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

Behavioral phenotypes of impulsivity related to the ANKK1 gene are independent of an acute stressor Background: The A1 allele of the ANKK1 TaqIA polymorphism (previously reported as located in the D2 dopamine receptor (DRD2) gene) is associated with reduced DRD2 density in the striatum and with clinical disorders, particularly addiction. It was hypothesized that impulsivity represents an endophenotype underlying these associations with the TaqIA and that environmental stress would moderate the strength of the gene-behavior relationship. Methods: TaqIA genotyping was conducted on 72 healthy young adults who were randomly allocated to either an acute psychosocial stress or relaxation induction condition. Behavioral phenotypes of impulsivity were measured using a card-sorting index of reinforcement sensitivity and computerized response inhibition and delay discounting tasks. Results: Separate analyses of variance revealed associations between the A1 allele and two laboratory measures of impulsivity. The presence of the TaqIA allele (A1+) was associated with slower card-sorting in the presence of small financial reinforcers, but was overcome in a second administration after either a five-minute rest or psychosocial stress induction. A1+ participants also demonstrated significantly poorer response inhibition and faster response times on a computerized stop inhibition task, independent of acute stress exposure. Conclusion: These findings indicate the A1 allele is associated with an endophenotype comprising both a "rash impulsive" behavioral style and reinforcement-related learning deficits. These effects are independent of stress. in several forms of aggression and violence, sexual impul- Background The phenotypes of multiple psychiatric disorders involve sivity, binge eating, obesity, self-harm and suicidal behav- features of impulsivity including attention deficit hyperac- ior [2]. As such, the study of factors that may contribute to tivity disorder (ADHD), bipolar disorder, mania, bulimia impulsivity is fundamental to understanding and treating nervosa, several personality disorders, schizophrenia and maladaptive human behavior. substance dependence [1]. Impulsivity is also implicated Page 1 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:54 http://www.behavioralandbrainfunctions.com/content/4/1/54 Dopamine is integral to leading theories of an impulsive humans [29]. Further, recent PET scan findings suggest personality phenotype [3,4] and plays a crucial role in acute stress-induced striatal dopamine release may be brain reinforcement circuits [2,5]. Personality theories of greater in individuals at risk of psychosis. A significant impulsivity also consistently emphasize the role of genet- decrease in [ C]raclopride binding potential (indicative ics, reflecting evidence from twin studies of high heritabil- of dopamine release), particularly in the ventral striatum, ity on self-report measures, including sensation seeking was reported for seven healthy students identified as at (55% [6]), novelty seeking (40% [7]) and "rash/ risk for psychosis due to elevated scores for physical anhe- unplanned" impulsivity (15–40% [8]). Subsequently, donia/negative schizotypy. In contrast, no such effect was genes associated with brain dopaminergic activity have found for 10 controls and 9 healthy adults scoring highly been commonly studied candidates. The presence of the on perceptual aberrations/positive schizotypy [30]. No A1 allele of the TaqIA polymorphism (rs1800497) in the previous study has examined the combined influence of ANKK1 gene [9] (i.e., A1A1 and A1A2 genotypes) has specific polymorphisms related to brain dopamine activ- been associated with reduced D2 dopamine receptor ity and acute stress, as a gene-environment interaction, on (DRD2) density in key structures linked to brain rein- impulsivity. forcement, particularly in the striatum. This association has been confirmed by both in vitro [10,11] and in vivo We designed a study to examine the complexity of the positron emission tomography (PET) studies [12,13]. The ANKK1 gene-environment interaction on impulsive TaqIA had been historically described as residing in the behavior by testing acute stress as a plausible environmen- D2 dopamine receptor (DRD2) gene but has more tal factor in