The DRD4 VNTR polymorphism influences reactivity to smoking cues

Molecular Psychiatry, 2005

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 ¼ 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 o0.05 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 (Po0.0006), 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.

The Pharmacogenomics Journal, 2004

Animal models have long implicated dopamine in stress-induced craving for a variety of addictive substances. However, translational studies of dopamine, stress and craving in humans are lacking. Based on the animal literature, this study's objective was to test the hypothesis that cigarette smokers carrying specific variants in dopamine-related genes would have heightened levels of cigarette craving following exposure to a laboratory stressor. Cigarette craving induced by controlled exposure to a laboratory stressor was assessed in healthy adult smokers (n ¼ 108) recruited by advertisement. Significantly stronger stress-induced cigarette craving was found for individuals carrying either the DRD2 (D2 dopamine receptor gene) A1, or the SLC6A3 (dopamine transporter gene) nine-repeat allelic variants. Stress-induced craving was markedly higher for those carrying both alleles, compared to those with neither, consistent with the separate biological pathways involved (receptor, transporter). Findings provide strong support for the possibility that dopamine involvement in stress-induced craving well established in animal models also applies to humans, and suggest a potential genetic risk factor for persistent smoking behavior.

Psychopharmacology, 2015

Rationale-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). Objective-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. Methods-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). Results-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 7 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 7 or more repeats did not. In addition, minor carriers for all 3 DRD4 SNPs displayed blunted overall response to nicotine.

American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2008

Nicotine enhances reward functions in the mesocorticolimbic dopamine system in general and the nucleus accumbens in particular. The genes encoding dopamine receptors are thus plausible candidates for involvement in nicotine dependence (ND). We investigated 13 single nucleotide polymorphisms (SNPs) spanning a region of the dopamine D 3 receptor gene (DRD3) to determine whether DRD3 is associated with ND. We studied a set of 2,037 subjects in 602 nuclear families representing two distinct American populations using three ND measures, namely, smoking quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerströ m Test for ND (FTND). In the family based association study, we found that SNP rs6280 showed a strong association with ND in European-Americans (EAs) and the pooled sample, whereas SNPs rs1486012 and rs963468 had weak associations with ND in African-Americans (AAs) and the pooled sample. Further haplotype analysis with all contiguous 3-SNP groups revealed relatively weak evidence for association of DRD3 with ND in the EA and pooled samples. The results indicate that DRD3 is significantly associated with ND in EAs, and that rs6280, a functional polymorphism causing an amino acid change of serine to glycine (Ser9Gly) in the N-terminal extracellular domain of the D 3 receptor, likely is causative of the association between DRD3 and ND.

Scientific Reports, 2020

Preclinical studies show that the dopamine D3 receptor (D3R) is involved in the reinstatement of drug seeking and motivation for drugs of abuse. A D3R gene variant, Ser9Gly (rs6280) has been linked to nicotine dependence, yet the mechanisms underlying its involvement in nicotine dependence is unclear. This study investigated the relationship between the Ser9Gly variant and measures of both nicotine reinforcement and cue-elicited craving. Phenotypes of smoking behaviors were assessed in genetically grouped (Glycine vs. No Glycine carriers) current smokers (n = 104, ≥ 10 cigarettes per day). Laboratory measures included a forced choice session (to measure reinforcement of nicotine containing vs. denicotinized cigarettes), and a cue-reactivity session (to measure smoking cues vs. neutral cues elicited craving). The forced choice procedure revealed that subjective ratings were significantly higher in response to nicotinized compared to denicotinized cigarettes; however the Ser9Gly varia...

Psychiatry Research, 2012

To test the importance of the dopamine D2 receptor (DRD2) region in nicotine dependence, 150 smokers and 228 controls were genotyped for the DRD2 C957T,-141delC and ANKK1 TaqIA polymorphisms (rs6277, rs1799732 and rs1800497, respectively). The-141delC SNP did not show any association but both the C957T and TaqIA SNPs showed association at the allele, genotype, haplotype and combined genotype levels. The 957C/TaqI A1 haplotype was more than 3.5 times as likely to be associated with nicotine dependence compared with the 957T/TaqI A1 haplotype (P = 0.003). Analysis of the combined genotypes of both SNPs revealed that individuals who were homozygous for the 957C-allele (CC) and had either one or two copies of the TaqI A1-allele were 3.3 times as likely to have nicotine dependence compared to all other genotype combinations (P = 0.0003) and that these genotypes accounted for approximately 13% of the susceptibility to nicotine addiction in our population. Our findings suggest that the DRD2 C957T polymorphism and the ANKK1 TaqIA polymorphism are key contributors to the genetic susceptibility of nicotine dependence.

Nicotine & Tobacco Research, 2009

Introduction: TaqIA polymorphism, a genetic variant associated with the expression level of dopamine D2 receptors in the brain, has been linked to various aspects of smoking behavior, including smoking prevalence, affective withdrawal symptoms, and smoking cessation outcome. However, its involvement in motivation to smoke cigarettes has not been elucidated.

2001

Abstract A large body of genetic epidemiological data strongly implicate genetic factors in the etiology of smoking behavior. Polymorphisms of genes in the dopaminergic system are plausible functional candidate genes and a linkage and an association study suggested that the type 5 dopamine receptor gene (DRD5) may be etiologically involved. We investigated the association of four DRD5 polymorphisms with smoking initiation and progression to nicotine dependence in a population-based sample of over 900 subjects.

The dopaminergic system has an important role in the rewarding properties of nicotine. Gene polymorphisms of DRD2 and DH that regulate dopamine neurotransmission or metabolism could influence smoking behavior. Additionally, the ability of a 5-HT2CR agonist to block mesolimbic dopamine activation produced by nicotine at the level of ventral tegmental area, suggests a possible interaction between dopaminergic and serotonergic systems in smoking initiation. In the present study, DRD2 TaqIA and DH -1021C>T polymorphisms and their interactions with 5-HT2CR -759C>T and -697G>C and 5HTTLPR S/L polymorphisms of serotonergic system were analyzed in 166 smoking initiators (SI) and 244 non-initiators (NI) of Greek origin, using PCR-RFLP method. No differences were found in genotype distributions of DRDR2 TaqIA and DH -1021C>T polymorphisms between SI and NI. Also, we found no interaction of DRD2 TaqIA and DH -1021C>T with smoking initiation. When DRD2 TaqIA polymorphism was comb...

Journal of the American Academy of Child and Adolescent Psychiatry, 2005

Objective: This study was designed to examine the role of DNA variants of the dopamine D4 receptor gene (DRD4) in smoking experimentation in adolescents and to determine the extent to which novelty seeking (NS) could account for a possible effect of DRD4 on tobacco use. Method: Participants were from a longitudinal study of an original birth cohort (born 1986-1988) of 384 children from a high-risk community sample. At age 15 years, adolescents completed a self-report questionnaire measuring tobacco consumption and temperament (Junior Temperament and Character Inventory). DNA was taken from 303 participants (144 males, 159 females) and genotyped for the DRD4 exon III polymorphism. Results: DRD4 was associated with smoking status and NS in males but not in females. Males with the seven repeat allele exhibited more smoking involvement (p < .002) and scored higher in NS (p < .002) than males without this allele. In addition, elevated tobacco use was related to a higher level of NS in both males and females (p < .001). Multiple regression analyses revealed that NS mediated the relationship between DRD4 and smoking in males. Conclusions: These findings highlight the importance of considering the mechanisms underlying the association between genetic factors and tobacco use separately by gender and, possibly, by developmental period.