, J; Vassilopoulos, D; Stefanis, C N

1999-12-01

Dopamine neurotransmission has been implicated in the pathophysiology of schizophrenia and, more recently, affective disorders. Among the dopamine receptors, D3 can be considered as particularly related to affective disorders due to its neuroanatomical localization in the limbic region of the brain and its relation to the serotoninergic activity of the CNS. The possible involvement of dopamine receptor D3 in unipolar (UP) major depression was investigated by a genetic association study of the D3 receptor gene locus (DRD3) on 36 UP patients and 38 ethnically matched controls. An allelic association of DRD3 (Bal I polymorphism) and UP illness was observed, with the Gly-9 allele (allele '2', 206/98 base-pairs long) being more frequent in patients than in controls (49% vs 29%, P < 0.02). The genotypes containing this allele (1-2 and 2-2) were found in 75% of patients vs 50% of controls (P < 0.03, odds ratio = 3.00, 95% CI = 1.12-8.05). The effect of the genotype remained significant (P < 0.02) after sex and family history were controlled by a multiple linear regression analysis. These results further support the hypothesis that dopaminergic mechanisms may be implicated in the pathogenesis of affective disorder. More specifically, the '2' allele of the dopamine receptor D3 gene seems to be associated with unipolar depression and can be considered as a 'phenotypic modifier' for major psychiatric disorders.

Subset of Cortical Layer 6b Neurons Selectively Innervates Higher Order Thalamic Nuclei in Mice.

PubMed

Hoerder-Suabedissen, Anna; Hayashi, Shuichi; Upton, Louise; Nolan, Zachary; Casas-Torremocha, Diana; Grant, Eleanor; Viswanathan, Sarada; Kanold, Patrick O; Clasca, Francisco; Kim, Yongsoo; Molnár, Zoltán

2018-05-01

The thalamus receives input from 3 distinct cortical layers, but input from only 2 of these has been well characterized. We therefore investigated whether the third input, derived from layer 6b, is more similar to the projections from layer 6a or layer 5. We studied the projections of a restricted population of deep layer 6 cells ("layer 6b cells") taking advantage of the transgenic mouse Tg(Drd1a-cre)FK164Gsat/Mmucd (Drd1a-Cre), that selectively expresses Cre-recombinase in a subpopulation of layer 6b neurons across the entire cortical mantle. At P8, 18% of layer 6b neurons are labeled with Drd1a-Cre::tdTomato in somatosensory cortex (SS), and some co-express known layer 6b markers. Using Cre-dependent viral tracing, we identified topographical projections to higher order thalamic nuclei. VGluT1+ synapses formed by labeled layer 6b projections were found in posterior thalamic nucleus (Po) but not in the (pre)thalamic reticular nucleus (TRN). The lack of TRN collaterals was confirmed with single-cell tracing from SS. Transmission electron microscopy comparison of terminal varicosities from layer 5 and layer 6b axons in Po showed that L6b varicosities are markedly smaller and simpler than the majority from L5. Our results suggest that L6b projections to the thalamus are distinct from both L5 and L6a projections.

DRD2 Schizophrenia-Risk Allele Is Associated With Impaired Striatal Functioning in Unaffected Siblings of Schizophrenia Patients

PubMed Central

Vink, Matthijs; de Leeuw, Max; Luykx, Jurjen J.; van Eijk, Kristel R.; van den Munkhof, Hanna E.; van Buuren, Mariët; Kahn, René S.

2016-01-01

A recent Genome-Wide Association Study showed that the rs2514218 single nucleotide polymorphism (SNP) in close proximity to dopamine receptor D2 is strongly associated with schizophrenia. Further, an in silico experiment showed that rs2514218 has a cis expression quantitative trait locus effect in the basal ganglia. To date, however, the functional consequence of this SNP is unknown. Here, we used functional Magnetic resonance imaging to investigate the impact of this risk allele on striatal activation during proactive and reactive response inhibition in 45 unaffected siblings of schizophrenia patients. We included siblings to circumvent the illness specific confounds affecting striatal functioning independent from gene effects. Behavioral analyses revealed no differences between the carriers (n = 21) and noncarriers (n = 24). Risk allele carriers showed a diminished striatal response to increasing proactive inhibitory control demands, whereas overall level of striatal activation in carriers was elevated compared to noncarriers. Finally, risk allele carriers showed a blunted striatal response during successful reactive inhibition compared to the noncarriers. These data are consistent with earlier reports showing similar deficits in schizophrenia patients, and point to a failure to flexibly engage the striatum in response to contextual cues. This is the first study to demonstrate an association between impaired striatal functioning and the rs2514218 polymorphism. We take our findings to indicate that striatal functioning is impaired in carriers of the DRD2 risk allele, likely due to dopamine dysregulation at the DRD2 location. PMID:26598739

Neuropsychiatric Genetics of Happiness, Friendships, and Politics: Hypothesizing Homophily (“Birds of a Feather Flock Together”) as a Function of Reward Gene Polymorphisms

PubMed Central

Blum, Kenneth; Oscar-Berman, Marlene; Bowirrat, Abdalla; Giordano, John; Madigan, Margaret; Braverman, Eric R.; Barh, Debmayla; Hauser, Mary; Borsten, Joan; Simpatico, Thomas

2013-01-01

Mindful of the new evolutionary ideas related to an emerging scientific focus known as omics, we propose that spiritual, social, and political behaviors may be tied in part to inheritable reward gene polymorphisms, as has been demonstrated for the addictions. If so, analyses of gene polymorphisms may assist in predicting liberalism or conservatism in partisan attachments. For example, both drinking (alcohol) and obesity seem to cluster in large social networks and are influenced by friends having the same genotype, in particular the DRD2 A1 allele. Likewise, voting, voting turnout and attachment to a particular political ideology is differentially related to various reward genes (e.g., 5HTT, MOA, DRD2, and DRD4), possibly predicting liberalism or conservatism. Moreover, voters’ genetic information may predict presidential outcomes more than the actual issues at hand or the presidential candidates themselves. Thus, political discussions on TV, radio, or other media may be morphed by one’s reward gene polymorphisms and as such, may explain the prevalence of generations of die-hard republicans and equally entrenched democratic legacies. Indeed, even in politics, birds of a feather (homophily) flock together. We caution that our proposal should be viewed mindfully awaiting additional research before definitive statements or conclusions can be derived from the studies to date, and we encourage large scale studies to confirm these earlier reports. PMID:23336089

Do genetic and individual risk factors moderate the efficacy of motivational enhancement therapy? Drinking outcomes with an emerging adult sample

PubMed Central

Feldstein Ewing, Sarah W.; LaChance, Heather A.; Bryan, Angela; Hutchison, Kent E.

2010-01-01

Research indicates that motivational enhancement therapy (MET) helps catalyze reductions in problem drinking among emerging adults. However, moderators of this intervention remain relatively unknown. Therefore, the objectives of this study were: (1) to test whether a single session of MET increased motivation to reduce drinking and drinking outcomes; and (2) to examine whether genetic dopamine D4 receptor L (DRD4 L) and individual personality risk factors (impulsivity and novelty seeking) moderated the effects of the MET. These hypotheses were evaluated by randomly assigning a sample of emerging adult problem drinkers (n = 67) to receive a single session of MET or alcohol education. Follow-up data indicated that only individuals who were low in impulsivity, novelty seeking and/or who had the short DRD4 variable number of tandem repeats genotype evidenced differentially increased behavior change (taking steps toward reducing drinking) following the MET. PMID:19298319

A human laboratory pilot study with baclofen in alcoholic individuals

PubMed Central

Leggio, Lorenzo; Zywiak, William H.; McGeary, John E.; Edwards, Steven; Fricchione, Samuel R.; Shoaff, Jessica R.; Addolorato, Giovanni; Swift, Robert M.; Kenna, George A.

2015-01-01

Preclinical and clinical studies show that the GABAB receptor agonist baclofen may represent a pharmacotherapy for alcohol dependence (AD). However, the mechanisms by which baclofen affects drinking are not well characterized; thus this pilot study investigated possible baclofen’s biobehavioral mechanisms. The design was a double-blind controlled randomized human laboratory pilot study. Fourteen non-treatment seeking alcohol-dependent heavy drinking subjects received either baclofen 10 mg t.i.d. or an active placebo (cyproheptadine 2 mg t.i.d., to control for sedation) for a 7-day period. At day 8, participants performed an alcohol cue-reactivity (CR) followed by an alcohol self-administration (ASA). Additionally, we explored possible moderators that might guide future larger studies, i.e. anxiety, family history and onset of alcoholism, and D4 dopamine receptor (DRD4) and 5-HTTLPR polymorphisms. The main results were a significant effect of baclofen for increasing stimulation (p=.001) and sedation (p<.01). Furthermore, when drinking during the ASA and the 2 days before was analyzed as a composite variable, there was a significant effect of baclofen to reduce alcohol consumption (p<.01). As for the exploratory analyses, baclofen’s effects to increase alcohol sedation and to reduce alcohol consumption were limited to those individuals with DRD4 ≥7 repeats (DRD4L). Yet, baclofen’s effects on alcohol consumption were also moderated by 5-HTTLPR LL genotype. In conclusion, baclofen’s ability to reduce alcohol drinking may be related to its effects on the biphasic effects of alcohol, but larger studies are needed to confirm these preliminary findings. PMID:23262301

Enhancing dopaminergic signaling and histone acetylation promotes long-term rescue of deficient fear extinction.

PubMed

Whittle, N; Maurer, V; Murphy, C; Rainer, J; Bindreither, D; Hauschild, M; Scharinger, A; Oberhauser, M; Keil, T; Brehm, C; Valovka, T; Striessnig, J; Singewald, N

2016-12-06

Extinction-based exposure therapy is used to treat anxiety- and trauma-related disorders; however, there is the need to improve its limited efficacy in individuals with impaired fear extinction learning and to promote greater protection against return-of-fear phenomena. Here, using 129S1/SvImJ mice, which display impaired fear extinction acquisition and extinction consolidation, we revealed that persistent and context-independent rescue of deficient fear extinction in these mice was associated with enhanced expression of dopamine-related genes, such as dopamine D1 (Drd1a) and -D2 (Drd2) receptor genes in the medial prefrontal cortex (mPFC) and amygdala, but not hippocampus. Moreover, enhanced histone acetylation was observed in the promoter of the extinction-regulated Drd2 gene in the mPFC, revealing a potential gene-regulatory mechanism. Although enhancing histone acetylation, via administering the histone deacetylase (HDAC) inhibitor MS-275, does not induce fear reduction during extinction training, it promoted enduring and context-independent rescue of deficient fear extinction consolidation/retrieval once extinction learning was initiated as shown following a mild conditioning protocol. This was associated with enhanced histone acetylation in neurons of the mPFC and amygdala. Finally, as a proof-of-principle, mimicking enhanced dopaminergic signaling by L-dopa treatment rescued deficient fear extinction and co-administration of MS-275 rendered this effect enduring and context-independent. In summary, current data reveal that combining dopaminergic and epigenetic mechanisms is a promising strategy to improve exposure-based behavior therapy in extinction-impaired individuals by initiating the formation of an enduring and context-independent fear-inhibitory memory.

Effects of dopaminergic genes, prenatal adversities, and their interaction on attention-deficit/hyperactivity disorder and neural correlates of response inhibition.

PubMed

van der Meer, Dennis; Hartman, Catharina A; van Rooij, Daan; Franke, Barbara; Heslenfeld, Dirk J; Oosterlaan, Jaap; Faraone, Stephen V; Buitelaar, Jan K; Hoekstra, Pieter J

2017-03-01

Attention-deficit/hyperactivity disorder (ADHD) is often accompanied by impaired response inhibition; both have been associated with aberrant dopamine signalling. Given that prenatal exposure to alcohol or smoking is known to affect dopamine-rich brain regions, we hypothesized that individuals carrying the ADHD risk alleles of the dopamine receptor D4 ( DRD4 ) and dopamine transporter ( DAT1 ) genes may be especially sensitive to their effects. Functional MRI data, information on prenatal adversities and genetic data were available for 239 adolescents and young adults participating in the multicentre ADHD cohort study NeuroIMAGE (average age 17.3 yr). We analyzed the effects of DRD4 and DAT1 , prenatal exposure to alcohol and smoking and their interactions on ADHD severity, response inhibition and neural activity. We found no significant gene × environment interaction effects. We did find that the DRD4 7-repeat allele was associated with less superior frontal and parietal brain activity and with greater activity in the frontal pole and occipital cortex. Prenatal exposure to smoking was also associated with lower superior frontal activity, but with greater activity in the parietal lobe. Further, those exposed to alcohol had more activity in the lateral orbitofrontal cortex, and the DAT1 risk variant was associated with lower cerebellar activity. Retrospective reports of maternal substance use and the cross-sectional study design restrict causal inference. While we found no evidence of gene × environment interactions, the risk factors under investigation influenced activity of brain regions associated with response inhibition, suggesting they may add to problems with inhibiting behaviour.

Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia.

PubMed

Bertolino, Alessandro; Fazio, Leonardo; Caforio, Grazia; Blasi, Giuseppe; Rampino, Antonio; Romano, Raffaella; Di Giorgio, Annabella; Taurisano, Paolo; Papp, Audrey; Pinsonneault, Julia; Wang, Danxin; Nardini, Marcello; Popolizio, Teresa; Sadee, Wolfgang

2009-02-01

Dopamine D2 receptor signalling is strongly implicated in the aetiology of schizophrenia. We have recently characterized the function of three DRD2 SNPs: rs12364283 in the promoter affecting total D2 mRNA expression; rs2283265 and rs1076560, respectively in introns 5 and 6, shifting mRNA splicing to two functionally distinct isoforms, the short form of D2 (D2S) and the long form (D2L). These two isoforms differentially contribute to dopamine signalling in prefrontal cortex and in striatum. We performed a case-control study to determine association of these variants and of their main haplotypes with several schizophrenia-related phenotypes. We demonstrate that the minor allele in the intronic variants is associated with reduced expression of %D2S of total mRNA in post-mortem prefrontal cortex, and with impaired working memory behavioural performance, both in patients and controls. However, the fMRI results show opposite effects in patients compared with controls: enhanced engagement of prefronto-striatal pathways in controls and reduced activity in patients. Moreover, the promoter variant is also associated with working memory activity in prefrontal cortex and striatum of patients, and less robustly with negative symptoms scores. Main haplotypes formed by the three DRD2 variants showed significant associations with these phenotypes consistent with those of the individual SNPs. Our results indicate that the three functional DRD2 variants modulate schizophrenia phenotypes possibly by modifying D2S/D2L ratios in the context of different total D2 density.

Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia

PubMed Central

Fazio, Leonardo; Caforio, Grazia; Blasi, Giuseppe; Rampino, Antonio; Romano, Raffaella; Di Giorgio, Annabella; Taurisano, Paolo; Papp, Audrey; Pinsonneault, Julia; Wang, Danxin; Nardini, Marcello; Popolizio, Teresa; Sadee, Wolfgang

2009-01-01

Dopamine D2 receptor signalling is strongly implicated in the aetiology of schizophrenia. We have recently characterized the function of three DRD2 SNPs: rs12364283 in the promoter affecting total D2 mRNA expression; rs2283265 and rs1076560, respectively in introns 5 and 6, shifting mRNA splicing to two functionally distinct isoforms, the short form of D2 (D2S) and the long form (D2L). These two isoforms differentially contribute to dopamine signalling in prefrontal cortex and in striatum. We performed a case–control study to determine association of these variants and of their main haplotypes with several schizophrenia-related phenotypes. We demonstrate that the minor allele in the intronic variants is associated with reduced expression of %D2S of total mRNA in post-mortem prefrontal cortex, and with impaired working memory behavioural performance, both in patients and controls. However, the fMRI results show opposite effects in patients compared with controls: enhanced engagement of prefronto-striatal pathways in controls and reduced activity in patients. Moreover, the promoter variant is also associated with working memory activity in prefrontal cortex and striatum of patients, and less robustly with negative symptoms scores. Main haplotypes formed by the three DRD2 variants showed significant associations with these phenotypes consistent with those of the individual SNPs. Our results indicate that the three functional DRD2 variants modulate schizophrenia phenotypes possibly by modifying D2S/D2L ratios in the context of different total D2 density. PMID:18829695

Functional Genetic Variation in Dopamine Signaling Moderates Prefrontal Cortical Activity During Risky Decision Making.

PubMed

Kohno, Milky; Nurmi, Erika L; Laughlin, Christopher P; Morales, Angelica M; Gail, Emma H; Hellemann, Gerhard S; London, Edythe D

2016-02-01

Brain imaging has revealed links between prefrontal activity during risky decision-making and striatal dopamine receptors. Specifically, striatal dopamine D2-like receptor availability is correlated with risk-taking behavior and sensitivity of prefrontal activation to risk in the Balloon Analogue Risk Task (BART). The extent to which these associations, involving a single neurochemical measure, reflect more general effects of dopaminergic functioning on risky decision making, however, is unknown. Here, 65 healthy participants provided genotypes and performed the BART during functional magnetic resonance imaging. For each participant, dopamine function was assessed using a gene composite score combining known functional variation across five genes involved in dopaminergic signaling: DRD2, DRD3, DRD4, DAT1, and COMT. The gene composite score was negatively related to dorsolateral prefrontal cortical function during risky decision making, and nonlinearly related to earnings on the task. Iterative permutations of all possible allelic variations (7777 allelic combinations) was tested on brain function in an independently defined region of the prefrontal cortex and confirmed empirical validity of the composite score, which yielded stronger association than 95% of all other possible combinations. The gene composite score also accounted for a greater proportion of variability in neural and behavioral measures than the independent effects of each gene variant, indicating that the combined effects of functional dopamine pathway genes can provide a robust assessment, presumably reflecting the cumulative and potentially interactive effects on brain function. Our findings support the view that the links between dopaminergic signaling, prefrontal function, and decision making vary as a function of dopamine signaling capacity.

Association between urine phthalate levels and poor attentional performance in children with attention-deficit hyperactivity disorder with evidence of dopamine gene-phthalate interaction.

PubMed

Park, Subin; Kim, Bung-Nyun; Cho, Soo-Churl; Kim, Yeni; Kim, Jae-Won; Lee, Ju-Young; Hong, Soon-Beom; Shin, Min-Sup; Yoo, Hee Jeong; Im, Hosub; Cheong, Jae Hoon; Han, Doug Hyun

2014-06-27

Although there is some evidence supporting the existence of an association between prenatal maternal or postnatal child's urine phthalate metabolite concentrations and poor attentional performances, the interaction between urine phthalate metabolite levels and genetic variation for neuropsychological deficit of attention-deficit hyperactivity disorder (ADHD) has not been examined. The aim of this study was to determine whether phthalate metabolites in urine are associated with poor neuropsychological performance in children with ADHD, and whether such association is affected by genotype-phthalate interaction. A cross-sectional examination of urine phthalate metabolite concentrations and the continuous performance test (CPT) were performed in 179 Korean children with ADHD recruited from department of psychiatry of university hospital. Correlations between urine phthalate metabolite concentrations and the CPT scores were investigated, and the interaction of phthalate metabolite levels with the selected polymorphisms at major candidate genes for ADHD, namely dopamine receptor D4 (DRD4), dopamine transporter, α-2A-adrenergic receptor, and norepinephrine transporter genes. For the subjects with the DRD4 4/4 genotype, there were significant associations of the urine phthalate metabolite concentrations with the number of omission errors, the number of commission errors, and the response time variability scores on the CPT. However, for the subjects without the DRD4 4/4 genotype, no significant associations were found. The results of this study suggest a possible association between phthalate metabolite concentrations and poor attentional performances of ADHD as well as a genetic influence on this association. Further prospective and epigenetic studies are needed to investigate causality and pathophysiological mechanisms.

Methamphetamine blocks exercise effects on Bdnf and Drd2 gene expression in frontal cortex and striatum.

PubMed

Thompson, Andrew B; Stolyarova, Alexandra; Ying, Zhe; Zhuang, Yumei; Gómez-Pinilla, Fernando; Izquierdo, Alicia

2015-12-01

Exposure to drugs of abuse can produce many neurobiological changes which may lead to increased valuation of rewards and decreased sensitivity to their costs. Many of these behavioral alterations are associated with activity of D2-expressing medium spiny neurons in the striatum. Additionally, Bdnf in the striatum has been shown to play a role in flexible reward-seeking behavior. Given that voluntary aerobic exercise can affect the expression of these proteins in healthy subjects, and that exercise has shown promise as an anti-addictive therapy, we set out to quantify changes in D2 and Bdnf expression in methamphetamine-exposed rats given access to running wheels. Sixty-four rats were treated for two weeks with an escalating dose of methamphetamine or saline, then either sacrificed, housed in standard cages, or given free access to a running wheel for 6 weeks prior to sacrifice. Rats treated with methamphetamine ran significantly greater distances than saline-treated rats, suggesting an augmentation in the reinforcement value of voluntary wheel running. Transcription of Drd2 and Bdnf was assessed via RT-qPCR. Protein expression levels of D2 and phosphorylation of the TrkB receptor were measured via western blot. Drd2 and Bdnf mRNA levels were impacted independently by exercise and methamphetamine, but exposure to methamphetamine prior to the initiation of exercise blocked the exercise-induced changes seen in rats treated with saline. Expression levels of both proteins were elevated immediately after methamphetamine, but returned to baseline after six weeks, regardless of exercise status. Copyright © 2015 Elsevier Ltd. All rights reserved.

ACE inhibitors could be therapeutic for antisocial personality disorder.

PubMed

Hobgood, Donna K

2013-11-01

Antisocial personality traits are an important topic for research. The societal cost of these behaviors encourages efforts at a better understanding of central nervous system causes. Catecholamine genes are being studied to facilitate this understanding, and some tentative findings are being reached about several of these genes. It seems that many genes play a role to produce antisocial behaviors so complexity of elucidating each gene is obvious. One conclusion that could be drawn from the current research findings is that DA2 like receptors (DRD2, DRD3, DRD4) with alleles that decrease neurotransmission are facilitatory of antisocial behaviors. DA2 like receptors cause neuronal firing to inhibit many peripheral functions through adenylyl cyclase inhibition. When these receptors are less active by genetically decreased density, lower affinity, or by low dopamine levels as final common pathways then inhibition is released and a state of disinhibition can be said to describe this state. Peripheral metabolism is increased and behavioral activation is noted. Renin is disinhibited in this setting thus allowing sympathetic nervous system activation. The fight or flight behaviors thus produced, in the extreme, would be the setting of antisocial behavior. Research validates this hypothesis. Understanding this final common pathway toward antisocial behavior should lead to better treatment for individuals with this pattern of behavior before they have caused harm to themselves and others. ACE inhibitors are well tolerated drugs used in the treatment of hypertension and heart failure and would also treat antisocial behavior disorders. Copyright © 2013 The Author. Published by Elsevier Ltd.. All rights reserved.

Genetic polymorphisms involved in dopaminergic neurotransmission and risk for Parkinson's disease in a Japanese population

PubMed Central

2011-01-01

Background Parkinson's disease (PD) is characterized by alterations in dopaminergic neurotransmission. Genetic polymorphisms involved in dopaminergic neurotransmission may influence susceptibility to PD. Methods We investigated the relationship of catechol-O-methyltransferase (COMT), monoamine oxidase B (MAOB), dopamine receptor (DR) D2 and DRD4 polymorphisms and PD risk with special attention to the interaction with cigarette smoking among 238 patients with PD and 369 controls in a Japanese population. Results Subjects with the AA genotype of MAOB rs1799836 showed a significantly increased risk of PD (odds ratio (OR) = 1.70, 95% confidence interval (CI) = 1.12 - 2.58) compared with the AG and GG genotypes combined. The AA genotype of COMT rs4680 was marginally associated with an increased risk of PD (OR = 1.86, 95% CI = 0.98 - 3.50) compared with the GG genotype. The DRD2 rs1800497 and DRD4 rs1800955 polymorphisms showed no association with PD. A COMT -smoking interaction was suggested, with the combined GA and AA genotypes of rs4680 and non-smoking conferring significantly higher risk (OR = 3.97, 95% CI = 2.13 - 7.41) than the AA genotype and a history of smoking (P for interaction = 0.061). No interactions of smoking with other polymorphisms were observed. Conclusions The COMT rs4680 and MAOB rs1799836 polymorphisms may increase susceptibility to PD risk among Japanese. Future studies involving larger control and case populations and better pesticide exposure histories will undoubtedly lead to a more thorough understanding of the role of the polymorphisms involved in the dopamine pathway in PD. PMID:21781348

Identification and characterization of tandem repeats in exon III of dopamine receptor D4 (DRD4) genes from different mammalian species.

PubMed

Larsen, Svend Arild; Mogensen, Line; Dietz, Rune; Baagøe, Hans Jørgen; Andersen, Mogens; Werge, Thomas; Rasmussen, Henrik Berg

2005-12-01

In this study we have identified and characterized dopamine receptor D4 (DRD4) exon III tandem repeats in 33 public available nucleotide sequences from different mammalian species. We found that the tandem repeat in canids could be described in a novel and simple way, namely, as a structure composed of 15- and 12- bp modules. Tandem repeats composed of 18-bp modules were found in sequences from the horse, zebra, onager, and donkey, Asiatic bear, polar bear, common raccoon, dolphin, harbor porpoise, and domestic cat. Several of these sequences have been analyzed previously without a tandem repeat being found. In the domestic cow and gray seal we identified tandem repeats composed of 36-bp modules, each consisting of two closely related 18-bp basic units. A tandem repeat consisting of 9-bp modules was identified in sequences from mink and ferret. In the European otter we detected an 18-bp tandem repeat, while a tandem repeat consisting of 27-bp modules was identified in a sequence from European badger. Both these tandem repeats were composed of 9-bp basic units, which were closely related with the 9-bp repeat modules identified in the mink and ferret. Tandem repeats could not be identified in sequences from rodents. All tandem repeats possessed a high GC content with a strong bias for C. On phylogenetic analysis of the tandem repeats evolutionary related species were clustered into the same groups. The degree of conservation of the tandem repeats varied significantly between species. The deduced amino acid sequences of most of the tandem repeats exhibited a high propensity for disorder. This was also the case with an amino acid sequence of the human DRD4 exon III tandem repeat, which was included in the study for comparative purposes. We identified proline-containing motifs for SH3 and WW domain binding proteins, potential phosphorylation sites, PDZ domain binding motifs, and FHA domain binding motifs in the amino acid sequences of the tandem repeats. The numbers of potential functional sites varied pronouncedly between species. Our observations provide a platform for future studies of the architecture and evolution of the DRD4 exon III tandem repeat, and they suggest that differences in the structure of this tandem repeat contribute to specialization and generation of diversity in receptor function.

Role of Dorsomedial Striatum Neuronal Ensembles in Incubation of Methamphetamine Craving after Voluntary Abstinence.

PubMed

Caprioli, Daniele; Venniro, Marco; Zhang, Michelle; Bossert, Jennifer M; Warren, Brandon L; Hope, Bruce T; Shaham, Yavin

2017-01-25

We recently developed a rat model of incubation of methamphetamine craving after choice-based voluntary abstinence. Here, we studied the role of dorsolateral striatum (DLS) and dorsomedial striatum (DMS) in this incubation. We trained rats to self-administer palatable food pellets (6 d, 6 h/d) and methamphetamine (12 d, 6 h/d). We then assessed relapse to methamphetamine seeking under extinction conditions after 1 and 21 abstinence days. Between tests, the rats underwent voluntary abstinence (using a discrete choice procedure between methamphetamine and food; 20 trials/d) for 19 d. We used in situ hybridization to measure the colabeling of the activity marker Fos with Drd1 and Drd2 in DMS and DLS after the tests. Based on the in situ hybridization colabeling results, we tested the causal role of DMS D 1 and D 2 family receptors, and DMS neuronal ensembles in "incubated" methamphetamine seeking, using selective dopamine receptor antagonists (SCH39166 or raclopride) and the Daun02 chemogenetic inactivation procedure, respectively. Methamphetamine seeking was higher after 21 d of voluntary abstinence than after 1 d (incubation of methamphetamine craving). The incubated response was associated with increased Fos expression in DMS but not in DLS; Fos was colabeled with both Drd1 and Drd2 DMS injections of SCH39166 or raclopride selectively decreased methamphetamine seeking after 21 abstinence days. In Fos-lacZ transgenic rats, selective inactivation of relapse test-activated Fos neurons in DMS on abstinence day 18 decreased incubated methamphetamine seeking on day 21. Results demonstrate a role of DMS dopamine D 1 and D 2 receptors in the incubation of methamphetamine craving after voluntary abstinence and that DMS neuronal ensembles mediate this incubation. In human addicts, abstinence is often self-imposed and relapse can be triggered by exposure to drug-associated cues that induce drug craving. We recently developed a rat model of incubation of methamphetamine craving after choice-based voluntary abstinence. Here, we used classical pharmacology, in situ hybridization, immunohistochemistry, and the Daun02 inactivation procedure to demonstrate a critical role of dorsomedial striatum neuronal ensembles in this new form of incubation of drug craving. Copyright © 2017 the authors 0270-6474/17/371014-14$15.00/0.

Tumor Dosimetry and Response for 153Sm-Ethylenediamine Tetramethylene Phosphonic Acid Therapy of High-Risk Osteosarcoma

PubMed Central

Senthamizhchelvan, Srinivasan; Hobbs, Robert F.; Song, Hong; Frey, Eric C.; Zhang, Zhe; Armour, Elwood; Wahl, Richard L.; Loeb, David M.; Sgouros, George

2012-01-01

153Sm-ethylenediamine tetramethylene phosphonic acid (153Sm-EDTMP) therapy for osteosarcoma is being investigated. In this study, we analyzed the influence of 153Sm-EDTMP administered activity (AA), osteosarcoma tumor density, mass, and the shape of the tumor on absorbed dose (AD). We also studied the biologic implication of the nonuniform tumor AD distribution using radio-biologic modeling and examined the relationship between tumor AD and response. Methods Nineteen tumors in 6 patients with recurrent, refractory osteosarcoma enrolled in a phase I or II clinical trial of 153Sm-EDTMP were analyzed using the 3-dimensional radiobiologic dosimetry (3D-RD) software package. Patients received a low dose of 153Sm-EDTMP (37.0–51.8 MBq/kg), followed on hematologic recovery by a second, high dose (222 MBq/kg). Treatment response was evaluated using either CT or MRI after each therapy. SPECT/CT of the tumor regions were obtained at 4 and 48 h or 72 h after 153Sm-EDTMP therapy for 3D-RD analysis. Mean tumor AD was also calculated using the OLINDA/EXM unit-density sphere model and was compared with the 3D-RD estimates. Results On average, a 5-fold increase in the AA led to a 4-fold increase in the mean tumor AD over the high- versus low-dose–treated patients. The range of mean tumor AD and equivalent uniform dose (EUD) for low-dose therapy were 1.48–14.6 and 0.98–3.90 Gy, respectively. Corresponding values for high-dose therapy were 2.93–59.3 and 1.89–12.3 Gy, respectively. Mean tumor AD estimates obtained from OLINDA/EXM were within 5% of the mean AD values obtained using 3D-RD. On an individual tumor basis, both mean AD and EUD were positively related to percentage tumor volume reduction (P = 0.031 and 0.023, respectively). Conclusion The variations in tumor density, mass, and shape seen in these tumors did not affect the mean tumor AD estimation significantly. The tumor EUD was approximately 2- and 3-fold lower than the mean AD for low-and high-dose therapy, respectively. A dose–response relationship was observed for transient tumor volume shrinkage. PMID:22251554

Tumor and red bone marrow dosimetry: comparison of methods for prospective treatment planning in pretargeted radioimmunotherapy.

PubMed

Woliner-van der Weg, Wietske; Schoffelen, Rafke; Hobbs, Robert F; Gotthardt, Martin; Goldenberg, David M; Sharkey, Robert M; Slump, Cornelis H; van der Graaf, Winette Ta; Oyen, Wim Jg; Boerman, Otto C; Sgouros, George; Visser, Eric P

2015-12-01

Red bone marrow (RBM) toxicity is dose-limiting in (pretargeted) radioimmunotherapy (RIT). Previous blood-based and two-dimensional (2D) image-based methods have failed to show a clear dose-response relationship. We developed a three-dimensional (3D) image-based RBM dosimetry approach using the Monte Carlo-based 3D radiobiological dosimetry (3D-RD) software and determined its additional value for predicting RBM toxicity. RBM doses were calculated for 13 colorectal cancer patients after pretargeted RIT with the two-step administration of an anti-CEA × anti-HSG bispecific monoclonal antibody and a (177)Lu-labeled di-HSG-peptide. 3D-RD RBM dosimetry was based on the lumbar vertebrae, delineated on single photon emission computed tomography (SPECT) scans acquired directly, 3, 24, and 72 h after (177)Lu administration. RBM doses were correlated to hematologic effects, according to NCI-CTC v3 and compared with conventional 2D cranium-based and blood-based dosimetry results. Tumor doses were calculated with 3D-RD, which has not been possible with 2D dosimetry. Tumor-to-RBM dose ratios were calculated and compared for (177)Lu-based pretargeted RIT and simulated pretargeted RIT with (90)Y. 3D-RD RBM doses of all seven patients who developed thrombocytopenia were higher (range 0.43 to 0.97 Gy) than that of the six patients without thrombocytopenia (range 0.12 to 0.39 Gy), except in one patient (0.47 Gy) without thrombocytopenia but with grade 2 leucopenia. Blood and 2D image-based RBM doses for patients with grade 1 to 2 thrombocytopenia were in the same range as in patients without thrombocytopenia (0.14 to 0.29 and 0.11 to 0.26 Gy, respectively). Blood-based RBM doses for two grade 3 to 4 patients were higher (0.66 and 0.51 Gy, respectively) than the others, and the cranium-based dose of only the grade 4 patient was higher (0.34 Gy). Tumor-to-RBM dose ratios would increase by 25% on average when treating with (90)Y instead of (177)Lu. 3D dosimetry identifies patients at risk of developing any grade of RBM toxicity more accurately than blood- or 2D image-based methods. It has the added value to enable calculation of tumor-to-RBM dose ratios.

Acute intravenous synaptamine complex variant KB220™ "normalizes" neurological dysregulation in patients during protracted abstinence from alcohol and opiates as observed using quantitative electroencephalographic and genetic analysis for reward polymorphisms: part 1, pilot study with 2 case reports.