this relationship. To reduce the influence of recently been referred to as being within the ANKK1 [9]. potential confounds associated with psychopathology, we In addition to these biological associations, a strong body studied a community sample of young adults screened for of evidence suggests the involvement of the A1 allele in a psychiatric illness. Consistent with the multidimensional range of behavioral disorders characterized by impulsiv- nature of impulsivity [31] the laboratory paradigm incor- ity, including severe alcohol and other substance abuse, porated three separate measures of impulsivity, assessing obesity, pathological gambling and ADHD [14-16]. While reinforcer-cued approach, delay discounting and response A1 allele prevalence has been found to differ between eth- disinhibition respectively. These three dimensions are nic populations [17], raising the issue of population strat- supported by the results of factor analytic studies [32] and ification effects, research has shown that even across neuroimaging research linking these to differential brain diverse ethnic groups there are still robust associations of activation patterns in areas connected to mesolimbic the TaqIA with behavior [18]. Associations with addictive dopamine circuits. Reinforcement-related processing and disorders have led to the hypothesis that ANKK1 is a rein- delay discounting are linked to greater activation in the forcement gene and those with the A1 allele are more ventral striatum [33], while response inhibition is associ- likely to manifest brain reinforcement mechanism deficits ated with orbitofrontal circuit activity [34]. We directly than those without this allele [2,5]. Specifically, it is sug- examined the relationship between the A1 allele, labora- gested that in an effort to compensate for inherited tory-induced acute psychosocial stress and laboratory dopaminergic system deficiencies, individuals may seek measures of impulsive behavior. to stimulate the mesocorticolimbic circuits and experi- ence heightened reinforcement related to behaviors that Methods Participants increase brain dopamine levels (such as substance use), contributing to impulsive behavior. More direct evidence The study was approved by the Queensland University of in rats supports an association between reduced D2 recep- Technology Human Research Ethics Committee (Refer- tor availability in the ventral striatum and trait reinforcer- ence 3459H). All participants (44 females and 29 males) oriented impulsivity [19]. provided signed informed consent. Participants (M = 19.29 years, SD = 1.89) were recruited from technical col- In behavioral genetics, simple Mendelian genetic influ- lege campuses through advertising. Potential participants ences are rare, with most traits reflecting the interplay of were screened at initial contact via self-report for inclusion genes and environment [20]. In particular, the ANKK1 criteria: 17 to 25 years old, no history of head injury or conferred risk appears to be conveyed via an interaction of psychiatric disorder, no current gum disease and sufficient A1 allelic risk and environmental stress [21-25]. For exam- English language to complete the questionnaires. ple, in a sample of alcoholic patients, negative life events and a harm avoidant personality were associated with Of the 73 participants, 51 (69.9%) were Australian-born severity of alcohol dependence in those carrying the A1 and 51 (69.9%) were of Caucasian/European ethnicity, allele (A1+) but not in A1- patients [23]. Acute environ- with 6 (8.2%) reporting Polynesian ethnicity, 5 (6.8%) mental stress is associated with impulsive behavior [26- Asian ethnicity, 1 (1.4%) Aboriginal and/or Torres Strait 28] and can increase dopamine neurotransmission in Islander ethnicity and 9 (12.3%) reporting 'Other' ethnic- Page 2 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:54 http://www.behavioralandbrainfunctions.com/content/4/1/54 ity. On the highest level of education attained, 60 (82.2%) choice delay discounting task (choices paired with participants reported completing high school. Seven smaller, sooner-obtained point reinforcers vs. larger, (9.6%) participants reported a forensic history, typically longer delayed point reinforcers) named the Two Choice involving minor offences. Despite prior screening criteria, Impulsivity Paradigm (TCIP) [31] followed by a stop sig- 2 (2.7%) participants reported a history of head injury in nal task assessing the ability to withhold a prepotent the demographic questionnaire, and 8 (11.0%) reported a response, the GoStop task [31]. Due to the nature of the history/prior diagnosis of a psychiatric disorder. However, scoring of these tasks and the potential influence of carry- all participants were assessed as having normal cognitive over practice effects, they could only be administered function by the Trail Making Test [35] and an absence of post-induction. Table 1 provides further detail on these psychiatric symptoms according to the General Health behavioral measures of impulsivity. Questionnaire-28 [36]. On this basis, their data were retained and used in subsequent analyses. TaqIA Genotyping Buccal mucosa cells were collected using Cytosoft brushes Procedure (Medical Packing Corporation, California, USA). Mouth Participants were randomly allocated to either an experi- swabs were used to obtain DNA samples to avoid a selec- mental stress induction (preparation period for a video- tive exclusion of participants with blood and injection taped speech) or relaxation induction condition (listening phobias. These cells were spun and DNA was extracted to relaxing music), with each induction lasting five min- from leucocytes using standard techniques and subse- utes. This experimental manipulation consistently quently used as a template for determination of genotypes increases subjective feelings of stress and accompanying [47]. ANKK1 TaqIA genotyping was performed by restric- neuroendocrine and cardiovascular responses [37-39]. tion fragment length polymorphism (RFLP) analysis of The experiment was conducted individually in order to PCR products. A genomic sequence of 501 bp of the cod- maximize the effect of the psychosocial stressor and min- ing region of ANKK1 was amplified by PCR using the for- imize social support confounds [40]. Specifically, those in ward primer 5'-GCACGTGCCACCATACCC-3' and the the acute stress condition were told they were to spend the reverse primer 5'-TGCAGAGCAGTCAGGCTG-3'. A total next five minutes preparing a speech on their least favorite of 5–10 ng of genomic DNA was amplified in a PCR mas- body part which may be videotaped at the end of the test- ter mix containing 0.2 μM of forward primer and 0.2 μM ing session. These instructions are similar to those used of reverse primer, 1× PCR buffer, 1.5 mM MgCl , 200 μM successfully in previous research on the effect of alcohol dNTPs and 1 unit of Platinum Taq DNA Polymerase (Inv- on psychological stress [41,42] and the effect of psychoso- itrogen) in a 25 μL volume. Amplification conditions cial stress on decision-making performance [43]. A video were: Step 1: 94°C for 4 min, Step 2: 94°C for 30 s, Step camera was positioned on a tripod and visibly connected 3: 68°C for 30 s, Step 4: 72°C for 30 s, Steps 2–4 were to the power supply in full view of the participant. repeated by 40 cycles followed by 72°C for 3 min. Ampli- fied PCR fragments were digested with TaqI restriction A behavioral measure of reinforcement sensitivity, the enzyme (New England Biolabs) and digested fragments Card Arranging Reward Responsiveness Objective Test were visualized via agarose gel electrophoresis. (CARROT) [44], was administered before and after the induction. This is a simple card-sorting task that measures TaqIA genotyping identified 45 (61.6%) participants as over four trials the extent to which participants increase A2/A2 genotype (i.e., A1- allelic status), 24 (32.9%) as A1/ their speed of performance when reinforced via small A2 genotype and 4 (5.5%) as A1/A1 genotype (with the financial rewards compared with non-reinforcement trials latter two genotypes classified as A1+ allelic status). These (see Table 1 for further details). The CARROT has sound frequencies are in Hardy-Weinberg equilibrium, χ (N = validity as a behavioral measure of Gray's reinforcement 73) = 0.11, p > 0.05. Subsequent analyses were performed sensitivity, with scores correlating with self-reported comparing presence or absence of the A1 allele (A1+ vs. "reward sensitivity" in an Australian university sample A1-). The gender and ethnicity distribution for these two [45]. Measures of state anxiety (State Trait Anxiety Inven- genotypes are presented in Table 2. Chi-square