Behavioral phenotypes of impulsivity related to the ANKK1 gene are independent of an acute stressor

The phenotypes of multiple psychiatric disorders involve features of impulsivity including attention deficit hyperactivity disorder (ADHD), bipolar disorder, mania, bulimia nervosa, several personality disorders, schizophrenia and substance dependence [1]. Impulsivity is also implicated in several forms of aggression and violence, sexual impulsivity, binge eating, obesity, self-harm and suicidal behavior [2]. As such, the study of factors that may contribute to impulsivity is fundamental to understanding and treating maladaptive human behavior.

Dopamine is integral to leading theories of an impulsive personality phenotype [3, 4] and plays a crucial role in brain reinforcement circuits [2, 5]. Personality theories of impulsivity also consistently emphasize the role of genetics, reflecting evidence from twin studies of high heritability on self-report measures, including sensation seeking (55% [6]), novelty seeking (40% [7]) and "rash/unplanned" impulsivity (15–40% [8]). Subsequently, genes associated with brain dopaminergic activity have been commonly studied candidates. The presence of the A1 allele of the Taq IA polymorphism (rs1800497) in the ANKK1 gene [9] (i.e., A1A1 and A1A2 genotypes) has been associated with reduced D2 dopamine receptor (DRD2) density in key structures linked to brain reinforcement, particularly in the striatum. This association has been confirmed by both in vitro [10, 11] and in vivo positron emission tomography (PET) studies [12, 13]. The Taq IA had been historically described as residing in the D2 dopamine receptor (DRD2) gene but has more recently been referred to as being within the ANKK1 [9]. In addition to these biological associations, a strong body of evidence suggests the involvement of the A1 allele in a range of behavioral disorders characterized by impulsivity, including severe alcohol and other substance abuse, obesity, pathological gambling and ADHD [14‐16]. While A1 allele prevalence has been found to differ between ethnic populations [17], raising the issue of population stratification effects, research has shown that even across diverse ethnic groups there are still robust associations of the Taq IA with behavior [18]. Associations with addictive disorders have led to the hypothesis that ANKK1 is a reinforcement gene and those with the A1 allele are more likely to manifest brain reinforcement mechanism deficits than those without this allele [2, 5]. Specifically, it is suggested that in an effort to compensate for inherited dopaminergic system deficiencies, individuals may seek to stimulate the mesocorticolimbic circuits and experience heightened reinforcement related to behaviors that increase brain dopamine levels (such as substance use), contributing to impulsive behavior. More direct evidence in rats supports an association between reduced D2 receptor availability in the ventral striatum and trait reinforcer-oriented impulsivity [19].

In behavioral genetics, simple Mendelian genetic influences are rare, with most traits reflecting the interplay of genes and environment [20]. In particular, the ANKK1 conferred risk appears to be conveyed via an interaction of A1 allelic risk and environmental stress [21‐25]. For example, in a sample of alcoholic patients, negative life events and a harm avoidant personality were associated with severity of alcohol dependence in those carrying the A1 allele (A1+) but not in A1- patients [23]. Acute environmental stress is associated with impulsive behavior [26‐28] and can increase dopamine neurotransmission in humans [29]. Further, recent PET scan findings suggest acute stress-induced striatal dopamine release may be greater in individuals at risk of psychosis. A significant decrease in [¹¹C]raclopride binding potential (indicative of dopamine release), particularly in the ventral striatum, was reported for seven healthy students identified as at risk for psychosis due to elevated scores for physical anhedonia/negative schizotypy. In contrast, no such effect was found for 10 controls and 9 healthy adults scoring highly on perceptual aberrations/positive schizotypy [30]. No previous study has examined the combined influence of specific polymorphisms related to brain dopamine activity and acute stress, as a gene-environment interaction, on impulsivity.

We designed a study to examine the complexity of the ANKK1 gene-environment interaction on impulsive behavior by testing acute stress as a plausible environmental factor in this relationship. To reduce the influence of potential confounds associated with psychopathology, we studied a community sample of young adults screened for psychiatric illness. Consistent with the multidimensional nature of impulsivity [31] the laboratory paradigm incorporated three separate measures of impulsivity, assessing reinforcer-cued approach, delay discounting and response disinhibition respectively. These three dimensions are supported by the results of factor analytic studies [32] and neuroimaging research linking these to differential brain activation patterns in areas connected to mesolimbic dopamine circuits. Reinforcement-related processing and delay discounting are linked to greater activation in the ventral striatum [33], while response inhibition is associated with orbitofrontal circuit activity [34]. We directly examined the relationship between the A1 allele, laboratory-induced acute psychosocial stress and laboratory measures of impulsive behavior.

Our study has, for the first time, examined several behavioral measures of impulsivity in combination with molecular genetic risk and acute psychosocial stress. We have shown that the Taq IA A1 allele is associated with preclinical behavioral risk in two dimensions of impulsivity, one characterized by impaired performance sensitive to reinforcers in the environment (though quickly overcome with repeated exposure) and the other by an accelerated and disinhibited approach style in the absence of incentive cues. This shared genetic risk was not associated with acute stress and may represent indirect evidence of a common etiology involving altered brain dopaminergic activity, consistent with reward deficiency theory [2, 5].

Similar reinforcement-related performance deficits associated with A1+ allelic status have been previously reversed under the influence of the dopamine agonist, bromocriptine [48]. While an acute stressor can increase dopamine neurotransmission in humans [29], our study has shown a baseline performance deficit and subsequent improvement for A1+ participants regardless of acute stress. These results may reflect the importance of dopaminergic activity in the reinforcement pathways for initial CARROT performance and an increased sensitivity of those with deficiencies conferred by the A1 allele to repeated cue exposure. The second finding of poorer response inhibition by A1+ participants has been shown in Spanish alcohol dependent male patients [49]. Our extension of these findings to a non-clinical sample comprising both male and female young adults provides strong support for an association of the A1 allele with an impulsive endophenotype, rather than as a confound with alcoholism. The combined rash impulsive profile shown on this task by A1+ young adults is also similar to that shown previously for adults diagnosed with ADHD, a disorder characterized by impulsivity [50].

We suggest the A1 allele confers a greater need for practice to overcome inherent reinforcement-related learning deficits associated with fewer dopamine receptors in key brain reinforcement sites. Once sensitized, the general acceleration of approach behavior may be associated with reduced inhibitory control observed in A1+ participants. Slower baseline approach in the presence of financial reinforcers could alternatively reflect an attentional bias towards reinforcement cues in the environment, thus indicating heightened reinforcement sensitivity in these individuals. This alternative is consistent with reward deficiency [2, 5].

The absence of Taq IA effects on implicit delay discounting contrasts with the impulsive profile suggested by effects on the other two behavioral measures. This may reflect a distinction between implicit and explicit awareness of reinforcers, given a contrasting recent report of an association between the A1 allele and an explicit delay discounting paradigm in an unselected university sample [51]. Future research should further examine a comparison between explicit and implicit cognitive processes with the A1 allele.

The absence of an effect of the acute psychosocial stressor on the ANKK1 Taq IA-impulsivity relationship, despite a significant increase in subjective anxiety, underscores the importance of the ANKK1 main effect on impulsivity. Further, while our results need to be replicated with a larger sample, they show that acute psychosocial stress is an unlikely explanation of why some individuals with the A1 allele exhibit impulsive tendencies. The addition of physiological and neuroendocrine stress measurement in future research is important. Future research should also investigate other plausible environmental moderators and mediators of this relationship, including chronic stress.