PubMed

Miller, David K; Bowirrat, Abdalla; Manka, Matthew; Miller, Merlene; Stokes, Stanley; Manka, Debra; Allen, Cameron; Gant, Charles; Downs, B William; Smolen, Andrew; Stevens, Emily; Yeldandi, Swetha; Blum, Kenneth

2010-11-01

It is well established that in both food- and drug-addicted individuals, there is dopamine resistance due to an association with the DRD2 gene A1 allele. Evidence is emerging whereby the potential of utilizing a natural, nonaddicting, safe, putative D2 agonist may find its place in recovery from reward deficiency syndrome (RDS) in patients addicted to psychoactive chemicals. Utilizing quantitative electroencephalography (qEEG) as an imaging tool, we show the impact of Synaptamine Complex Variant KB220™ as a putative activator of the mesolimbic system. We demonstrate for the first time that its intravenous administration reduces or "normalizes" aberrant electrophysiological parameters of the reward circuitry site. For this pilot study, we report that the qEEGs of an alcoholic and a heroin abuser with existing abnormalities (ie, widespread theta and widespread alpha activity, respectively) during protracted abstinence are significantly normalized by the administration of 1 intravenous dose of Synaptamine Complex Variant KB220™. Both patients were genotyped for a number of neurotransmitter reward genes to determine to what extent they carry putative dopaminergic risk alleles that may predispose them for alcohol or heroin dependence, respectively. The genes tested included the dopamine transporter (DAT1, locus symbol SLC6A3), dopamine D4 receptor exon 3 VNTR (DRD4), DRD2 TaqIA (rs1800497), COMT val158 met SNP (rs4680), monoamine oxidase A upstream VNTR (MAOA-uVNTR), and serotonin transporter-linked polymorphic region (5HTTLPR, locus symbol SLC6A4). We emphasize that these are case studies, and it would be unlikely for all individuals to carry all putative risk alleles. Based on previous research and our qEEG studies (parts 1 and 2 of this study), we cautiously suggest that long-term activation of dopaminergic receptors (ie, DRD2 receptors) will result in their proliferation and lead to enhanced "dopamine sensitivity" and an increased sense of happiness, particularly in carriers of the DRD2 A1 allele. This is supported by a clinical trial on Synaptamine Complex Variant KB220™ using intravenous administration in > 600 alcoholic patients, resulting in significant reductions in RDS behaviors. It is also confirmed by the expanded oral study on Synaptose Complex KB220Z™, published as part 2 of this study. Future studies must await both functional magnetic resonance imaging and positron emission tomography scanning to determine the acute and chronic effects of oral KB220™ on numbers of D2 receptors and direct interaction at the nucleus accumbens. Confirmation of these results in large, population-based, case-controlled experiments is necessary. These studies would provide important information that could ultimately lead to significant improvement in recovery for those with RDS and dopamine deficiency as a result of a multiple neurotransmitter signal transduction breakdown in the brain reward cascade.

MISR Level 3 Radiance Versioning

Atmospheric Science Data Center

2016-11-04

... ESDT Product File Name Prefix Current Quality Designations MIL3DRD, MIL3MRD, MIL3QRD, and MIL3YRD ... Data Product Specification Rev K  (PDF). Update to work with new format of the input PGE 1 files.   F02_0007 ...

Effects of dopaminergic genes, prenatal adversities, and their interaction on attention-deficit/hyperactivity disorder and neural correlates of response inhibition

PubMed Central

van der Meer, Dennis; Hartman, Catharina A.; van Rooij, Daan; Franke, Barbara; Heslenfeld, Dirk J.; Oosterlaan, Jaap; Faraone, Stephen V.; Buitelaar, Jan K.; Hoekstra, Pieter J.

2017-01-01

Background Attention-deficit/hyperactivity disorder (ADHD) is often accompanied by impaired response inhibition; both have been associated with aberrant dopamine signalling. Given that prenatal exposure to alcohol or smoking is known to affect dopamine-rich brain regions, we hypothesized that individuals carrying the ADHD risk alleles of the dopamine receptor D4 (DRD4) and dopamine transporter (DAT1) genes may be especially sensitive to their effects. Methods Functional MRI data, information on prenatal adversities and genetic data were available for 239 adolescents and young adults participating in the multicentre ADHD cohort study NeuroIMAGE (average age 17.3 yr). We analyzed the effects of DRD4 and DAT1, prenatal exposure to alcohol and smoking and their interactions on ADHD severity, response inhibition and neural activity. Results We found no significant gene × environment interaction effects. We did find that the DRD4 7-repeat allele was associated with less superior frontal and parietal brain activity and with greater activity in the frontal pole and occipital cortex. Prenatal exposure to smoking was also associated with lower superior frontal activity, but with greater activity in the parietal lobe. Further, those exposed to alcohol had more activity in the lateral orbitofrontal cortex, and the DAT1 risk variant was associated with lower cerebellar activity. Limitations Retrospective reports of maternal substance use and the cross-sectional study design restrict causal inference. Conclusion While we found no evidence of gene × environment interactions, the risk factors under investigation influenced activity of brain regions associated with response inhibition, suggesting they may add to problems with inhibiting behaviour. PMID:28234207

Development and Prospective Federal State-Wide Evaluation of a Device for Height-Based Dose Recommendations in Prehospital Pediatric Emergencies: A Simple Tool to Prevent Most Severe Drug Errors.

PubMed

Kaufmann, Jost; Roth, Bernhard; Engelhardt, Thomas; Lechleuthner, Alex; Laschat, Michael; Hadamitzky, Christoph; Wappler, Frank; Hellmich, Martin

2018-01-01

Drug dosing errors pose a particular threat to children in prehospital emergency care. With the Pediatric emergency ruler (PaedER), we developed a simple height-based dose recommendation system and evaluated its effectiveness in a pre-post interventional trial as the Ethics Committee disapproved randomization due to the expected positive effect of the PaedER on outcome. Pre-interventional data were retrospectively retrieved from the electronic records and medical protocols of the Cologne Emergency Medical Service over a two-year period prior to the introduction of the PaedER. Post-interventional data were collected prospectively over a six-year period in a federal state-wide open trial. The administered doses of either intravenous or intraosseous fentanyl, midazolam, ketamine or epinephrine were recorded. Primary outcome measure was the number and severity of drug dose deviation from recommended dose (DRD) based on the patient's weight. Fifty-nine pre-interventional and 91 post-interventional prehospital drug administrations in children were analyzed. The rate of DRD > 300% overall medications were 22.0% in the pre- and 2.2% in the post-interventional group (p < 0.001). All administrations of epinephrine occurred excessive (DRD > 300%) in pre-interventional and none in post-interventional patients (p < 0.001). The use of the PaedER resulted in a 90% reduction of medication errors (95% CI: 57% to 98%; p < 0.001) and prevented all potentially life-threatening errors associated with epinephrine administration. There is an urgent need to increase the safety of emergency drug dosing in children during emergencies. A simple height-based system can support health care providers and helps to avoid life-threatening medication errors.

First-in-Human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors.

PubMed

Stein, Mark N; Bertino, Joseph R; Kaufman, Howard L; Mayer, Tina; Moss, Rebecca; Silk, Ann; Chan, Nancy; Malhotra, Jyoti; Rodriguez, Lorna; Aisner, Joseph; Aiken, Robert D; Haffty, Bruce G; DiPaola, Robert S; Saunders, Tracie; Zloza, Andrew; Damare, Sherri; Beckett, Yasmeen; Yu, Bangning; Najmi, Saltanat; Gabel, Christian; Dickerson, Siobhan; Zheng, Ling; El-Deiry, Wafik S; Allen, Joshua E; Stogniew, Martin; Oster, Wolfgang; Mehnert, Janice M

2017-08-01

Purpose: ONC201 is a small-molecule selective antagonist of the G protein-coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D). Experimental Design: This open-label study treated 10 patients during dose escalation with histologically confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design. An additional 18 patients were treated at the RP2D in an expansion phase to collect additional safety, pharmacokinetic, and pharmacodynamic information. Results: No grade >1 drug-related adverse events occurred, and the RP2D was defined as 625 mg. Pharmacokinetic analysis revealed a C max of 1.5 to 7.5 μg/mL (∼3.9-19.4 μmol/L), mean half-life of 11.3 hours, and mean AUC of 37.7 h·μg/L. Pharmacodynamic assays demonstrated induction of caspase-cleaved keratin 18 and prolactin as serum biomarkers of apoptosis and DRD2 antagonism, respectively. No objective responses by RECIST were achieved; however, radiographic regression of several individual metastatic lesions was observed along with prolonged stable disease (>9 cycles) in prostate and endometrial cancer patients. Conclusions: ONC201 is a selective DRD2 antagonist that is well tolerated, achieves micromolar plasma concentrations, and is biologically active in advanced cancer patients when orally administered at 625 mg every 3 weeks. Clin Cancer Res; 23(15); 4163-9. ©2017 AACR . ©2017 American Association for Cancer Research.

Motivational salience and genetic variability of dopamine D2 receptor expression interact in the modulation of interference processing

PubMed Central

Richter, Anni; Richter, Sylvia; Barman, Adriana; Soch, Joram; Klein, Marieke; Assmann, Anne; Libeau, Catherine; Behnisch, Gusalija; Wüstenberg, Torsten; Seidenbecher, Constanze I.; Schott, Björn H.

2013-01-01

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. PMID:23760450

Interaction between childhood adversity and functional polymorphisms in the dopamine pathway on first-episode psychosis.

PubMed

Trotta, Antonella; Iyegbe, Conrad; Yiend, Jenny; Dazzan, Paola; David, Anthony S; Pariante, Carmine; Mondelli, Valeria; Colizzi, Marco; Murray, Robin M; Di Forti, Marta; Fisher, Helen L

2018-04-10

There is consistent evidence of a cumulative relationship between childhood adversity and psychosis, with number of adversities experienced increasing the probability of psychosis onset. It is possible that genetic factors moderate the association between childhood adversity and psychosis, potentially by influencing how an individual reacts biologically and/or psychologically following exposure to adversity, in such a way as to set them off on the path to psychosis. However, identifying the specific genetic variants involved and how they interact with childhood adversity remains challenging. We examined whether the association between cumulative exposure to childhood adversity and development of psychotic disorder was moderated by the COMT Val 158 Met, AKT1 rs2494732 or DRD2 rs1076560 polymorphisms, known to affect dopamine levels. Participants were 285 first-presentation psychosis cases and 256 geographically-matched controls drawn from the Genetics and Psychosis (GAP) study. Childhood adversity was assessed using the Childhood Experience of Care and Abuse Questionnaire (CECA.Q) and blood- and cheek-derived genotype data were collected. Our findings revealed no main effect of COMT Val 158 Met, AKT1 rs2494732 and DRD2 rs1076560 polymorphisms on psychosis case status or reports of childhood adversity. Individuals reporting a history of multiple adversities were more likely to be psychosis patients than controls, regardless of their genetic risk. There was no evidence of candidate genotype by childhood adversity interactions in relation to psychosis onset. These findings did not provide evidence of a possible role of COMT Val 158 Met, AKT1 rs2494732 or DRD2 rs1076560 genotypes in modifying the association between childhood adversity and onset of psychosis. Copyright © 2018 Elsevier B.V. All rights reserved.

Enhancing dopaminergic signaling and histone acetylation promotes long-term rescue of deficient fear extinction

PubMed Central

Whittle, N; Maurer, V; Murphy, C; Rainer, J; Bindreither, D; Hauschild, M; Scharinger, A; Oberhauser, M; Keil, T; Brehm, C; Valovka, T; Striessnig, J; Singewald, N

2016-01-01

Extinction-based exposure therapy is used to treat anxiety- and trauma-related disorders; however, there is the need to improve its limited efficacy in individuals with impaired fear extinction learning and to promote greater protection against return-of-fear phenomena. Here, using 129S1/SvImJ mice, which display impaired fear extinction acquisition and extinction consolidation, we revealed that persistent and context-independent rescue of deficient fear extinction in these mice was associated with enhanced expression of dopamine-related genes, such as dopamine D1 (Drd1a) and -D2 (Drd2) receptor genes in the medial prefrontal cortex (mPFC) and amygdala, but not hippocampus. Moreover, enhanced histone acetylation was observed in the promoter of the extinction-regulated Drd2 gene in the mPFC, revealing a potential gene-regulatory mechanism. Although enhancing histone acetylation, via administering the histone deacetylase (HDAC) inhibitor MS-275, does not induce fear reduction during extinction training, it promoted enduring and context-independent rescue of deficient fear extinction consolidation/retrieval once extinction learning was initiated as shown following a mild conditioning protocol. This was associated with enhanced histone acetylation in neurons of the mPFC and amygdala. Finally, as a proof-of-principle, mimicking enhanced dopaminergic signaling by L-dopa treatment rescued deficient fear extinction and co-administration of MS-275 rendered this effect enduring and context-independent. In summary, current data reveal that combining dopaminergic and epigenetic mechanisms is a promising strategy to improve exposure-based behavior therapy in extinction-impaired individuals by initiating the formation of an enduring and context-independent fear-inhibitory memory. PMID:27922638

Antihypertensive effect of etamicastat in dopamine D2 receptor-deficient mice.

PubMed

Armando, Ines; Asico, Laureano D; Wang, Xiaoyan; Jones, John E; Serrão, Maria Paula; Cuevas, Santiago; Grandy, David K; Soares-da-Silva, Patricio; Jose, Pedro A

2018-04-13

Abnormalities of the D 2 R gene (DRD2) play a role in the pathogenesis of human essential hypertension; variants of the DRD2 have been reported to be associated with hypertension. Disruption of Drd2 (D 2 -/- ) in mice increases blood pressure. The hypertension of D 2 -/- mice has been related, in part, to increased sympathetic activity, renal oxidative stress, and renal endothelin B receptor (ETBR) expression. We tested in D 2 -/- mice the effect of etamicastat, a reversible peripheral inhibitor of dopamine-β-hydroxylase that reduces the biosynthesis of norepinephrine from dopamine and decreases sympathetic nerve activity. Blood pressure was measured in anesthetized D 2 -/- mice treated with etamicastat by gavage, (10 mg/kg), conscious D 2 -/- mice, and D 2 +/+ littermates, and mice with the D 2 R selectively silenced in the kidney, treated with etamicastat in the drinking water (10 mg/kg per day). Tissue and urinary catecholamines and renal expression of selected G protein-coupled receptors, enzymes related to the production of reactive oxygen species, and sodium transporters were also measured. Etamicastat decreased blood pressure both in anesthetized and conscious D 2 -/- mice and mice with renal-selective silencing of D 2 R to levels similar or close to those measured in D 2 +/+ littermates. Etamicastat decreased cardiac and renal norepinephrine and increased cardiac and urinary dopamine levels in D 2 -/- mice. It also normalized the increased renal protein expressions of ETBR, NADPH oxidase isoenzymes, and urinary 8-isoprostane, as well as renal NHE3 and NCC, and increased the renal expression of D 1 R but not D 5 R in D 2 -/- mice. In conclusion, etamicastat is effective in normalizing the increased blood pressure and some of the abnormal renal biochemical alterations of D 2 -/- mice.

Changes in Expression of Dopamine, Its Receptor, and Transporter in Nucleus Accumbens of Heroin-Addicted Rats with Brain-Derived Neurotrophic Factor (BDNF) Overexpression.

PubMed

Li, Yixin; Xia, Baijuan; Li, Rongrong; Yin, Dan; Liang, Wenmei

2017-06-09

BACKGROUND The aim of this study was to explore how changes in the expression of BDNF in MLDS change the effect of BDNF on dopamine (DA) neurons, which may have therapeutic implications for heroin addiction. MATERIAL AND METHODS We established a rat model of heroin addiction and observed changes in the expression of BDNF, DA, dopamine receptor (DRD), dopamine transporter (DAT), and other relevant pathways in NAc. We also assessed the effect of BDNF overexpression in the NAc, behavioral changes of heroin-conditioned place preference (CPP), and naloxone withdrawal in rats with high levels of BDNF. We established 5 adult male rat groups: heroin addiction, lentivirus transfection, blank virus, sham operation, and control. The PCR gene chip was used to study gene expression changes. BDNF lentivirus transfection was used for BDNF overexpression. A heroin CPP model and a naloxone withdrawal model of rats were established. RESULTS Expression changes were found in 20 of the 84 DA-associated genes in the NAc of heroin-addicted rats. Weight loss and withdrawal symptoms in the lentivirus group for naloxone withdrawal was less than in the blank virus and the sham operation group. These 2 latter groups also showed significant behavioral changes, but such changes were not observed in the BDNF lentivirus group before or after training. DRD3 and DAT increased in the NAc of the lentivirus group. CONCLUSIONS BDNF and DA in the NAc are involved in heroin addiction. BDNF overexpression in NAc reduces withdrawal symptoms and craving behavior for medicine induced by environmental cues for heroin-addicted rats. BDNF participates in the regulation of the dopamine system by acting on DRD3 and DAT.

DRD2/AKT1 interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia

PubMed Central

Blasi, Giuseppe; Napolitano, Francesco; Ursini, Gianluca; Taurisano, Paolo; Romano, Raffaella; Caforio, Grazia; Fazio, Leonardo; Gelao, Barbara; Di Giorgio, Annabella; Iacovelli, Luisa; Sinibaldi, Lorenzo; Popolizio, Teresa; Usiello, Alessandro; Bertolino, Alessandro

2011-01-01

The D2/AKT1/GSK-3β signaling pathway has been involved in the downstream intracellular effects of dopamine, in the pathophysiology of cognitive deficits and related brain activity in schizophrenia, as well as in response to treatment with antipsychotics. Polymorphisms in the D2 (DRD2 rs1076560) and AKT1 (AKT1 rs1130233) genes have been associated with their respective protein expression and with higher-order cognition and brain function, including attention. Given the strong potential for their relationship, we investigated the interaction of these polymorphisms on multiple molecular and in vivo phenotypes associated with this signaling pathway. We measured AKT1 and GSK-3β proteins and phosphorylation in human peripheral blood mononuclear cells, functional MRI cingulate response during attentional control, behavioral accuracy during sustained attention, and response to 8 wk of treatment with olanzapine in a total of 190 healthy subjects and 66 patients with schizophrenia. In healthy subjects, we found that the interaction between the T allele of DRD2 rs1076560 and the A allele of AKT1 rs1130233 was associated with reduced AKT1 protein levels and reduced phosphorylation of GSK-3β, as well as with altered cingulate response and reduced behavioral accuracy during attentional processing. On the other hand, interaction of these two alleles was associated with greater improvement of Positive and Negative Syndrome Scale scores in patients with schizophrenia after treatment with olanzapine. The present results indicate that these functional polymorphisms are epistatically associated with multiple phenotypes of relevance to schizophrenia. Our results also lend support to further investigation of this downstream molecular pathway in the etiology and treatment of this disorder. PMID:21187413

DRD2/AKT1 interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia.

PubMed

Blasi, Giuseppe; Napolitano, Francesco; Ursini, Gianluca; Taurisano, Paolo; Romano, Raffaella; Caforio, Grazia; Fazio, Leonardo; Gelao, Barbara; Di Giorgio, Annabella; Iacovelli, Luisa; Sinibaldi, Lorenzo; Popolizio, Teresa; Usiello, Alessandro; Bertolino, Alessandro

2011-01-18

The D2/AKT1/GSK-3β signaling pathway has been involved in the downstream intracellular effects of dopamine, in the pathophysiology of cognitive deficits and related brain activity in schizophrenia, as well as in response to treatment with antipsychotics. Polymorphisms in the D2 (DRD2 rs1076560) and AKT1 (AKT1 rs1130233) genes have been associated with their respective protein expression and with higher-order cognition and brain function, including attention. Given the strong potential for their relationship, we investigated the interaction of these polymorphisms on multiple molecular and in vivo phenotypes associated with this signaling pathway. We measured AKT1 and GSK-3β proteins and phosphorylation in human peripheral blood mononuclear cells, functional MRI cingulate response during attentional control, behavioral accuracy during sustained attention, and response to 8 wk of treatment with olanzapine in a total of 190 healthy subjects and 66 patients with schizophrenia. In healthy subjects, we found that the interaction between the T allele of DRD2 rs1076560 and the A allele of AKT1 rs1130233 was associated with reduced AKT1 protein levels and reduced phosphorylation of GSK-3β, as well as with altered cingulate response and reduced behavioral accuracy during attentional processing. On the other hand, interaction of these two alleles was associated with greater improvement of Positive and Negative Syndrome Scale scores in patients with schizophrenia after treatment with olanzapine. The present results indicate that these functional polymorphisms are epistatically associated with multiple phenotypes of relevance to schizophrenia. Our results also lend support to further investigation of this downstream molecular pathway in the etiology and treatment of this disorder.

Gene-environment interaction in problematic substance use: interaction between DRD4 and insecure attachments.

PubMed

Olsson, Craig A; Moyzis, Robert K; Williamson, Elizabeth; Ellis, Justine A; Parkinson-Bates, Mandy; Patton, George C; Dwyer, Terry; Romaniuk, Helena; Moore, Elya E

2013-07-01

To investigate the combined effect of an exon III variable number tandem repeat in the dopamine receptor gene (DRD4) and insecure attachment style on risk for tobacco, cannabis and alcohol use problems in young adulthood. It was hypothesized that (1) individuals with 5, 6, 7 or 8 repeats (labelled 7R+) would be at increased risk for problematic drug use, and (2) risk for drug use would be further increased in individuals with 7R+ repeats who also have a history of insecure parent-child attachment relations. Data were drawn from the Victorian Adolescent Health Cohort Study, an eight-wave longitudinal study of adolescent and young adult development. DRD4 genotypes were available for 839 participants. Risk attributable to the combined effects of 7R+ genotype and insecure attachments was evaluated within a sufficient causes framework under the assumptions of additive interaction using a two-by-four table format with a common reference group. 7R+ alleles were associated with higher tobacco, cannabis and alcohol use (binging). Insecure attachments were associated with higher tobacco and cannabis use but lower alcohol use. For tobacco, there was evidence of interaction for anxious but not avoidant attachments. For cannabis, there was evidence of interaction for both anxious and avoidant attachments, although the interaction for anxious attachments was more substantial. There is no evidence of interaction for binge drinking. Results are consistent with a generic reward deficit hypothesis of drug addiction for which the 7R+ disposition may play a role. Interaction between 7R+ alleles and attachment insecurity may intensify risk for problematic tobacco and cannabis use. © 2011 Murdoch Childrens Research Institute.

Association between Urine Phthalate Levels and Poor Attentional Performance in Children with Attention-Deficit Hyperactivity Disorder with Evidence of Dopamine Gene-Phthalate Interaction

PubMed Central

Park, Subin; Kim, Bung-Nyun; Cho, Soo-Churl; Kim, Yeni; Kim, Jae-Won; Lee, Ju-Young; Hong, Soon-Beom; Shin, Min-Sup; Yoo, Hee Jeong; Im, Hosub; Cheong, Jae Hoon; Han, Doug Hyun

2014-01-01

Although there is some evidence supporting the existence of an association between prenatal maternal or postnatal child’s urine phthalate metabolite concentrations and poor attentional performances, the interaction between urine phthalate metabolite levels and genetic variation for neuropsychological deficit of attention-deficit hyperactivity disorder (ADHD) has not been examined. The aim of this study was to determine whether phthalate metabolites in urine are associated with poor neuropsychological performance in children with ADHD, and whether such association is affected by genotype-phthalate interaction. A cross-sectional examination of urine phthalate metabolite concentrations and the continuous performance test (CPT) were performed in 179 Korean children with ADHD recruited from department of psychiatry of university hospital. Correlations between urine phthalate metabolite concentrations and the CPT scores were investigated, and the interaction of phthalate metabolite levels with the selected polymorphisms at major candidate genes for ADHD, namely dopamine receptor D4 (DRD4), dopamine transporter, α-2A-adrenergic receptor, and norepinephrine transporter genes. For the subjects with the DRD4 4/4 genotype, there were significant associations of the urine phthalate metabolite concentrations with the number of omission errors, the number of commission errors, and the response time variability scores on the CPT. However, for the subjects without the DRD4 4/4 genotype, no significant associations were found. The results of this study suggest a possible association between phthalate metabolite concentrations and poor attentional performances of ADHD as well as a genetic influence on this association. Further prospective and epigenetic studies are needed to investigate causality and pathophysiological mechanisms. PMID:24978879

Activation of the dopamine receptor type-2 (DRD2) promoter by 9-cis retinoic acid in a cellular model of Cushing's disease mediates the inhibition of cell proliferation and ACTH secretion without a complete corticotroph-to-melanotroph transdifferentiation.

PubMed

Occhi, Gianluca; Regazzo, Daniela; Albiger, Nora Maria; Ceccato, Filippo; Ferasin, Sergio; Scanarini, Massimo; Denaro, Luca; Cosma, Chiara; Plebani, Mario; Cassarino, Maria Francesca; Mantovani, Giovanna; Stalla, Günter K; Pecori Giraldi, Francesca; Paez-Pareda, Marcelo; Scaroni, Carla

2014-09-01

Cushing's disease (CD) is a rare condition in which hypercortisolemia is secondary to excessive ACTH release from a pituitary corticotroph adenoma. CD is associated with significant morbidity and mortality, and a safe therapy that effectively targets the pituitary tumor is still lacking. Retinoic acid (RA) and dopamine agonists (DAs) have recently been considered as monotherapy in CD patients, and satisfactory results have been reported, albeit in a limited number of patients. Given the permissive role of RA on the dopamine receptor type-2 (DRD2), the aim of the present study was to see whether a combination of 9-cis RA and the DA bromocriptine (Br) might represent a possible treatment for CD. Here we show that 9-cis RA induces a functional DRD2 in the pituitary corticotroph cell line AtT20, and increases cell sensitivity to Br via a mechanism only partially related to corticotroph-to-melanotroph transdifferentiation. In addition, 9-cis RA and Br act synergistically to modulate cell viability, with favorable implications for clinical use. In nearly 45% of corticotropinoma-derived primary cultures, the combined administration of 9-cis RA and Br lowered the steady-state level of the ACTH precursor proopiomelanocortin (POMC) more efficiently than either of the drugs alone. In conclusion, the effects of a combination of 9-cis RA and Br on ACTH synthesis/secretion and cell viability in AtT20, and on POMC transcriptional activity in human corticotropinomas might represent a suitable starting point for assessing the potential of this treatment regimen for ACTH-secreting pituitary adenomas. This study thus has potentially important implications for novel therapeutic approaches to CD.

Association between the seven-repeat allele of the dopamine-4 receptor gene (DRD4) and spontaneous food intake in pre-school children.

PubMed

Silveira, Patrícia Pelufo; Portella, André Krumel; Kennedy, James L; Gaudreau, Hélène; Davis, Caroline; Steiner, Meir; Soares, Claudio N; Matthews, Stephen G; Sokolowski, Marla B; Dubé, Laurette; Loucks, Eric B; Hamilton, Jill; Meaney, Michael J; Levitan, Robert D

2014-02-01

Studies in adults show associations between the hypofunctional seven-repeat allele (7R) of the dopamine-4 receptor gene (DRD4), increased eating behaviour and/or obesity, particularly in females. We examined whether 7R is associated with total caloric intake and/or food choices in pre-schoolers. 150 four-year-old children taking part in a birth cohort study in Canada were administered a snack test meal in a laboratory setting. Mothers also filled out a food frequency questionnaire to address childrens' habitual food consumption. Total caloric and individual macronutrient intakes during the snack meal and specific types of foods as reported in the food diaries were compared across 7R allele carriers vs. non-carriers, using current BMI as a co-variate. We found significant sex by genotype interactions for fat and protein intake during the snack test. Post hoc testing revealed that in girls, but not boys, 7R carriers ate more fat and protein than did non-carriers. Based on the food diaries, across both sexes, 7R carriers consumed more portions of ice cream and less vegetables, eggs, nuts and whole bread, suggesting a less healthy pattern of habitual food consumption. The 7R allele of DRD4 influences macronutrient intakes and specific food choices as early as four years of age. The specific pattern of results further suggests that prior associations between the 7R allele and adult overeating/obesity may originate in food choices observable in the preschool years. Longitudinal follow-up of these children will help establish the relevance of these findings for obesity risk and prevention. Copyright © 2013 Elsevier Ltd. All rights reserved.

Chronic hyperprolactinemia evoked by disruption of lactotrope dopamine D2 receptors impacts on liver and adipocyte genes related to glucose and insulin balance.

PubMed

Luque, Guillermina María; Lopez-Vicchi, Felicitas; Ornstein, Ana María; Brie, Belén; De Winne, Catalina; Fiore, Esteban; Perez-Millan, Maria Inés; Mazzolini, Guillermo; Rubinstein, Marcelo; Becu-Villalobos, Damasia

2016-12-01

We studied the impact of high prolactin titers on liver and adipocyte gene expression related to glucose and insulin homeostasis in correlation with obesity onset. To that end we used mutant female mice that selectively lack dopamine type 2 receptors (D2Rs) from pituitary lactotropes (lacDrd2KO), which have chronic high prolactin levels associated with increased body weight, marked increments in fat depots, adipocyte size, and serum lipids, and a metabolic phenotype that intensifies with age. LacDrd2KO mice of two developmental ages, 5 and 10 mo, were used. In the first time point, obesity and increased body weight are marginal, although mice are hyperprolactinemic, whereas at 10 mo there is marked adiposity with a 136% increase in gonadal fat and a 36% increase in liver weight due to lipid accumulation. LacDrd2KO mice had glucose intolerance, hyperinsulinemia, and impaired insulin response to glucose already in the early stages of obesity, but changes in liver and adipose tissue transcription factors were time and tissue dependent. In chronic hyperprolactinemic mice liver Prlr were upregulated, there was liver steatosis, altered expression of the lipogenic transcription factor Chrebp, and blunted response of Srebp-1c to refeeding at 5 mo of age, whereas no effect was observed in the glycogenesis pathway. On the other hand, in adipose tissue a marked decrease in lipogenic transcription factor expression was observed when morbid obesity was already settled. These adaptive changes underscore the role of prolactin signaling in different tissues to promote energy storage. Copyright © 2016 the American Physiological Society.

Histone deacetylase inhibitors reverse age-related increases in side effects of haloperidol in mice.

PubMed

Montalvo-Ortiz, Janitza L; Fisher, Daniel W; Rodríguez, Guadalupe; Fang, Deyu; Csernansky, John G; Dong, Hongxin

2017-08-01

Older patients can be especially susceptible to antipsychotic-induced side effects, and the pharmacodynamic mechanism underlying this phenomenon remains unclear. We hypothesized that age-related epigenetic alterations lead to decreased expression and functionality of the dopamine D2 receptor (D2R), contributing to this susceptibility. In this study, we treated young (2-3 months old) and aged (22-24 months old) C57BL/6 mice with the D2R antagonist haloperidol (HAL) once a day for 14 days to evaluate HAL-induced motor side effects. In addition, we pretreated separate groups of young and aged mice with histone deacetylase (HDAC) inhibitors valproic acid (VPA) or entinostat (MS-275) and then administered HAL. Our results show that the motor side effects of HAL are exaggerated in aged mice as compared to young mice and that HDAC inhibitors are able to reverse the severity of these deficits. HAL-induced motor deficits in aged mice are associated with an age- and drug-dependent decrease in striatal D2R protein levels and functionality. Further, histone acetylation was reduced while histone tri-methylation was increased at specific lysine residues of H3 and H4 within the Drd2 promoter in the striatum of aged mice. HDAC inhibitors, particularly VPA, restored striatal D2R protein levels and functionality and reversed age- and drug-related histone modifications at the Drd2 promoter. These results suggest that epigenetic changes at the striatal Drd2 promoter drive age-related increases in antipsychotic side effect susceptibility, and HDAC inhibitors may be an effective adjunct treatment strategy to reduce side effects in aged populations.

The associations among the dopamine D2 receptor Taq1, emotional intelligence, creative potential measured by divergent thinking, and motivational state and these associations' sex differences.

PubMed

Takeuchi, Hikaru; Tomita, Hiroaki; Taki, Yasuyuki; Kikuchi, Yoshie; Ono, Chiaki; Yu, Zhiqian; Sekiguchi, Atsushi; Nouchi, Rui; Kotozaki, Yuka; Nakagawa, Seishu; Miyauchi, Carlos M; Iizuka, Kunio; Yokoyama, Ryoichi; Shinada, Takamitsu; Yamamoto, Yuki; Hanawa, Sugiko; Araki, Tsuyoshi; Hashizume, Hiroshi; Kunitoki, Keiko; Sassa, Yuko; Kawashima, Ryuta

2015-01-01

Previous neuroscientific studies have shown that the dopaminergic system plays an important role in creative potential measured by divergent thinking (CPMDT), emotional control, and motivational state. However, although associations between two of these four components have been previously established (e.g., the association between CPMDT and emotional control, the association between CPMDT and motivational state, etc.), the interactions between these four remain unknown. The purpose of this study was to reveal these interactions using path analyses. The Taq1A polymorphism of the dopamine D2 receptor (DRD2) gene was used for this purpose. For measuring emotional intelligence (EI), we used the Japanese version of the Emotional Intelligence Scale. CPMDT was measured using the S-A creativity test. Motivational state was measured using the Vigor subscale of the Japanese version of the Profile of Mood Scale (POMS). Data from 766 healthy, right-handed individuals (426 men and 340 women; 20.7 ± 1.9 years of age) were used in this study. There were significant and robust positive relationships among measures of CPMDT, EI, and motivational state across sex. In addition, the polymorphism of the DRD2 gene was significantly associated with EI, specifically in females. Path analysis in females indicates that the model in which (a) the DRD2 polymorphism primarily facilitates EI, (b) EI in turn facilitates CPMDT and leads to a better motivational state, and (c) a better motivational state also directly facilitates CPMDT explains the data in the most accurate manner. This study suggested a comprehensive picture of the cascade of the associations among dopamine, EI, motivational state, and CPMDT at least in females.

ADHD Candidate Gene Study in a Population-Based Birth Cohort: Association with DBH and DRD2

ERIC Educational Resources Information Center

Nyman, Emma S.; Ogdie, Matthew N.; Loukola, Anu; Varilo, Teppo; Taanila, Anja; Hurtig, Tuula; Moilanen, Irma K.; Loo, Sandra K.; McGough, James J.; Jarvelin, Marjo-Riitta; Smalley, Susan L.

2007-01-01

A study aims to examine the genetic contribution if any to attention-deficit/hyperactivity disorder (ADHD). The results confirm the hypothesis and the association of dopamine [beta]-hydroxylase and dopamine receptor D2 genes with ADHD.

Bidirectional genetic and environmental influences on mother and child behavior: the family system as the unit of analyses.

PubMed

Mills-Koonce, W Roger; Propper, Cathi B; Gariepy, Jean-Louis; Blair, Clancy; Garrett-Peters, Patricia; Cox, Martha J

2007-01-01

Family systems theory proposes that an individual's functioning depends on interactive processes within the self and within the context of dyadic family subsystems. Previous research on these processes has focused largely on behavioral, cognitive, and psychophysiological properties of the individual and the dyad. The goals of this study were to explore genetic and environmental interactions within the family system by examining how the dopamine receptor D2 gene (DRD2) A1+ polymorphism in mothers and children relates to maternal sensitivity, how maternal and child characteristics might mediate those effects, and whether maternal sensitivity moderates the association between DRD2 A1+ and child affective problems. Evidence is found for an evocative effect of child polymorphism on parenting behavior, and for a moderating effect of child polymorphism on the association between maternal sensitivity and later child affective problems. Findings are discussed from a family systems perspective, highlighting the role of the family as a context for gene expression in both mothers and children.

Genetic Moderation of Intervention Efficacy: Dopaminergic Genes, The Incredible Years, and Externalizing Behavior in Children.

PubMed

Chhangur, Rabia R; Weeland, Joyce; Overbeek, Geertjan; Matthys, Walter; Orobio de Castro, Bram; van der Giessen, Danielle; Belsky, Jay

2017-05-01

This study investigated whether children scoring higher on a polygenic plasticity index based on five dopaminergic genes (DRD4, DRD2, DAT1, MAOA, and COMT) benefited the most from the Incredible Years (IY) parent program. Data were used from a randomized controlled trial including 341 Dutch families with 4- to 8-year-old children (55.7% boys) showing moderate to high levels of problem behavior. IY proved to be most effective in decreasing parent-reported (but not observed) externalizing behavior in boys (but not girls) carrying more rather than fewer dopaminergic plasticity alleles; this Gene × Intervention effect was most pronounced in the case of boys whose parents' manifested the most positive change in parenting in response to the intervention. These results proved robust across a variety of sampling specifications (e.g., intention to treat, ethnicity). © 2016 The Authors. Child Development © 2016 Society for Research in Child Development, Inc.