analyses tory – State form, STAI-S) [46] and feelings of relaxation using Fisher's Exact Test showed no significant associa- or stress via a 100 mm Visual Analogue Scale (VAS) meas- tions of allelic status (A1+ vs. A1-) with gender (p = 0.33) ure were also administered pre and post. Participants were or with ethnicity (Caucasian vs. non-Caucasian, p = screened for psychopathology (General Health Question- 0.999). Further, there were no significant main or interac- naire-28) [36] and adequate cognitive function (Trail tive effects of gender or ethnicity (Caucasian vs. non-Cau- Making Test) [35]. After questionnaire completion partic- casian) with genotype on the baseline impulsivity ipants provided mouth swabs. Two computerized impul- measure tested, p > 0.05. sivity tasks were administered after the induction and second CARROT administration. These were a forced- Page 3 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:54 http://www.behavioralandbrainfunctions.com/content/4/1/54 Table 1: Procedure: Tests of behavioral impulsivity Test Description Dependent Variable CARROT [44] Participants complete four trials of sorting a pack of cards, each CARROT score of reinforcement sensitivity, calculated by card with five digits, into three corresponding trays. The first trial subtracting the mean of the number of cards sorted in T2 (T1) involves sorting 60 cards while being timed, with this time and T4 from the number of cards sorted in T3. CARROT = used as the time limit for subsequent trials. In trial two (T2), the T3 - ((T2+T4)/2). participant sorts a pack of 100 cards until told to stop. The third trial (T3) involves sorting 100 cards again with the time restriction of the previous trial, but with a small monetary reward offered for every five cards correctly sorted. A 20 cent coin is placed in front of the participant as the fifth card is sorted into the correct trays. The fourth trial (T4) is identical to T2 and controls for fatigue or practice effects on response speed. After T4, the participant is given the money earned during T3. TCIP [31] A forced-choice, reinforcement-directed computerized task, 1. Proportion of more immediate reinforcer choices modeled on delay discounting and delay of gratification tasks. (higher = more impulsive) Participants press a mouse button to select one of two shapes (a 2. Reaction times when making these more immediate square and a circle), each associated with either a short delay (in reinforcer choices (faster = more impulsive). this case, 5 seconds) followed by a small reinforcer (in this case, 5 points) or a longer delay (15 seconds) followed by a larger reinforcer (15 points). For this experiment, the parameters were set to include 10 training trials followed by 40 session trials using the "Reward Feedback" option. Pairing of shapes with immediate/ delayed conditions was counterbalanced within each experimental induction group. Reinforcement contingencies were not made explicit, with participants implicitly learning the relationship between the number of reward points displayed on the screen and each preceding geometric shape choice. GoStop [31] Like other stop response inhibition procedures, participants are 1. Percent inhibited responses (proportion of Stop trials required to attend to a series of visual stimuli, respond when a where no response occurs) (lower = more impulsive). target "go" signal appears, and withhold responding when a "stop" 2. Stop Latency (time in ms between the Stop Signal onset signal or non-target stimulus appears. In the GoStop, the stimuli and response) (quicker = more impulsive). are a series of five-digit numbers presented in black font one at a time on the screen. The "go" signal is a number that matches the previous number identically and is also presented in black. The "stop" signal is a matching number that changes color from black to red font some time after the stimulus onset. In addition to No- Stop (only the "go" signal) and Stop trials, at least half of the trials are Novel trials, with randomly generated non-matching numbers presented in black. For this experiment, the parameters were the default option of two blocks, seven stop trials (default is 10), 28 non-stop trials (default is 40), and 56 novel trials (minimum of one Novel stimulus following every Stop and No-Stop Trial). Stop Interval settings (ms from stimulus