Dopamine D4 receptor gene exon III polymorphism associated with binge drinking attitudinal phenotype.

Department of Community Health, Saint Louis University, MO 63103, USA.
Alcohol (Fayetteville, N.Y.) (Impact Factor: 2.41). 05/2009; 43(3):179-84. DOI: 10.1016/j.alcohol.2009.02.001
Source: PubMed

ABSTRACT Although binge drinking is a serious public health problem, relatively few studies have investigated the relationship between specific dopaminergic genes such as the dopamine D4 receptor (DRD4) and binge drinking attitudinal phenotypes. This study used the DNA subsample (N=233, mean age 19.8, standard deviation,0.89) of the National Longitudinal Study of Adolescent Health to investigate the association between a 48 base-pair variable number of tandem repeats in the DRD4 gene and a measure of binge drinking. Multivariate regression models indicated that the 7-repeat (7R) allele of the exon III polymorphism is significantly positively associated (beta=0.16, P<.05) with binge drinking while controlling for low self-control and demographic variables. Findings were sturdy across race and gender. The present study provides unique evidence to the genetic underpinnings of binge drinking. Results suggest that the 7R allele may be an important contributor to the liability to binge drinking.

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    ABSTRACT: The long allele of DRD4 is associated with greater susceptibility to peer influences on alcohol use in young adulthood, but it is unclear whether this increased susceptibility extends to other developmental periods. This study examined the interactive effects of DRD4 polymorphism and friends' alcohol use from adolescence to adulthood. Participants (N=340; 59% female; 98% White) reported on their own and their friends' alcohol use at four time points between mean ages 17 and 33. Autoregressive cross-lagged models evaluated reciprocal relationships between friends' alcohol use and participants' own alcohol use and frequency of heavy drinking over time. Multigroup modeling tested differences in model paths and covariances across high vs. low risk DRD4 polymorphisms. Alcohol use at age 33 was predicted by previous friends' alcohol use and correlated with current friends' alcohol use only for carriers of the DRD4 long allele. Regardless of DRD4 genotype, friends' alcohol use at age 17 predicted greater alcohol use and more frequent heavy drinking at age 23. Alcohol use and/or heavy drinking predicted greater friends' alcohol use at later time points for both genotype groups across adolescence and adulthood. The long allele of DRD4 is associated with increased susceptibility to peer influences on alcohol use in young adulthood, but not earlier in development. Adults with the long allele of DRD4 may benefit from interventions educating them about this risk and equipping them with strategies to reduce affiliations with and influence of drinking friends. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Drug and Alcohol Dependence 10/2014; 145C:168-173. DOI:10.1016/j.drugalcdep.2014.10.009 · 3.28 Impact Factor
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    ABSTRACT: Alleles of the highly polymorphic human dopamine D4 receptor (D4R) gene (DRD4) containing a 48-base nucleotide sequence tandemly repeated seven times (DRD4.7), within the region coding for the receptor protein’s third intracellular loop, have been widely and reproducibly found in novelty seekers, substance abusers, pathological gamblers, and individuals diagnosed with attention-deficit hyperactivity disorder (ADHD). The in vivo physiological consequences of the DRD4.7 polymorphism, which inserts additional amino acids into the receptor’s G proteinbinding third intracellular domain, remain to be established. One hypothesis predicts the resultant protein of the DRD4.7 allele is deficient in G protein-coupled signaling relative to other variants. If attenuated D4R-mediated signaling contributes to the complex behavioral phenotypes associated with the DRD4.7 allele, then wild-type (WT) mice and mice completely lacking D4Rs (D4R KO), congenic on the C57Bl/6J background, might be expected to display significantly different behavioral responses to environmental and chemical stimuli known to affect dopamine signaling, such as novelty (e.g., open field; novel object) and psychostimulant drugs (e.g., methylphenidate, MP). In a battery of behavioral tests to evaluate approach-avoidance components of the behavioral response to novelty, D4R KO mice respond in a manner consistent with previous findings that suggest minimal D4R-mediated effects on novelty-induced exploratory drive, but enhanced anxiety in the absence of D4R signaling. D4R KO mice show a greater locomotor response to high doses of acute MP, and less sensitivity to the stereotypyinducing effects of high doses of acute MP, but do not differ from WT littermates in the behavioral response to lower doses of MP. D4R KO mice develop significantly greater behavioral sensitization to chronic administration of a moderate dose of MP compared to WT littermates. Affymetrix microarray analysis of prefrontal cortex (PFC) tissue from WT and D4R KO mice sensitized to chronic MP identified several gene transcripts differentially regulated by D4R signaling with potential relevance to the synaptic plasticity associated with behavioral sensitization to MP. A model of D4R activity in PFC neurotransmission is presented to explain the role of D4R signaling in the control of cortical glutamatergic output. Exploring the role of D4R signaling is of clinical relevance to the etiology of ADHD and substance abuse disorders, and may clarify the risks associated with psychostimulant pharmacotherapy of ADHD
    08/2009, Degree: PhD, Supervisor: David K Grandy
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    ABSTRACT: Background: 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. Methods: 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. Results: 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. Conclusion: The 7R allele of DRD4 influ-ences 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.
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