Habit learning and the genetics of the dopamine D3 receptor: evidence from patients with schizophrenia and healthy controls.

PubMed

Kéri, Szabolcs; Juhász, Anna; Rimanóczy, Agnes; Szekeres, György; Kelemen, Oguz; Cimmer, Csongor; Szendi, István; Benedek, György; Janka, Zoltán

2005-06-01

In this study, the authors investigated the relationship between the Ser9Gly (SG) polymorphism of the dopamine D3 receptor (DRD3) and striatal habit learning in healthy controls and patients with schizophrenia. Participants were given the weather prediction task, during which probabilistic cue-response associations were learned for tarot cards and weather outcomes (rain or sunshine). In both healthy controls and patients with schizophrenia, participants with Ser9Ser (SS) genotype did not learn during the early phase of the task (1-50 trials), whereas participants with SG genotype did so. During the late phase of the task (51-100 trials), both participants with SS and SG genotype exhibited significant learning. Learning rate was normal in patients with schizophrenia. These results suggest that the DRD3 variant containing glycine is associated with more efficient striatal habit learning in healthy controls and patients with schizophrenia. (c) 2005 APA, all rights reserved.

Looking for reward in all the wrong places: dopamine receptor gene polymorphisms indirectly affect aggression through sensation-seeking.

PubMed

Chester, David S; DeWall, C Nathan; Derefinko, Karen J; Estus, Steven; Lynam, Donald R; Peters, Jessica R; Jiang, Yang

2016-10-01

Individuals with genotypes that code for reduced dopaminergic brain activity often exhibit a predisposition toward aggression. However, it remains largely unknown how dopaminergic genotypes may increase aggression. Lower-functioning dopamine systems motivate individuals to seek reward from external sources such as illicit drugs and other risky experiences. Based on emerging evidence that aggression is a rewarding experience, we predicted that the effect of lower-functioning dopaminergic functioning on aggression would be mediated by tendencies to seek the environment for rewards. Caucasian female and male undergraduates (N = 277) were genotyped for five polymorphisms of the dopamine D2 receptor (DRD2) gene; they reported their previous history of aggression and their dispositional reward-seeking. Lower-functioning DRD2 profiles were associated with greater sensation-seeking, which then predicted greater aggression. Our findings suggest that lower-functioning dopaminergic activity puts individuals at risk for violence because it motivates them to experience aggression's hedonically rewarding qualities.

DRD2 Promoter Region Variation Predicts Antipsychotic-Induced Weight Gain in First Episode Schizophrenia

PubMed Central

Lencz, Todd; Robinson, Delbert G.; Napolitano, Barbara; Sevy, Serge; Kane, John M.; Goldman, David; Malhotra, Anil K.

2010-01-01

Many antipsychotic medications carry a substantial liability for weight gain, and one mechanism common to all antipsychotics is binding to the dopamine D2 receptor. We therefore examined the relationship between −141C Ins/Del (rs1799732), a functional promoter region polymorphism in DRD2, and antipsychotic-induced weight gain in 58 first episode schizophrenia patients enrolled in a randomized trial of risperidone (RIS) vs. olanzapine (OLZ). Carriers of the deletion allele (n=29) were compared to Ins/Ins homozygotes (non-carriers, n=29) in a mixed model encompassing 10 weight measurements over 16 weeks. Deletion allele carriers demonstrated significantly more weight gain after 6 weeks of treatment regardless of assigned medication. While deletion carriers were prescribed higher doses of OLZ (but not RIS), dose did not appear to account for the genotype effects on weight gain. Given previous evidence that deletion carriers demonstrate reduced symptom response to medication, additional study of appropriate treatment options for these patients appears warranted. PMID:20664489

Further evidence of the limited role of candidate genes in relation to infant-mother attachment outcomes.

PubMed

Leerkes, Esther M; Gedaly, Lindsey R; Zhou, Nan; Calkins, Susan; Henrich, Vincent C; Smolen, Andrew

2017-02-01

In this paper, we examine the associations between specific candidate genes (DRD2, DRD4, COMT, biallelic and tri-allelic 5HTTLPR, and OXTR) and infant attachment outcomes as main effects and in conjunction with maternal sensitivity. The sample included 200 infants (97 European American, 94 African-American, and 9 biracial) and their mothers. Maternal sensitivity and overtly negative maternal behavior were observed when infants were 6 months and 1 year old in distress-eliciting contexts, attachment was assessed via the Strange Situation at age 1, and DNA samples were collected when children were 2 years old. Consistent with recent research in large samples, there was little evidence that these genes are associated with attachment security, disorganization, or distress as main effects (in additive, dominant, and homozygous models) or in conjunction with maternal sensitivity or overtly negative behavior (primarily dominance models). Furthermore, there was little evidence that associations vary as a function of race.

Further Evidence of the Limited Role of Candidate Genes in Relation to Infant-Mother Attachment Outcomes

PubMed Central

Leerkes, Esther M.; Gedaly, Lindsey R.; Zhou, Nan; Calkins, Susan; Henrich, Vincent C.; Smolen, Andrew

2017-01-01

In this paper, we examine the associations between specific candidate genes (DRD2, DRD4, COMT, biallelic and tri-allelic 5HTTLPR, and OXTR) and infant attachment outcomes as main effects and in conjunction with maternal sensitivity. The sample included 200 infants (97 European American, 94 African American, and 9 bi-racial) and their mothers. Maternal sensitivity and overtly negative maternal behavior were observed when infants were 6 months and 1 year old in distress-eliciting contexts, attachment was assessed via the Strange Situation at age 1, and DNA samples were collected when children were 2 years old. Consistent with recent research in large samples (Luijk et al., 2011; Roisman et al., 2013), there was little evidence that these genes are associated with attachment security, disorganization, or distress as main effects (in additive, dominant, and homozygous models) or in conjunction with maternal sensitivity or overtly negative behavior (primarily dominance models). Furthermore, there was little evidence that associations vary as a function of race. PMID:27852134

151. Bromocriptine Challenge Affects Working Memory Processing in Humans Depending on DRD2-Related Genes

PubMed Central

Pergola, Giulio; Selvaggi, Pierluigi; Gelao, Barbara; Di Carlo, Pasquale; Nettis, Maria Antonietta; Amico, Graziella; Felici, Valentina; Fazio, Leonardo; Rampino, Antonio; Sambataro, Fabio; Blasi, Giuseppe; Bertolino, Alessandro

2017-01-01

Abstract Background: Dopamine D2 receptors (D2R) contribute to the inverted-U shaped relationship between dopamine dorsolateral prefrontal cortex (DLPFC) and working memory (WM). Genetic variation in DRD2 coding for D2Rs modulates D2 signaling, but other genes in its pathway may be involved. In a previous work, using gene co-expression networks we identified 84 partner genes coregulated with DRD2 and eight single nucleotide polymorphisms (SNPs) predicting coexpression of the whole gene set in the human DLPFC [1]. These SNPs combined into a polygenic coexpression index (PCI) predicted WM performance and DLPFC activity in two independent samples of living healthy humans [1]. Here, we asked whether response to D2R targeting drugs is associated with this PCI. Thus, we investigated the interaction between WM behavioral/brain response to the D2R agonist Bromocriptine (BRO) and the PCI. [1] Pergola G, Di Carlo P, et al. (In press). Translational Psychiatry. Methods: Fifty healthy volunteers entered a double-blind, crossover, randomized, placebo-controlled fMRI study with BRO 1.25 mg and performed the N-Back WM task during the fMRI scanning session. We computed the PCI for all participants and investigated its association with WM-related behavior and brain activity using general linear models. Results: A PCI by drug interaction was significant on both DLPFC signal (right BA46, 242 voxels, F(1, 48) = 24; right BA9, 177 voxels, F(1, 48) = 19; P < .05 cluster-level FWE corrected) and behavioral scores, F(1, 46) = 4.6, P = .045, using a U-shaped quadratic model. The U-shaped relationship between the PCI and WM processing found on placebo was reversed on BRO. Furthermore, the increase in behavioral performance on BRO correlated with a decrease in BA46 activity, t(48) = −2.0, P = .049). Conclusion: The combined effect of multiple alleles on DRD2 coexpression covaried with drug response such that different allelic patterns were associated with similar responses, as in the inverted U-shaped model of WM. Thus, multiple genes and multiple allelic patterns are implicated in the inverted U-shaped dopamine/WM relationship. This relationship is reversed when individuals are administered BRO, suggesting that brain and behavioral response to this pharmacological challenge depends on a pleiotropic individual genetic background. Hence, pharmacogenomics in schizophrenia should take into account allelic patterns associated with molecular phenomena such as gene expression to predict drug response.

Bioconversion of plant carotenoids to vitamin A in Filipino school-aged children varies inversely with vitamin A status.

PubMed

Ribaya-Mercado, J D; Solon, F S; Solon, M A; Cabal-Barza, M A; Perfecto, C S; Tang, G; Solon, J A; Fjeld, C R; Russell, R M

2000-08-01

It is important to understand the factors affecting strategies to improve the vitamin A status of populations. We reported previously that a 3-d deuterated-retinol-dilution (DRD) procedure might be used to indicate total body stores of vitamin A. We studied the ability of 3-d DRD to detect changes in the body pool size of vitamin A and the effect of vitamin A status on the bioconversion of plant carotenoids to vitamin A. Two separate, unrelated studies were conducted in 7-13-y-old children with poor or marginal serum retinol concentrations (0.32-0.93 micromol/L) by feeding them controlled diets daily for 5 d/wk for 12 wk, after treatment with an anthelmintic drug. In school 1 (n = 27), lunch and 2 snacks that were provided at school contained 2258 retinol equivalents/d (mostly from orange fruit and vegetables) and 5.3 MJ/d from 33 g fat, 37 g protein, and 209 g carbohydrates; in school 2 (n = 25), 2 snacks provided 2.5 MJ/d from 9.4 g fat, 9.6 g protein, and 119 g carbohydrates, but no carotenes. In school 1, mean serum beta-carotene increased from 0.12 to 0.62 micromol/L (P = 0.0001) and serum retinol increased from 0.68 to 1. 06 micromol/L (P = 0.0001). In school 2, serum beta-carotene increased from 0.06 to 0.11 micromol/L (P = 0.0001) and serum retinol increased from 0.66 to 0.86 micromol/L (P = 0.0001). In school 1, but not school 2, improvement in serum retinol varied inversely with baseline retinol (r = -0.38, P = 0.048). In both schools, 3-d DRD showed reductions in the ratio of serum deuterated to nondeuterated retinol (D:H retinol) postintervention, denoting improvements in vitamin A status; the higher D:H retinol (ie, the poorer the status) at baseline, the greater the reduction in D:H retinol postintervention (school 1: r = -0.99, P = 0.0001; school 2: r = -0.89, P = 0.0001). Three-day DRD can detect changes in the body pool size of vitamin A, although a predictive equation to quantitate total body stores of vitamin A with the use of 3-d data needs to be developed. Bioconversion of plant carotenoids to vitamin A varies inversely with vitamin A status; improvement in status after dietary interventions is strongly influenced by total body stores of vitamin A and is influenced little or not at all by serum retinol.

NRPD4, a protein related to the RPB4 subunit of RNA polymerase II, is a component of RNA polymerases IV and V and is required for RNA-directed DNA methylation

PubMed Central

He, Xin-Jian; Hsu, Yi-Feng; Pontes, Olga; Zhu, Jianhua; Lu, Jian; Bressan, Ray A.; Pikaard, Craig; Wang, Co-Shine; Zhu, Jian-Kang

2009-01-01

RNA-directed DNA methylation (RdDM) is an RNAi-based mechanism for establishing transcriptional gene silencing in plants. The plant-specific RNA polymerases IV and V are required for the generation of 24-nucleotide (nt) siRNAs and for guiding sequence-specific DNA methylation by the siRNAs, respectively. However, unlike the extensively studied multisubunit Pol II, our current knowledge about Pol IV and Pol V is restricted to only the two largest subunits NRPD1a/NRPD1 and NRPD1b/NRPE1 and the one second-largest subunit NRPD2a. It is unclear whether other subunits may be required for the functioning of Pol IV and Pol V in RdDM. From a genetic screen for second-site suppressors of the DNA demethylase mutant ros1, we identified a new component (referred to as RDM2) as well as seven known components (NRPD1, NRPE1, NRPD2a, AGO4, HEN1, DRD1, and HDA6) of the RdDM pathway. The differential effects of the mutations on two mechanistically distinct transcriptional silencing reporters suggest that RDM2, NRPD1, NRPE1, NRPD2a, HEN1, and DRD1 function only in the siRNA-dependent pathway of transcriptional silencing, whereas HDA6 and AGO4 have roles in both siRNA-dependent and -independent pathways of transcriptional silencing. In the rdm2 mutants, DNA methylation and siRNA accumulation were reduced substantially at loci previously identified as endogenous targets of Pol IV and Pol V, including 5S rDNA, MEA-ISR, AtSN1, AtGP1, and AtMU1. The amino acid sequence of RDM2 is similar to that of RPB4 subunit of Pol II, but we show evidence that RDM2 has diverged significantly from RPB4 and cannot function in Pol II. An association of RDM2 with both NRPD1 and NRPE1 was observed by coimmunoprecipitation and coimmunolocalization assays. Our results show that RDM2/NRPD4/NRPE4 is a new component of the RdDM pathway in Arabidopsis and that it functions as part of Pol IV and Pol V. PMID:19204117

NRPD4, a Protein Related to the RPB4 Subunit of RNA Polymerase II, is a Component of RNA Polymerases IV and V and is Required for RNA-directed DNA methylation

DOE Office of Scientific and Technical Information (OSTI.GOV)

He, Xin-Jian; Hsu, Yi-Feng; Pontes, Olga

2009-01-01

RNA-directed DNA methylation (RdDM) is an RNAi-based mechanism for establishing transcriptional gene silencing in plants. The plant-specific RNA polymerases IV and V are required for the generation of 24-nucleotide (nt) siRNAs and for guiding sequence-specific DNA methylation by the siRNAs, respectively. However, unlike the extensively studied multisubunit Pol II, our current knowledge about Pol IV and Pol V is restricted to only the two largest subunits NRPD1a/NRPD1 and NRPD1b/NRPE1 and the one second-largest subunit NRPD2a. It is unclear whether other subunits may be required for the functioning of Pol IV and Pol V in RdDM. From a genetic screen formore » second-site suppressors of the DNA demethylase mutant ros1, we identified a new component (referred to as RDM2) as well as seven known components (NRPD1, NRPE1, NRPD2a, AGO4, HEN1, DRD1, and HDA6) of the RdDM pathway. The differential effects of the mutations on two mechanistically distinct transcriptional silencing reporters suggest that RDM2, NRPD1, NRPE1, NRPD2a, HEN1, and DRD1 function only in the siRNA-dependent pathway of transcriptional silencing, whereas HDA6 and AGO4 have roles in both siRNA-dependent and -independent pathways of transcriptional silencing. In the rdm2 mutants, DNA methylation and siRNA accumulation were reduced substantially at loci previously identified as endogenous targets of Pol IV and Pol V, including 5S rDNA, MEA-ISR, AtSN1, AtGP1, and AtMU1. The amino acid sequence of RDM2 is similar to that of RPB4 subunit of Pol II, but we show evidence that RDM2 has diverged significantly from RPB4 and cannot function in Pol II. An association of RDM2 with both NRPD1 and NRPE1 was observed by coimmunoprecipitation and coimmunolocalization assays. Our results show that RDM2/NRPD4/NRPE4 is a new component of the RdDM pathway in Arabidopsis and that it functions as part of Pol IV and Pol V.« less

77 FR 38713 - Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-28

... Management and Budget (OMB) for review and clearance in accordance with the Paperwork Reduction Act of 1995... burden, to (1) Office of Information and Regulatory Affairs, Office of Management and Budget, Attention... one taxable year, an 85 percent dividends received deduction (DRD) with respect to certain cash...

An Exploratory Study on DRD2 and Creative Potential

ERIC Educational Resources Information Center

Zhang, Shun; Zhang, Muzi; Zhang, Jinghuan

2014-01-01

One critical step toward to a better understanding of creativity is to unveil its underlying genetic architectures. Recently, several studies have been conducted to investigate the effects of dopamine (DA) and 5-hydroxytryptamine (5-HT) related genetic polymorphisms on creativity. Among DA related genes, dopamine D2 receptor gene…

A National Approach to Reimbursement Decision-Making on Drugs for Rare Diseases in Canada? Insights from Across the Ponds.

PubMed

Short, Hilary; Stafinski, Tania; Menon, Devidas

2015-05-01

Regardless of the type of health system or payer, coverage decisions on drugs for rare diseases (DRDs) are challenging. While these drugs typically represent the only active treatment option for a progressive and/or life-threatening condition, evidence of clinical benefit is often limited because of small patient populations and the costs are high. Thus, decisions come with considerable uncertainty and risk. In Canada, interest in developing a pan-Canadian decision-making approach informed by international experiences exists. To develop an inventory of existing policies and processes for making coverage decisions on DRDs around the world. A systematic review of published and unpublished documents describing current policies and processes in the top 20 gross domestic product countries was conducted. Bibliographic databases, the Internet and government/health technology assessment organization websites in each country were searched. Two researchers independently extracted information and tabulated it to facilitate qualitative comparative analyses. Policy experts from each country were contacted and asked to review the information collected for accuracy and completeness. Almost all countries have multiple mechanisms through which coverage for a DRD may be sought. However, they typically begin with a review that follows the same process as drugs for more common conditions (i.e., the centralized review process), although specific submission requirements could differ (e.g., no need to submit a cost-effectiveness analysis). When drugs fail to receive a positive recommendation/decision, they are reconsidered by "safety net"-type programs. Eligibility criteria vary across countries, as do the decision options, which may be applied to individual patients or patient groups. With few exceptions, countries have not created separate centralized review processes for DRDs. Instead, they have modified components of existing mechanisms and added safety nets. Copyright © 2015 Longwoods Publishing.

Hessian fly larval attack triggers elevated expression of disease resistance dirigent-like protein-encoding gene, HfrDrd, in resistant wheat.

USDA-ARS?s Scientific Manuscript database

Dirigent proteins regulate coupling of monolignol plant phenols to generate the structural cell wall polymers lignins and lignans that are involved in structural fortification of cell wall and defense against pathogens and pests. Microarray expression profiling of resistant wheat (Triticum aestivum)...

Radiolocation Techniques (Les Techniques de Radiolocalisation

DTIC Science & Technology

1992-11-01

Dr R. Klemm DrD Rother FGAN- FFM SEL/LS/E Neuenahrer Strasse 20 Lorenzstrasse 10 D-5307 Wachtberg 7 D-7000 Stuttgart 40 Germany Germany Prof. G...des solutions. accas I lFionograinme, donc: aui profil. Cat article rapporte tine partie des Etudes mendes an La indthodo proposde s’inspirc de cette

Dopamine D4 Receptor Gene Associated with Fairness Preference in Ultimatum Game

PubMed Central

Zhong, Songfa; Israel, Salomon; Shalev, Idan; Xue, Hong; Ebstein, Richard P.; Chew, Soo Hong

2010-01-01

In experimental economics, the preference for reciprocal fairness has been observed in the controlled and incentivized laboratory setting of the ultimatum game, in which two individuals decide on how to divide a sum of money, with one proposing the share while the second deciding whether to accept. Should the proposal be accepted, the amount is divided accordingly. Otherwise, both would receive no money. A recent twin study has shown that fairness preference inferred from responder behavior is heritable, yet its neurogenetic basis remains unknown. The D4 receptor (DRD4) exon3 is a well-characterized functional polymorphism, which is known to be associated with attention deficit hyperactivity disorder and personality traits including novelty seeking and self-report altruism. Applying a neurogenetic approach, we find that DRD4 is significantly associated with fairness preference. Additionally, the interaction among this gene, season of birth, and gender is highly significant. This is the first result to link preference for reciprocal fairness to a specific gene and suggests that gene × environment interactions contribute to economic decision making. PMID:21072167

Lack of association between TaqI A1 Allele of dopamine D2 receptor gene and alcohol-use disorders in Atayal natives of Taiwan

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chia-Hsiang Chen; Shih-Hsiang Chien; Hai-Gwo Hwu

1996-09-20

Association studies between the A1 allele of the dopamine D2 receptor (DRD2) gene TaqI A polymorphism and alcoholism remain controversial. A recent study from Japan demonstrated that the A1 allele is associated with severe alcoholism in the Japanese population. We were interested in knowing if this association also exists in the Atayals of Taiwan, who were found to have a higher prevalence of alcohol-use disorders than the Han Chinese in Taiwan. Genotype and allele frequencies were determined in alcohol-abusing, alcohol-dependent, and nonalcoholic control Atayal natives in Taiwan. A1 allele frequencies in alcohol-dependent, alcohol-abusing, and normal control Atayals were 0.39, 0.42,more » and 0.39, respectively. No difference in A1 allele frequency was found among these three groups. Our data do not support the hypothesis that the A1 allele of the TaqI A polymorphism of the DRD2 gene increases susceptibility to alcohol-use disorders in the Atayals of Taiwan. 18 refs., 1 tab.« less

Schizophrenia-Related Microdeletion Impairs Emotional Memory through MicroRNA-Dependent Disruption of Thalamic Inputs to the Amygdala.

PubMed

Eom, Tae-Yeon; Bayazitov, Ildar T; Anderson, Kara; Yu, Jing; Zakharenko, Stanislav S

2017-05-23

Individuals with 22q11.2 deletion syndrome (22q11DS) are at high risk of developing psychiatric diseases such as schizophrenia. Individuals with 22q11DS and schizophrenia are impaired in emotional memory, anticipating, recalling, and assigning a correct context to emotions. The neuronal circuits responsible for these emotional memory deficits are unknown. Here, we show that 22q11DS mouse models have disrupted synaptic transmission at thalamic inputs to the lateral amygdala (thalamo-LA projections). This synaptic deficit is caused by haploinsufficiency of the 22q11DS gene Dgcr8, which is involved in microRNA processing, and is mediated by the increased dopamine receptor Drd2 levels in the thalamus and by reduced probability of glutamate release from thalamic inputs. This deficit in thalamo-LA synaptic transmission is sufficient to cause fear memory deficits. Our results suggest that dysregulation of the Dgcr8-Drd2 mechanism at thalamic inputs to the amygdala underlies emotional memory deficits in 22q11DS. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Dopamine D4 Receptor Gene Polymorphism in a Sample of Egyptian Children With Attention-Deficit Hyperactivity Disorder (ADHD).

PubMed

ElBaz Mohamed, Farida; Kamal, Tarek Mostafa; Zahra, Sally Soliman; Khfagy, Mona Abdel Hakiem; Youssef, Azza Mohamed

2017-02-01

This study aimed to detect DRD4 receptor gene polymorphisms in attention-deficit hyperactivity disorder (ADHD) children and to correlate their phenotype-genotype. Fifty children with ADHD were diagnosed by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria and were subjected to Conners Parent Rating Scale. All cases and controls were subjected to history taking, physical examination, IQ assessment, and dopamine receptor D4 (DRD4) exon 3 genotyping. The 7-repeat allele was present only in controls, whereas 2-repeat allele was present in the ADHD children (heterozygous 2-repeat allele in 16% and homozygous in 26% of cases). Eight percent of cases had homozygous 4-repeat allele vs 28% of controls, whereas 10% of cases had heterozygous 4-repeat allele vs 6% of controls, with its predominance in controls. The 2-repeat and 4-repeat alleles have been associated with more inattention, hyperactivity, and impulsivity phenotypes. In conclusion, children with ADHD had a significant presence of the 2-repeat allele and absence of the 7-repeat allele.

Association study between schizophrenia and dopamine D3 receptor gene polymorphism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tanaka, Toshihisa; Takahashi, Makoto; Maeda, Masaya

Crocq et al. reported the existence of an association between schizophrenia and homozygosity of a BalI polymorphism in the first exon of the dopamine D3 receptor (DRD3) gene. In response to this report, further studies were conducted; however, these studies yielded conflicting results. In the present study, we examined 100 unrelated Japanese schizophrenics and 100 normal controls to determine any association between this polymorphism and schizophrenia. Results suggest that neither allele nor genotype frequencies of the DRD3 gene in the schizophrenics as a whole are significantly different from those of the controls. Further, we found no association between any allelemore » or genotype and any clinical subtype based on family history of schizophrenia and age-at-onset. A significantly high frequency of homozygosity of a dopamine D3 receptor gene allele was not observed in the schizophrenics as a whole, or in clinical subtypes. Our results suggest that an association between the dopamine D3 receptor gene and schizophrenia is unlikely to exist. 26 refs., 1 tab.« less

Association study of dopamine D3 receptor gene and schizophrenia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kennedy, J.L.; Billett, E.A.; Macciardi, F.M.

Several groups have reported an association between schizophrenia and the MscI polymorphism in the first exon of the dopamine D3 receptor gene (DRD3). We studied this polymorphism using a North American sample (117 patients plus 188 controls) and an Italian sample (97 patients plus 64 controls). In the first part of the study, we compared allele frequencies of schizophrenia patients and unmatched controls and observed a significant difference in the total sample (P = 0.01). The second part of the study involved a case control approach in which each schizophrenia patient was matched to a control of the same sex,more » and of similar age and ethnic background. The DRD3 allele frequencies of patients and controls revealed no significant difference between the two groups in the Italian (N = 53) or the North American (N = 54) matched populations; however, when these two matched samples were combined, a significant difference was observed (P = 0.026). Our results suggest that the MscI polymorphism may be associated with schizophrenia in the populations studied. 32 refs., 2 tabs.« less

Lack of Association Between Polymorphisms in Dopa Decarboxylase and Dopamine Receptor-1 Genes With Childhood Autism in Chinese Han Population.

PubMed

Yu, Hong; Liu, Jun; Yang, Aiping; Yang, Guohui; Yang, Wenjun; Lei, Heyue; Quan, Jianjun; Zhang, Zengyu

2016-04-01

Genetic factors play an important role in childhood autism. This study is to determine the association of single-nucleotide polymorphisms in dopa decarboxylase (DDC) and dopamine receptor-1 (DRD1) genes with childhood autism, in a Chinese Han population. A total of 211 autistic children and 250 age- and gender-matched healthy controls were recruited. The severity of disease was determined by Children Autism Rating Scale scores. TaqMan Probe by real-time polymerase chain reaction was used to determine genotypes and allele frequencies of single-nucleotide polymorphism rs6592961 in DDC and rs251937 in DRD1. Case-control and case-only studies were respectively performed, to determine the contribution of both single-nucleotide polymorphisms to the predisposition of disease and its severity. Our results showed that there was no significant association of the genotypes and allele frequencies of both single-nucleotide polymorphisms concerning childhood autism and its severity. More studies with larger samples are needed to corroborate their predicting roles. © The Author(s) 2015.

Allelic variation in dopamine D2 receptor gene is associated with attentional impulsiveness on the Barratt Impulsiveness Scale (BIS-11).

PubMed

Taylor, Jasmine B; Cummins, Tarrant D R; Fox, Allison M; Johnson, Beth P; Tong, Janette H; Visser, Troy A W; Hawi, Ziarih; Bellgrove, Mark A

2017-01-20

Previous studies have postulated that noradrenergic and/or dopaminergic gene variations are likely to underlie individual differences in impulsiveness, however, few have shown this. The current study examined the relationship between catecholamine gene variants and self-reported impulsivity, as measured by the Barratt Impulsiveness Scale (Version 11; BIS-11) Methods: Six hundred and seventy-seven non-clinical adults completed the Barratt Impulsiveness Scale (BIS-11). DNA was analysed for a set of 142 single-nucleotide polymorphisms (SNPs) across 20 autosomal catecholamine genes. Association was tested using an additive regression model with permutation testing used to control for the influence of multiple comparison. Analysis revealed an influence of rs4245146 of the dopamine D2 receptor (DRD2) gene on the BIS-11 attention first-order factor, such that self-reported attentional impulsiveness increased in an additive fashion with each copy of the T allele. These findings provide preliminary evidence that allelic variation in DRD2 may influence impulsiveness by increasing the propensity for attentional lapses.

Supportive Family Environments, Genes That Confer Sensitivity, and Allostatic Load Among Rural African American Emerging Adults: A Prospective Analysis

PubMed Central

Brody, Gene H.; Yu, Tianyi; Chen, Yi-fu; Kogan, Steven M.; Evans, Gary W.; Windle, Michael; Gerrard, Meg; Gibbons, Frederick X.; Simons, Ronald L.; Philibert, Robert A.

2012-01-01

The purpose of this study was to investigate interactions between exposure to supportive family environments and genetic characteristics, which were hypothesized to forecast variations in allostatic load (AL) in a representative sample of 315 rural African American youths. Data on family environments were gathered when youths were 11–13, and genetic data were collected when they were 16, years of age. Data on AL were obtained at the beginning of emerging adulthood, age 19 years. The data analyses revealed that, as predicted, emerging adults exposed to less supportive family environments across preadolescence manifested higher levels of AL when they carried the short (s) allele at the 5-HTTLPR and an allele of DRD4 with 7 or more repeats. This is an E(family environment) × G(5-HTTLPR status) × G(DRD4 status) interaction. These data suggest that African American youths carrying genes that confer sensitivity who are exposed to less supportive family environments may be at greater risk for adverse physical health consequences that AL presages. PMID:22468688

Characterization of dopamine D1 and D2 receptor-expressing neurons in the mouse hippocampus.

PubMed

Gangarossa, Giuseppe; Longueville, Sophie; De Bundel, Dimitri; Perroy, Julie; Hervé, Denis; Girault, Jean-Antoine; Valjent, Emmanuel

2012-12-01

The hippocampal formation is part of an anatomical system critically involved in learning and memory. Increasing evidence suggests that dopamine plays an important role in learning and memory as well as in several forms of synaptic plasticity. However, the precise identification of neuronal populations expressing D1 or D2 dopamine receptors within the hippocampus is still lacking. To clarify this issue, we used BAC transgenic mice expressing enhanced green fluorescent protein (EGFP) under the control of the promoter of dopamine D1 or D2 receptors. In Drd1a-EGFP mice, sparse GFP-expressing neurons were detected among glutamatergic projecting neurons of the granular layer of the dentate gyrus and GABAergic interneurons located in the hilus. A dense immunofluorescence was observed in the outer and medial part of the molecular layer of the dentate gyrus as well as in the inner part of the molecular layer of CA1 corresponding to the terminals of pyramidal neurons of the entorhinal cortex defining the perforant and the temporo-ammonic pathway respectively. Finally, scattered D1 receptor-expressing neurons were also identified as GABAergic interneurons in the CA3/CA1 fields of the hippocampus. In Drd2-EGFP transgenic mice, GFP was exclusively detected in the glutamatergic mossy cells located in the polymorphic layer of the dentate gyrus. This pattern was confirmed in Drd2-Cre mice crossed with NLS-LacZ-Tau(mGFP) :LoxP and RCE:LoxP reporter lines. Our results demonstrate that D1 and D2 receptor-expressing neurons are strictly segregated in the mouse hippocampus. By clarifying the identity of D1 and D2 receptor-expressing neurons in the hippocampus, this study establishes a basis for future investigations aiming at elucidating their roles in the hippocampal network. Copyright © 2012 Wiley Periodicals, Inc.

Dissociable Genetic Contributions to Error Processing: A Multimodal Neuroimaging Study

PubMed Central

Agam, Yigal; Vangel, Mark; Roffman, Joshua L.; Gallagher, Patience J.; Chaponis, Jonathan; Haddad, Stephen; Goff, Donald C.; Greenberg, Jennifer L.; Wilhelm, Sabine; Smoller, Jordan W.; Manoach, Dara S.

2014-01-01

Background Neuroimaging studies reliably identify two markers of error commission: the error-related negativity (ERN), an event-related potential, and functional MRI activation of the dorsal anterior cingulate cortex (dACC). While theorized to reflect the same neural process, recent evidence suggests that the ERN arises from the posterior cingulate cortex not the dACC. Here, we tested the hypothesis that these two error markers also have different genetic mediation. Methods We measured both error markers in a sample of 92 comprised of healthy individuals and those with diagnoses of schizophrenia, obsessive-compulsive disorder or autism spectrum disorder. Participants performed the same task during functional MRI and simultaneously acquired magnetoencephalography and electroencephalography. We examined the mediation of the error markers by two single nucleotide polymorphisms: dopamine D4 receptor (DRD4) C-521T (rs1800955), which has been associated with the ERN and methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133), which has been associated with error-related dACC activation. We then compared the effects of each polymorphism on the two error markers modeled as a bivariate response. Results We replicated our previous report of a posterior cingulate source of the ERN in healthy participants in the schizophrenia and obsessive-compulsive disorder groups. The effect of genotype on error markers did not differ significantly by diagnostic group. DRD4 C-521T allele load had a significant linear effect on ERN amplitude, but not on dACC activation, and this difference was significant. MTHFR C677T allele load had a significant linear effect on dACC activation but not ERN amplitude, but the difference in effects on the two error markers was not significant. Conclusions DRD4 C-521T, but not MTHFR C677T, had a significant differential effect on two canonical error markers. Together with the anatomical dissociation between the ERN and error-related dACC activation, these findings suggest that these error markers have different neural and genetic mediation. PMID:25010186

The Dopamine Receptor D4 Gene (DRD4) and Financial Risk-Taking: Stimulating and Instrumental Risk-Taking Propensity and Motivation to Engage in Investment Activity

PubMed Central

Muda, Rafał; Kicia, Mariusz; Michalak-Wojnowska, Małgorzata; Ginszt, Michał; Filip, Agata; Gawda, Piotr; Majcher, Piotr

2018-01-01

The Dopamine receptor D4 gene (DRD4) has been previously linked to financial risk-taking propensity. Past works demonstrated that individuals with a specific variant of the DRD4 gene (7R+) are more risk-seeking than people without it (7R−). The most prominent explanation for this effect is the fact that 7R+ individuals are less sensitive to dopamine and thus seek more stimulation to generate “normal” dopaminergic activity and feel pleasure. However, results about this relationship have not been conclusive, and some revealed a lack of the relationship. In the current work, we tested if those unclear results might be explained by the motivation that underlies the risk-taking activity; i.e., if people take risks to feel excitement or if they take risk to obtain a specific goal. In our study we tested the differences in risk-taking between 7R+ and 7R− among people who are experienced in financial risk-taking (113 investors) and non-experienced financial decision makers (104 non-investors). We measured risk-taking propensity with the Holt-Laury test and the Stimulating-Instrumental Risk Inventory. Moreover, we asked investors about their motivations for engaging in investment activity. Our study is the next one to report a lack of differences in risk-taking between 7R+ and 7R− individuals. As well, our results did not indicate any differences between the 7R+ and 7R− investors in motivation to engage in investment activity. We only observed that risk-taking propensity was higher among investors than non-investors and this was noticed for all measures. More research is needed to better understand the genetic foundations of risk-taking, which could answer the question about the substantial variation in the domain of risky financial decisions. PMID:29551965

An Examination of the Behavioral and Neuropsychological Correlates of Three ADHD Candidate Gene Polymorphisms (DRD4 7+, DBH TaqI A2, and DAT1 40bp VNTR) in Hyperactive and Normal Children Followed to Adulthood

PubMed Central

Barkley, Russell A.; Smith, Karen M.; Fischer, Mariellen; Navia, Bradford

2008-01-01

Several candidate gene polymorphisms have been implicated in attention deficit hyperactivity disorder (ADHD), including DAT1 40bp VNTR, DRD4 7+, and DBH TaqI A2 alleles. We used the Milwaukee longitudinal study of hyperactive (N=122) and normal (N=67) children to compare participants with and without these respective polymorphisms on ADHD-related behavioral ratings at childhood, 8 years later in adolescence, and 13+ years later into young adulthood. Neuropsychological tests were given at the adolescent and young adulthood follow-up. No differences were found between the DRD4-7+ and 7- repeat polymorphism. The DBH TaqI A2 allele, when homozygous, was associated with being more hyperactive in childhood, having more pervasive behavior problems at adolescence, and earning less money on a Card Playing Task in adulthood. At adolescence, poorer test scores were also found only in the hyperactive group with homozygous for this allele. The DAT1 40bp VNTR heterozygous 9/10 repeat, however, differed from the 10/10 repeat pair in many respects, having greater ADHD and externalizing symptoms at all three follow-ups, more cross-situational behavioral problems at both childhood and adolescence, poorer mother-teen relations at adolescence, and lower class rankings in high school. Participants with the 9/10 pair in the control group also had lower work performance, a lower grade point average in high school, greater teacher rated externalizing symptoms at adolescence, and greater omission errors on a continuous performance test in adulthood. The DAT1 40bp VNTR 9/10 polymorphism pairing appears to be reliably associated with greater symptoms of ADHD and externalizing behavior from childhood to adulthood, and with family, educational, and occupational impairments. We also present a contrary view on the appropriate endophenotypes for use in behavioral genetic research on ADHD. PMID:16741944

Association of dopamine receptor D2 gene (DRD2) Taq1 polymorphisms with eating behaviors and obesity among Chinese and Indian Malaysian university students.