onset, SOA) were set as default (four intervals of 50 ms, 150 ms, 250 ms, and 350 ms, quasi- randomized throughout the session). Stimuli were presented for 500 ms each followed by 600 ms blackout between stimuli presentations. CARROT, Card Arranging Reward Responsiveness Objective Test; TCIP, Two Choice Impulsivity Paradigm. Data Analyses Results This experimental design was mixed (Time: pre, post × Experimental manipulation checks Genotype: A1A1 and A1A2 vs. A2A2 genotypes × Induc- Manipulation checks via paired t-tests on pre- and post- tion: stress, rest), with time as repeated measures for the induction STAI-S scores confirmed the validity of the CARROT only (and for manipulation checks involving the induction. Those exposed to the stress induction reported STAI and VAS measures). A square root transformation significantly more anxiety after exposure (M = 40.67, SD corrected a significant positive skew on TCIP mean choice = 12.17) than at baseline (M = 36.78, SD = 10.75), t(35) latency for immediate reinforcers. Separate analyses of = -2.50, p = 0.017. Those exposed to the relaxation induc- variance were conducted for each dependent variable of tion significantly reduced their anxiety scores from base- each task. While only pertinent results are reported, the line (M = 37.35, SD = 11.72) to post-induction (M = full results of all analyses are available from the author. 31.24, SD = 8.15), t(36) = 4.59, p < 0.001. Further tests Page 4 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:54 http://www.behavioralandbrainfunctions.com/content/4/1/54 Table 2: ANKK1 TaqIA A1 allele classification frequencies (% of Correlations between impulsivity measures total) by self-reported gender and ethnicity Table 3 presents the intercorrelations between the three laboratory paradigms used to measure impulsivity, Subgroup A1+ A1- namely the CARROT, TCIP and GoStop task variables. As shown, correlations between the three paradigms are all Gender Male 9 (12.3%) 20 (27.4%) low, supporting their relative independence. Female 19 (26.0%) 25 (34.2%) Total 28 (38.4%) 45 (61.6%) Reinforcement sensitivity: CARROT scores Ethnicity A Genotype × Induction × Time split-plot ANOVA Aboriginal and/or Torres Strait Islander 1 (1.4%) 0 (0%) revealed a multivariate two-way interaction between time Caucasian/European 20 (27.8%) 31 (43.1%) and genotype on CARROT scores, F(1,69) = 5.41, p = Polynesian 1 (1.4%) 5 (6.9%) 0.023, η = 0.073. Further comparisons revealed that at Asian 3 (4.2%) 2 (2.8%) Other 3 (4.2%) 6 (8.3%) baseline, A1+ participants were slower in card sorting Total 28 (38.9%) 44 (61.1%) under reinforcement conditions versus non-reinforce- ment conditions, compared with A1- participants, F(1,71) A1+ participants have at least one A1 allele and A1- participants are 2 = 6.98, p = 0.010, η = 0.089. These CARROT scores homozygous for A2. improved for A1+ participants after exposure to either induction (F(1,71) = 16.02, p < 0.001, η = 0.184), but revealed no baseline differences between the two induc- not for A1- participants (F(1,71) = .62, p = 0.43, η = tion groups, t(71) = 0.22, p = 0.83, and no effect of TaqIA 0.009) (Figure 1). There were no interactive or main genotype on anxiety scores at baseline or over time (p > effects of the stress manipulation (p > 0.05). 0.05). These test results were replicated using the VAS Delay discounting: TCIP measures measure of stress, further supporting the validity of the stress manipulation. Separate Genotype × Induction between-groups ANOVAs were conducted for TCIP measures, proportion of smaller Tobacco smoking status confound check sooner 'immediate' reinforcer choices made and square A self-report measure of tobacco smoking showed 27 root transformed mean response latencies for 'immediate' (37.0%) of the sample were current smokers. A chi-square reinforcer selections (Table 4). There were no significant analysis of smoking status by TaqIA allelic status by induc- effects of allelic status or the stress manipulation (p > tion condition using Fisher's exact Test showed no signif- 0.05). icant association of smoking status with allelic status for either the rest induction (p = 0.9999) or stress induction (p = 0.50) groups. Table 3: Intercorrelations between laboratory measures of impulsivity 1 2 3 4 5 6 7 8 9 101112 1. CARROT1 - -.02 .10 .08 .04 -.13 -.01 .03 -.02 .13 .10 .02 2. CARROT2 - .01 .00 .04 -.05 -.08 .05 -.14 .17 .05 -.01 3. TCIP PrChIm - -.68** .07 -.01 .09 .04 .07 .00 .05 -.05 4. TCIP MChLIm - -.07 .09 .04 .05 .11 -.16 -.06 .08 5. GS St50Inpc - .71** .39** .28* .39** .51** .46** .74** 6. GS St150Inpc - .54** .37** .36** .34** .32** .67** 7. GS St250Inpc - .58** .31* .20 .14 .52** 8. GS St350Inpc - .19 .07 .11 .28* 9. GS St50StL - .42** .44** .60** 10. GS St150StL - .62** .68** 11. GS St250StL -.68** 12. GS St350StL - Note. CARROT = Card Arranging Reward Responsiveness Objective Test score – first (1) and second administration (2); TCIP = Two Choice Impulsivity Paradigm, PrChIm = Proportion of Immediate Choices made, MChLIm = Mean choice latency (ms) to choose the option paired with an 'immediate' reinforcer, from presentation of stimuli to response; GS = GoStop task, St[50]Inpc = % inhibition at [50], [150], [250], and [350] ms SOAs; St[50]StL = response latency on Stop trials at [50], [150], [250], and [350] ms SOAs. ** Correlation is significant at the 0.01 level (2-tailed). * Correlation is significant at the 0.05 level (2-tailed). Page 5 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:54 http://www.behavioralandbrainfunctions.com/content/4/1/54 -1 -2 -3 -4 -5 Pre-Induction Post-Induction CARROT administration session A1+ Rest (n=11) A1+ Stress (n=17) A1- Rest (n=26) A1- Stress (n=19) Figure 1 Reward sensitivity (CARROT scores) pre- and post-induction (rest vs. stress) by ANKK1 TaqIA allelic status (A1+ vs. A1-) Reward sensitivity (CARROT scores) pre- and post-induction (rest vs. stress) by ANKK1 TaqIA allelic status (A1+ vs. A1-). Error bars display ± 2 SEM. Table 4: TCIP Delay Discounting by ANKK1 TaqIA genotype and induction condition (Rest A1+ n = 11, A1- n = 25; Acute Stress A1+ n = 17, A1- n = 18) Proportion Impulsive Choices Mean Immediate Choice Latency (ms) Induction Condition and Allele MSD M SD Rest A1+ 0.34 0.22 2500.73 1094.28 A1- 0.39 0.28 2515.80 1283.48 Stress A1+ 0.36 0.20 2220.12 900.13 A1- 0.46 0.30 2223.33 804.80 Means based on untransformed raw latencies. Page 6 of 9 (page number not for citation purposes) CARROT score Behavioral and Brain Functions 2008, 4:54 http://www.behavioralandbrainfunctions.com/content/4/1/54 Inhibitory control: GoStop measures Discussion We examined the interaction and main effects of the A1 Our study has, for the first time, examined several behav- allele and stress exposure via separate mixed-design ANO- ioral measures of impulsivity in combination with molec- VAs for the two indices of rash impulsiveness, poorer stop ular genetic risk and acute psychosocial stress. We have inhibition and faster mean response latencies when shown that the TaqIA A1 allele is associated with preclini- responding to the stop signal. Mean latency data at 50 ms cal behavioral risk in two dimensions of impulsivity, one SOA (stimulus onset asynchrony) contained 21% missing characterized by impaired performance sensitive to rein- data (15 participants successfully inhibited the prepotent forcers in the environment (though quickly overcome response 100% of the time) and was thus excluded from with repeated exposure) and the other by an accelerated analysis. For both measures, main effects of TaqIA geno- and disinhibited approach style in the absence of incen- type emerged, with A1+ participants demonstrating tive cues. This shared genetic risk was not associated with poorer stop inhibition (F(1,68) = 4.22, p = 0.04, η = acute stress and may represent indirect evidence of a com- 0.058) and quicker mean latencies on stop trials (F(1,66) mon etiology involving altered brain dopaminergic activ- = 9.45, p = 0.003, η = 0.125) than A1- participants across ity, consistent with reward deficiency theory [2,5]. all SOAs (Figure 2). Again, there were no interactive or main effects of the stress manipulation (p > 0.05). There Similar reinforcement-related performance deficits associ- were consistent effects of SOA on both response inhibi- ated with A1+ allelic status have been previously reversed tion (F(4,66) = 90.52, p < 0.001, η = 0.80) and mean under the influence of the dopamine agonist, bromocrip- stop response latency (F(2,65) = 288.69, p < 0.0001, η = tine [48]. While an acute stressor can increase dopamine 0.90), with poorer stop inhibition and faster incorrect neurotransmission in humans [29], our study has shown responses