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. Keywords DRD2; inhibition; impulsivity; amphetamine; Stop TaskIndividuals vary in behavioral inhibition, or the predisposition to respond to stimuli without regard to negative consequences. These individual differences have been observed in healthy populations (de Wit, Crean, & Richards, 2000), as well as in psychiatric samples such as patients with attention deficit/hyperactivity disorder and substance use disorders (Colzato, van Correspondence concerning this article should be addressed to Harriet de Wit, Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, 5841 South Maryland Avenue, MC3077, Chicago, IL 60637. hdew@uchicago.edu. & Hommel, 2007;Schachar, Tannock, & Logan, 1993). One possible source of the observed variability is genetic variation in the neurotransmitter systems responsible for the phenotype. Several lines of evidence suggest that dopamine plays an important role in inhibition in both humans (Friedel, 2004) and nonhumans (Cardinal, Pennicott, Sugathapala, Robbins, & Everitt, 2001;Dulawa, Grandy, Low, Paulus, & Geyer, 1999;Puumala, & Sirvio, 1998;Rubinstein et al., 1997;Winstanley, Theobald, Cardinal, & Robbins, 2004. Specifically, there is evidence that the dopamine receptor D2 (DRD2) is important for inhibi...

Csnk1e Is a Genetic Regulator of Sensitivity to Psychostimulants and Opioids

“…Because epidemiological studies indicate that sensitivity to drug liking in humans can predict an individual's susceptibility to drug abuse (Haertzen et al, 1983;Schuckit, 2009), drug sensitivity and abuse are hypothesized to share a genetic basis. This hypothesis is supported by genetic association studies in humans that have identified genes that influence both acute sensitivity (Hamidovic et al, 2009(Hamidovic et al, , 2010Lott et al, 2005Lott et al, , 2006Dlugos et al, 2011) and dependence (Ho et al, 2010).…”

Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis

“…For instance, we did not explore the moderating role of participant age, level of education, waiting time between drug administration and testing, length of testing session, or time of day. Moderators of great interest, which might be expected to affect results based on previous studies but which could not be assessed because of insufficient available data, include individuals' baseline cognitive ability and individuals' variants of dopamine-related genes such as COMT and DRD2 (see Hamidovic et al, 2009;Mattay et al, 2003; but see also Wardle, Hart, Palmer, & de Wit, 2013, for null results). Consistent with the nonmonotonic relation between dopamine activity and performance, there is evidence that stimulants can impair performance in normal individuals who are especially high performing (Farah, Haimm, Sankoorikal, & Chatterjee, 2009;De Wit et al, 2002;De Wit, Crean, & Richards, 2000;Mattay et al, 2000).…”

“…Correlations were obtained from Ilieva, Boland, and Farah (2013; Flanker, Go/No-Go, n-back, Digit Span Backward and Forward, delayed memory for words and faces; 46 participants); Mintzer and Griffiths (2007; n-back, Sternberg memory task, delayed memory for words; 18 participants); and Hamidovic, Dlugos, Skol, Palmer, and de Wit (2009), combined with a set of unpublished data from Dr. Harriet de Wit's laboratory (Stop Signal task, 299 participants). When correlations for a given task (e.g., n-back) were available from more than one data set, we estimated a composite through meta-analyzing the available correlations based on a random effects model.…”

Constraints on decision making: Implications from genetics, personality, and addiction

“…As well, anxious individuals appear to be hypersensitive to negative consequences following their actions and are risk-averse (Maner & Schmidt, 2006;Meyer-Lindenberg, 2010;Mitte, 2008;Raghunathan & Pham, 1999). Perhaps surprisingly, these personality traits have all been associated with individual differences in dopamine expression (Hamidovic, Dlugos, Skol, Palmer, & de Wit, 2009;Laine, Ahonen, Rasanen, & Tiihonen, 2001;Lawford, Young, Noble, Kann, & Ritchie, 2006;Montag et al, 2008), reinforcement sensitivity (Maner & Schmidt, 2006), and/or vulnerability to addiction (Conrod & Woicik, 2002). Hence in the present study we utilized the PST to elucidate individual differences in decision making related to personality.…”