PubMed

Lek, Fang-Ying; Ong, Hing-Huat; Say, Yee-How

2018-01-01

This study investigated the association of DRD2 Taq1A, Taq1B and Taq1D gene polymorphisms with eating behavior, the preference/intake frequency/craving of high-fat foods and obesity in 394 Malaysian adults (161 males, 233 females; 308 Chinese, 86 Indians; 67 obese, 327 non-obese). Eating behaviors namely Cognitive Restraint, Uncontrolled Eating and Emotional Eating scores were assessed by the Three Factor Eating Questionnaire-R18. The preference/intake frequency/craving of 26 common high-fat Malaysian foods was assessed using a 7-point hedonic scale. Anthropometric measurements were taken and Taq1 gene polymorphisms were genotyped by PCR-Restriction Fragment Length Polymorphism using DNA extracted from mouthwash samples. The overall minor allele frequencies of Taq1A, Taq1B and Taq1D according to ethnicities (Chinese/Indian) were 0.37/0.29, 0.39/0.28, 0.06/0.30, respectively; genotype and allele distributions of Taq1B and Taq1D were significantly different between ethnicities. Eating behaviorscores were not significantly different between gender and ethnicities. Those with A1 or B1 allele had lower Cognitive Restraint score and higher Uncontrolled Eating score, while those with A1/A1 or B1/B1 genotype had higher fast food preference. D1 allele was associated with increased starchy food craving and mamak (Malaysian Indian-Muslim) food preference, but not eating behavior scores. All three gene variants were not associated with obesity and adiposity. Taken together, we posit that three DRD2 Taq1 gene polymorphisms influence the eating behavior and preference/intake frequency/craving of certain high-fat foods in Malaysian adults, but their role in obesity and adiposity is still inconclusive and needs further investigation.

A record-linkage study of drug-related death and suicide after hospital discharge among drug-treatment clients in Scotland, 1996-2006.

PubMed

Merrall, Elizabeth L C; Bird, Sheila M; Hutchinson, Sharon J

2013-02-01

To investigate the relationship between time after hospital discharge and drug-related death (DRD) and suicide among drug users in Scotland, while controlling for potential confounders. Cohort study. The 69 457 individuals who registered for drug treatment in Scotland during 1 April 1996-31 March 2006. Time-at-risk was from the date of an individual's first attendance at drug treatment services after 1 April 1996 until the earlier date of death or end-of-study, 31 March 2006, and was categorized according to time since the most recent hospitalization, as during hospitalization, within 28 days, 29-90 days, 91 days to 1 year and >1 year since discharge from most recent hospital stay versus 'never admitted' (reference). Time-periods soon after discharge were associated with increased risk of DRD. DRD rates per 1000 person-years were: 87 (95% CI: 72-103) during hospitalization, 21 (18-25) within 28 days, 12 (10-15) during 29-90 days and 8.5 (7.5-9.5) during 91 days to 1 year after discharge versus 4.2 (3.7-4.7) when >1 year after most recent hospitalization and 1.9 (1.7-2.1) for those never admitted. Adjusted hazard ratios by time since hospital discharge (versus never admitted) were: 9.6 (95% CI: 8-12) within 28 days, 5.6 (4.6-6.8) during days 29-90, thereafter 4.0 (3.5-4.7) and 2.3 (2.0-2.7) when >1 year. Non-drug-related suicides were less frequent than DRDs (269 versus 1383) but a similar risk pattern was observed. In people receiving treatment for drug dependence, discharge from a period of hospitalization marks the start of a period of heightened vulnerability to drug-related death. © 2012 The Authors, Addiction © 2012 Society for the Study of Addiction.

An initial investigation of associations between dopamine-linked genetic variation and smoking motives in African Americans.

PubMed

Bidwell, L C; McGeary, J E; Gray, J C; Palmer, R H C; Knopik, V S; MacKillop, J

2015-11-01

Nicotine dependence (ND) is a heterogeneous phenotype with complex genetic influences that may vary across ethnicities. The use of intermediate phenotypes may clarify genetic influences and reveal specific etiological pathways. Prior work in European Americans has found that the four Primary Dependence Motives (PDM) subscales (Automaticity, Craving, Loss of Control, and Tolerance) of the Wisconsin Inventory of Smoking Motives represent core features of nicotine dependence and are promising intermediate phenotypes for understanding genetic pathways to ND. However, no studies have examined PDM as an intermediate phenotype in African American smokers, an ethnic population that displays unique patterns of smoking and genetic variation. In the current study, 268 African American daily smokers completed a phenotypic assessment and provided a sample of DNA. Associations among haplotypes in the NCAM1-TTC12-ANKK1-DRD2 gene cluster, a dopamine-related gene region associated with ND, PDM intermediate phenotypes, and ND were examined. Dopamine-related genetic variation in the DBH and COMT genes was also considered on an exploratory basis. Mediational analysis was used to test the indirect pathway from genetic variation to smoking motives to nicotine dependence. NCAM1-TTC12-ANKK1-DRD2 region variation was significantly associated with the Automaticity subscale and, further, Automaticity significantly mediated associations among NCAM1-TTC12-ANKK1-DRD2 cluster variants and ND. DBH was also significantly associated with Automaticity, Craving, and Tolerance; Automaticity and Tolerance also served as mediators of the DBH-ND relationship. These results suggest that PDM, Automaticity in particular, may be a viable intermediate phenotype for understanding dopamine-related genetic influences on ND in African American smokers. Findings support a model in which putatively dopaminergic variants exert influence on ND through an effect on patterns of automatic routinized smoking. Copyright © 2015 Elsevier Inc. All rights reserved.

Association between Dopamine D4 Receptor Polymorphism and Age Related Changes in Brain Glucose Metabolism

PubMed Central

Volkow, Nora D.; Tomasi, Dardo; Wang, Gene-Jack; Telang, Frank; Fowler, Joanna S.; Goldstein, Rita Z.; Klein, Nelly; Wong, Christopher; Swanson, James M.; Shumay, Elena

2013-01-01

Aging is associated with reductions in brain glucose metabolism in some cortical and subcortical regions, but the rate of decrease varies significantly between individuals, likely reflecting genetic and environmental factors and their interactions. Here we test the hypothesis that the variant of the dopamine receptor D4 (DRD4) gene (VNTR in exon 3), which has been associated with novelty seeking and sensitivity to environmental stimuli (negative and positive) including the beneficial effects of physical activity on longevity, influence the effects of aging on the human brain. We used positron emission tomography (PET) and [18F]fluoro-D-glucose (18FDG) to measure brain glucose metabolism (marker of brain function) under baseline conditions (no stimulation) in 82 healthy individuals (age range 22–55 years). We determined their DRD4 genotype and found an interaction with age: individuals who did not carry the 7-repeat allele (7R−, n = 53) had a significant (p<0.0001) negative association between age and relative glucose metabolism (normalized to whole brain glucose metabolism) in frontal (r = −0.52), temporal (r = −0.51) and striatal regions (r = −0.47, p<0.001); such that older individuals had lower metabolism than younger ones. In contrast, for carriers of the 7R allele (7R+ n = 29), these correlations with age were not significant and they only showed a positive association with cerebellar glucose metabolism (r = +0.55; p = 0.002). Regression slopes of regional brain glucose metabolism with age differed significantly between the 7R+ and 7R− groups in cerebellum, inferior temporal cortex and striatum. These results provide evidence that the DRD4 genotype might modulate the associations between regional brain glucose metabolism and age and that the carriers of the 7R allele appear to be less sensitive to the effects of age on brain glucose metabolism. PMID:23717434

DISRUPTION OF CONDITIONED REWARD ASSOCIATION BY TYPICAL AND ATYPICAL ANTIPSYCHOTICS

PubMed Central

Danna, C.L.; Elmer, G.I.

2013-01-01

Antipsychotic drugs are broadly classified into typical and atypical compounds; they vary in their pharmacological profile however a common component is their antagonist effects at the D2 dopamine receptors (DRD2). Unfortunately, diminished DRD2 activation is generally thought to be associated with the severity of neuroleptic-induced anhedonia. The purpose of this study was to determine the effect of the atypical antipsychotic olanzapine and typical antipsychotic haloperidol in a paradigm that reflects the learned transfer of incentive motivational properties to previously neutral stimuli, namely autoshaping. In order to provide a dosing comparison to a therapeutically relevant endpoint, both drugs were tested against amphetamine-induced disruption of prepulse inhibition as well. In the autoshaping task, rats were exposed to repeated pairings of stimuli that were differentially predictive of reward delivery. Conditioned approach to the reward predictive cue (sign-tracking) and to the reward (goal-tracking) increased during repeated pairings in the vehicle treated rats. Haloperidol and olanzapine completely abolished this behavior at relatively low doses (100 μg/kg). This same dose was the threshold dose for each drug to antagonize the sensorimotor gating deficits produced by amphetamine. At lower doses (3–30 μg/kg) both drugs produced a dose-dependent decrease in conditioned approach to the reward predictive cue. There was no difference between drugs at this dose range which indicates that olanzapine disrupts autoshaping at a significantly lower proposed DRD2 receptor occupancy. Interestingly, neither drug disrupted conditioned approach to the reward at the same dose range that disrupted conditioned approach to the reward predictive cue. Thus, haloperidol and olanzapine, at doses well below what is considered therapeutically relevant, disrupts the attribution of incentive motivational value to previously neutral cues. Drug effects on this dimension of reward processing are an important consideration in the development of future pharmacological treatments for schizophrenia. PMID:20416333

Specific personality traits and dopamine, serotonin genes in anxiety-depressive alcoholism among Han Chinese in Taiwan.

PubMed

Lin, Shu-Cheng; Wu, Pei-Lin; Ko, Huei-Chen; Wu, Jo Yung-Wei; Huang, San-Yuan; Lin, Wei-Wen; Lu, Ru-Band

2007-10-01

Cloninger [Cloninger CR. 1987. Neurogenetic adaptive mechanisms in alcoholism. Science 236: 410-416.] had proposed a psychobiological model suggesting that three main personality dimensions distinguish the alcoholism into two subtypes (type I and type II). However, the classification was equivocal for clinical diagnosis. Recently, anxiety-depressive alcohol dependence (ANX/DEP ALC) has been posited as a genetically specific subtype of alcoholism. Its clinical characteristics were similar to individuals with type I alcoholism [Cloninger, C.R. 1987. Neurogenetic adaptive mechanisms in alcoholism. Science 236: 410-6.] such as having a high comorbidity with mood disorder, late-onset and more anxious/depressed traits. We attempted to investigate whether the dopamine D2 receptor (DRD2) and the serotonin transporter promoter region (5-HTTLPR) genes were involved in Novelty Seeking (NS) and Harm Avoidance (HA) of ANX/DEP ALC. We recruited 46 pure alcohol dependents (Pure ALC) and 87 anxiety-depression alcohol dependents (ANX/DEP ALC). All participants were diagnosed by DSM-IV criteria, genotyped by the PCR method and assessed with Tridimensional Personality Questionnaire (TPQ). Both NS and HA were high in ANX/DEP ALC (p = 0.021; p = 0.001, respectively). The association between NS and ANX/DEP ALC only existed in subjects with DRD2 TaqI A1(+) allele (A1/A1 or A1/A2 genotypes) (p = 0.004) and in those with S/S genotype of 5-HTTLPR (p = 0.005). With the stratification of DRD2 TaqI A1(+) allele, high NS of ANX/DEP ALC existed only in carriers of 5-HTTLPR S/S genotype (p=0.001). Moreover, ANX/DEP ALC was related to high HA only in samples carrying 5-HTTLPR S/L or L/L genotype (p = 0.02). These findings provided the empirical genetic characterization of the specific personality traits in ANX/DEP ALC among Han Chinese population in Taiwan.

Collaborative Analysis of DRD4 and DAT Genotypes in Population-Defined ADHD Subtypes

ERIC Educational Resources Information Center

Todd, Richard D.; Huang, Hongyan; Smalley, Susan L.; Nelson, Stanley F.; Willcutt, Erik G.; Pennington, Bruce F.; Smith, Shelley D.; Faraone, Stephen V.; Neuman, Rosalind J.

2005-01-01

Background: It has been proposed that some of the variability in reporting of associations between attention deficit hyperactivity disorder (ADHD) and candidate genes may result from mixing of genetically heterogeneous forms of ADHD using DSM-IV criteria. The goal of the current study is to test whether population-based ADHD subtypes defined by…

Evaluation of discrepancies between thermoluminescent dosimeter and direct-reading dosimeter results

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shaw, K.R.

1993-07-01

Currently at Oak Ridge National Laboratory (ORNL), the responses of thermoluminescent dosimeters (TLDs) and direct-reading dosimeters (DRDs) are not officially compared or the discrepancies investigated. However, both may soon be required due to the new US Department of Energy (DOE) Radiological Control Manual. In the past, unofficial comparisons of the two dosimeters have led to discrepancies of up to 200%. This work was conducted to determine the reasons behind such discrepancies. For tests conducted with the TLDs, the reported dose was most often lower than the delivered dose, while DRDs most often responded higher than the delivered dose. Trends weremore » identified in personnel DRD readings, and ft was concluded that more training and more control of the DRDs could improve their response. TLD responses have already begun to be improved; a new background subtraction method was implemented in April 1993, and a new dose algorithm is being considered. It was concluded that the DOE Radiological Control Manual requirements are reasonable for identifying discrepancies between dosimeter types, and more stringent administrative limits might even be considered.« less

Differential Susceptibility in Early Literacy Instruction through Computer Games: The Role of the Dopamine D4 Receptor Gene (DRD4)

ERIC Educational Resources Information Center

Kegel, Cornelia A. T.; Bus, Adriana G.; van IJzendoorn, Marinus H.

2011-01-01

Not every child seems equally susceptible to the same parental, educational, or environmental influences even if cognitive level is similar. This study is the first randomized controlled trial to apply the differential susceptibility paradigm to education in relation to children's genotype and early literacy skills. A randomized pretest-posttest…

No association detected between a D{sub 3} receptor gene-expressed variant and schizophrenia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rothschild, L.G.; Badner, J.; Cravchik, A.

1996-04-09

A missense polymorphism (glycine to serine) in the first exon of the dopamine D{sub 3} (DRD3) gene was examined in a sib-pairs schizophrenia collection by the transmission test for linkage disequilibrium (TDT). No association due to linkage disequilibrium was detected using TDT. Additionally, no evidence for excess homozygosity was found. 26 refs., 3 tabs.

Associations between Dopamine and Serotonin Genes and Job Satisfaction: Preliminary Evidence from the Add Health Study

ERIC Educational Resources Information Center

Song, Zhaoli; Li, Wendong; Arvey, Richard D.

2011-01-01

Previous behavioral genetic studies have found that job satisfaction is partially heritable. We went a step further to examine particular genetic markers that may be associated with job satisfaction. Using an oversample from the National Adolescent Longitudinal Study (Add Health Study), we found 2 genetic markers, dopamine receptor gene DRD4 VNTR…

Gene-Environment Interactions across Development: Exploring DRD2 Genotype and Prenatal Smoking Effects on Self-Regulation

ERIC Educational Resources Information Center

Wiebe, Sandra A.; Espy, Kimberly Andrews; Stopp, Christian; Respass, Jennifer; Stewart, Peter; Jameson, Travis R.; Gilbert, David G.; Huggenvik, Jodi I.

2009-01-01

Genetic factors dynamically interact with both pre- and postnatal environmental influences to shape development. Considerable attention has been devoted to gene-environment interactions (G x E) on important outcomes (A. Caspi & T. E. Moffitt, 2006). It is also important to consider the possibility that these G x E effects may vary across…

Genetics of Preparation and Response Control in ADHD: The Role of DRD4 and DAT1

ERIC Educational Resources Information Center

Albrecht, Björn; Brandeis, Daniel; Uebel-von Sandersleben, Henrik; Valko, Lilian; Heinrich, Hartmut; Xu, Xiaohui; Drechsler, Renate; Heise, Alexander; Kuntsi, Jonna; Müller, Ueli C.; Asherson, Philip; Steinhausen, Hans-Christoph; Rothenberger, Aribert; Banaschewski, Tobias

2014-01-01

Background: Difficulties with performance and brain activity related to attentional orienting (Cue-P3), cognitive or response preparation (Cue-CNV) and inhibitory response control (Nogo-P3) during tasks tapping executive functions are familial in ADHD and may represent endophenotypes. The aim of this study was to clarify the impact of dopamine…

Friendships Moderate an Association Between a Dopamine Gene Variant and Political Ideology.

PubMed

Settle, Jaime E; Dawes, Christopher T; Christakis, Nicholas A; Fowler, James H

2010-01-01

Scholars in many fields have long noted the importance of social context in the development of political ideology. Recent work suggests that political ideology also has a heritable component, but no specific gene variant or combination of variants associated with political ideology have so far been identified. Here, we hypothesize that individuals with a genetic predisposition toward seeking out new experiences will tend to be more liberal, but only if they are embedded in a social context that provides them with multiple points of view. Using data from the National Longitudinal Study of Adolescent Health, we test this hypothesis by investigating an association between self-reported political ideology and the 7R variant of the dopamine receptor D4 gene (DRD4), which has previously been associated with novelty seeking. Among those with DRD4-7R, we find that the number of friendships a person has in adolescence is significantly associated with liberal political ideology. Among those without the gene variant, there is no association. This is the first study to elaborate a specific gene-environment interaction that contributes to ideological self-identification, and it highlights the importance of incorporating both nature and nurture into the study of political preferences.

Friendships Moderate an Association Between a Dopamine Gene Variant and Political Ideology

PubMed Central

Settle, Jaime E.; Dawes, Christopher T.; Christakis, Nicholas A.; Fowler, James H.

2012-01-01

Scholars in many fields have long noted the importance of social context in the development of political ideology. Recent work suggests that political ideology also has a heritable component, but no specific gene variant or combination of variants associated with political ideology have so far been identified. Here, we hypothesize that individuals with a genetic predisposition toward seeking out new experiences will tend to be more liberal, but only if they are embedded in a social context that provides them with multiple points of view. Using data from the National Longitudinal Study of Adolescent Health, we test this hypothesis by investigating an association between self-reported political ideology and the 7R variant of the dopamine receptor D4 gene (DRD4), which has previously been associated with novelty seeking. Among those with DRD4-7R, we find that the number of friendships a person has in adolescence is significantly associated with liberal political ideology. Among those without the gene variant, there is no association. This is the first study to elaborate a specific gene-environment interaction that contributes to ideological self-identification, and it highlights the importance of incorporating both nature and nurture into the study of political preferences. PMID:22282583

Variants in the dopamine-4-receptor gene promoter are not associated with sensation seeking in skiers.

PubMed

Thomson, Cynthia J; Rajala, Amelia K; Carlson, Scott R; Rupert, Jim L

2014-01-01

Sensation seeking is a personality trait that has been associated with disinhibited behaviours including substance use and gambling, but also with high-risk sport practices including skydiving, paragliding, and downhill skiing. Twin studies have shown that sensation seeking is moderately heritable, and candidate genes encoding components involved in dopaminergic transmission have been investigated as contributing to this type of behaviour. To determine whether variants in the regulatory regions of the dopamine-4-receptor gene (DRD4) influenced sport-specific sensation seeking, we analyzed five polymorphisms (-1106T/C, -906T/C, -809G/A, -291C/T, 120-bp duplication) in the promoter region of the gene in a cohort of skiers and snowboarders (n = 599) that represented a broad range of sensation seeking behaviours. We grouped subjects by genotype at each of the five loci and compared impulsive sensation seeking and domain-specific (skiing) sensation seeking between groups. There were no significant associations between genotype(s) and general or domain-specific sensation seeking in the skiers and snowboarders, suggesting that while DRD4 has previously been implicated in sensation seeking, the promoter variants investigated in this study do not contribute to sensation seeking in this athlete population.

Music genetics research: Association with musicality of a polymorphism in the AVPR1A gene.

PubMed

Mariath, Luiza Monteavaro; Silva, Alexandre Mauat da; Kowalski, Thayne Woycinck; Gattino, Gustavo Schulz; Araujo, Gustavo Andrade de; Figueiredo, Felipe Grahl; Tagliani-Ribeiro, Alice; Roman, Tatiana; Vianna, Fernanda Sales Luiz; Schuler-Faccini, Lavínia; Schuch, Jaqueline Bohrer

2017-01-01

Musicality is defined as a natural tendency, sensibility, knowledge, or talent to create, perceive, and play music. Musical abilities involve a great range of social and cognitive behaviors, which are influenced by both environmental and genetic factors. Although a number of studies have yielded insights into music genetics research, genes and biological pathways related to these traits are not fully understood. Our hypothesis in the current study is that genes associated with different behaviors could also influence the musical phenotype. Our aim was to investigate whether polymorphisms in six genes (AVPR1A, SLC6A4, ITGB3, COMT, DRD2 and DRD4) related to social and cognitive traits are associated with musicality in a sample of children. Musicality was assessed through an individualized music therapy assessment profile (IMTAP) which has been validated in Brazil to measure musical ability. We show here that the RS1 microsatellite of the AVPR1A gene is nominally associated with musicality, corroborating previous results linking AVPR1A with musical activity. This study is one of the first to investigate musicality in a comprehensive way, and it contributes to better understand the genetic basis underlying musical ability.

Music genetics research: Association with musicality of a polymorphism in the AVPR1A gene

PubMed Central

Mariath, Luiza Monteavaro; da Silva, Alexandre Mauat; Kowalski, Thayne Woycinck; Gattino, Gustavo Schulz; de Araujo, Gustavo Andrade; Figueiredo, Felipe Grahl; Tagliani-Ribeiro, Alice; Roman, Tatiana; Vianna, Fernanda Sales Luiz; Schuler-Faccini, Lavínia; Schuch, Jaqueline Bohrer

2017-01-01

Abstract Musicality is defined as a natural tendency, sensibility, knowledge, or talent to create, perceive, and play music. Musical abilities involve a great range of social and cognitive behaviors, which are influenced by both environmental and genetic factors. Although a number of studies have yielded insights into music genetics research, genes and biological pathways related to these traits are not fully understood. Our hypothesis in the current study is that genes associated with different behaviors could also influence the musical phenotype. Our aim was to investigate whether polymorphisms in six genes (AVPR1A, SLC6A4, ITGB3, COMT, DRD2 and DRD4) related to social and cognitive traits are associated with musicality in a sample of children. Musicality was assessed through an individualized music therapy assessment profile (IMTAP) which has been validated in Brazil to measure musical ability. We show here that the RS1 microsatellite of the AVPR1A gene is nominally associated with musicality, corroborating previous results linking AVPR1A with musical activity. This study is one of the first to investigate musicality in a comprehensive way, and it contributes to better understand the genetic basis underlying musical ability. PMID:28534928

Maternal DRD2, SLC6A3, and OXTR genotypes as potential moderators of the relation between maternal history of care and maternal cortisol secretion in the context of mother-infant separation.

PubMed

Ludmer, Jaclyn A; Jamieson, Brittany; Gonzalez, Andrea; Levitan, Robert; Kennedy, James; Villani, Vanessa; Masellis, Mario; Basile, Vincenzo S; Atkinson, Leslie

2017-10-01

A mother's cortisol secretion is importantly associated with her own mental health and her infant's cortisol secretion. This study investigated the influences of maternal history of care and maternal DRD2, SLC6A3, and OXTR genotypes on maternal cortisol in the context of infant stress. A community sample of 296 mother-infant dyads completed a maternal separation at infant age 17 months. Maternal salivary cortisol, buccal cells, and self-reported history of care were collected. Multilevel models revealed that history of care had a greater influence on maternal baseline cortisol (but not cortisol trajectory) for mothers with more plasticity alleles of SLC6A3 (10R) and OXTR (G), relative to mothers with fewer or no plasticity alleles. Findings indicate that a mother's history of care is related to her cortisol secretion in anticipation of infant stress, but that this relation depends on her genetic characteristics. Findings are discussed in relation to the maternal protective system and anticipatory cortisol secretion. Copyright © 2017 Elsevier B.V. All rights reserved.

Dopaminergic Polymorphisms, Academic Achievement, and Violent Delinquency.

PubMed

Yun, Ilhong; Lee, Julak; Kim, Seung-Gon

2015-12-01

Recent research in the field of educational psychology points to the salience of self-control in accounting for the variance in students' report card grades. At the same time, a novel empirical study from molecular genetics drawing on the National Longitudinal Study of Adolescent Health (Add Health) data has revealed that polymorphisms in three dopaminergic genes (dopamine transporter [DAT1], dopamine D2 receptor [DRD2], and dopamine D4 receptor [DRD4]) are also linked to adolescents' grade point averages (GPAs). Juxtaposing these two lines of research, the current study reanalyzed the Add Health genetic subsample to assess the relative effects of these dopaminergic genes and self-control on GPAs. The results showed that the effects of the latter were far stronger than those of the former. The interaction effects between the dopaminergic genes and a set of environmental factors on academic performance were also examined, producing findings that are aligned with the "social push hypothesis" in behavioral genetics. Finally, based on the criminological literature on the link between academic performance and delinquency, we tested whether dopaminergic effects on violent delinquency were mediated by GPAs. The results demonstrated that academic performance fully mediated the linkage between these genes and violent delinquency. © The Author(s) 2014.

Genetics and Other Risk Factors for Past Concussions in Active-Duty Soldiers.

PubMed

Dretsch, Michael N; Silverberg, Noah; Gardner, Andrew J; Panenka, William J; Emmerich, Tanja; Crynen, Gogce; Ait-Ghezala, Ghania; Chaytow, Helena; Mathura, Venkat; Crawford, Fiona C; Iverson, Grant L

2017-02-15

Risk factors for concussion in active-duty military service members are poorly understood. The present study examined the association between self-reported concussion history and genetics (apolipoprotein E [APOE], brain-derived neurotrophic factor [BDNF], and D2 dopamine receptor genes [DRD2]), trait personality measures (impulsive-sensation seeking and trait aggression-hostility), and current alcohol use. The sample included 458 soldiers who were preparing to deploy for Operation Iraqi Freedom/Operation Enduring Freedom. For those with the BDNF Met/Met genotype, 57.9% (11/19) had a history of one or more prior concussions, compared with 35.6% (154/432) of those with other BDNF genotypes (p = 0.049, odds ratio [OR] = 2.48). APOE and DRD2 genotypes were not associated with risk for past concussions. Those with the BDNF Met/Met genotype also reported greater aggression and hostility personality characteristics. When combined in a predictive model, prior military deployments, being male, and having the BDNF Met/Met genotype were independently associated with increased lifetime history of concussions in active-duty soldiers. Replication in larger independent samples is necessary to have more confidence in both the positive and negative genetic associations reported in this study.

Psychological interventions for diabetes-related distress in adults with type 2 diabetes mellitus.

PubMed

Chew, Boon How; Vos, Rimke C; Metzendorf, Maria-Inti; Scholten, Rob Jpm; Rutten, Guy Ehm

2017-09-27

Many adults with type 2 diabetes mellitus (T2DM) experience a psychosocial burden and mental health problems associated with the disease. Diabetes-related distress (DRD) has distinct effects on self-care behaviours and disease control. Improving DRD in adults with T2DM could enhance psychological well-being, health-related quality of life, self-care abilities and disease control, also reducing depressive symptoms. To assess the effects of psychological interventions for diabetes-related distress in adults with T2DM. We searched the Cochrane Library, MEDLINE, Embase, PsycINFO, CINAHL, BASE, WHO ICTRP Search Portal and ClinicalTrials.gov. The date of the last search was December 2014 for BASE and 21 September 2016 for all other databases. We included randomised controlled trials (RCTs) on the effects of psychological interventions for DRD in adults (18 years and older) with T2DM. We included trials if they compared different psychological interventions or compared a psychological intervention with usual care. Primary outcomes were DRD, health-related quality of life (HRQoL) and adverse events. Secondary outcomes were self-efficacy, glycosylated haemoglobin A1c (HbA1c), blood pressure, diabetes-related complications, all-cause mortality and socioeconomic effects. Two review authors independently identified publications for inclusion and extracted data. We classified interventions according to their focus on emotion, cognition or emotion-cognition. We performed random-effects meta-analyses to compute overall estimates. We identified 30 RCTs with 9177 participants. Sixteen trials were parallel two-arm RCTs, and seven were three-arm parallel trials. There were also seven cluster-randomised trials: two had four arms, and the remaining five had two arms. The median duration of the intervention was six months (range 1 week to 24 months), and the median follow-up period was 12 months (range 0 to 12 months). The trials included a wide spectrum of interventions and were both individual- and group-based.A meta-analysis of all psychological interventions combined versus usual care showed no firm effect on DRD (standardised mean difference (SMD) -0.07; 95% CI -0.16 to 0.03; P = 0.17; 3315 participants; 12 trials; low-quality evidence), HRQoL (SMD 0.01; 95% CI -0.09 to 0.11; P = 0.87; 1932 participants; 5 trials; low-quality evidence), all-cause mortality (11 per 1000 versus 11 per 1000; risk ratio (RR) 1.01; 95% CI 0.17 to 6.03; P = 0.99; 1376 participants; 3 trials; low-quality evidence) or adverse events (17 per 1000 versus 41 per 1000; RR 2.40; 95% CI 0.78 to 7.39; P = 0.13; 438 participants; 3 trials; low-quality evidence). We saw small beneficial effects on self-efficacy and HbA1c at medium-term follow-up (6 to 12 months): on self-efficacy the SMD was 0.15 (95% CI 0.00 to 0.30; P = 0.05; 2675 participants; 6 trials; low-quality evidence) in favour of psychological interventions; on HbA1c there was a mean difference (MD) of -0.14% (95% CI -0.27 to 0.00; P = 0.05; 3165 participants; 11 trials; low-quality evidence) in favour of psychological interventions. Our included trials did not report diabetes-related complications or socioeconomic effects.Many trials were small and were at high risk of bias for incomplete outcome data as well as possible performance and detection biases in the subjective questionnaire-based outcomes assessment, and some appeared to be at risk of selective reporting. There are four trials awaiting further classification. These are parallel RCTs with cognition-focused and emotion-cognition focused interventions. There are another 18 ongoing trials, likely focusing on emotion-cognition or cognition, assessing interventions such as diabetes self-management support, telephone-based cognitive behavioural therapy, stress management and a web application for problem solving in diabetes management. Most of these trials have a community setting and are based in the USA. Low-quality evidence showed that none of the psychological interventions would improve DRD more than usual care. Low-quality evidence is available for improved self-efficacy and HbA1c after psychological interventions. This means that we are uncertain about the effects of psychological interventions on these outcomes. However, psychological interventions probably have no substantial adverse events compared to usual care. More high-quality research with emotion-focused programmes, in non-US and non-European settings and in low- and middle-income countries, is needed.

Negative effects of diabetes-related distress on health-related quality of life: an evaluation among the adult patients with type 2 diabetes mellitus in three primary healthcare clinics in Malaysia.

PubMed

Chew, Boon-How; Mohd-Sidik, Sherina; Shariff-Ghazali, Sazlina

2015-11-24

Patients with type 2 diabetes mellitus (T2D) often experienced change in life, altered self-esteem and increased feelings of uncertainty about the future that challenge their present existence and their perception of quality of life (QoL). There was a dearth of data on the association between diabetes-related distress (DRD) and health-related quality of life (HRQoL). This study examined the determinants of HRQoL, in particular the association between DRD and HRQoL by taking into account the socio-demographic-clinical variables, including depressive symptoms (DS) in adult patients with T2D. This cross-sectional study was conducted in 2012-2013 in three public health clinics in Malaysia. The World Health Organization Quality of Life-Brief (WHOQOL-BREF), 17-items Diabetes Distress Scale (DDS-17), and 9-items Patient Health Questionnaire (PHQ-9) were used to measure HRQoL, DRD and DS, respectively. The aim of this research was to examine the association between the socio-demographic-clinical variables and HRQoL as well as each of the WHOQOL-BREF domain score using multivariable regression analyses. The response rate was 93.1% (700/752). The mean (SD) for age was 56.9 (10.18). The majority of the patients were female (52.8%), Malay (53.1%) and married (79.1%). About 60% of the patients had good overall HRQoL. The mean (SD) for Overall QoL, Physical QoL, Psychological QoL, Social Relationship QoL and Environmental QoL were 61.7 (9.86), 56.7 (10.64), 57.9 (11.73), 66.8 (15.01) and 65.3 (13.02), respectively. The mean (SD) for the total DDS-17 score was 37.1 (15.98), with 19.6% (136/694) had moderate distress. DDS-17 had a negative association with HRQoL but religiosity had a positive influence on HRQoL (B ranged between 3.07 and 4.76). Women, especially younger Malays, who had diabetes for a shorter period of time experienced better HRQoL. However, patients who were not married, had dyslipidaemia, higher levels of total cholesterol and higher PHQ-9 scores had lower HRQoL. Macrovascular complications showed the largest negative effect on the overall HRQoL (adjusted B = -4.98, 95% CI -8.56 to -1.40). The majority of primary care adult with T2D had good overall HRQoL. Furthermore, the independent determinants for HRQoL had also concurred with many past studies. In addition, the researchers found that DRD had negative effects on HRQoL, but religiosity had positive influence on HRQoL. Appropriate support such as primary care is needed for adult patients with T2D to improve their life and their HRQoL. NMRR-12-1167-14158.