as SOA increased. a baseline performance deficit and subsequent improve- ment for A1+ participants regardless of acute stress. These results may reflect the importance of dopaminergic activ- ity in the reinforcement pathways for initial CARROT per- formance and an increased sensitivity of those with A1+ A1- deficiencies conferred by the A1 allele to repeated cue exposure. The second finding of poorer response inhibi- tion by A1+ participants has been shown in Spanish alco- hol 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 endopheno- type, rather than as a confound with alcoholism. The combined rash impulsive profile shown on this task by 50 150 250 350 A1+ young adults is also similar to that shown previously SOA (ms) for adults diagnosed with ADHD, a disorder characterized 220 by impulsivity [50]. We suggest the A1 allele confers a greater need for practice to overcome inherent reinforcement-related learning def- icits associated with fewer dopamine receptors in key brain reinforcement sites. Once sensitized, the general acceleration of approach behavior may be associated with 40 reduced inhibitory control observed in A1+ participants. Slower baseline approach in the presence of financial reinforcers could alternatively reflect an attentional bias 150 250 350 towards reinforcement cues in the environment, thus SOA (ms) indicating heightened reinforcement sensitivity in these individuals. This alternative is consistent with reward defi- ciency [2,5]. ( sto a stop Figure 2 A s a ) p func Stop signal trial inh tion of stimulus onse s (m ibi s)tio ofn AN (%KK1 Taq ) and (B) t asy IA alle mean r nchro lic gro esny (S pon ups se la OA, (A1+ vs ten ms cy on ) o . A1- f the ), (A) Stop inhibition (%) and (B) mean response The absence of TaqIA effects on implicit delay discounting latency on stop trials (ms) of ANKK1 TaqIA allelic contrasts with the impulsive profile suggested by effects groups (A1+ vs. A1-), as a function of stimulus onset asynchrony (SOA, ms) of the stop signal. on the other two behavioral measures. This may reflect a distinction between implicit and explicit awareness of Page 7 of 9 (page number not for citation purposes) M ean S top Latency (m s) Stop Inhibition (%) Behavioral and Brain Functions 2008, 4:54 http://www.behavioralandbrainfunctions.com/content/4/1/54 sive, addictive, and compulsive behaviors. 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Thompson J, Thomas N, Singleton A, Piggott M, Lloyd S, Perry EK, Our findings have helped elucidate the nature of an Morris CM, Perry RH, Ferrier IN, Court JA: D2 dopamine recep- impulsivity endophenotype associated with the A1 allele tor gene (DRD2) TaqI A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with of the ANKK1 TaqIA polymorphism that is differentially the A1 allele. Pharmacogenetics 1997, 7:479-484. related to a rash impulsive behavioral style and reinforce- 12. Pohjalainen T, Rinne JO, Nagren K, Lehikoinen P, Anttila K, Syvalahti EKG, Hietala J: The A1 allele of the human D2 dopamine ment-related performance deficits. This phenotype is receptor gene predicts low D2 receptor availability in unaffected by acute stress exposure. healthy volunteers. Mol Psychiatry 1998, 3:256-260. 13. Jonsson EG, Nothen MM, Grunhage F, Farde L, Nakashima Y, Prop- ping P, Sedvall GC: Polymorphisms in the dopamine D2 recep- Competing interests tor gene and their relationships to striatal dopamine The authors declare that they have no competing interests. receptor density of healthy volunteers. Mol Psychiatry 1999, 4:290-296. 14. Noble EP: D2 dopamine receptor gene in psychiatric and neu- Authors' contributions rologic disorders and its phenotypes. Am J Med Genet 2003, MW participated in the design of the study and coordina- 116:103-125. 