Article

Dopamine Transporter Gene (DAT1) Associated with Appetite Suppression to Methylphenidate in a Case–Control Study of Binge Eating Disorder

Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
Neuropsychopharmacology (Impact Factor: 7.05). 11/2007; 32(10):2199-206. DOI: 10.1038/sj.npp.1301348
Source: PubMed

ABSTRACT

Response to psychomotor stimulants is highly variable across individuals. Such inconsistencies are influenced by many factors including drug dose and polymorphic differences in genes that encode proteins, such as the dopamine transporter (DAT1), which are relevant to the site of action of these substances. The current study used a double blind, crossover (methylphenidate vs placebo) design to assess DAT1 genotype differences on appetite ratings to a snack-food cue in subjects with binge eating disorder (BED) (n=32) and healthy age-matched controls (n=46). ANOVA results indicated a significant genotype x diagnostic group interaction whereby BED subjects with at least one copy of the 9-repeat allele showed a significant suppression of appetite in response to methylphenidate compared with controls with this allele, or to subjects with the 10/10 genotype (irrespective of diagnosis) whose drug response was indistinguishable from placebo. The most probable explanation for these findings is that some, currently unknown, genetic variant, which is overrepresented in those with BED, interacts with DAT1 to suppress appetite in response to stimulant administration. The current findings have implications for treatment response to drugs currently in use (or being developed) for the treatment of overeating and overweight.

Download full-text

Full-text

Available from: Caroline Davis, Feb 03, 2015
  • Source
    • "Deficient inhibitory control, delay aversion and self-medication appear critical . One or more deficits in central dopamine function merit strong consideration as mediators (e.g., Levitan et al. 2004a, b; Davis et al. 2007b; Campbell and Eisenberg 2007; Pagoto et al. 2009). Thus, dopamine genomic variants associated with ADD, such as the 7-repeat allele of the dopamine-4 receptor gene, link with obesity (Levitan et al. 2004a, b, 2006; Kaplan et al. 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Fetal growth and development associates with poor lifetime health outcomes. Despite the strength of the epidemiological evidence, there is little research that describes the functional pathways linking fetal development to brain-based disorders and metabolic health. We used a longitudinal cohort (Maternal Adversity, Vulnerability and Neurodevelopment; MAVAN) to study children of mothers recruited at mid-gestation and examine neurodevelopmental outcomes focusing on the association between birth weight and phenotypes associated with attention deficit disorder and obesity. These studies provide preliminary support for a ‘thrifty’ eating hypothesis that emphasizes the potential adaptive value of altered appetite regulation in the face of predicted nutritional deprivation, with impaired fetal growth as a marker for the in utero states that would produce such a prediction. We suggest that the effects might be mediated by altered activity across the mesocorticolimbic dopamine.
    Full-text · Article · Jan 2014 · Research and Perspectives in Endocrine Interactions
  • Source
    • "For DRD4, we compared carriers of the low function 7-repeat (7R) allele to women who did not possess this allele, as is typically done in studies examining DRD4 (e.g., Benjamin et al., 1996; Ebstein et al., 1996; Eisenberg et al., 2007b; Kaplan et al., 2008; Levitan et al., 2010). For DAT, given previous findings suggesting the hyperfunctionality of the 10/10 genotype (Davis et al., 2007; Heinz et al., 2000; Prata et al., 2009; VanNess et al., 2005), we treated the 10/10 genotype as high function and compared 10- allele homozygotes to individuals carrying a copy of the 9 allele. Due to the extremely low frequency of other alleles (i.e. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We explored the influence of interactions between polymorphisms acting upon postsynaptic receptors (DRD2 TaqA1 rs1800497 and DRD4 7R) and dopamine regulators (COMT rs4680 and DAT1) on the expression of eating symptoms and personality traits in women with bulimia-spectrum eating disorders. We had 269 bulimic women provide blood for genetic assays, and measured eating-disorder symptoms and psychopathological traits using structured interviews and self-report questionnaires. We observed two epistatic interactions on symptom indices: interactions (in predicted directions) of DRD2 by DAT were seen on Body Mass Index (p=.023), and of DRD4 by COMT on self-harming behaviors (p=.014)--with genetic effects that would correspond to reduced dopamine transmission coinciding with more-pathological scores. Our findings suggest that genes acting in the dopamine system interact to influence both eating-related and personality psychopathology, with the result that lower levels of dopamine neuro-transmission correspond to increased psychopathology and body mass in women with bulimia-spectrum disorders. We discuss the implications of our observations.
    Full-text · Article · Jun 2012 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
  • Source
    • "Individuals vary in their therapeutic and acute behavioral responses to stimulant drugs. This variability has been observed in clinical populations, such as patients treated for Binge Eating Disorder (Davis et al. 2007), Attention- Deficit Hyperactivity Disorder (Spencer et al. 1996) and narcolepsy (Mitler et al. 1993). Variability has also been reported in healthy volunteers, who receive acute doses of stimulants in laboratory studies (Brauer and de Wit 1996; Lott et al. 2005; de Wit et al. 1986; Gabbay 2003). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Individuals vary in their subjective responses to stimulant drugs, and these differences are believed to be partially genetic in origin. We evaluated associations between mood, cognitive and cardiovascular responses to d-amphetamine and four polymorphisms in the dopamine transporter (SLC6A3): rs460000, rs3756450, rs37022 and rs6869645. Healthy Caucasian male and female volunteers (N = 152) participated in a double-blind, crossover design study in which they received placebo, 10 and 20 mg of d-amphetamine. We measured self-reported rating of mood, performance on the Digit Symbol Substitution Task, blood pressure and heart rate. Individuals with the C/C genotype at rs460000 (N = 83) reported approximately twofold higher ratings of stimulation and euphoria relative to the A/A+A/C (N = 69) genotype group, at both the 10 and 20 mg doses. No other responses or SNPs showed significant effects. rs460000 is in perfect LD with rs463379 (CEU: D′ = 1; r 2 = 1), which was not studied here, but has been associated with etiology of Attention Deficit Hyperactivity Disorder (ADHD). These findings suggest a pleiotropic effect of this polymorphic locus on both ADHD and sensitivity to the subjective effects of amphetamine.
    Full-text · Article · Mar 2010 · Behavior Genetics
Show more