Genetic Moderation of Early Child-Care Effects on Social Functioning Across Childhood: A Developmental Analysis

ERIC Educational Resources Information Center

Belsky, Jay; Pluess, Michael

2013-01-01

Data from 508 Caucasian children in the NICHD Study of Early Child Care and Youth Development shows that the DRD4 (but not 5-HTTLPR) polymorphism moderates the effect of child-care quality (but not quantity or type) on caregiver-reported externalizing problems at 54 months and in kindergarten and teacher-reported social skills at kindergarten and…

Symptoms of Attention-Deficit/Hyperactivity Disorder in Down Syndrome: Effects of the Dopamine Receptor D4 Gene

ERIC Educational Resources Information Center

Mason, Gina Marie; Spanó, Goffredina; Edgin, Jamie

2015-01-01

This study examined individual differences in ADHD symptoms and executive function (EF) in children with Down syndrome (DS) in relation to the dopamine receptor D4 (DRD4) gene, a gene often linked to ADHD in people without DS. Participants included 68 individuals with DS (7-21 years), assessed through laboratory tasks, caregiver reports, and…

High Sibling Correlation on Methylphenidate Response but No Association with DAT1-10R Homozygosity in Dutch Sibpairs with ADHD

ERIC Educational Resources Information Center

van der Meulen, Emma M.; Bakker, Steven C.; Pauls, David L.; Oteman, Nicole; Kruitwagen, Cas L. J. J.; Pearson, Peter L.; Sinke, Richard J.; Buitelaar, Jan K.

2005-01-01

Background: A minority of patients with attention-deficit hyperactivity disorder (ADHD) do not respond favorably to methylphenidate. This has been partially associated with homozygosity for the Dopamine transporter (DAT1) 10-repeat allele and the presence of one or two Dopamine D4 receptor (DRD4) 7-repeat alleles. This study examined the sibling…

Dopamine D1 receptor modulation in nucleus accumbens lowers voluntary wheel running in rats bred to run high distances.

PubMed

Roberts, Michael D; Gilpin, Leigh; Parker, Kyle E; Childs, Thomas E; Will, Matthew J; Booth, Frank W

2012-02-01

Dopamine signaling in the nucleus accumbens (NAc) has been postulated to influence reward development towards drugs of abuse and exercise. Herein, we used generation 4-5 rats that were selectively bred to voluntary run high (HVR) versus low (LVR) distances in order to examine if dopamine-like 1 (D1) receptor modulation in the NAc differentially affects nightly voluntary wheel running between these lines. A subset of generation 5-6 HVR and LVR rats were also used to study the mRNA expression of key genes related to reward and addiction in the NAc (i.e., DRD1, DRD5, DRD2, Nr4a2, FosB, and BDNF). In a crossover fashion, a D1-like agonist SKF 82958 (2 μg per side) or D1-like full antagonist SCH 23390 (4 μg per side) was bilaterally injected into the NAc of HVR and LVR female Wistar rats prior to their high running nights. Notably, during hours 2-4 (between 2000 and 2300) of the dark cycle there was a significant decrement in running distances in the HVR rats treated with the D1 agonist (p=0.025) and antagonist (p=0.017) whereas the running distances in LVR rats were not affected. Interestingly, HVR and LVR rats possessed similar NAc concentrations of the studied mRNAs. These data suggest that: a) animals predisposed to run high distances on a nightly basis may quickly develop a rewarding response to exercise due to an optimal D1-like receptor signaling pathway in the NAc that can be perturbed by either activation or blocking, b) D1-like agonist or antagonist injections do not increase running distances in rats that are bred to run low nightly distances, and c) running differences between HVR and LVR animals are seemingly not due to the expression of the studied mRNAs. Given the societal prevalence of obesity and extraneous physical inactivity, future studies should be performed in order to further determine the culprit for the low running phenotype observed in LVR animals. Copyright © 2011. Published by Elsevier Inc.

Cerebellum Transcriptome of Mice Bred for High Voluntary Activity Offers Insights into Locomotor Control and Reward-Dependent Behaviors.

PubMed

Caetano-Anollés, Kelsey; Rhodes, Justin S; Garland, Theodore; Perez, Sam D; Hernandez, Alvaro G; Southey, Bruce R; Rodriguez-Zas, Sandra L

2016-01-01

The role of the cerebellum in motivation and addictive behaviors is less understood than that in control and coordination of movements. High running can be a self-rewarding behavior exhibiting addictive properties. Changes in the cerebellum transcriptional networks of mice from a line selectively bred for High voluntary running (H) were profiled relative to an unselected Control (C) line. The environmental modulation of these changes was assessed both in activity environments corresponding to 7 days of Free (F) access to running wheel and to Blocked (B) access on day 7. Overall, 457 genes exhibited a significant (FDR-adjusted P-value < 0.05) genotype-by-environment interaction effect, indicating that activity genotype differences in gene expression depend on environmental access to running. Among these genes, network analysis highlighted 6 genes (Nrgn, Drd2, Rxrg, Gda, Adora2a, and Rab40b) connected by their products that displayed opposite expression patterns in the activity genotype contrast within the B and F environments. The comparison of network expression topologies suggests that selection for high voluntary running is linked to a predominant dysregulation of hub genes in the F environment that enables running whereas a dysregulation of ancillary genes is favored in the B environment that blocks running. Genes associated with locomotor regulation, signaling pathways, reward-processing, goal-focused, and reward-dependent behaviors exhibited significant genotype-by-environment interaction (e.g. Pak6, Adora2a, Drd2, and Arhgap8). Neuropeptide genes including Adcyap1, Cck, Sst, Vgf, Npy, Nts, Penk, and Tac2 and related receptor genes also exhibited significant genotype-by-environment interaction. The majority of the 183 differentially expressed genes between activity genotypes (e.g. Drd1) were under-expressed in C relative to H genotypes and were also under-expressed in B relative to F environments. Our findings indicate that the high voluntary running mouse line studied is a helpful model for understanding the molecular mechanisms in the cerebellum that influence locomotor control and reward-dependent behaviors.

Cerebellum Transcriptome of Mice Bred for High Voluntary Activity Offers Insights into Locomotor Control and Reward-Dependent Behaviors

PubMed Central

Caetano-Anollés, Kelsey; Rhodes, Justin S.; Garland, Theodore; Perez, Sam D.; Hernandez, Alvaro G.; Southey, Bruce R.; Rodriguez-Zas, Sandra L.

2016-01-01

The role of the cerebellum in motivation and addictive behaviors is less understood than that in control and coordination of movements. High running can be a self-rewarding behavior exhibiting addictive properties. Changes in the cerebellum transcriptional networks of mice from a line selectively bred for High voluntary running (H) were profiled relative to an unselected Control (C) line. The environmental modulation of these changes was assessed both in activity environments corresponding to 7 days of Free (F) access to running wheel and to Blocked (B) access on day 7. Overall, 457 genes exhibited a significant (FDR-adjusted P-value < 0.05) genotype-by-environment interaction effect, indicating that activity genotype differences in gene expression depend on environmental access to running. Among these genes, network analysis highlighted 6 genes (Nrgn, Drd2, Rxrg, Gda, Adora2a, and Rab40b) connected by their products that displayed opposite expression patterns in the activity genotype contrast within the B and F environments. The comparison of network expression topologies suggests that selection for high voluntary running is linked to a predominant dysregulation of hub genes in the F environment that enables running whereas a dysregulation of ancillary genes is favored in the B environment that blocks running. Genes associated with locomotor regulation, signaling pathways, reward-processing, goal-focused, and reward-dependent behaviors exhibited significant genotype-by-environment interaction (e.g. Pak6, Adora2a, Drd2, and Arhgap8). Neuropeptide genes including Adcyap1, Cck, Sst, Vgf, Npy, Nts, Penk, and Tac2 and related receptor genes also exhibited significant genotype-by-environment interaction. The majority of the 183 differentially expressed genes between activity genotypes (e.g. Drd1) were under-expressed in C relative to H genotypes and were also under-expressed in B relative to F environments. Our findings indicate that the high voluntary running mouse line studied is a helpful model for understanding the molecular mechanisms in the cerebellum that influence locomotor control and reward-dependent behaviors. PMID:27893846

Sleep Deprivation Diminishes Attentional Control Effectiveness and Impairs Flexible Adaptation to Changing Conditions.

PubMed

Whitney, Paul; Hinson, John M; Satterfield, Brieann C; Grant, Devon A; Honn, Kimberly A; Van Dongen, Hans P A

2017-11-22

Insufficient sleep is a global public health problem resulting in catastrophic accidents, increased mortality, and hundreds of billions of dollars in lost productivity. Yet the effect of sleep deprivation (SD) on decision making and performance is often underestimated by fatigued individuals and is only beginning to be understood by scientists. The deleterious impact of SD is frequently attributed to lapses in vigilant attention, but this account fails to explain many SD-related problems, such as loss of situational awareness and perseveration. Using a laboratory study protocol, we show that SD individuals can maintain information in the focus of attention and anticipate likely correct responses, but their use of such a top-down attentional strategy is less effective at preventing errors caused by competing responses. Moreover, when the task environment requires flexibility, performance under SD suffers dramatically. The impairment in flexible shifting of attentional control we observed is distinct from lapses in vigilant attention, as corroborated by the specificity of the influence of a genetic biomarker, the dopaminergic polymorphism DRD2 C957T. Reduced effectiveness of top-down attentional control under SD, especially when conditions require flexibility, helps to explain maladaptive performance that is not readily explained by lapses in vigilant attention.

Rasgrf2 controls dopaminergic adaptations to alcohol in mice.

PubMed

Easton, Alanna C; Rotter, Andrea; Lourdusamy, Anbarasu; Desrivières, Sylvane; Fernández-Medarde, Alberto; Biermann, Teresa; Fernandes, Cathy; Santos, Eugenio; Kornhuber, Johannes; Schumann, Gunter; Müller, Christian P

2014-10-01

Alcohol abuse leads to serious health problems with no effective treatment available. Recent evidence suggests a role for ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) in alcoholism. Rasgrf2 is a calcium sensor and MAPK/ERK activating protein, which has been linked to neurotransmitter release and monoaminergic receptor adaptations. Rasgrf2 knock out (KO) mice do not develop a dopamine response in the nucleus accumbens after an alcohol challenge and show a reduced consumption of alcohol. The present study aims to further characterise the role of Rasgrf2 in dopaminergic activation beyond the nucleus accumbens following alcohol treatment. Using in vivo microdialysis we found that alcohol induces alterations in dopamine levels in the dorsal striatum between wildtype (WT) and Rasgrf2 KO mice. There was no difference in the expression of dopamine transporter (DAT), dopamine receptor regulating factor (DRRF), or dopamine D2 receptor (DRD2) mRNA in the brain between Rasgrf2 KO and WT mice. After sub-chronic alcohol treatment, DAT and DRRF, but not DRD2 mRNA expression differed between WT and Rasgrf2 KO mice. Brain adaptations were positively correlated with splenic expression levels. These data suggest that Rasgrf2 controls dopaminergic signalling and adaptations to alcohol also in other brain regions, beyond the nucleus accumbens. Copyright © 2014 Elsevier Inc. All rights reserved.

Variants in the Dopamine-4-Receptor Gene Promoter Are Not Associated with Sensation Seeking in Skiers

PubMed Central

Thomson, Cynthia J.; Rajala, Amelia K.; Carlson, Scott R.; Rupert, Jim L.

2014-01-01

Sensation seeking is a personality trait that has been associated with disinhibited behaviours including substance use and gambling, but also with high-risk sport practices including skydiving, paragliding, and downhill skiing. Twin studies have shown that sensation seeking is moderately heritable, and candidate genes encoding components involved in dopaminergic transmission have been investigated as contributing to this type of behaviour. To determine whether variants in the regulatory regions of the dopamine-4-receptor gene (DRD4) influenced sport-specific sensation seeking, we analyzed five polymorphisms (−1106T/C, −906T/C, −809G/A, −291C/T, 120-bp duplication) in the promoter region of the gene in a cohort of skiers and snowboarders (n = 599) that represented a broad range of sensation seeking behaviours. We grouped subjects by genotype at each of the five loci and compared impulsive sensation seeking and domain-specific (skiing) sensation seeking between groups. There were no significant associations between genotype(s) and general or domain-specific sensation seeking in the skiers and snowboarders, suggesting that while DRD4 has previously been implicated in sensation seeking, the promoter variants investigated in this study do not contribute to sensation seeking in this athlete population. PMID:24691022

Linkage results on 11q21-22 in Eastern Quebec pedigrees densely affected by schizophrenia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maziade, M.; Raymond, V.; Cliche, D.

The 11q21-22 region is of interest for schizophrenia because several candidate genes are located in this section of the genome. The 11q21-22 region, including DRD2, was surveyed by linkage analysis in a sample (N = 242) made of four large multigenerational pedigrees densely affected by schizophrenia (SZ) and eight others by bipolar disorder (BP). These pedigrees were ascertained in a large area of Eastern Quebec and Northern New Brunswick and are still being extended. Family members were administered a {open_quotes}consensus best-estimate diagnosis procedure{close_quotes} (DSM-III-R criteria) blind to probands and relatives` diagnosis and to pedigree assignment (SZ or BP). For linkagemore » analysis, 11 microsatellite polymorphism (CA repeat) markers, located at 11q21-22, and comprising DRD2, were genotyped. Results show no evidence of a major gene for schizophrenia. However, a maximum lod score of 3.41 at the D11S35 locus was observed in an affected-only analysis of one large SZ family, pedigree 255. Whether or not the positive linkage trend in pedigree 255 reflects a true linkage for a small proportion of SZ needs to be confirmed through the extension of this kindred and through replication. 36 refs., 2 tabs.« less

The ANKK1 kinase gene and psychiatric disorders.

PubMed

Ponce, Guillermo; Pérez-González, Rocío; Aragüés, María; Palomo, Tomás; Rodríguez-Jiménez, Roberto; Jiménez-Arriero, Miguel Angel; Hoenicka, Janet

2009-07-01

The TaqIA single nucleotide polymorphism (SNP, rs1800497), which is located in the gene that codes for the putative kinase ANKK1 (ANKK1) near the termination codon of the D2 dopamine receptor gene (DRD2; chromosome 11q22-q23), is the most studied genetic variation in a broad range of psychiatric disorders and personality traits. A large number of individual genetic association studies have found that the TaqIA SNP is linked to alcoholism and antisocial traits. In addition, it has also been related to other conditions such as schizophrenia, eating disorders, and some behavioral childhood disorders. The TaqIA A1 allele is mainly associated with addictions, antisocial disorders, eating disorders, and attention-deficit/hyperactivity disorders, while the A2 allele occurs more frequently in schizophrenic and obsessive-compulsive patients. Current data show that the TaqIA polymorphism may be a marker of both DRD2 and ANKK1 genetic variants. ANKK1 would belong to a family of kinases involved in signal transduction. This raises the question of whether signaling players intervene in the pathophysiology of psychiatric disorders. Basic research on the ANKK1 protein and its putative interaction with the D2 dopamine receptor could shed light on this issue.

Serotonin and Dopamine Gene Variation and Theory of Mind Decoding Accuracy in Major Depression: A Preliminary Investigation.

PubMed

Zahavi, Arielle Y; Sabbagh, Mark A; Washburn, Dustin; Mazurka, Raegan; Bagby, R Michael; Strauss, John; Kennedy, James L; Ravindran, Arun; Harkness, Kate L

2016-01-01

Theory of mind-the ability to decode and reason about others' mental states-is a universal human skill and forms the basis of social cognition. Theory of mind accuracy is impaired in clinical conditions evidencing social impairment, including major depressive disorder. The current study is a preliminary investigation of the association of polymorphisms of the serotonin transporter (SLC6A4), dopamine transporter (DAT1), dopamine receptor D4 (DRD4), and catechol-O-methyl transferase (COMT) genes with theory of mind decoding in a sample of adults with major depression. Ninety-six young adults (38 depressed, 58 non-depressed) completed the 'Reading the Mind in the Eyes task' and a non-mentalistic control task. Genetic associations were only found for the depressed group. Specifically, superior accuracy in decoding mental states of a positive valence was seen in those homozygous for the long allele of the serotonin transporter gene, 9-allele carriers of DAT1, and long-allele carriers of DRD4. In contrast, superior accuracy in decoding mental states of a negative valence was seen in short-allele carriers of the serotonin transporter gene and 10/10 homozygotes of DAT1. Results are discussed in terms of their implications for integrating social cognitive and neurobiological models of etiology in major depression.

Social rank-associated stress vulnerability predisposes individuals to cocaine attraction.

PubMed

Yanovich, Chen; Kirby, Michael L; Michaelevski, Izhak; Yadid, Gal; Pinhasov, Albert

2018-01-29

Studies of personality have suggested that dissimilarities in ability to cope with stressful situations results in differing tendency to develop addictive behaviors. The present study used selectively bred stress-resilient, socially-dominant (Dom) and stress-vulnerable, socially-submissive (Sub) mice to investigate the interaction between environmental stress and inbred predisposition to develop addictive behavior to cocaine. In a Conditioned Place Preference (CPP) paradigm using cocaine, Sub mice displayed an aversion to drug, whereas Dom mice displayed drug attraction. Following a 4-week regimen of Chronic Mild Stress (CMS), Sub mice in CPP displayed a marked increase (>400%) in cocaine attraction, whereas Dom mice did not differ in attraction from their non-stressed state. Examination of hippocampal gene expression revealed in Sub mice, exposure to external stimuli, stress or cocaine, increased CRH expression (>100%), which was evoked in Dom mice only by cocaine exposure. Further, stress-induced decreases in DRD1 (>60%) and DRD2 (>50%) expression in Sub mice differed markedly from a complete lack of change in Dom mice. From our findings, we propose that social stratification dictates vulnerability to stress-induced attraction that may lead to addiction via differential regulation of hippocampal response to dopaminergic input, which in turn may influence differing tendency to develop addictive behaviors.

Contingency Contractor Optimization Phase 3 Sustainment Requirements Document Contingency Contractor Optimization Tool - Prototype

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bandlow, Alisa; Durfee, Justin David; Frazier, Christopher Rawls

2016-05-01

This requirements document serves as an addendum to the Contingency Contractor Optimization Phase 2, Requirements Document [1] and Phase 3 Requirements Document [2]. The Phase 2 Requirements document focused on the high-level requirements for the tool. The Phase 3 Requirements document provided more detailed requirements to which the engineering prototype was built in Phase 3. This document will provide detailed requirements for features and enhancements being added to the production pilot in the Phase 3 Sustainment.

Withdrawal from Buprenorphine/Naloxone and Maintenance with a Natural Dopaminergic Agonist: A Cautionary Note.

PubMed

Blum, Kenneth; Oscar-Berman, Marlene; Femino, John; Waite, Roger L; Benya, Lisa; Giordano, John; Borsten, Joan; Downs, William B; Braverman, Eric R; Loehmann, Raquel; Dushaj, Kristina; Han, David; Simpatico, Thomas; Hauser, Mary; Barh, Debmalya; McLaughlin, Thomas

2013-04-23

While numerous studies support the efficacy of methadone and buprenorphine for the stabilization and maintenance of opioid dependence, clinically significant opioid withdrawal symptoms occur upon tapering and cessation of dosage. We present a case study of a 35 year old Caucasian female (Krissie) who was prescribed increasing dosages of prescription opioids after carpel tunnel surgery secondary to chronic pain from reflex sympathetic dystrophy and fibromyalgia. Over the next 5 years, daily dosage requirements increased to over 80 mg of Methadone and 300 ug/hr Fentanyl transdermal patches, along with combinations of 12-14 1600 mcg Actig lollipop and oral 100 mg Morphine and 30 mg oxycodone 1-2 tabs q4-6hr PRN for breakthrough pain. Total monthly prescription costs including supplemental benzodiazepines, hypnotics and stimulants exceeded $50,000. The patient was subsequently transferred to Suboxone® in 2008, and the dosage was gradually tapered until her admission for inpatient detoxification with KB220Z a natural dopaminergic agonist. We carefully documented her withdrawal symptoms when she precipitously stopped taking buprenorphine/naloxone and during follow-up while taking KB220Z daily. We also genotyped the patient using a reward gene panel including (9 genes 18 alleles): DRD 2,3,4; MOA-A; COMT; DAT1; 5HTTLLR; OPRM1; and GABRA3. At 432 days post Suboxone® withdrawal the patient is being maintained on KB220Z, has been urine tested and is opioid free. Genotyping data revealed a moderate genetic risk for addiction showing a hypodopaminergic trait. This preliminary case data suggest that the daily use of KB220Z could provide a cost effective alternative substitution adjunctive modality for Suboxone®. We encourage double-blind randomized -placebo controlled studies to test the proposition that KB220Z may act as a putative natural opioid substitution maintenance adjunct.

F229. THE BIOLOGICAL UNDERPINNINGS OF TREATMENT RESPONSE IN DELUSIONAL DISORDER: A SYSTEMATIC REVIEW OF QUALITATIVE EVIDENCE-TO-DATE

PubMed Central

González-Rodríguez, Alexandre; Estrada, Francesc; Montalvo, Itziar; Monreal, José Antonio; Palao, Diego; Labad, Javier

2018-01-01

Abstract Background The dopamine hypothesis of schizophrenia has been extensively proposed as a neurobiological mechanism that explains the relationship between schizophrenic symptoms and hyperdopaminergic states. This hypothesis is supported by direct and indirect evidence, and it mainly postulates that antipsychotics act blocking dopamine receptors. When focusing on delusional disorder patients, especially delusional disorder somatic type, a great effort towards the search for a biological basis of treatment response has been recently demonstrated. Thus, the main goal of this systematic review was to examine the evidence explaining the biological underpinnings of treatment response in delusional disorder. Methods A systematic review was performed using Pubmed, Scopus and PsycINFO databases (from 1990 to October 2017), according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The following search terms were used: [(‘treat*’ OR ‘therap*’ OR ‘biol*’) AND (‘delusional disorder’)]. This systematic computerized search was completed by additional studies hand-checked through reference lists from the included studies and review articles. Studies were only included if the met our inclusion criteria: (a) the International Classification of Diseases (ICD) or Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnosis for delusional disorder, (b) be published in peer-reviewed journals, (c) in English, German or Spanish, (d) and reporting a hypothesis for the biological basis of treatment response in delusional disorder, irrespective of method and study design. Exclusion criteria were: (a) studies including organic delusional disorder or (b) somatic delusions secondary to other psychiatric diagnoses. The literature search strategy, data extraction and synthesis was conducted independently by two authors (A.G.R, F.E.). When disagreement, it was solved by consensus. Results A total of 59 articles were identified, of which 12 met our inclusion criteria. Four hypotheses were addressed: (1) Dopaminergic dysfunction (n=4): ziprasidone-induced supersensitivity psychosis by chronic blockade of D2 Dopamine Receptor (DRD2) (n=1); pretreatment levels of plasma homovallinic acid (pHVA) (n=1); dopamine transporter (DAT) dysfunction (n=1) and effectiveness of aripiprazole (DRD2 agonist) (n=1). (2) Serotonergic dysfunction (n=6): drug occupancy in 5-HT1A and 5-HT2A receptors (n=3) and efficacy of 5-HT2 antagonists (n=3). Brain dysfunction (n=7): hypoperfusion in cerebral blood flow in temporal and parietal lobes, left side (n=5), right side (n=1) and lack of basal ganglia and subcortical gray matter lesions (n=1). Genetic evidence (n=1): implications of DRD2 Ser311Cys, DRD3 Ser9Gly and TH VNTR polymorphisms. Discussion The strongests biological contributors for treatment response in delusional disorder seem to be those implicating monoaminergic systems, particularly dopamine and serotonergic neurotransmitters. Although the low level of evidence, the serotonergic dysfunction may be associated with response rates, especially in delusional disorder somatic type. The link between genetic variants of dopamine receptors and neuroimaging findings in delusional disorder may open new avenues for the search of the biological underpinnings of treatment response. The evidence for an integrated model involving dopamine and serotonin systems bears further investigations.

Reducing drug related deaths: a pre-implementation assessment of knowledge,barriers and enablers for naloxone distribution through general practice

PubMed Central

2014-01-01

Background The Scottish Naloxone Programme aims to reduce Scotland’s high number of drug-related deaths (DRDs) caused by opiate overdose. It is currently implemented through specialist drug services but General Practitioners (GPs) are likely to have contact with drug using patients and their families and are therefore in an ideal position to direct them to naloxone schemes, or provide it themselves. This research gathered baseline data on GP’s knowledge of and willingness to be involved in DRD prevention, including naloxone administration, prior to the implementation of primary care based delivery. Methods Mixed methods were used comprising a quantitative, postal survey and qualitative telephone interviews. A questionnaire was sent to 500 GPs across Scotland. An initial mailing was followed by a reminder. A shortened questionnaire containing seven key questions was posted as a final reminder. Telephone interviews were conducted with 17 GPs covering a range of demographic characteristics and drug user experience. Results A response rate of 55% (240/439) was achieved. There was some awareness of the naloxone programme but little involvement (3.3%), 9% currently provided routine overdose prevention, there was little involvement in displaying overdose prevention information (<20%). Knowledge of DRD risk was mixed. There was tentative willingness to be involved in naloxone prescribing with half of respondents willing to provide this to drug users or friends/family. However half were uncertain GP based naloxone provision was essential to reduce DRDs. Factors enabling naloxone distribution were: evidence of effectiveness, appropriate training, and adding to the local formulary. Interviewees had limited awareness of what naloxone distribution in primary care may involve and considered naloxone supply as a specialist service rather than a core GP role. Wider attitudinal barriers to involvement with this group were expressed. Conclusions There was poor awareness of the Scottish National Naloxone Programme in participants. Results indicated GPs did not currently feel sufficiently skilled or knowledgeable to be involved in naloxone provision. Appropriate training was identified as a key requirement. PMID:24428947

Neurogentics of Dopaminergic Receptor Super-sensitivity in Activation of Brain Reward Circuitry and Relapse: Proposing “Deprivation-Amplification Relapse Therapy” (DART)

PubMed Central

Downs, B. William; Bowirrat, Abdalla; Waite, Roger L.; Braverman, Eric R.; Madigan, Margaret; Oscar-Berman, Marlene; DiNubile, Nicholas; Gold, Mark

2013-01-01

Background and Hypothesis It is well known that after prolonged abstinence, individuals who imbibe or use their drug of choice experience a powerful euphoria that precipitates serious relapse. While a biological explanation for this conundrum has remained elusive, we hypothesize that this clinically observed “super sensitivity” might be tied to genetic dopaminergic polymorphisms. Another therapeutic conundrum relates to the paradoxical finding that the dopaminergic agonist bromocriptine induces stronger activation of brain reward circuitry in individuals who carry the DRD2 A1 allele compared to DRD2 A2 allele carriers. Based upon the fact that carriers of the A1 allele relative to the A2 allele of the DRD2 gene have significantly lower D2 receptor density, a reduced sensitivity to dopamine agonist activity would be expected in the former. Thus, it is perplexing that with low D2 density there is an increase in reward sensitivity with the dopamine agonist bromocriptine. Moreover, under chronic or long-term therapy, the potential proliferation of D2 receptors with bromocriptine has been shown in vitro. This seems to lead to a positive outcome and significantly better treatment compliance only in A1 carriers. Proposal and Conclusion We propose that low D2 receptor density and polymorphisms of the D2 gene are associated with risk for relapse of substance abuse including alcohol dependence, heroin craving, cocaine dependence, methamphetamine abuse, nicotine sensitization, and glucose craving. With this in mind, we suggest a putative physiological mechanism that may help to explain the enhanced sensitivity following intense acute dopaminergic D2 receptor activation: “denervation supersensitivity.” Thus, the administration of dopamine D2 agonists would target D2 sensitization and attenuate relapse, especially in D2 receptor A1 allele carriers. This hypothesized mechanism is supported by clinical trials utilizing the amino-acid neurotransmitter precursors, enkephalinase and catechol-O-methyl-transferase (COMT) enzyme inhibition, which have resulted in attenuated relapse rates in Reward Deficiency Syndrome (RDS) probands. Future warranted translational research with positive outcome showing prevented or lower relapse in RDS will ultimately support the proposed concept, which we term “Deprivation-Amplification Relapse Therapy (DART).” PMID:19940429

Cosmetics Europe compilation of historical serious eye damage/eye irritation in vivo data analysed by drivers of classification to support the selection of chemicals for development and evaluation of alternative methods/strategies: the Draize eye test Reference Database (DRD).

PubMed

Barroso, João; Pfannenbecker, Uwe; Adriaens, Els; Alépée, Nathalie; Cluzel, Magalie; De Smedt, Ann; Hibatallah, Jalila; Klaric, Martina; Mewes, Karsten R; Millet, Marion; Templier, Marie; McNamee, Pauline

2017-02-01

A thorough understanding of which of the effects assessed in the in vivo Draize eye test are responsible for driving UN GHS/EU CLP classification is critical for an adequate selection of chemicals to be used in the development and/or evaluation of alternative methods/strategies and for properly assessing their predictive capacity and limitations. For this reason, Cosmetics Europe has compiled a database of Draize data (Draize eye test Reference Database, DRD) from external lists that were created to support past validation activities. This database contains 681 independent in vivo studies on 634 individual chemicals representing a wide range of chemical classes. A description of all the ocular effects observed in vivo, i.e. degree of severity and persistence of corneal opacity (CO), iritis, and/or conjunctiva effects, was added for each individual study in the database, and the studies were categorised according to their UN GHS/EU CLP classification and the main effect driving the classification. An evaluation of the various in vivo drivers of classification compiled in the database was performed to establish which of these are most important from a regulatory point of view. These analyses established that the most important drivers for Cat 1 Classification are (1) CO mean ≥ 3 (days 1-3) (severity) and (2) CO persistence on day 21 in the absence of severity, and those for Cat 2 classification are (3) CO mean ≥ 1 and (4) conjunctival redness mean ≥ 2. Moreover, it is shown that all classifiable effects (including persistence and CO = 4) should be present in ≥60 % of the animals to drive a classification. As a consequence, our analyses suggest the need for a critical revision of the UN GHS/EU CLP decision criteria for the Cat 1 classification of chemicals. Finally, a number of key criteria are identified that should be taken into consideration when selecting reference chemicals for the development, evaluation and/or validation of alternative methods and/or strategies for serious eye damage/eye irritation testing. Most important, the DRD is an invaluable tool for any future activity involving the selection of reference chemicals.

Micromorphological changes in cardiac tissue of drug-related deaths with emphasis on chronic illicit opioid abuse

PubMed Central

Seltenhammer, Monika H; Marchart, Katharina; Paula, Pia; Kordina, Nicole; Klupp, Nikolaus; Schneider, Barbara; Fitzl, Christine; Risser, Daniele U

2013-01-01

Aims The main intention of this retrospective study was to investigate whether chronic illicit drug abuse, especially the intravenous use of opioids (heroin), could potentially trigger the development of myocardial fibrosis in drug addicts. Design A retrospective case–control study was performed using myocardial tissue samples from both drug-related deaths (DRD) with verifiable opioid abuse and non-drug-related deaths in the same age group. Setting Department of Forensic Medicine, Medical University of Vienna, Austria (1993–94). Participants Myocardial specimens were retrieved from 76 deceased intravenous opioid users and compared to those of 23 deceased non-drug users. Measurements Drug quantification was carried out using the enzyme-multiplied immunoassay technique (EMIT), followed by [gas chromatography–mass spectrometry (GC–MS), MAT 112®], and analysed using the Integrator 3390A by Hewlett Packard® and LABCOM.1 computer (MSS-G.G.). The amount of fibrous connective tissue (FCT) in the myocardium was determined by using the morphometric software LUCIA Net version 1.16.2©, Laboratory Imaging, with NIS Elements 3.0®. Findings Drug analysis revealed that 67.11% were polydrug users and the same proportion was classified as heroin addicts (6-monoacetylmorphine, 6-MAM)—32.89% were users of pure heroin. In 76.32% of DRD cases, codeine was detected. Only 2.63% consumed cocaine. The mean morphine concentrations were 389.03 ng/g in the cerebellum and 275.52 ng/g in the medulla oblongata, respectively. Morphometric analysis exhibited a strong correlation between DRD and myocardial fibrosis. The mean proportion of FCT content in the drug group was 7.6 ± 2.9% (females: 6.30 ± 2.19%; males: 7.91 ± 3.01%) in contrast to 5.2 ± 1.7% (females: 4.45 ± 1.23%; males: 5.50 ± 1.78%) in the control group, indicating a significant difference (P = 0.0012), and a significant difference in the amount of FCT between females and males (P = 0.0383). There was no significant interaction of age and FCT (P = 0.8472). Conclusions There is a long-term risk of cardiac dysfunction following chronic illicit drug abuse with opioids as a principal component. Regular cardiological examination of patients receiving substitution treatment with morphine is strongly recommended. PMID:23297783

Multigene interactions and the prediction of depression in the Wisconsin Longitudinal Study

PubMed Central

Roetker, Nicholas S; Yonker, James A; Lee, Chee; Chang, Vicky; Basson, Jacob J; Roan, Carol L; Hauser, Taissa S; Hauser, Robert M

2012-01-01

Objectives Single genetic loci offer little predictive power for the identification of depression. This study examined whether an analysis of gene–gene (G × G) interactions of 78 single nucleotide polymorphisms (SNPs) in genes associated with depression and age-related diseases would identify significant interactions with increased predictive power for depression. Design A retrospective cohort study. Setting A survey of participants in the Wisconsin Longitudinal Study. Participants A total of 4811 persons (2464 women and 2347 men) who provided saliva for genotyping; the group comes from a randomly selected sample of Wisconsin high school graduates from the class of 1957 as well as a randomly selected sibling, almost all of whom are non-Hispanic white. Primary outcome measure Depression as determine by the Composite International Diagnostic Interview–Short-Form. Results Using a classification tree approach (recursive partitioning (RP)), the authors identified a number of candidate G × G interactions associated with depression. The primary SNP splits revealed by RP (ANKK1 rs1800497 (also known as DRD2 Taq1A) in men and DRD2 rs224592 in women) were found to be significant as single factors by logistic regression (LR) after controlling for multiple testing (p=0.001 for both). Without considering interaction effects, only one of the five subsequent RP splits reached nominal significance in LR (FTO rs1421085 in women, p=0.008). However, after controlling for G × G interactions by running LR on RP-specific subsets, every split became significant and grew larger in magnitude (OR (before) → (after): men: GNRH1 novel SNP: (1.43 → 1.57); women: APOC3 rs2854116: (1.28 → 1.55), ACVR2B rs3749386: (1.11 → 2.17), FTO rs1421085: (1.32 → 1.65), IL6 rs1800795: (1.12 → 1.85)). Conclusions The results suggest that examining G × G interactions improves the identification of genetic associations predictive of depression. 4 of the SNPs identified in these interactions were located in two pathways well known to impact depression: neurotransmitter (ANKK1 and DRD2) and neuroendocrine (GNRH1 and ACVR2B) signalling. This study demonstrates the utility of RP analysis as an efficient and powerful exploratory analysis technique for uncovering genetic and molecular pathway interactions associated with disease aetiology. PMID:22761283

In vitro expressed GPCR inserted in polymersome membranes for ligand-binding studies.

