Evaluation of genetic variability in the dopamine receptor D2 in relation to behavioral inhibition and impulsivity/sensation seeking: an exploratory study with d-amphetamine in healthy participants

Abstract

The dopamine D2 receptor (DRD2) appears to be involved in impulsive behaviors, and particularly in behavioral inhibition. We sought to determine whether inhibition and impulsivity were related to genetic polymorphisms in the DRD2 gene (DRD2) in healthy volunteers (N = 93). Participants received placebo or d-amphetamine in random order. They performed the stop task, measuring behavioral inhibition, and rated their mood states on each session. They also completed the Zuckerman-Kuhlman Personality Questionnaire, including an Impulsivity subscale. We investigated the association between 12 single nucleotide polymorphisms (SNPs) and haplotypes in DRD2 and stop task performance in the nondrug (i.e., placebo) session and on the personality measure of impulsivity. We secondarily evaluated the DRD2 SNPs in relation to response to d-amphetamine on stop task performance and mood ratings. Mood was not related to genotypes in either the drug free condition or in response to drug. However, 2 SNPs, rs4648317 and rs12364283, and a haplotype block consisting of those SNPs, were associated with better performance on the stop task in the drug free condition and lower scores on the Impulsivity subscale. We also found that rs12364283 was associated with effects of d-amphetamine on stop task performance: d-amphetamine decreased stop reaction time (RT) in the A/A group but increased stop RT in the combined A/G + G/G genotype. Of the SNPs we evaluated, rs12364283, which has been associated with DRD2 expression, was the most significantly associated with inhibition and impulsivity. The significant relationship between DRD2 genotype and both behavioral inhibition and impulsivity suggests a possible common genetic influence on behavioral and self-report measures of impulsivity.

Figure 1

Linkage disequilibrium (LD) plot of the 12 DRD2 loci included in the analysis. LD values represented are D′. The haplotype structure of DRD2 is similar to the haplotypes identified in the HapMap Project.

Figure 2

(A) Mean stop reaction time (RT) plus or minus standard error of the mean after placebo (0) and d-amphetamine (5, 10, 20 mg) in participants grouped by DRD2 rs12364283 genotype. In the placebo condition, A/A carriers (n = 75) took longer to inhibit a response in comparison with the combined A/G + G/G group (n = 14; ^# p ≤.01). In comparison with the placebo condition, administration of 5 (^*p ≤.05), 10 (^**p ≤.001), and 20 mg (^*p ≤.05) of d-amphetamine decreased stop RTs in the A/A group. In the A/G + G/G genotype, 10 mg of d-amphetamine increased stop RTs (^*p ≤.05). (B) Mean go RT plus or minus standard error of the mean in participants grouped by DRD2 rs12364283. Go RTs did not differ between the two genotypic groups of rs12364283. ^# p ≤.01. ^*p ≤.05. ^**p ≤.001.