PubMed

May, Sylvia; Andreasson-Ochsner, Mirjam; Fu, Zhikang; Low, Ying Xiu; Tan, Darren; de Hoog, Hans-Peter M; Ritz, Sandra; Nallani, Madhavan; Sinner, Eva-Kathrin

2013-01-07

The dopamine receptor D2 (DRD2), a G-protein coupled receptor is expressed into PBd(22)-PEO(13) and PMOXA(20)-PDMS(54)-PMOXA(20) block copolymer vesicles. The conformational integrity of the receptor is confirmed by antibody- and ligand-binding assays. Replacement of bound dopamine is demonstrated on surface-immobilized polymersomes, thus making this a promising platform for drug screening. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Working memory brain activity and capacity link MAOA polymorphism to aggressive behavior during development

PubMed Central

Ziermans, T; Dumontheil, I; Roggeman, C; Peyrard-Janvid, M; Matsson, H; Kere, J; Klingberg, T

2012-01-01

A developmental increase in working memory capacity is an important part of cognitive development, and low working memory (WM) capacity is a risk factor for developing psychopathology. Brain activity represents a promising endophenotype for linking genes to behavior and for improving our understanding of the neurobiology of WM development. We investigated gene–brain–behavior relationships by focusing on 18 single-nucleotide polymorphisms (SNPs) located in six dopaminergic candidate genes (COMT, SLC6A3/DAT1, DBH, DRD4, DRD5, MAOA). Visuospatial WM (VSWM) brain activity, measured with functional magnetic resonance imaging, and VSWM capacity were assessed in a longitudinal study of typically developing children and adolescents. Behavioral problems were evaluated using the Child Behavior Checklist (CBCL). One SNP (rs6609257), located ∼6.6 kb downstream of the monoamine oxidase A gene (MAOA) on human chromosome X, significantly affected brain activity in a network of frontal, parietal and occipital regions. Increased activity in this network, but not in caudate nucleus or anterior prefrontal regions, was correlated with VSWM capacity, which in turn predicted externalizing (aggressive/oppositional) symptoms, with higher WM capacity associated with fewer externalizing symptoms. There were no direct significant correlations between rs6609257 and behavioral symptoms. These results suggest a mediating role of WM brain activity and capacity in linking the MAOA gene to aggressive behavior during development. PMID:22832821

Testing differential susceptibility: Plasticity genes, the social environment, and their interplay in adolescent response inhibition.

PubMed

Richards, Jennifer S; Arias Vásquez, Alejandro; van Rooij, Daan; van der Meer, Dennis; Franke, Barbara; Hoekstra, Pieter J; Heslenfeld, Dirk J; Oosterlaan, Jaap; Faraone, Stephen V; Hartman, Catharina A; Buitelaar, Jan K

2017-06-01

Impaired inhibitory control is a key feature of attention-deficit/hyperactivity disorder (ADHD). We investigated gene-environment interaction (GxE) as a possible contributing factor to response inhibition variation in context of the differential susceptibility theory. This states individuals carrying plasticity gene variants will be more disadvantaged in negative, but more advantaged in positive environments. Behavioural and neural measures of response inhibition were assessed during a Stop-signal task in participants with (N = 197) and without (N = 295) ADHD, from N = 278 families (age M = 17.18, SD =3.65). We examined GxE between candidate plasticity genes (DAT1, 5-HTT, DRD4) and social environments (maternal expressed emotion, peer affiliation). A DRD4 × Positive peer affiliation interaction was found on the right fusiform gyrus (rFG) activation during successful inhibition. Further, 5-HTT short allele carriers showed increased rFG activation during failed inhibitions. Maternal warmth and positive peer affiliation were positively associated with right inferior frontal cortex activation during successful inhibition. Deviant peer affiliation was positively related to the error rate. While a pattern of differential genetic susceptibility was found, more clarity on the role of the FG during response inhibition is warranted before firm conclusions can be made. Positive and negative social environments were related to inhibitory control. This extends previous research emphasizing adverse environments.

Genetic variants associated with addictive behavior in Colombian addicted and non-addicted to heroin or cocaine.

PubMed

Isaza, Carlos; Henao, Julieta; Beltrán, Leonardo; Porras, Liliana; Gonzalez, Martha; Cruz, Raquel; Carracedo, Angel

2013-01-01

Determine the prevalence and compare some genetic markers involved in addictive behavior in a group of addicts to derivative of coca (cocaine/crack) or heroin and a control group of non-addicted people matched for gender, age and ethnicity. A 120 addicts and 120 non-addicts Colombian male were surveyed and genotyped for 18 polymorphism of the OPRM1, DRD2, DRD4, SLC6A3, SLC6A4, ABCB1, DβH and CYP2B6 genes. For the identification of alleles markers were used mini-sequencing and fragment multiplex PCR techniques; ethnicity of cases and controls was analyzed with 61 AIMs. The age of onset use of heroin or coca derivatives (cocaine/crack) was 16.5±6 years and 99.2% of them consume several illicit drugs. It showed that controls and addicts belong to the same ethnic group. Significant differences between addicts and controls in relation to schooling, marital status, social security family history of substance abuse (p <0.001), Int8-VNTR SLC6A3 gene (p= 0.015) and SNP 3435C>T ABCB1 gene (p= 0.001) were found. The present results indicate that the VNTR- 6R polymorphism of the gene SLC6A3 and the genotype 3435CC in the ABCB1 gene, are both associated with addictive behavior to heroin or cocaine.

Left Parietal Functional Connectivity Mediates the Association Between COMT rs4633 and Verbal Intelligence in Healthy Adults

PubMed Central

Xu, Qiang; Fu, Jilian; Liu, Feng; Qin, Wen; Liu, Bing; Jiang, Tianzi; Yu, Chunshui

2018-01-01

In Chinese Han population, Catechol-O-methyltransferase gene (COMT) rs4633 is found to be associated with impaired cognitive process. We aimed to investigate the association between COMT rs4633 and verbal intelligence and the underlying neural mechanisms in Chinese Han healthy young adults. In 256 Chinese Han healthy young adults, we explored the modulatory effects of COMT rs4633 on verbal intelligence quotient (VIQ) and functional connectivity density (FCD) of the brain and the mediation effect of FCD on the association between COMT and VIQ. We further investigated the association between the expression patterns of dopamine receptor genes and the effect of COMT on FCD in the human brain. COMT rs4633 TT homozygotes exhibited lower VIQ than CC homozygotes and TC heterozygotes, higher long-range FCD (lrFCD) than CC homozygotes and TC heterozygotes in the left superior frontal gyrus. TT homozygotes and TC heterozygotes showed higher lrFCD than CC homozygotes in the left inferior parietal lobule. The lrFCD differences across genotypic subgroups were negatively associated with the expression of DRD2 and DRD3 genes. The left parietal lrFCD mediated the association between COMT rs4633 and VIQ. These findings provide a biological pathway that COMT rs4633 affects verbal intelligence via modulating the lrFCD of the left inferior parietal lobule. PMID:29692704

Adolescent behavioral and neural reward sensitivity: a test of the differential susceptibility theory

PubMed Central

Richards, J S; Arias Vásquez, A; von Rhein, D; van der Meer, D; Franke, B; Hoekstra, P J; Heslenfeld, D J; Oosterlaan, J; Faraone, S V; Buitelaar, J K; Hartman, C A

2016-01-01

Little is known about the causes of individual differences in reward sensitivity. We investigated gene–environment interactions (GxE) on behavioral and neural measures of reward sensitivity, in light of the differential susceptibility theory. This theory states that individuals carrying plasticity gene variants will be more disadvantaged in negative, but more advantaged in positive environments. Reward responses were assessed during a monetary incentive delay task in 178 participants with and 265 without attention-deficit/hyperactivity disorder (ADHD), from N=261 families. We examined interactions between variants in candidate plasticity genes (DAT1, 5-HTT and DRD4) and social environments (maternal expressed emotion and peer affiliation). HTTLPR short allele carriers showed the least reward speeding when exposed to high positive peer affiliation, but the most when faced with low positive peer affiliation or low maternal warmth. DAT1 10-repeat homozygotes displayed similar GxE patterns toward maternal warmth on general task performance. At the neural level, DRD4 7-repeat carriers showed the least striatal activation during reward anticipation when exposed to high maternal warmth, but the most when exposed to low warmth. Findings were independent of ADHD severity. Our results partially confirm the differential susceptibility theory and indicate the importance of positive social environments in reward sensitivity and general task performance for persons with specific genotypes. PMID:27045841

Working memory brain activity and capacity link MAOA polymorphism to aggressive behavior during development.

PubMed

Ziermans, T; Dumontheil, I; Roggeman, C; Peyrard-Janvid, M; Matsson, H; Kere, J; Klingberg, T

2012-02-28

A developmental increase in working memory capacity is an important part of cognitive development, and low working memory (WM) capacity is a risk factor for developing psychopathology. Brain activity represents a promising endophenotype for linking genes to behavior and for improving our understanding of the neurobiology of WM development. We investigated gene-brain-behavior relationships by focusing on 18 single-nucleotide polymorphisms (SNPs) located in six dopaminergic candidate genes (COMT, SLC6A3/DAT1, DBH, DRD4, DRD5, MAOA). Visuospatial WM (VSWM) brain activity, measured with functional magnetic resonance imaging, and VSWM capacity were assessed in a longitudinal study of typically developing children and adolescents. Behavioral problems were evaluated using the Child Behavior Checklist (CBCL). One SNP (rs6609257), located ~6.6 kb downstream of the monoamine oxidase A gene (MAOA) on human chromosome X, significantly affected brain activity in a network of frontal, parietal and occipital regions. Increased activity in this network, but not in caudate nucleus or anterior prefrontal regions, was correlated with VSWM capacity, which in turn predicted externalizing (aggressive/oppositional) symptoms, with higher WM capacity associated with fewer externalizing symptoms. There were no direct significant correlations between rs6609257 and behavioral symptoms. These results suggest a mediating role of WM brain activity and capacity in linking the MAOA gene to aggressive behavior during development.

Thalamic miR-338-3p mediates auditory thalamocortical disruption and its late onset in 22q11.2 microdeletion models

PubMed Central

Chun, Sungkun; Du, Fei; Westmoreland, Joby J.; Han, Seung Baek; Wang, Yong-Dong; Eddins, Donnie; Bayazitov, Ildar T.; Devaraju, Prakash; Yu, Jing; Mellado Lagarde, Marcia M.; Anderson, Kara; Zakharenko, Stanislav S.

2016-01-01

Although 22q11.2 deletion syndrome (22q11DS) is associated with early-life behavioral abnormalities, affected individuals are also at high risk for the development of schizophrenia symptoms, including psychosis, later in life. Auditory thalamocortical projections recently emerged as a neural circuit specifically disrupted in 22q11DS mouse models, in which haploinsufficiency of the microRNA-processing gene Dgcr8 resulted in the elevation of the dopamine receptor Drd2 in the auditory thalamus, an abnormal sensitivity of thalamocortical projections to antipsychotics, and an abnormal acoustic-startle response. Here we show that these auditory thalamocortical phenotypes have a delayed onset in 22q11DS mouse models and are associated with an age-dependent reduction of the microRNA miR-338-3p, which targets Drd2 and is enriched in the thalamus of both humans and mice. Replenishing depleted miR-338-3p in mature 22q11DS mice rescued the thalamocortical abnormalities, and miR-338-3p deletion/knockdown mimicked thalamocortical and behavioral deficits and eliminated their age dependence. Therefore, miR-338-3p depletion is necessary and sufficient to disrupt auditory thalamocortical signaling in 22q11DS mouse models and may mediate the pathogenic mechanism of 22q11DS-related psychosis and control its late onset. PMID:27892953

Tank waste remediation system functions and requirements document

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carpenter, K.E

1996-10-03

This is the Tank Waste Remediation System (TWRS) Functions and Requirements Document derived from the TWRS Technical Baseline. The document consists of several text sections that provide the purpose, scope, background information, and an explanation of how this document assists the application of Systems Engineering to the TWRS. The primary functions identified in the TWRS Functions and Requirements Document are identified in Figure 4.1 (Section 4.0) Currently, this document is part of the overall effort to develop the TWRS Functional Requirements Baseline, and contains the functions and requirements needed to properly define the top three TWRS function levels. TWRS Technicalmore » Baseline information (RDD-100 database) included in the appendices of the attached document contain the TWRS functions, requirements, and architecture necessary to define the TWRS Functional Requirements Baseline. Document organization and user directions are provided in the introductory text. This document will continue to be modified during the TWRS life-cycle.« less

20 CFR 655.167 - Document retention requirements.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Document retention requirements. 655.167... retention requirements. (a) Entities required to retain documents. All employers filing an Application for... retain the documents and records proving compliance with this subpart. (b) Period of required retention...

24 CFR 5.502 - Requirements concerning documents.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 24 Housing and Urban Development 1 2010-04-01 2010-04-01 false Requirements concerning documents... § 5.502 Requirements concerning documents. For any notice or document (decision, declaration, consent... regulations for requirements concerning communications with persons with disabilities.) ...

Predicting the Underwater Sound of Moderate and Heavy Rainfall from Laboratory Measurements of Radiation from Single Large Raindrops

DTIC Science & Technology

1992-03-01

Elementary Linear Algebra with Applications, pp. 301- 323, John Wiley and Sons Inc., 1987. Atlas, D., and Ulbrich, C. E. W., "The Physical Basis for...vector drd In this case, the linear system is said to be inconsistent ( Anton and Rorres, 1987). In contrast, for an underdetermined system (where the...ocean acoustical tomography and seismology. In simplest terms, the general linear inverse problem consists of fimding the desired solution to a set of m

76 FR 26750 - Agency Information Collection Activities: Documentation Requirements for Articles Entered Under...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-09

... Activities: Documentation Requirements for Articles Entered Under Various Special Tariff Treatment Provisions...: Documentation Requirements for Articles Entered Under Various Special Tariff Treatment Provisions. This request... collection: Title: Documentation Requirements for Articles Entered Under Various Special Tariff Treatment...

76 FR 39416 - Agency Information Collection Activities: Documentation Requirements for Articles Entered Under...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-06

... Activities: Documentation Requirements for Articles Entered Under Various Special Tariff Treatment Provisions... accordance with the Paperwork Reduction Act: Documentation Requirements for Articles Entered Under Various... techniques or other forms of information. Title: Documentation Requirements for Articles Entered Under...

5 CFR 1315.9 - Required documentation.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 3 2010-01-01 2010-01-01 false Required documentation. 1315.9 Section 1315.9 Administrative Personnel OFFICE OF MANAGEMENT AND BUDGET OMB DIRECTIVES PROMPT PAYMENT § 1315.9 Required documentation. Agencies are required to ensure the following payment documentation is established...

Spectrum analysis on quality requirements consideration in software design documents.

PubMed

Kaiya, Haruhiko; Umemura, Masahiro; Ogata, Shinpei; Kaijiri, Kenji

2013-12-01

Software quality requirements defined in the requirements analysis stage should be implemented in the final products, such as source codes and system deployment. To guarantee this meta-requirement, quality requirements should be considered in the intermediate stages, such as the design stage or the architectural definition stage. We propose a novel method for checking whether quality requirements are considered in the design stage. In this method, a technique called "spectrum analysis for quality requirements" is applied not only to requirements specifications but also to design documents. The technique enables us to derive the spectrum of a document, and quality requirements considerations in the document are numerically represented in the spectrum. We can thus objectively identify whether the considerations of quality requirements in a requirements document are adapted to its design document. To validate the method, we applied it to commercial software systems with the help of a supporting tool, and we confirmed that the method worked well.

50 CFR 300.185 - Documentation, reporting and recordkeeping requirements for consignment documents and re-export...

Code of Federal Regulations, 2012 CFR

2012-10-01

... recordkeeping requirements for consignment documents and re-export certificates. 300.185 Section 300.185..., reporting and recordkeeping requirements for consignment documents and re-export certificates. (a) Imports... apply only to entries for consumption. The reporting requirements of paragraph (a)(3) of this section do...

50 CFR 300.185 - Documentation, reporting and recordkeeping requirements for consignment documents and re-export...

Code of Federal Regulations, 2014 CFR

2014-10-01

... recordkeeping requirements for consignment documents and re-export certificates. 300.185 Section 300.185..., reporting and recordkeeping requirements for consignment documents and re-export certificates. (a) Imports... apply only to entries for consumption. The reporting requirements of paragraph (a)(3) of this section do...

50 CFR 300.185 - Documentation, reporting and recordkeeping requirements for consignment documents and re-export...

Code of Federal Regulations, 2013 CFR

2013-10-01

... recordkeeping requirements for consignment documents and re-export certificates. 300.185 Section 300.185..., reporting and recordkeeping requirements for consignment documents and re-export certificates. (a) Imports... apply only to entries for consumption. The reporting requirements of paragraph (a)(3) of this section do...

22 CFR 40.71 - Documentation requirements for immigrants.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Documentation requirements for immigrants. 40... NONIMMIGRANTS AND IMMIGRANTS UNDER THE IMMIGRATION AND NATIONALITY ACT, AS AMENDED Documentation Requirements § 40.71 Documentation requirements for immigrants. INA 212(a)(7)(A) is not applicable at the time of...

Basic Hitchhiker Payload Requirements

NASA Technical Reports Server (NTRS)

Horan, Stephen

1999-01-01

This document lists the requirements for the NMSU Hitchhiker experiment payload that were developed as part of the EE 498/499 Capstone Design class during the 1999-2000 academic year. This document is used to describe the system needs as described in the mission document. The requirements listed here are those primarily used to generate the basic electronic and data processing requirements developed in the class design document. The needs of the experiment components are more fully described in the draft NASA hitchhiker customer requirements document. Many of the details for the overall payload are given in full detail in the NASA hitchhiker documentation.

Functions and requirements document for interim store solidified high-level and transuranic waste

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith-Fewell, M.A., Westinghouse Hanford

1996-05-17

The functions, requirements, interfaces, and architectures contained within the Functions and Requirements (F{ampersand}R) Document are based on the information currently contained within the TWRS Functions and Requirements database. The database also documents the set of technically defensible functions and requirements associated with the solidified waste interim storage mission.The F{ampersand}R Document provides a snapshot in time of the technical baseline for the project. The F{ampersand}R document is the product of functional analysis, requirements allocation and architectural structure definition. The technical baseline described in this document is traceable to the TWRS function 4.2.4.1, Interim Store Solidified Waste, and its related requirements, architecture,more » and interfaces.« less

Cue-elicited craving for food: a fresh approach to the study of binge eating.

PubMed

Sobik, Laura; Hutchison, Kent; Craighead, Linda

2005-06-01

Recent research has indicated that craving for food can be elicited by exposure to food cues, suggesting that exposure to food cues may represent a useful experimental paradigm to investigate mechanisms related to binge eating. The first objective of the present research was to replicate previous reports that exposure to food cues elicits craving for food. In addition, this investigation was designed to extend the extant literature by testing the effects of 'priming' portions of food, by examining the association between reactivity to food cues and indicators of binge eating, and to examine the role of a putative genetic factor previously found to be associated with cue-elicited craving for alcohol and tobacco. In Study 1, 48 individuals completed measures of craving and mood after exposure to control cues, after exposure to food cues, and after consuming each of three small portions of food. In Study 2, 31 individuals with subclinical symptoms of binge eating completed the same procedures. The results suggested that food cues reliably elicited craving, increased attention to the cues, and decreased positive affect in both samples, although reactivity was greater among the sample with greater eating pathology. Correlational analyses suggested that reactivity to food cues was correlated with binge eating and body mass index among women but not men. Results also suggest that the DRD4 VNTR polymorphism influences cue-elicited craving for food, although the influence of the DRD4 may depend on the population under study.

Differential genetic susceptibility to child risk at birth in predicting observed maternal behavior.

PubMed

Fortuna, Keren; van Ijzendoorn, Marinus H; Mankuta, David; Kaitz, Marsha; Avinun, Reut; Ebstein, Richard P; Knafo, Ariel

2011-01-01

This study examined parenting as a function of child medical risks at birth and parental genotype (dopamine D4 receptor; DRD4). Our hypothesis was that the relation between child risks and later maternal sensitivity would depend on the presence/absence of a genetic variant in the mothers, thus revealing a gene by environment interaction (GXE). Risk at birth was defined by combining risk indices of children's gestational age at birth, birth weight, and admission to the neonatal intensive care unit. The DRD4-III 7-repeat allele was chosen as a relevant genotype as it was recently shown to moderate the effect of environmental stress on parental sensitivity. Mothers of 104 twin pairs provided DNA samples and were observed with their children in a laboratory play session when the children were 3.5 years old. Results indicate that higher levels of risk at birth were associated with less sensitive parenting only among mothers carrying the 7-repeat allele, but not among mothers carrying shorter alleles. Moreover, mothers who are carriers of the 7-repeat allele and whose children scored low on the risk index were observed to have the highest levels of sensitivity. These findings provide evidence for the interactive effects of genes and environment (in this study, children born at higher risk) on parenting, and are consistent with a genetic differential susceptibility model of parenting by demonstrating that some parents are inherently more susceptible to environmental influences, both good and bad, than are others.

Identification of G Protein-Coupled Receptors (GPCRs) in Primary Cilia and Their Possible Involvement in Body Weight Control.

PubMed

Omori, Yoshihiro; Chaya, Taro; Yoshida, Satoyo; Irie, Shoichi; Tsujii, Toshinori; Furukawa, Takahisa

2015-01-01

Primary cilia are sensory organelles that harbor various receptors such as G protein-coupled receptors (GPCRs). We analyzed subcellular localization of 138 non-odorant GPCRs. We transfected GPCR expression vectors into NIH3T3 cells, induced ciliogenesis by serum starvation, and observed subcellular localization of GPCRs by immunofluorescent staining. We found that several GPCRs whose ligands are involved in feeding behavior, including prolactin-releasing hormone receptor (PRLHR), neuropeptide FF receptor 1 (NPFFR1), and neuromedin U receptor 1 (NMUR1), localized to the primary cilia. In addition, we found that a short form of dopamine receptor D2 (DRD2S) is efficiently transported to the primary cilia, while a long form of dopamine receptor D2 (DRD2L) is rarely transported to the primary cilia. Using an anti-Prlhr antibody, we found that Prlhr localized to the cilia on the surface of the third ventricle in the vicinity of the hypothalamic periventricular nucleus. We generated the Npy2r-Cre transgenic mouse line in which Cre-recombinase is expressed under the control of the promoter of Npy2r encoding a ciliary GPCR. By mating Npy2r-Cre mice with Ift80 flox mice, we generated Ift80 conditional knockout (CKO) mice in which Npy2r-positive cilia were diminished in number. We found that Ift80 CKO mice exhibited a body weight increase. Our results suggest that Npy2r-positive cilia are important for body weight control.

Living in the moment: Effects of time perspective and emotional valence of episodic thinking on delay discounting

PubMed Central

Lin, Henry; Epstein, Leonard H.

2014-01-01

Excessive delay discounting (DD) has been related to various maladaptive behaviors, and may stem from a myopic focus on immediate gratification. Neuroimaging studies have shown that episodic future thinking (EFT) – vivid mental simulation of future experiences – may reduce DD by promoting consideration of delayed outcomes. However, the EFT manipulations in these experiments may have induced positive affect, which could independently enhance executive functions that facilitate self-regulation. To clarify the mechanism of this effect, 87 participants were randomized to visualize neutral- or positive-valenced events expected to occur in the present or in the future while completing a standardized DD questionnaire. Working memory capacity, inhibitory control, the genotypes of 3 functional dopaminergic polymorphisms (DRD1 rs686, DRD2 rs1800497 and COMT rs4680), as well as an additive dopamine genetic risk score were assessed as potential moderators. The results indicate that EFT reduces DD primarily by shifting the time perspective of intertemporal decision-making, and that this effect is moderated by working memory capacity. In addition, positive episodic thinking may independently attenuate the protective effects of high working memory capacity, high inhibitory control, and lower dopamine genetic risk scores on DD. The current findings dovetail with previous research to suggest that the time perspective and emotional valence of episodic thinking may dynamically shape intertemporal choice, perhaps in part by transiently modulating executive function and dopaminergic neurotransmission. PMID:24512061

Effects of dopamine D2 receptor (DRD2) and transporter (SLC6A3) polymorphisms on smoking cue-induced cigarette craving among African-American smokers.

PubMed

Erblich, J; Lerman, C; Self, D W; Diaz, G A; Bovbjerg, D H

2005-04-01

Cue-induced craving for addictive substances has long been known to contribute to the problem of persistent addiction in humans. Research in animals over the past decade has solidly established the central role of dopamine in cue-induced craving for addictive substances, including nicotine. Analogous studies in humans, however, are lacking, especially among African-American smokers, who have lower quit rates than Caucasian smokers. Based on the animal literature, the study's objective was to test the hypothesis that smokers carrying specific variants in dopamine-related genes previously associated with risk for addictive behaviors would exhibit heightened levels of cigarette craving following laboratory exposure to cues. To this end, cigarette craving was induced in healthy African-American smokers (n=88) through laboratory exposure to smoking cues. Smokers carrying either the DRD2 (D2 dopamine receptor gene) TaqI A1 RFLP or the SLC6A3 (dopamine transporter gene) 9-repeat VNTR polymorphisms had stronger cue-induced cravings than noncarriers (Ps <0.05 and 0.01, respectively). Consistent with the separate biological pathways involved (receptor, transporter), carriers of both polymorphisms had markedly higher craving responses compared to those with neither (P<0.0006), reflecting additive effects. Findings provide support for the role of dopamine in cue-induced craving in humans, and suggest a possible genetic risk factor for persistent smoking behavior in African-American smokers.

Fine-resolution voxel S values for constructing absorbed dose distributions at variable voxel size.

PubMed

Dieudonné, Arnaud; Hobbs, Robert F; Bolch, Wesley E; Sgouros, George; Gardin, Isabelle

2010-10-01

This article presents a revised voxel S values (VSVs) approach for dosimetry in targeted radiotherapy, allowing dose calculation for any voxel size and shape of a given SPECT or PET dataset. This approach represents an update to the methodology presented in MIRD pamphlet no. 17. VSVs were generated in soft tissue with a fine spatial sampling using the Monte Carlo (MC) code MCNPX for particle emissions of 9 radionuclides: (18)F, (90)Y, (99m)Tc, (111)In, (123)I, (131)I, (177)Lu, (186)Re, and (201)Tl. A specific resampling algorithm was developed to compute VSVs for desired voxel dimensions. The dose calculation was performed by convolution via a fast Hartley transform. The fine VSVs were calculated for cubic voxels of 0.5 mm for electrons and 1.0 mm for photons. Validation studies were done for (90)Y and (131)I VSV sets by comparing the revised VSV approach to direct MC simulations. The first comparison included 20 spheres with different voxel sizes (3.8-7.7 mm) and radii (4-64 voxels) and the second comparison a hepatic tumor with cubic voxels of 3.8 mm. MC simulations were done with MCNPX for both. The third comparison was performed on 2 clinical patients with the 3D-RD (3-Dimensional Radiobiologic Dosimetry) software using the EGSnrc (Electron Gamma Shower National Research Council Canada)-based MC implementation, assuming a homogeneous tissue-density distribution. For the sphere model study, the mean relative difference in the average absorbed dose was 0.20% ± 0.41% for (90)Y and -0.36% ± 0.51% for (131)I (n = 20). For the hepatic tumor, the difference in the average absorbed dose to tumor was 0.33% for (90)Y and -0.61% for (131)I and the difference in average absorbed dose to the liver was 0.25% for (90)Y and -1.35% for (131)I. The comparison with the 3D-RD software showed an average voxel-to-voxel dose ratio between 0.991 and 0.996. The calculation time was below 10 s with the VSV approach and 50 and 15 h with 3D-RD for the 2 clinical patients. This new VSV approach enables the calculation of absorbed dose based on a SPECT or PET cumulated activity map, with good agreement with direct MC methods, in a faster and more clinically compatible manner.

ICESat (GLAS) Science Processing Software Document Series. Volume 3; GLAS Science Software Requirements Document; Ver 2.1

NASA Technical Reports Server (NTRS)

Jester, Peggy L.; Lee, Jeffrey; Zukor, Dorothy J. (Technical Monitor)

2001-01-01

This document addresses the software requirements of the Geoscience Laser Altimeter System (GLAS) Standard Data Software (SDS) supporting the GLAS instrument on the EOS ICESat Spacecraft. This Software Requirements Document represents the initial collection of the technical engineering information for the GLAS SDS. This information is detailed within the second of four main volumes of the Standard documentation, the Product Specification volume. This document is a "roll-out" from the governing volume outline containing the Concept and Requirements sections.

10 CFR 1707.203 - Filing requirements for demands or requests for documents or testimony.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 4 2011-01-01 2011-01-01 false Filing requirements for demands or requests for documents... Production of Documents § 1707.203 Filing requirements for demands or requests for documents or testimony. You must comply with the following requirements whenever you issue demands or requests to a DNFSB...

Research on Generating Method of Embedded Software Test Document Based on Dynamic Model

NASA Astrophysics Data System (ADS)

Qu, MingCheng; Wu, XiangHu; Tao, YongChao; Liu, Ying

2018-03-01

This paper provides a dynamic model-based test document generation method for embedded software that provides automatic generation of two documents: test requirements specification documentation and configuration item test documentation. This method enables dynamic test requirements to be implemented in dynamic models, enabling dynamic test demand tracking to be easily generated; able to automatically generate standardized, standardized test requirements and test documentation, improved document-related content inconsistency and lack of integrity And other issues, improve the efficiency.

48 CFR 11.101 - Order of precedence for requirements documents.

Code of Federal Regulations, 2011 CFR

2011-10-01

.... (2) Performance-oriented documents (e.g., a PWS or SOO). (See 2.101.) (3) Detailed design-oriented... requirements documents. 11.101 Section 11.101 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION ACQUISITION PLANNING DESCRIBING AGENCY NEEDS Selecting and Developing Requirements Documents 11...

SIENA Customer Problem Statement and Requirements

DOE Office of Scientific and Technical Information (OSTI.GOV)

L. Sauer; R. Clay; C. Adams

2000-08-01

This document describes the problem domain and functional requirements of the SIENA framework. The software requirements and system architecture of SIENA are specified in separate documents (called SIENA Software Requirement Specification and SIENA Software Architecture, respectively). While currently this version of the document describes the problems and captures the requirements within the Analysis domain (concentrating on finite element models), it is our intention to subsequent y expand this document to describe problems and capture requirements from the Design and Manufacturing domains. In addition, SIENA is designed to be extendible to support and integrate elements from the other domains (see SIENAmore » Software Architecture document).« less

45 CFR 164.316 - Policies and procedures and documentation requirements.

Code of Federal Regulations, 2013 CFR

2013-10-01

... when it last was in effect, whichever is later. (ii) Availability (Required). Make documentation.... (iii) Updates (Required). Review documentation periodically, and update as needed, in response to...

20 CFR 655.1319 - Document retention requirements.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Document retention requirements. 655.1319... Employment in the United States (H-2A Workers) § 655.1319 Document retention requirements. (a) Entities... retention. Records and documents must be retained for a period of 3 years from the date of certification of...

46 CFR 67.105 - Requirement for determination.

Code of Federal Regulations, 2013 CFR

2013-10-01

... DOCUMENTATION OF VESSELS Tonnage and Dimension Requirements for Vessel Documentation § 67.105 Requirement for determination. The gross and net tonnage and dimensions of a vessel must be determined: (a) For initial documentation; (b) Whenever there is a change in the gross or net tonnage or dimensions of a documented vessel...

46 CFR 67.105 - Requirement for determination.

Code of Federal Regulations, 2014 CFR

2014-10-01

... DOCUMENTATION OF VESSELS Tonnage and Dimension Requirements for Vessel Documentation § 67.105 Requirement for determination. The gross and net tonnage and dimensions of a vessel must be determined: (a) For initial documentation; (b) Whenever there is a change in the gross or net tonnage or dimensions of a documented vessel...

46 CFR 67.105 - Requirement for determination.

Code of Federal Regulations, 2012 CFR

2012-10-01

... DOCUMENTATION OF VESSELS Tonnage and Dimension Requirements for Vessel Documentation § 67.105 Requirement for determination. The gross and net tonnage and dimensions of a vessel must be determined: (a) For initial documentation; (b) Whenever there is a change in the gross or net tonnage or dimensions of a documented vessel...

46 CFR 67.105 - Requirement for determination.

Code of Federal Regulations, 2010 CFR

2010-10-01

... DOCUMENTATION OF VESSELS Tonnage and Dimension Requirements for Vessel Documentation § 67.105 Requirement for determination. The gross and net tonnage and dimensions of a vessel must be determined: (a) For initial documentation; (b) Whenever there is a change in the gross or net tonnage or dimensions of a documented vessel...

46 CFR 67.105 - Requirement for determination.

Code of Federal Regulations, 2011 CFR

2011-10-01

... DOCUMENTATION OF VESSELS Tonnage and Dimension Requirements for Vessel Documentation § 67.105 Requirement for determination. The gross and net tonnage and dimensions of a vessel must be determined: (a) For initial documentation; (b) Whenever there is a change in the gross or net tonnage or dimensions of a documented vessel...

25 CFR 559.7 - May a tribe submit documents required by this part electronically?

Code of Federal Regulations, 2013 CFR

2013-04-01

... 25 Indians 2 2013-04-01 2013-04-01 false May a tribe submit documents required by this part... NOTIFICATIONS AND SUBMISSIONS § 559.7 May a tribe submit documents required by this part electronically? Yes. Tribes wishing to submit documents electronically should contact the Commission for guidance on...

25 CFR 559.7 - May a tribe submit documents required by this part electronically?

Code of Federal Regulations, 2014 CFR

2014-04-01

... 25 Indians 2 2014-04-01 2014-04-01 false May a tribe submit documents required by this part... NOTIFICATIONS AND SUBMISSIONS § 559.7 May a tribe submit documents required by this part electronically? Yes. Tribes wishing to submit documents electronically should contact the Commission for guidance on...

42 CFR 102.53 - Documentation a survivor must submit to be deemed eligible by the Secretary.

Code of Federal Regulations, 2012 CFR

2012-10-01

... AND HUMAN SERVICES VACCINES SMALLPOX COMPENSATION PROGRAM Required Documentation To Be Deemed Eligible... documentation required in: (1) Section 102.51(a)(2)-(4) (documentation requirements for smallpox vaccine recipients), in the case of a deceased smallpox vaccine recipient. The survivor requester may submit a...

42 CFR 102.53 - Documentation a survivor must submit to be deemed eligible by the Secretary.

Code of Federal Regulations, 2014 CFR

2014-10-01

... AND HUMAN SERVICES VACCINES SMALLPOX COMPENSATION PROGRAM Required Documentation To Be Deemed Eligible... documentation required in: (1) Section 102.51(a)(2)-(4) (documentation requirements for smallpox vaccine recipients), in the case of a deceased smallpox vaccine recipient. The survivor requester may submit a...

42 CFR 102.53 - Documentation a survivor must submit to be deemed eligible by the Secretary.

Code of Federal Regulations, 2013 CFR

2013-10-01

... AND HUMAN SERVICES VACCINES SMALLPOX COMPENSATION PROGRAM Required Documentation To Be Deemed Eligible... documentation required in: (1) Section 102.51(a)(2)-(4) (documentation requirements for smallpox vaccine recipients), in the case of a deceased smallpox vaccine recipient. The survivor requester may submit a...

42 CFR 102.53 - Documentation a survivor must submit to be deemed eligible by the Secretary.

Code of Federal Regulations, 2011 CFR

2011-10-01

... AND HUMAN SERVICES VACCINES SMALLPOX COMPENSATION PROGRAM Required Documentation To Be Deemed Eligible... documentation required in: (1) Section 102.51(a)(2)-(4) (documentation requirements for smallpox vaccine recipients), in the case of a deceased smallpox vaccine recipient. The survivor requester may submit a...

42 CFR 102.53 - Documentation a survivor must submit to be deemed eligible by the Secretary.

Code of Federal Regulations, 2010 CFR

2010-10-01

... AND HUMAN SERVICES VACCINES SMALLPOX COMPENSATION PROGRAM Required Documentation To Be Deemed Eligible... documentation required in: (1) Section 102.51(a)(2)-(4) (documentation requirements for smallpox vaccine recipients), in the case of a deceased smallpox vaccine recipient. The survivor requester may submit a...

Preliminary evidence that negative symptom severity relates to multilocus genetic profile for dopamine signaling capacity and D2 receptor binding in healthy controls and in schizophrenia.

PubMed

Eisenstein, Sarah A; Bogdan, Ryan; Chen, Ling; Moerlein, Stephen M; Black, Kevin J; Perlmutter, Joel S; Hershey, Tamara; Barch, Deanna M

2017-03-01

Deficits in central, subcortical dopamine (DA) signaling may underlie negative symptom severity, particularly anhedonia, in healthy individuals and in schizophrenia. To investigate these relationships, we assessed negative symptoms with the Schedule for the Assessment of Negative Symptoms and the Brief Negative Symptom Scale (BNSS) and self-reported anhedonia with the Scales for Physical and Social Anhedonia (SPSA), Temporal Experience of Pleasure Scale, and Snaith-Hamilton Pleasure Scale in 36 healthy controls (HC), 27 siblings (SIB) of individuals with schizophrenia, and 66 individuals with schizophrenia or schizoaffective disorder (SCZ). A subset of participants (N = 124) were genotyped for DA-related polymorphisms in genes for DRD4, DRD2/ANKK1, DAT1, and COMT, which were used to construct biologically-informed multi-locus genetic profile (MGP) scores reflective of subcortical dopaminergic signaling. DA receptor type 2 (D2R) binding was assessed among a second subset of participants (N = 23) using PET scans with the D2R-selective, non-displaceable radioligand (N-[ 11 C]methyl)benperidol. Higher MGP scores, reflecting elevated subcortical dopaminergic signaling capacity, were associated with less negative symptom severity, as measured by the BNSS, across all participants. In addition, higher striatal D2R binding was associated with less physical and social anhedonia, as measured by the SPSA, across HC, SIB, and SCZ. The current preliminary findings support the hypothesis that subcortical DA function may contribute to negative symptom severity and self-reported anhedonia, independent of diagnostic status. Copyright © 2016 Elsevier Ltd. All rights reserved.

Dopamine receptor D2 (DRD2), dopamine transporter solute carrier family C6, member 4 (SLC6A3), and catechol-O-methyltransferase (COMT) genes as moderators of the relation between maternal history of maltreatment and infant emotion regulation.

PubMed

Villani, Vanessa; Ludmer, Jaclyn; Gonzalez, Andrea; Levitan, Robert; Kennedy, James; Masellis, Mario; Basile, Vincenzo S; Wekerle, Christine; Atkinson, Leslie

2018-05-01

Although infants less than 18 months old are capable of engaging in self-regulatory behavior (e.g., avoidance, withdrawal, and orienting to other aspects of their environment), the use of self-regulatory strategies at this age (as opposed to relying on caregivers) is associated with elevated behavioral and physiological distress. This study investigated infant dopamine-related genotypes (dopamine receptor D2 [DRD2], dopamine transporter solute carrier family C6, member 4 [SLC6A3], and catechol-O-methyltransferase [COMT]) as they interact with maternal self-reported history of maltreatment to predict observed infant independent emotion regulation behavior. A community sample (N = 193) of mother-infant dyads participated in a toy frustration challenge at infant age 15 months, and infant emotion regulation behavior was coded. Buccal cells were collected for genotyping. Maternal maltreatment history significantly interacted with infant SLC6A3 and COMT genotypes, such that infants with more 10-repeat and valine alleles of SLC6A3 and COMT, respectively, relative to infants with fewer or no 10-repeat and valine alleles, utilized more independent (i.e., maladaptive) regulatory behavior if mother reported a more extensive maltreatment history, as opposed to less. The findings indicate that child genetic factors moderate the intergenerational impact of maternal maltreatment history. The results are discussed in terms of potential mechanism of Gene × Environment interaction.

Preliminary Evidence that Negative Symptom Severity Relates to Multilocus Genetic Profile for Dopamine Signaling Capacity and D2 Receptor Binding in Healthy Controls and in Schizophrenia

PubMed Central

Eisenstein, Sarah A.; Bogdan, Ryan; Chen, Ling; Moerlein, Stephen M.; Black, Kevin J.; Perlmutter, Joel S.; Hershey, Tamara; Barch, Deanna M.

2017-01-01

Deficits in central, subcortical dopamine (DA) signaling may underlie negative symptom severity, particularly anhedonia, in healthy individuals and in schizophrenia. To investigate these relationships, we assessed negative symptoms with the Schedule for the Assessment of Negative Symptoms and the Brief Negative Symptom Scale (BNSS) and self-reported anhedonia with the Scales for Physical and Social Anhedonia (SPSA), Temporal Experience of Pleasure Scale, and Snaith-Hamilton Pleasure Scale in 36 healthy controls (HC), 27 siblings (SIB) of individuals with schizophrenia, and 66 individuals with schizophrenia or schizoaffective disorder (SCZ). A subset of participants (N = 124) were genotyped for DA-related polymorphisms in genes for DRD4, DRD2/ANKK1, DAT1, and COMT, which were used to construct biologically-informed multi-locus genetic profile (MGP) scores reflective of subcortical dopaminergic signaling. DA receptor type 2 (D2R) binding was assessed among a second subset of participants (N = 23) using PET scans with the D2R-selective, non-displaceable radioligand (N-[11C]methyl)benperidol. Higher MGP scores, reflecting elevated subcortical dopaminergic signaling capacity, were associated with less negative symptom severity, as measured by the BNSS, across all participants. In addition, higher striatal D2R binding was associated with less physical and social anhedonia, as measured by the SPSA, across HC, SIB, and SCZ. The current preliminary findings support the hypothesis that subcortical DA function may contribute to negative symptom severity and self-reported anhedonia, independent of diagnostic status. PMID:27886638

[Genetic association between the reduced amplitude of the P300 and the allele A1 of the gene which codifies the D2 dopamine receptor (DRD2) as possible biological markers for alcoholism].

PubMed

Nácher, V

Over the last twenty years much work has been done to study the P300 in alcoholism. A systematically reduced amplitude, both in patients and in populations at risk (children of alcoholics) was found. Besides, studies on twins indicate that the waves of the evoked potentials are under genetic control. Furthermore, advances in molecular genetic techniques have clarified the part played by the allele A1 of the gene which codifies the D2 dopamine receptor in alcoholism. Only in recent years have studies been published relating them and in these they are considered to be risk markers for alcoholism. However, contradictory results have been obtained. The objective of this study is to review part of the literature and find evidence for and against the characteristics observed in the P300 and the possible part played by the DRD2 gene in the aetiology of alcoholism and the relationship between them. At the same time we consider the most relevant theoretical aspects of the role played by dopamine in the central nervous system, since some studies have shown that it is involved in the generation of P300 and reinforcement due to alcohol consumptions. Finally, we discuss the advantages and disadvantages that should be taken into account when considering the low amplitude of P300 and the presence of the A1 allele as diagnostic markers to identify populations at risk and thus avoid appearance of the disorder.

Distress and Its Effect on Adherence to Antidiabetic Medications Among Type 2 Diabetes Patients in Coastal South India

PubMed Central

Kumar, Nithin; Unnikrishnan, Bhaskaran; Thapar, Rekha; Mithra, Prasanna; Kulkarni, Vaman; Holla, Ramesh; Bhagawan, Darshan; Kumar, Avinash; Aithal, Shodhan

2017-01-01

Background: Distress can bring about an unfavorable attitude among the patients toward tackling their disease which can affect adherence to medications. The purpose of this study was to assess the effect of distress on adherence to medication among patients with diabetes. Methodology: In this cross-sectional study, 124 type 2 diabetes patients above 18 years, attending the hospitals affiliated to Kasturba Medical College, Mangalore, selected using nonprobability sampling were interviewed to assess the presence of diabetes-related distress (DRD) and their level of adherence to medications. Distress was assessed using diabetes distress scale. Morisky Adherence Questionnaire was used to assess the level of adherence. Approval was obtained from the Institutional Ethics Committee. Multivariate logistic regression was conducted to assess the influence of domains of distress on adherence to antidiabetic medication and P < 0.05 was considered statistically significant. Results: In our study, 41.9% (n = 52) of the participants had high diabetes distress. Exactly 43.5% (n = 54) of the participants had low adherence to antidiabetic medications. On univariate analysis, participants with low regimen distress, low physician distress, and low interpersonal distress were found to have good adherence to antidiabetic medication. However, on multivariate analysis, only low regimen distress was found to be significantly associated with good adherence to medication among the study participants. Conclusion: DRD is a problem in our study participants which affects the adherence to medications. Identifying distress at an early stage can help doctors formulate and implement remedial measures, thereby improving adherence to medications. PMID:28781491

Striatal Neurons Expressing D1 and D2 Receptors are Morphologically Distinct and Differently Affected by Dopamine Denervation in Mice

PubMed Central

Gagnon, D.; Petryszyn, S.; Sanchez, M. G.; Bories, C.; Beaulieu, J. M.; De Koninck, Y.; Parent, A.; Parent, M.

2017-01-01

The loss of nigrostriatal dopamine neurons in Parkinson’s disease induces a reduction in the number of dendritic spines on medium spiny neurons (MSNs) of the striatum expressing D1 or D2 dopamine receptor. Consequences on MSNs expressing both receptors (D1/D2 MSNs) are currently unknown. We looked for changes induced by dopamine denervation in the density, regional distribution and morphological features of D1/D2 MSNs, by comparing 6-OHDA-lesioned double BAC transgenic mice (Drd1a-tdTomato/Drd2-EGFP) to sham-lesioned animals. D1/D2 MSNs are uniformly distributed throughout the dorsal striatum (1.9% of MSNs). In contrast, they are heterogeneously distributed and more numerous in the ventral striatum (14.6% in the shell and 7.3% in the core). Compared to D1 and D2 MSNs, D1/D2 MSNs are endowed with a smaller cell body and a less profusely arborized dendritic tree with less dendritic spines. The dendritic spine density of D1/D2 MSNs, but also of D1 and D2 MSNs, is significantly reduced in 6-OHDA-lesioned mice. In contrast to D1 and D2 MSNs, the extent of dendritic arborization of D1/D2 MSNs appears unaltered in 6-OHDA-lesioned mice. Our data indicate that D1/D2 MSNs in the mouse striatum form a distinct neuronal population that is affected differently by dopamine deafferentation that characterizes Parkinson’s disease. PMID:28128287

Striatal Neurons Expressing D1 and D2 Receptors are Morphologically Distinct and Differently Affected by Dopamine Denervation in Mice.

PubMed

Gagnon, D; Petryszyn, S; Sanchez, M G; Bories, C; Beaulieu, J M; De Koninck, Y; Parent, A; Parent, M

2017-01-27

The loss of nigrostriatal dopamine neurons in Parkinson's disease induces a reduction in the number of dendritic spines on medium spiny neurons (MSNs) of the striatum expressing D 1 or D 2 dopamine receptor. Consequences on MSNs expressing both receptors (D 1 /D 2 MSNs) are currently unknown. We looked for changes induced by dopamine denervation in the density, regional distribution and morphological features of D 1 /D 2 MSNs, by comparing 6-OHDA-lesioned double BAC transgenic mice (Drd1a-tdTomato/Drd2-EGFP) to sham-lesioned animals. D 1 /D 2 MSNs are uniformly distributed throughout the dorsal striatum (1.9% of MSNs). In contrast, they are heterogeneously distributed and more numerous in the ventral striatum (14.6% in the shell and 7.3% in the core). Compared to D 1 and D 2 MSNs, D 1 /D 2 MSNs are endowed with a smaller cell body and a less profusely arborized dendritic tree with less dendritic spines. The dendritic spine density of D 1 /D 2 MSNs, but also of D 1 and D 2 MSNs, is significantly reduced in 6-OHDA-lesioned mice. In contrast to D 1 and D 2 MSNs, the extent of dendritic arborization of D 1 /D 2 MSNs appears unaltered in 6-OHDA-lesioned mice. Our data indicate that D 1 /D 2 MSNs in the mouse striatum form a distinct neuronal population that is affected differently by dopamine deafferentation that characterizes Parkinson's disease.

Effects of short- and long-term risperidone treatment on prolactin levels in children with autism.

PubMed

Anderson, George M; Scahill, Lawrence; McCracken, James T; McDougle, Christopher J; Aman, Michael G; Tierney, Elaine; Arnold, L Eugene; Martin, Andrés; Katsovich, Liliya; Posey, David J; Shah, Bhavik; Vitiello, Benedetto

2007-02-15

The effects of short- and long-term risperidone treatment on serum prolactin were assessed in children and adolescents with autism. Patients with autism (N = 101, 5-17 years of age) were randomized to an 8-week trial of risperidone or placebo and 63 then took part in a 4-month open-label follow-up phase. Serum samples were obtained at Baseline and Week-8 (N = 78), and at 6-month (N = 43) and 22-month (N = 30) follow-up. Serum prolactin was determined by immunoradiometric assay; dopamine type-2 receptor (DRD2) polymorphisms were genotyped. Baseline prolactin levels were similar in the risperidone (N = 42) and placebo (N = 36) groups (9.3 +/- 7.5 and 9.3 +/- 7.6 ng/ml, respectively). After 8 weeks of risperidone, prolactin increased to 39.0 +/- 19.2 ng/ml, compared with 10.1 +/- 8.8 ng/ml for placebo (p < .0001). Prolactin levels were also significantly increased at 6 months (32.4 +/- 17.8 ng/ml; N = 43, p < .0001) and at 22 months (N = 30, 25.3 +/- 15.6 ng/ml, p < .0001). Prolactin levels were not associated with adverse effects and DRD2 alleles (Taq1A, -141C Ins/Del, C957T) did not significantly influence baseline levels or risperidone-induced increases in prolactin. Risperidone treatment was associated with two- to four-fold mean increases in serum prolactin in children with autism. Although risperidone-induced increases tended to diminish with time, further research on the consequences of long-term prolactin elevations in children and adolescents is needed.

Diversity in Pathways to Common Childhood Disruptive Behavior Disorders

PubMed Central

Martel, Michelle M.; Nikolas, Molly; Jernigan, Katherine; Friderici, Karen; Nigg, Joel T.

2014-01-01

Oppositional-Defiant Disorder (ODD) and Attention-Deficit/Hyperactivity Disorder (ADHD) are highly comorbid, a phenomenon thought to be due to shared etiological factors and mechanisms. Little work has attempted to chart multiple-level-of-analysis pathways (i.e., simultaneously including biological, environmental, and trait influences) to ODD and ADHD, the goal of the present investigation. 559 children/adolescents (325 boys) between the ages of 6 and 18 participated in a multi-stage, comprehensive diagnostic procedure. 148 were classified as ODD; 309 were classified as ADHD, based on parent, teacher, and clinician ratings. Children provided buccal or salivary samples of DNA, assayed for select markers in DRD4 and 5HTT. Parents completed the Alabama Parenting Questionnaire and the California Q-Sort. Children completed the Child Perception of Interparental Conflict Scale. Correlational associations consistent with multiple-level-of-analysis pathways to ODD and ADHD emerged. For ODD, children with the short allele of the 5HTT promoter polymorphism had higher neuroticism and ODD symptoms regardless of level of self-blame in relation to inter-parental conflict, whereas children without this allele had more ODD symptoms only in the context of more self-blame for inter-parental conflict. For ADHD (and ODD), children homozygous for the long allele of DRD4 120bp insertion polymorphism had lower conscientiousness when exposed to inconsistent parenting, whereas children without this genotype were more resilient to effects of inconsistent discipline on conscientiousness. Thus, ODD and ADHD appear to demonstrate somewhat distinct correlational associations between etiological factors and mechanisms consistent with pathway models using a multiple-level-of-analysis approach. PMID:22584505

Identification of G Protein-Coupled Receptors (GPCRs) in Primary Cilia and Their Possible Involvement in Body Weight Control

PubMed Central

Omori, Yoshihiro; Chaya, Taro; Yoshida, Satoyo; Irie, Shoichi; Tsujii, Toshinori; Furukawa, Takahisa

2015-01-01

Primary cilia are sensory organelles that harbor various receptors such as G protein-coupled receptors (GPCRs). We analyzed subcellular localization of 138 non-odorant GPCRs. We transfected GPCR expression vectors into NIH3T3 cells, induced ciliogenesis by serum starvation, and observed subcellular localization of GPCRs by immunofluorescent staining. We found that several GPCRs whose ligands are involved in feeding behavior, including prolactin-releasing hormone receptor (PRLHR), neuropeptide FF receptor 1 (NPFFR1), and neuromedin U receptor 1 (NMUR1), localized to the primary cilia. In addition, we found that a short form of dopamine receptor D2 (DRD2S) is efficiently transported to the primary cilia, while a long form of dopamine receptor D2 (DRD2L) is rarely transported to the primary cilia. Using an anti-Prlhr antibody, we found that Prlhr localized to the cilia on the surface of the third ventricle in the vicinity of the hypothalamic periventricular nucleus. We generated the Npy2r-Cre transgenic mouse line in which Cre-recombinase is expressed under the control of the promoter of Npy2r encoding a ciliary GPCR. By mating Npy2r-Cre mice with Ift80 flox mice, we generated Ift80 conditional knockout (CKO) mice in which Npy2r-positive cilia were diminished in number. We found that Ift80 CKO mice exhibited a body weight increase. Our results suggest that Npy2r-positive cilia are important for body weight control. PMID:26053317

Dopamine and cognitive control: sex-by-genotype interactions influence the capacity to switch attention.

PubMed

Gurvich, C; Rossell, S L

2015-03-15

Cognitive performance in healthy persons varies widely between individuals. Sex differences in cognition are well reported, and there is an emerging body of evidence suggesting that the relationship between dopaminergic neurotransmission, implicated in many cognitive functions, is modulated by sex. Here, we examine the influence of sex and genetic variations along the dopaminergic pathway on aspects of cognitive control. A total of 415 healthy individuals, selected from an international consortium linked to Brain Research and Integrative Neuroscience Network (BRAINnet), were genotyped for two common and functional genetic variations of dopamine regulating genes: the catechol-O-methyltransferase [COMT] gene (rs4680) and the dopamine receptor D2 [DRD2] gene (rs6277). Cognitive measures were selected to explore sustained attention (using a continuous performance task), switching of attention (using a Trails B adaptation) and working memory (a visual computerised adaptation of digit span). While there were no main effects for genotype across any tasks, analyses revealed significant sex by genotype interactions for the capacity to switch attention. In relation to COMT, superior performance was noted in females with the Val/Val genotype and for DRD2, superior performance was seen for TT females and CC males. These findings highlight the importance of considering genetic variation in baseline dopamine levels in addition to sex, when considering the impact of dopamine on cognition in healthy populations. These findings also have important implications for the many neuropsychiatric disorders that implicate dopamine, cognitive changes and sex differences. Copyright © 2014 Elsevier B.V. All rights reserved.

In vivo transcription of R-plasmid deoxyribonucleic acid in Escherichia coli strains with altered antibiotic resistance levels and/or conjugal proficiency.

PubMed Central

Davis, R; Vapnek, D

1976-01-01

The amounts of plasmid deoxyribonucleic acid (DNA) and the levels of the in vivo transcription of the Escherichia coli plasmids R538-1 (repressed for conjugal transfer) and R538-1drd (derepressed for transfer) were determined by DNA-DNA hybridization and DNA-ribonucleic acid hybridization, respectively. The results demonstrate that the level of plasmid transcription is increased by two-fold in the strain carrying the derepressed plasmid, compared to an isogenic strain carrying the repressed plasmid, whereas the amount of plasmid DNA is approximately the same, suggesting that the transfer genes are under transcriptional control. Levels of plasmid DNA, plasmid DNA transcription, and chloramphenicol acetyltransferase activity were also compared in a mutant strain that carried the R538-1drd plasmid and was resistant to high levels of antibiotics. This strain produces about 13 copies of plasmid DNA per chromosome compared to five copies for the parent strain. The level of transcription of plasmid DNA was found to be twofold higher in the high-level resistant strain, whereas the level of chloramphenition, acetyltransferase activity was increased by 10-fold. In addition the levels of plasmid DNA transcription and chloramphenicol acetyltransferase activity in the high-level resistant strain were found to be further increased by the presence of high levels of chloramphenicol in the growth medium. The amount of plasmid DNA remained constant under these conditions, indicating that high levels of chloramphenicol can stimulate the expression of plasmid genes at the level of transcription in this strain. PMID:767321

Specific Reaction Patterns to Distinct Positive Emotional Cues Related to Incentive Motivation in Dependence of the Taq1A-Polymorphism: Molecular Genetic Associations of Early and Late Event-Related Potentials.

PubMed

Munk, Aisha J L; Wielpuetz, Catrin; Osinsky, Roman; Müller, Erik M; Grant, Phillip; Hennig, Jürgen

2016-01-01

Early and late event-related potential (ERP) responses, representing early subconscious and late motivational processes, were recorded for positive emotional words related to 'wanting' and 'liking', in dependence of the dopamine-related Taq1A genotype (ANKK1/DRD2). Research suggests that 'wanting' as opposed to 'liking' is related to dopaminergic processes. Therefore, it was hypothesized that risk allele carriers of the Taq1A polymorphism exhibit late ERP changes in reaction to words representing incentive motivation, i.e. 'wanting' (word categories 'lust' and 'anticipation'), but not to words representing 'liking' ('closeness'). Seventy-two male participants performed an emotional-word Stroop task during EEG recording and were genotyped according to the Taq1A polymorphism of ANKK1/DRD2. Positive emotional words related to anticipation and lust revealed blunted responses in the late positive potential (LPP) in carriers of the A1 allele, an effect absent in response to 'liking'-related words. These differences were not evident in the earlier posterior negativity (EPN). As no differences in dependence of the Taq1A genotype were observed in reaction to 'wanting'- and 'liking'-related words in the EPN, but merely in the LPP, it can be assumed that incentive-motivational stimuli only modify motivation-related ERP responses in carriers of the A1 allele of the Taq1A polymorphism, indicating the role of dopamine in late ERP components. © 2016 S. Karger AG, Basel.

Cognitive and neural correlates of the 5-repeat allele of the dopamine D4 receptor gene in a population lacking the 7-repeat allele.

PubMed

Takeuchi, Hikaru; Tomita, Hiroaki; Taki, Yasuyuki; Kikuchi, Yoshie; Ono, Chiaki; Yu, Zhiqian; Sekiguchi, Atsushi; Nouchi, Rui; Kotozaki, Yuka; Nakagawa, Seishu; Miyauchi, Carlos Makoto; Iizuka, Kunio; Yokoyama, Ryoichi; Shinada, Takamitsu; Yamamoto, Yuki; Hanawa, Sugiko; Araki, Tsuyoshi; Hashizume, Hiroshi; Kunitoki, Keiko; Sassa, Yuko; Kawashima, Ryuta

2015-04-15

The 5-repeat allele of a common length polymorphism in the gene that encodes the dopamine D4 receptor (DRD4) is robustly associated with the risk of attention deficit hyperactivity disorder (ADHD) and substantially exists in Asian populations, which have a lower ADHD prevalence. In this study, we investigated the effect of this allele on microstructural properties of the brain and on its functional activity during externally directed attention-demanding tasks and creative performance in the 765 Asian subjects. For this purpose, we employed diffusion tensor imaging, N-back functional magnetic resonance imaging paradigms, and a test to measure creativity by divergent thinking. The 5-repeat allele was significantly associated with increased originality in the creative performance, increased mean diffusivity (the measure of how the tissue includes water molecules instead of neural and vessel components) in the widespread gray and white matter areas of extensive areas, particularly those where DRD4 is expressed, and reduced task-induced deactivation in the areas that are deactivated during the tasks in the course of both the attention-demanding working memory task and simple sensorimotor task. The observed neural characteristics of 5-repeat allele carriers may lead to an increased risk of ADHD and behavioral deficits. Furthermore, the increased originality of creative thinking observed in the 5-repeat allele carriers may support the notion of the side of adaptivity of the widespread risk allele of psychiatric diseases. Copyright © 2015. Published by Elsevier Inc.

Developmentally Sensitive Interaction Effects of Genes and the Social Environment on Total and Subcortical Brain Volumes.

PubMed

Richards, Jennifer S; Arias Vásquez, Alejandro; Franke, Barbara; Hoekstra, Pieter J; Heslenfeld, Dirk J; Oosterlaan, Jaap; Faraone, Stephen V; Buitelaar, Jan K; Hartman, Catharina A

2016-01-01

Smaller total brain and subcortical volumes have been linked to psychopathology including attention-deficit/hyperactivity disorder (ADHD). Identifying mechanisms underlying these alterations, therefore, is of great importance. We investigated the role of gene-environment interactions (GxE) in interindividual variability of total gray matter (GM), caudate, and putamen volumes. Brain volumes were derived from structural magnetic resonance imaging scans in participants with (N = 312) and without ADHD (N = 437) from N = 402 families (age M = 17.00, SD = 3.60). GxE effects between DAT1, 5-HTT, and DRD4 and social environments (maternal expressed warmth and criticism; positive and deviant peer affiliation) as well as the possible moderating effect of age were examined using linear mixed modeling. We also tested whether findings depended on ADHD severity. Deviant peer affiliation was associated with lower caudate volume. Participants with low deviant peer affiliations had larger total GM volumes with increasing age. Likewise, developmentally sensitive GxE effects were found on total GM and putamen volume. For total GM, differential age effects were found for DAT1 9-repeat and HTTLPR L/L genotypes, depending on the amount of positive peer affiliation. For putamen volume, DRD4 7-repeat carriers and DAT1 10/10 homozygotes showed opposite age relations depending on positive peer affiliation and maternal criticism, respectively. All results were independent of ADHD severity. The presence of differential age-dependent GxE effects might explain the diverse and sometimes opposing results of environmental and genetic effects on brain volumes observed so far.

Developmentally Sensitive Interaction Effects of Genes and the Social Environment on Total and Subcortical Brain Volumes

PubMed Central

Arias Vásquez, Alejandro; Franke, Barbara; Hoekstra, Pieter J.; Heslenfeld, Dirk J.; Oosterlaan, Jaap; Faraone, Stephen V.

2016-01-01

Smaller total brain and subcortical volumes have been linked to psychopathology including attention-deficit/hyperactivity disorder (ADHD). Identifying mechanisms underlying these alterations, therefore, is of great importance. We investigated the role of gene-environment interactions (GxE) in interindividual variability of total gray matter (GM), caudate, and putamen volumes. Brain volumes were derived from structural magnetic resonance imaging scans in participants with (N = 312) and without ADHD (N = 437) from N = 402 families (age M = 17.00, SD = 3.60). GxE effects between DAT1, 5-HTT, and DRD4 and social environments (maternal expressed warmth and criticism; positive and deviant peer affiliation) as well as the possible moderating effect of age were examined using linear mixed modeling. We also tested whether findings depended on ADHD severity. Deviant peer affiliation was associated with lower caudate volume. Participants with low deviant peer affiliations had larger total GM volumes with increasing age. Likewise, developmentally sensitive GxE effects were found on total GM and putamen volume. For total GM, differential age effects were found for DAT1 9-repeat and HTTLPR L/L genotypes, depending on the amount of positive peer affiliation. For putamen volume, DRD4 7-repeat carriers and DAT1 10/10 homozygotes showed opposite age relations depending on positive peer affiliation and maternal criticism, respectively. All results were independent of ADHD severity. The presence of differential age-dependent GxE effects might explain the diverse and sometimes opposing results of environmental and genetic effects on brain volumes observed so far. PMID:27218681

Effects of aripiprazole and the Taq1A polymorphism in the dopamine D2 receptor gene on the clinical response and plasma monoamine metabolites level during the acute phase of schizophrenia.

PubMed

Miura, Itaru; Takeuchi, Satoshi; Katsumi, Akihiko; Mori, Azuma; Kanno, Keiko; Yang, Qiaohui; Mashiko, Hirobumi; Numata, Yoshihiko; Niwa, Shin-Ichi

2012-02-01

The Taq1A polymorphism in the dopamine D2 receptor (DRD2) gene could be related to the response to antipsychotics. We examined the effects of the Taq1A polymorphism on the plasma monoamine metabolites during the treatment of schizophrenia with aripiprazole, a DRD2 partial agonist. Thirty Japanese patients with schizophrenia were treated with aripiprazole for 6 weeks. We measured plasma levels of homovanillic acid (pHVA) and 3-methoxy-4hydroxyphenylglycol (pMHPG) before and after treatment. The Taq1A polymorphism was genotyped with polymerase chain reaction. Aripiprazole improved the acute symptoms of schizophrenia and decreased pHVA in responders (P = 0.023) but not in nonresponders (P = 0.28). Although A1 allele carriers showed a tendency to respond to aripiprazole (61.5%) compared to A1 allele noncarriers (29.4%) (P = 0.078), there was not statistically significant difference in the response between the 2 genotype groups. There were significant effect for response (P = 0.013) and genotype × response interaction (P = 0.043) on the change of pHVA. The changes of pHVA differ between responders and nonresponders in A1 allele carriers but not in A1 allele noncarriers. There were no genotype or response effects or genotype × response interaction on the changes of the plasma levels of 3-methoxy-4hydroxyphenylglycol. Our preliminary results suggest that Taq1A polymorphism may be partly associated with changes in pHVA during acute schizophrenia.

A family study of DRD3 rs6280, SLC1A2 rs3794087 and MAPT rs1052553 variants in essential tremor.

PubMed

Jiménez-Jiménez, Félix Javier; García-Martín, Elena; Alonso-Navarro, Hortensia; Lorenzo-Betancor, Oswaldo; Ortega-Cubero, Sara; Pastor, Pau; Calleja, Marisol; Agúndez, José A G

2016-10-01

Despite many data suggesting a role of genetic factors in the risk for essential tremor (ET), the responsible genes have not been identified. We analyzed in ET Spanish families three single nucleotide polymorphisms (SNPs): DRD3 rs6280, SLC1A2 rs3794087, and MAPT rs1052553) previously related to an increased risk for developing the disease. We recruited 45 subjects with ET and 13 subjects without tremor belonging to 11 families who were evaluated because of familial tremor. Diagnosis of probable or definite ET was done according to TRIG criteria. Genotyping of the 3 SNPs was done using TaqMan-based qPCR assays. Data were compared with those of healthy controls of our laboratory. Family-based association testing for disease traits was performed as well. rs6280 and rs3794087 genotype and allelic frequencies did not differ significantly between subjects with ET and healthy controls. However, rs1052553AA genotype and the allele rs1052553A allele were significantly more frequent among ET patients. rs1052553A allele was non-significantly overrepresented in ET patients compared with controls when considering only the more severely affected member of each ET family. Family-based association test for disease traits showed lack of association between ET and the three SNPs studied. Our results showed a lack of association between rs6280 and rs3794087 with the risk for ET, though a marginal increased risk for ET was observed among the rs1052553A allele carriers, which was not confirmed with a family-based association study.

The Functional DRD3 Ser9Gly Polymorphism (rs6280) Is Pleiotropic, Affecting Reward as Well as Movement

PubMed Central

Savitz, Jonathan; Hodgkinson, Colin A.; Martin-Soelch, Chantal; Shen, Pei-Hong; Szczepanik, Joanna; Nugent, Allison; Herscovitch, Peter; Grace, Anthony A.; Goldman, David; Drevets, Wayne C.

2013-01-01

Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [11C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis. PMID:23365649

The 30/20 GHz flight experiment system, phase 2. Volume 3: Experiment system requirement document

NASA Technical Reports Server (NTRS)

Bronstein, L.; Kawamoto, Y.; Ribarich, J. J.; Scope, J. R.; Forman, B. J.; Berman, S. G.; Reisenfeld, S.

1981-01-01

An approach to the requirements document to be used to procure the system by NASA is presented. The basic approach is similar to the requirements document used in the commercial communication satellite. Enough detail requirements are given to define the system without tight constraints.

Fluor Daniel Hanford contract standards/requirements identification document

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bennett, G.L.

1997-04-24

This document, the Standards/Requirements Identification Document (S/RID) for the Fluor Daniel Hanford Contract, represents the necessary and sufficient requirements to provide an adequate level of protection of the worker, public health and safety, and the environment.

IDC Re-Engineering Phase 2 System Specification Document Version 1.5

DOE Office of Scientific and Technical Information (OSTI.GOV)

Satpathi, Meara Allena; Burns, John F.; Harris, James M.

This document contains the system specifications derived to satisfy the system requirements found in the IDC System Requirements Document for the IDC Re-Engineering Phase 2 project. This System Specification Document (SSD) defines waveform data processing requirements for the International Data Centre (IDC) of the Comprehensive Nuclear Test Ban Treaty Organization (CTBTO). The routine processing includes characterization of events with the objective of screening out events considered to be consistent with natural phenomena or non-nuclear, man-made phenomena. This document does not address requirements concerning acquisition, processing and analysis of radionuclide data but does include requirements for the dissemination of radionuclide datamore » and products.« less

Using SCR methods to analyze requirements documentation

NASA Technical Reports Server (NTRS)

Callahan, John; Morrison, Jeffery

1995-01-01

Software Cost Reduction (SCR) methods are being utilized to analyze and verify selected parts of NASA's EOS-DIS Core System (ECS) requirements documentation. SCR is being used as a spot-inspection tool. Through this formal and systematic approach of the SCR requirements methods, insights as to whether the requirements are internally inconsistent or incomplete as the scenarios of intended usage evolve in the OC (Operations Concept) documentation. Thus, by modelling the scenarios and requirements as mode charts using the SCR methods, we have been able to identify problems within and between the documents.

Tarjetas v.1.2015.7.23

DOE Office of Scientific and Technical Information (OSTI.GOV)

Burchard, Ross L.; Pierson, Kathleen P.; Trumbo, Derek

Tarjetas is used to generate requirements from source documents. These source documents are in a hierarchical XML format that have been produced from PDF documents processed through the “Reframe” software package. The software includes the ability to create Topics and associate text Snippets with those topics. Requirements are then generated and text Snippets with their associated Topics are referenced to the requirement. The software maintains traceability from the requirement ultimately to the source document that produced the snippet

18 CFR 5.24 - Applications not requiring a draft NEPA document.

Code of Federal Regulations, 2013 CFR

2013-04-01

... requiring a draft NEPA document. 5.24 Section 5.24 Conservation of Power and Water Resources FEDERAL ENERGY... APPLICATION PROCESS § 5.24 Applications not requiring a draft NEPA document. (a) If the Commission determines... environmental impact statement and that a draft environmental assessment will not be required, the Commission...

18 CFR 5.24 - Applications not requiring a draft NEPA document.

Code of Federal Regulations, 2012 CFR

2012-04-01

... requiring a draft NEPA document. 5.24 Section 5.24 Conservation of Power and Water Resources FEDERAL ENERGY... APPLICATION PROCESS § 5.24 Applications not requiring a draft NEPA document. (a) If the Commission determines... environmental impact statement and that a draft environmental assessment will not be required, the Commission...

18 CFR 5.24 - Applications not requiring a draft NEPA document.

Code of Federal Regulations, 2014 CFR

2014-04-01

... requiring a draft NEPA document. 5.24 Section 5.24 Conservation of Power and Water Resources FEDERAL ENERGY... APPLICATION PROCESS § 5.24 Applications not requiring a draft NEPA document. (a) If the Commission determines... environmental impact statement and that a draft environmental assessment will not be required, the Commission...

12 CFR 16.17 - Filing requirements and inspection of documents.

Code of Federal Regulations, 2010 CFR

2010-01-01

... the submission of any fee required under § 16.33 of this part. (e) Any filing of amendments or... 12 Banks and Banking 1 2010-01-01 2010-01-01 false Filing requirements and inspection of documents... SECURITIES OFFERING DISCLOSURE RULES § 16.17 Filing requirements and inspection of documents. (a) Except as...

TRACER - TRACING AND CONTROL OF ENGINEERING REQUIREMENTS

NASA Technical Reports Server (NTRS)

Turner, P. R.

1994-01-01

TRACER (Tracing and Control of Engineering Requirements) is a database/word processing system created to document and maintain the order of both requirements and descriptive material associated with an engineering project. A set of hierarchical documents are normally generated for a project whereby the requirements of the higher level documents levy requirements on the same level or lower level documents. Traditionally, the requirements are handled almost entirely by manual paper methods. The problem with a typical paper system, however, is that requirements written and changed continuously in different areas lead to misunderstandings and noncompliance. The purpose of TRACER is to automate the capture, tracing, reviewing, and managing of requirements for an engineering project. The engineering project still requires communications, negotiations, interactions, and iterations among people and organizations, but TRACER promotes succinct and precise identification and treatment of real requirements separate from the descriptive prose in a document. TRACER permits the documentation of an engineering project's requirements and progress in a logical, controllable, traceable manner. TRACER's attributes include the presentation of current requirements and status from any linked computer terminal and the ability to differentiate headers and descriptive material from the requirements. Related requirements can be linked and traced. The program also enables portions of documents to be printed, individual approval and release of requirements, and the tracing of requirements down into the equipment specification. Requirement "links" can be made "pending" and invisible to others until the pending link is made "binding". Individuals affected by linked requirements can be notified of significant changes with acknowledgement of the changes required. An unlimited number of documents can be created for a project and an ASCII import feature permits existing documents to be incorporated. TRACER can automatically renumber section headers when inserting or deleting sections of a document and generate sign-off forms for any approval process as well as a table of contents. TRACER was implemented on an IBM PC under PC-DOS. The program requires 640K RAM, a hard disk, and PC-DOS version 3.3 or higher. It was written in CLIPPER (Summer '87). TRACER is available on two 5.25 inch 1.2Mb MS-DOS format diskettes. The executable program is also provided with the distribution. TRACER is a copyrighted work with all copyright vested in the National Aeronautics and Space Administration. IBM PC and PC-DOS are registered trademarks of International Business Machines. CLIPPER is a trademark of Nantucket Corporation.

7 CFR 1423.6 - Financial information documentation requirements.

Code of Federal Regulations, 2010 CFR

2010-01-01

... CORPORATION APPROVED WAREHOUSES § 1423.6 Financial information documentation requirements. To be approved under this part, a warehouse operator shall submit a current financial statement at the time of... 7 Agriculture 10 2010-01-01 2010-01-01 false Financial information documentation requirements...

TWRS configuration management requirement source document

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vann, J.M.

The TWRS Configuration Management (CM) Requirement Source document prescribes CM as a basic product life-cycle function by which work and activities are conducted or accomplished. This document serves as the requirements basis for the TWRS CM program. The objective of the TWRS CM program is to establish consistency among requirements, physical/functional configuration, information, and documentation for TWRS and TWRS products, and to maintain this consistency throughout the life-cycle of TWRS and the product, particularly as changes are being made.

Automated documentation generator for advanced protein crystal growth

NASA Technical Reports Server (NTRS)

Maddux, Gary A.; Provancha, Anna; Chattam, David

1994-01-01

To achieve an environment less dependent on the flow of paper, automated techniques of data storage and retrieval must be utilized. This software system, 'Automated Payload Experiment Tool,' seeks to provide a knowledge-based, hypertext environment for the development of NASA documentation. Once developed, the final system should be able to guide a Principal Investigator through the documentation process in a more timely and efficient manner, while supplying more accurate information to the NASA payload developer. The current system is designed for the development of the Science Requirements Document (SRD), the Experiment Requirements Document (ERD), the Project Plan, and the Safety Requirements Document.

Analysis of M16A1 Basic Rifle Marksmanship Training

DTIC Science & Technology

1985-01-01

preparatory marks- manship); A lecture is an oral explanation presented by a trainer to a group of trainees. Trainee participation is limited to...program employs two of.these* (the MIS Sighting Device and the Shot Group Analysis r;drd), while tri,. F-rt iHt -nning program emoloys only the Shot...stroi.’,. ti’, i:4 .’,, tlt i dlri’•.. . i•- iht hours. It is fol lowc-d 1ý ; .. ract !,ý i i Nit’oa ’ecord Firc oxcrc is.. Th I; practi(v tirint ir i a1

25 CFR 162.528 - What documents are required for BIA approval of a WEEL?

Code of Federal Regulations, 2013 CFR

2013-04-01

... LEASES AND PERMITS Wind and Solar Resource Leases Weel Approval § 162.528 What documents are required for... required by § 162.527; (d) Statement from the appropriate tribal authority that the proposed use is in... environmental and land use requirements, including any documentation prepared under § 162.027(b); (f) An...

25 CFR 162.528 - What documents are required for BIA approval of a WEEL?

Code of Federal Regulations, 2014 CFR

2014-04-01

... LEASES AND PERMITS Wind and Solar Resource Leases Weel Approval § 162.528 What documents are required for... required by § 162.527; (d) Statement from the appropriate tribal authority that the proposed use is in... environmental and land use requirements, including any documentation prepared under § 162.027(b); (f) An...

36 CFR 1251.10 - What are the filing requirements for a demand for documents or testimony?

Code of Federal Regulations, 2011 CFR

2011-07-01

... date that records or testimony is required. Demands submitted in less than 45 days before records or... requirements for a demand for documents or testimony? 1251.10 Section 1251.10 Parks, Forests, and Public... the filing requirements for a demand for documents or testimony? You must comply with the following...

36 CFR 1251.10 - What are the filing requirements for a demand for documents or testimony?

Code of Federal Regulations, 2010 CFR

2010-07-01

... date that records or testimony is required. Demands submitted in less than 45 days before records or... requirements for a demand for documents or testimony? 1251.10 Section 1251.10 Parks, Forests, and Public... the filing requirements for a demand for documents or testimony? You must comply with the following...

7 CFR 1710.405 - Supplemental financing documents.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 11 2010-01-01 2010-01-01 false Supplemental financing documents. 1710.405 Section... GUARANTEES Application Requirements and Procedures for Loans § 1710.405 Supplemental financing documents. (a) The borrower is responsible for ensuring that the loan documents required for supplemental financing...

Concept document of the repository-based software engineering program: A constructive appraisal

NASA Technical Reports Server (NTRS)

1992-01-01

A constructive appraisal of the Concept Document of the Repository-Based Software Engineering Program is provided. The Concept Document is designed to provide an overview of the Repository-Based Software Engineering (RBSE) Program. The Document should be brief and provide the context for reading subsequent requirements and product specifications. That is, all requirements to be developed should be traceable to the Concept Document. Applied Expertise's analysis of the Document was directed toward assuring that: (1) the Executive Summary provides a clear, concise, and comprehensive overview of the Concept (rewrite as necessary); (2) the sections of the Document make best use of the NASA 'Data Item Description' for concept documents; (3) the information contained in the Document provides a foundation for subsequent requirements; and (4) the document adequately: identifies the problem being addressed; articulates RBSE's specific role; specifies the unique aspects of the program; and identifies the nature and extent of the program's users.

78 FR 13368 - Agency Information Collection Activities: Application for Employment Authorization, Form I-765...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-27

... of total applicants who require English translations of their supporting documents. The percentage of supporting documents for each individual applicant that require translation into English. The time required to find, hire or otherwise obtain translations of supporting documents for immigration benefit...

23 CFR 1340.5 - Documentation requirements.

Code of Federal Regulations, 2010 CFR

2010-04-01

... STATE OBSERVATIONAL SURVEYS OF SEAT BELT USE § 1340.5 Documentation requirements. All sample design, data collection, and estimation procedures used in State surveys conducted in accordance with this part must be well documented. At a minimum, the documentation must: (a) For sample design— (1) Define all...

23 CFR 1340.5 - Documentation requirements.

Code of Federal Regulations, 2011 CFR

2011-04-01

... STATE OBSERVATIONAL SURVEYS OF SEAT BELT USE § 1340.5 Documentation requirements. All sample design, data collection, and estimation procedures used in State surveys conducted in accordance with this part must be well documented. At a minimum, the documentation must: (a) For sample design— (1) Define all...

Monitored Geologic Repository Project Description Document

DOE Office of Scientific and Technical Information (OSTI.GOV)

P. M. Curry

2001-01-30

The primary objective of the Monitored Geologic Repository Project Description Document (PDD) is to allocate the functions, requirements, and assumptions to the systems at Level 5 of the Civilian Radioactive Waste Management System (CRWMS) architecture identified in Section 4. It provides traceability of the requirements to those contained in Section 3 of the ''Monitored Geologic Repository Requirements Document'' (MGR RD) (YMP 2000a) and other higher-level requirements documents. In addition, the PDD allocates design related assumptions to work products of non-design organizations. The document provides Monitored Geologic Repository (MGR) technical requirements in support of design and performance assessment in preparing formore » the Site Recommendation (SR) and License Application (LA) milestones. The technical requirements documented in the PDD are to be captured in the System Description Documents (SDDs) which address each of the systems at Level 5 of the CRWMS architecture. The design engineers obtain the technical requirements from the SDDs and by reference from the SDDs to the PDD. The design organizations and other organizations will obtain design related assumptions directly from the PDD. These organizations may establish additional assumptions for their individual activities, but such assumptions are not to conflict with the assumptions in the PDD. The PDD will serve as the primary link between the technical requirements captured in the SDDs and the design requirements captured in US Department of Energy (DOE) documents. The approved PDD is placed under Level 3 baseline control by the CRWMS Management and Operating Contractor (M and O) and the following portions of the PDD constitute the Technical Design Baseline for the MGR: the design characteristics listed in Table 1-1, the MGR Architecture (Section 4.1), the Technical Requirements (Section 5), and the Controlled Project Assumptions (Section 6).« less

Electrical, Electronic, and Electromechanical (EEE) parts management and control requirements for NASA space flight programs

NASA Technical Reports Server (NTRS)

1989-01-01

This document establishes electrical, electronic, and electromechanical (EEE) parts management and control requirements for contractors providing and maintaining space flight and mission-essential or critical ground support equipment for NASA space flight programs. Although the text is worded 'the contractor shall,' the requirements are also to be used by NASA Headquarters and field installations for developing program/project parts management and control requirements for in-house and contracted efforts. This document places increased emphasis on parts programs to ensure that reliability and quality are considered through adequate consideration of the selection, control, and application of parts. It is the intent of this document to identify disciplines that can be implemented to obtain reliable parts which meet mission needs. The parts management and control requirements described in this document are to be selectively applied, based on equipment class and mission needs. Individual equipment needs should be evaluated to determine the extent to which each requirement should be implemented on a procurement. Utilization of this document does not preclude the usage of other documents. The entire process of developing and implementing requirements is referred to as 'tailoring' the program for a specific project. Some factors that should be considered in this tailoring process include program phase, equipment category and criticality, equipment complexity, and mission requirements. Parts management and control requirements advocated by this document directly support the concept of 'reliability by design' and are an integral part of system reliability and maintainability. Achieving the required availability and mission success objectives during operation depends on the attention given reliability and maintainability in the design phase. Consequently, it is intended that the requirements described in this document are consistent with those of NASA publications, 'Reliability Program Requirements for Aeronautical and Space System Contractors,' NHB 5300.4(1A-l); 'Maintainability Program Requirements for Space Systems,' NHB 5300.4(1E); and 'Quality Program Provisions for Aeronautical and Space System Contractors,' NHB 5300.4(1B).

76 FR 5537 - Electronic On-Board Recorders and Hours of Service Supporting Documents

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-01

...The Federal Motor Carrier Safety Administration (FMCSA) proposes to amend the Federal Motor Carrier Safety Regulations (FMCSRs) to require certain motor carriers operating commercial motor vehicles (CMVs) in interstate commerce to use electronic on-board recorders (EOBRs) to document their drivers' hours of service (HOS). Under this proposal, all motor carriers currently required to maintain Records of Duty Status (RODS) for HOS recordkeeping would be required to use EOBRs to systematically and effectively monitor their drivers' compliance with HOS requirements. Additionally, this proposal sets forth the supporting documents that all motor carriers currently required to use RODS would still be required to obtain and keep, as required by section 113(a) of the Hazardous Materials Transportation Authorization Act (HMTAA). It explains, however, that although motor carriers subject to the proposed EOBR requirements would still need to retain some supporting documents, they would be relieved of the requirements to retain supporting documents to verify driving time. FMCSA also proposes to require all motor carriers--both RODS and timecard users--to systematically monitor their drivers' compliance with HOS requirements. Motor carriers would be given 3 years after the effective date of the final rule to comply with these requirements.

78 FR 40758 - Agency Information Collection Activities: Application for Temporary Protected Status, Form I-821...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-08

... applicants who require English translations of their supporting documents. The percentage of supporting documents for each individual applicant that require translation into English. The time required to find, hire, or otherwise obtain translations of supporting documents for immigration benefit requests. The...

19 CFR 122.157 - Documents required for clearance.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 19 Customs Duties 1 2010-04-01 2010-04-01 false Documents required for clearance. 122.157 Section 122.157 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF THE TREASURY AIR COMMERCE REGULATIONS Flights to and From Cuba § 122.157 Documents required for...

7 CFR 1488.8 - Documents required after delivery.

Code of Federal Regulations, 2014 CFR

2014-01-01

... Financing of Export Sales of Agricultural Commodities From Private Stocks Under CCC Export Credit Sales Program (GSM-5) Documents Required for Financing § 1488.8 Documents required after delivery. (a) CCC will... regulations within forty-five days, or any extension thereof by the Treasurer or Assistant Treasurer, CCC...

7 CFR 1488.8 - Documents required after delivery.

Code of Federal Regulations, 2012 CFR

2012-01-01

... Financing of Export Sales of Agricultural Commodities From Private Stocks Under CCC Export Credit Sales Program (GSM-5) Documents Required for Financing § 1488.8 Documents required after delivery. (a) CCC will... regulations within forty-five days, or any extension thereof by the Treasurer or Assistant Treasurer, CCC...

7 CFR 1488.8 - Documents required after delivery.

Code of Federal Regulations, 2013 CFR

2013-01-01

... Financing of Export Sales of Agricultural Commodities From Private Stocks Under CCC Export Credit Sales Program (GSM-5) Documents Required for Financing § 1488.8 Documents required after delivery. (a) CCC will... regulations within forty-five days, or any extension thereof by the Treasurer or Assistant Treasurer, CCC...

10 CFR 95.37 - Classification and preparation of documents.

Code of Federal Regulations, 2010 CFR

2010-01-01

... classification decisions. (c) Markings required on face of documents. (1) For derivative classification of... to a document must be placed in a conspicuous fashion in letters at the top and bottom of the outside... on the face of the document: Reproduction or Further Dissemination Requires Approval of If any...

10 CFR 95.37 - Classification and preparation of documents.

Code of Federal Regulations, 2011 CFR

2011-01-01

... classification decisions. (c) Markings required on face of documents. (1) For derivative classification of... to a document must be placed in a conspicuous fashion in letters at the top and bottom of the outside... on the face of the document: Reproduction or Further Dissemination Requires Approval of If any...

Inattention and Reaction Time Variability Are Linked to Ventromedial Prefrontal Volume in Adolescents.

PubMed

Albaugh, Matthew D; Orr, Catherine; Chaarani, Bader; Althoff, Robert R; Allgaier, Nicholas; D'Alberto, Nicholas; Hudson, Kelsey; Mackey, Scott; Spechler, Philip A; Banaschewski, Tobias; Brühl, Rüdiger; Bokde, Arun L W; Bromberg, Uli; Büchel, Christian; Cattrell, Anna; Conrod, Patricia J; Desrivières, Sylvane; Flor, Herta; Frouin, Vincent; Gallinat, Jürgen; Goodman, Robert; Gowland, Penny; Grimmer, Yvonne; Heinz, Andreas; Kappel, Viola; Martinot, Jean-Luc; Paillère Martinot, Marie-Laure; Nees, Frauke; Orfanos, Dimitri Papadopoulos; Penttila, Jani; Poustka, Luise; Paus, Tomáš; Smolka, Michael N; Struve, Maren; Walter, Henrik; Whelan, Robert; Schumann, Gunter; Garavan, Hugh; Potter, Alexandra S

2017-11-01

Neuroimaging studies of attention-deficit/hyperactivity disorder (ADHD) have most commonly reported volumetric abnormalities in the basal ganglia, cerebellum, and prefrontal cortices. Few studies have examined the relationship between ADHD symptomatology and brain structure in population-based samples. We investigated the relationship between dimensional measures of ADHD symptomatology, brain structure, and reaction time variability-an index of lapses in attention. We also tested for associations between brain structural correlates of ADHD symptomatology and maps of dopaminergic gene expression. Psychopathology and imaging data were available for 1538 youths. Parent ratings of ADHD symptoms were obtained using the Development and Well-Being Assessment and the Strengths and Difficulties Questionnaire (SDQ). Self-reports of ADHD symptoms were assessed using the youth version of the SDQ. Reaction time variability was available in a subset of participants. For each measure, whole-brain voxelwise regressions with gray matter volume were calculated. Parent ratings of ADHD symptoms (Development and Well-Being Assessment and SDQ), adolescent self-reports of ADHD symptoms on the SDQ, and reaction time variability were each negatively associated with gray matter volume in an overlapping region of the ventromedial prefrontal cortex. Maps of DRD1 and DRD2 gene expression were associated with brain structural correlates of ADHD symptomatology. This is the first study to reveal relationships between ventromedial prefrontal cortex structure and multi-informant measures of ADHD symptoms in a large population-based sample of adolescents. Our results indicate that ventromedial prefrontal cortex structure is a biomarker for ADHD symptomatology. These findings extend previous research implicating the default mode network and dopaminergic dysfunction in ADHD. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Comprehensive DNA methylation analysis of human neuroblastoma cells treated with blonanserin.

PubMed

Murata, Yui; Nishioka, Masaki; Bundo, Miki; Sunaga, Fumiko; Kasai, Kiyoto; Iwamoto, Kazuya

2014-03-20

Blonanserin is a second-generation antipsychotic drug for schizophrenia. The pharmacological actions of blonanserin are shown to be the antagonism of dopamine receptor 2 and serotonin receptors. However, its molecular mechanisms in brain cells have not been fully characterized. Accumulating evidence suggests that antipsychotic drugs and mood stabilizers show epigenetic effects on a wide range of genes in animal and cellular models. We performed genome-wide DNA methylation analysis targeting 479,814 CpG sites of cultured human neuroblastoma cells administered with blonanserin. We found that 3,057 CpG sites showed statistically significant changes in DNA methylation at two different doses of blonanserin (1.36 nM and 13.6 nM). These included hypermethylated CpG sites that were enriched in genes related to axonogenesis and cell morphogenesis involved in neuron differentiation. We also showed that the global effect on DNA methylome depends on the concentration of the drug. With a high dose of blonanserin, the overall methylation levels across all CpG sites significantly increased. These increases in DNA methylation were prominent in the CpG sites distant from promoter regions. We further examined DNA methylation changes in specific genes implicated for the actions of antipsychotic drugs, such as the dopamine receptor 2 (DRD2) gene and the serotonin receptor 2A (HTR2A) gene. We observed that CpG sites that were located within DRD2 and HTR2A genes were significantly hypermethylated by blonanserin. The DNA methylation changes induced by the treatment with blonanserin will be useful for understanding its pharmacological actions at the cellular level. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Right secondary somatosensory cortex-a promising novel target for the treatment of drug-resistant neuropathic orofacial pain with repetitive transcranial magnetic stimulation.

PubMed

Lindholm, Pauliina; Lamusuo, Salla; Taiminen, Tero; Pesonen, Ullamari; Lahti, Ari; Virtanen, Arja; Forssell, Heli; Hietala, Jarmo; Hagelberg, Nora; Pertovaara, Antti; Parkkola, Riitta; Jääskeläinen, Satu

2015-07-01

High-frequency repetitive transcranial magnetic stimulation (rTMS) of the motor cortex has analgesic effect; however, the efficacy of other cortical targets and the mode of action remain unclear. We examined the effects of rTMS in neuropathic orofacial pain, and compared 2 cortical targets against placebo. Furthermore, as dopaminergic mechanisms modulate pain responses, we assessed the influence of the functional DRD2 gene polymorphism (957C>T) and the catechol-O-methyltransferase (COMT) Val158Met polymorphism on the analgesic effect of rTMS. Sixteen patients with chronic drug-resistant neuropathic orofacial pain participated in this randomized, placebo-controlled, crossover study. Navigated high-frequency rTMS was given to the sensorimotor (S1/M1) and the right secondary somatosensory (S2) cortices. All subjects were genotyped for the DRD2 957C>T and COMT Val158Met polymorphisms. Pain, mood, and quality of life were monitored throughout the study. The numerical rating scale pain scores were significantly lower after the S2 stimulation than after the S1/M1 (P = 0.0071) or the sham (P = 0.0187) stimulations. The Brief Pain Inventory scores were also lower 3 to 5 days after the S2 stimulation than those at pretreatment baseline (P = 0.0127 for the intensity of pain and P = 0.0074 for the interference of pain) or after the S1/M1 (P = 0.001 and P = 0.0001) and sham (P = 0.0491 and P = 0.0359) stimulations. No correlations were found between the genetic polymorphisms and the analgesic effect in the present small clinical sample. The right S2 cortex is a promising new target for the treatment of neuropathic orofacial pain with high-frequency rTMS.

Developmental Deltamethrin Exposure Causes Persistent Changes in Dopaminergic Gene Expression, Neurochemistry, and Locomotor Activity in Zebrafish.

PubMed

Kung, Tiffany S; Richardson, Jason R; Cooper, Keith R; White, Lori A

2015-08-01

Pyrethroids are commonly used insecticides that are considered to pose little risk to human health. However, there is an increasing concern that children are more susceptible to the adverse effects of pesticides. We used the zebrafish model to test the hypothesis that developmental exposure to low doses of the pyrethroid deltamethrin results in persistent alterations in dopaminergic gene expression, neurochemistry, and locomotor activity. Zebrafish embryos were treated with deltamethrin (0.25-0.50 μg/l), at concentrations below the LOAEL, during the embryonic period [3-72 h postfertilization (hpf)], after which transferred to fresh water until the larval stage (2-weeks postfertilization). Deltamethrin exposure resulted in decreased transcript levels of the D1 dopamine (DA) receptor (drd1) and increased levels of tyrosine hydroxylase at 72 hpf. The reduction in drd1 transcripts persisted to the larval stage and was associated with decreased D2 dopamine receptor transcripts. Larval fish, exposed developmentally to deltamethrin, had increased levels of homovanillic acid, a DA metabolite. Since the DA system is involved in locomotor activity, we measured the swim activity of larval fish following a transition to darkness. Developmental exposure to deltamethrin significantly increased larval swim activity which was attenuated by concomitant knockdown of the DA transporter. Acute exposure to methylphenidate, a DA transporter inhibitor, increased swim activity in control larva, while reducing swim activity in larva developmentally exposed to deltamethrin. Developmental exposure to deltamethrin causes locomotor deficits in larval zebrafish, which is likely mediated by dopaminergic dysfunction. This highlights the need to understand the persistent effects of low-dose neurotoxicant exposure during development. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Developmental Deltamethrin Exposure Causes Persistent Changes in Dopaminergic Gene Expression, Neurochemistry, and Locomotor Activity in Zebrafish

PubMed Central

Kung, Tiffany S.; Richardson, Jason R.; Cooper, Keith R.; White, Lori A.

2015-01-01

Pyrethroids are commonly used insecticides that are considered to pose little risk to human health. However, there is an increasing concern that children are more susceptible to the adverse effects of pesticides. We used the zebrafish model to test the hypothesis that developmental exposure to low doses of the pyrethroid deltamethrin results in persistent alterations in dopaminergic gene expression, neurochemistry, and locomotor activity. Zebrafish embryos were treated with deltamethrin (0.25–0.50 μg/l), at concentrations below the LOAEL, during the embryonic period [3–72 h postfertilization (hpf)], after which transferred to fresh water until the larval stage (2-weeks postfertilization). Deltamethrin exposure resulted in decreased transcript levels of the D1 dopamine (DA) receptor (drd1) and increased levels of tyrosine hydroxylase at 72 hpf. The reduction in drd1 transcripts persisted to the larval stage and was associated with decreased D2 dopamine receptor transcripts. Larval fish, exposed developmentally to deltamethrin, had increased levels of homovanillic acid, a DA metabolite. Since the DA system is involved in locomotor activity, we measured the swim activity of larval fish following a transition to darkness. Developmental exposure to deltamethrin significantly increased larval swim activity which was attenuated by concomitant knockdown of the DA transporter. Acute exposure to methylphenidate, a DA transporter inhibitor, increased swim activity in control larva, while reducing swim activity in larva developmentally exposed to deltamethrin. Developmental exposure to deltamethrin causes locomotor deficits in larval zebrafish, which is likely mediated by dopaminergic dysfunction. This highlights the need to understand the persistent effects of low-dose neurotoxicant exposure during development. PMID:25912032

DRD2 genotype-based variation of default mode network activity and of its relationship with striatal DAT binding.

PubMed

Sambataro, Fabio; Fazio, Leonardo; Taurisano, Paolo; Gelao, Barbara; Porcelli, Annamaria; Mancini, Marina; Sinibaldi, Lorenzo; Ursini, Gianluca; Masellis, Rita; Caforio, Grazia; Di Giorgio, Annabella; Niccoli-Asabella, Artor; Popolizio, Teresa; Blasi, Giuseppe; Bertolino, Alessandro

2013-01-01

The default mode network (DMN) comprises a set of brain regions with "increased" activity during rest relative to cognitive processing. Activity in the DMN is associated with functional connections with the striatum and dopamine (DA) levels in this brain region. A functional single-nucleotide polymorphism within the dopamine D2 receptor gene (DRD2, rs1076560 G > T) shifts splicing of the 2 D2 isoforms, D2 short and D2 long, and has been associated with striatal DA signaling as well as with cognitive processing. However, the effects of this polymorphism on DMN have not been explored. The aim of this study was to evaluate the effects of rs1076560 on DMN and striatal connectivity and on their relationship with striatal DA signaling. Twenty-eight subjects genotyped for rs1076560 underwent functional magnetic resonance imaging during a working memory task and 123 55 I-Fluoropropyl-2-beta-carbomethoxy-3-beta(4-iodophenyl) nortropan Single Photon Emission Computed Tomography ([(123)I]-FP-CIT SPECT) imaging (a measure of dopamine transporter [DAT] binding). Spatial group-independent component (IC) analysis was used to identify DMN and striatal ICs. Within the anterior DMN IC, GG subjects had relatively greater connectivity in medial prefrontal cortex (MPFC), which was directly correlated with striatal DAT binding. Within the posterior DMN IC, GG subjects had reduced connectivity in posterior cingulate relative to T carriers. Additionally, rs1076560 genotype predicted connectivity differences within a striatal network, and these changes were correlated with connectivity in MPFC and posterior cingulate within the DMN. These results suggest that genetically determined D2 receptor signaling is associated with DMN connectivity and that these changes are correlated with striatal function and presynaptic DA signaling.

DRD2 Genotype-Based Variation of Default Mode Network Activity and of Its Relationship With Striatal DAT Binding

PubMed Central

Sambataro, Fabio; Fazio, Leonardo; Taurisano, Paolo; Gelao, Barbara; Porcelli, Annamaria; Mancini, Marina; Sinibaldi, Lorenzo; Ursini, Gianluca; Masellis, Rita; Caforio, Grazia; Di Giorgio, Annabella; Niccoli-Asabella, Artor; Popolizio, Teresa; Blasi, Giuseppe; Bertolino, Alessandro

2013-01-01

The default mode network (DMN) comprises a set of brain regions with “increased” activity during rest relative to cognitive processing. Activity in the DMN is associated with functional connections with the striatum and dopamine (DA) levels in this brain region. A functional single-nucleotide polymorphism within the dopamine D2 receptor gene (DRD2, rs1076560 G > T) shifts splicing of the 2 D2 isoforms, D2 short and D2 long, and has been associated with striatal DA signaling as well as with cognitive processing. However, the effects of this polymorphism on DMN have not been explored. The aim of this study was to evaluate the effects of rs1076560 on DMN and striatal connectivity and on their relationship with striatal DA signaling. Twenty-eight subjects genotyped for rs1076560 underwent functional magnetic resonance imaging during a working memory task and 123 55 I-Fluoropropyl-2-beta-carbomethoxy-3-beta(4-iodophenyl) nortropan Single Photon Emission Computed Tomography ([123I]-FP-CIT SPECT) imaging (a measure of dopamine transporter [DAT] binding). Spatial group-independent component (IC) analysis was used to identify DMN and striatal ICs. Within the anterior DMN IC, GG subjects had relatively greater connectivity in medial prefrontal cortex (MPFC), which was directly correlated with striatal DAT binding. Within the posterior DMN IC, GG subjects had reduced connectivity in posterior cingulate relative to T carriers. Additionally, rs1076560 genotype predicted connectivity differences within a striatal network, and these changes were correlated with connectivity in MPFC and posterior cingulate within the DMN. These results suggest that genetically determined D2 receptor signaling is associated with DMN connectivity and that these changes are correlated with striatal function and presynaptic DA signaling. PMID:21976709

Dynamic interaction between fetal adversity and a genetic score reflecting dopamine function on developmental outcomes at 36 months.

PubMed

Bischoff, Adrianne R; Pokhvisneva, Irina; Léger, Étienne; Gaudreau, Hélène; Steiner, Meir; Kennedy, James L; O'Donnell, Kieran J; Diorio, Josie; Meaney, Michael J; Silveira, Patrícia P

2017-01-01

Fetal adversity, evidenced by poor fetal growth for instance, is associated with increased risk for several diseases later in life. Classical cut-offs to characterize small (SGA) and large for gestational age (LGA) newborns are used to define long term vulnerability. We aimed at exploring the possible dynamism of different birth weight cut-offs in defining vulnerability in developmental outcomes (through the Bayley Scales of Infant and Toddler Development), using the example of a gene vs. fetal adversity interaction considering gene choices based on functional relevance to the studied outcome. 36-month-old children from an established prospective birth cohort (Maternal Adversity, Vulnerability, and Neurodevelopment) were classified according to birth weight ratio (BWR) (SGA ≤0.85, LGA >1.15, exploring a wide range of other cut-offs) and genotyped for polymorphisms associated with dopamine signaling (TaqIA-A1 allele, DRD2-141C Ins/Ins, DRD4 7-repeat, DAT1-10- repeat, Met/Met-COMT), composing a score based on the described function, in which hypofunctional variants received lower scores. There were 251 children (123 girls and 128 boys). Using the classic cut-offs (0.85 and 1.15), there were no statistically significant interactions between the neonatal groups and the dopamine genetic score. However, when changing the cut-offs, it is possible to see ranges of BWR that could be associated with vulnerability to poorer development according to the variation in the dopamine function. The classic birth weight cut-offs to define SGA and LGA newborns should be seen with caution, as depending on the outcome in question, the protocols for long-term follow up could be either too inclusive-therefore most costly, or unable to screen true vulnerabilities-and therefore ineffective to establish early interventions and primary prevention.

The genetic validation of heterogeneity in schizophrenia.

PubMed

Tsutsumi, Atsushi; Glatt, Stephen J; Kanazawa, Tetsufumi; Kawashige, Seiya; Uenishi, Hiroyuki; Hokyo, Akira; Kaneko, Takao; Moritani, Makiko; Kikuyama, Hiroki; Koh, Jun; Matsumura, Hitoshi; Yoneda, Hiroshi

2011-10-07

Schizophrenia is a heritable disorder, however clear genetic architecture has not been detected. To overcome this state of uncertainty, the SZGene database has been established by including all published case-control genetic association studies appearing in peer-reviewed journals. In the current study, we aimed to determine if genetic variants strongly suggested by SZGene are associated with risk of schizophrenia in our case-control samples of Japanese ancestry. In addition, by employing the additive model for aggregating the effect of seven variants, we aimed to verify the genetic heterogeneity of schizophrenia diagnosed by an operative diagnostic manual, the DSM-IV. Each positively suggested genetic polymorphism was ranked according to its p-value, then the seven top-ranked variants (p < 0.0005) were selected from DRD2, DRD4, GRIN2B, TPH1, MTHFR, and DTNBP1 (February, 2007). 407 Schizophrenia cases and 384 controls participated in this study. To aggregate the vulnerability of the disorder based on the participants' genetic information, we calculated the "risk-index" by adding the number of genetic risk factors. No statistically significant deviation between cases and controls was observed in the genetic risk-index derived from all seven variants on the top-ranked polymorphisms. In fact, the average risk-index score in the schizophrenia group (6.5+/-1.57) was slightly lower than among controls (6.6+/-1.39). The current work illustrates the difficulty in identifying universal and definitive risk-conferring polymorphisms for schizophrenia. Our employed number of samples was small, so we can not preclude the possibility that some or all of these variants are minor risk factors for schizophrenia in the Japanese population. It is also important to aggregate the updated positive variants in the SZGene database when the replication work is conducted.

Putative presynaptic dopamine dysregulation in schizophrenia is supported by molecular evidence from post-mortem human midbrain

PubMed Central

Purves-Tyson, T D; Owens, S J; Rothmond, D A; Halliday, G M; Double, K L; Stevens, J; McCrossin, T; Shannon Weickert, C

2017-01-01

The dopamine hypothesis of schizophrenia posits that increased subcortical dopamine underpins psychosis. In vivo imaging studies indicate an increased presynaptic dopamine synthesis capacity in striatal terminals and cell bodies in the midbrain in schizophrenia; however, measures of the dopamine-synthesising enzyme, tyrosine hydroxylase (TH), have not identified consistent changes. We hypothesise that dopamine dysregulation in schizophrenia could result from changes in expression of dopamine synthesis enzymes, receptors, transporters or catabolic enzymes. Gene expression of 12 dopamine-related molecules was examined in post-mortem midbrain (28 antipsychotic-treated schizophrenia cases/29 controls) using quantitative PCR. TH and the synaptic dopamine transporter (DAT) proteins were examined in post-mortem midbrain (26 antipsychotic-treated schizophrenia cases per 27 controls) using immunoblotting. TH and aromatic acid decarboxylase (AADC) mRNA and TH protein were unchanged in the midbrain in schizophrenia compared with controls. Dopamine receptor D2 short, vesicular monoamine transporter (VMAT2) and DAT mRNAs were significantly decreased in schizophrenia, with no change in DRD3 mRNA, DRD3nf mRNA and DAT protein between diagnostic groups. However, DAT protein was significantly increased in putatively treatment-resistant cases of schizophrenia compared to putatively treatment-responsive cases. Midbrain monoamine oxidase A (MAOA) mRNA was increased, whereas MAOB and catechol-O-methyl transferase mRNAs were unchanged in schizophrenia. We conclude that, whereas some mRNA changes are consistent with increased dopamine action (decreased DAT mRNA), others suggest reduced dopamine action (increased MAOA mRNA) in the midbrain in schizophrenia. Here, we identify a molecular signature of dopamine dysregulation in the midbrain in schizophrenia that mainly includes gene expression changes of molecules involved in dopamine synthesis and in regulating the time course of dopamine action. PMID:28094812