15. Bobb AJ, Castellanos FX, Addington AM, Rapoport JL: Molecular tion, carried out the experiments, performed the statistical genetic studies of ADHD: 1991 to 2004. Am J Med Genet 2006, analyses and drafted the manuscript as part of a PhD the- 141:551-565. sis. CM participated in the design and coordinated the 16. Sery O, Drtilkova I, Theiner P, Pitelova R, Staif R, Znojil V, Lochman J, Didden W: Polymorphism of DRD2 gene and ADHD. Neuro DNA extraction and genotyping. BL participated in the Endocrinol Lett 2006, 27(1-2):236-240. design. BL and CM were PhD co-supervisors. RY partici- 17. Barr CL, Kidd KK: Population frequencies of the A1 allele at pated in the design and coordination, helped to draft the the dopamine D2 receptor locus. Biol Psychiatry 1993, 34:204-209. manuscript and was primary PhD supervisor. All authors 18. Young RM, Lawford BR, Nutting A, Noble EP: Advances in molec- read and approved the final manuscript. ular genetics and the prevention and treatment of substance misuse: implications of association studies of the A1 allele of the D2 dopamine receptor gene. Addict Behav 2004, Acknowledgements 29:1275-1294. Supported by an Australian Postgraduate Award (MW) and Institute of 19. Dalley JW, Fryer TD, Brichard L, Robinson ESJ, Theobald DEH, Laane Health and Biomedical Innovation Postgraduate Award (MW). We thank K, Pena Y, Murphy ER, Shah Y, Probst K, Abakumova I, Aigbirhio FI, Richards HK, Hong Y, Baron J-C, Everitt BJ, Robbins TW: Nucleus Donald M. Dougherty for providing the software for the delay discounting accumbens D2/3 receptors predict trait impulsivity and and stop inhibition tasks. We also thank Christopher D. Swagell and Ade- cocaine reinforcement. Science 2007, 315:1267-1270. lene Liao for assistance with genotyping. 20. Caspi A, Moffitt TE: Gene-environment interactions in psychi- atry: joining forces with neuroscience. Nature Rev Neurosci 2006, 7:583-590. References 21. Young RM, Lawford BR, Noble EP, Kann B, Wilkie A, Ritchie T, 1. American Psychiatric Association: Diagnostic and Statistical Manual of Arnold L, Shadforth S: Harmful drinking in military veterans Mental Disorders 4th edition. Washington, DC: American Psychiatric with post-traumatic stress disorder: association with the D2 Press; 1994. dopamine receptor A1 allele. Alcohol Alcohol 2002, 37:451-456. 2. Blum K, Braverman ER, Holder JM, Lubar JF, Monastra VJ, Miller D, 22. Berman SM, Noble EP: The D2 dopamine receptor (DRD2) Lubar JO, Chen TJH, Comings DE: Reward deficiency syndrome: gene and family stress: interactive effects on cognitive func- a biogenetic model for the diagnosis and treatment of impul- tions in children. Behav Genet 1997, 27:33-43. Page 8 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:54 http://www.behavioralandbrainfunctions.com/content/4/1/54 23. Bau CH, Almeida S, Hutz MH: The TaqI A1 allele of the 45. Kambouropoulos N, Staiger PK: Personality and responses to dopamine D2 receptor gene and alcoholism in Brazil: associ- appetitive and aversive stimuli: the joint influence of behav- ation and interaction with stress and harm avoidance on ioural approach and behavioural inhibition systems. Pers Indiv severity prediction. Am J Med Genet 2000, 96:302-306. Diff 2004, 37:1153-1165. 24. 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Steele CM, Josephs RA: Drinking your troubles away II: an attention-allocation model of alcohol's effect on psychologi- Your research papers will be: cal stress. J Abn Psychol 1988, 97:196-205. available free of charge to the entire biomedical community 43. Preston SD, Tansfield RBS, Buchanan TW, Bechara A: Effects of anticipatory stress on decision making in a gambling task. peer reviewed and published immediately upon acceptance Behav Neurosci 2007, 121:257-263. cited in PubMed and archived on PubMed Central 44. Powell J, Al-Adawi S, Morgan J, Greenwood RJ: Motivational defi- cits after brain injury: effects of bromocriptine in 11 patients. yours — you keep the copyright J Neurol Neurosurg Psychiatry 1996, 60:416-421. BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 9 of 9 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Behavioral and Brain Functions Springer Journals

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

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Springer Journals
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Copyright © 2008 by White et al; licensee BioMed Central Ltd.
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Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
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1744-9081
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10.1186/1744-9081-4-54
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19025655
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Abstract

Background: The A1 allele of the ANKK1 TaqIA polymorphism (previously reported as located in the D2 dopamine receptor (DRD2) gene) is associated with reduced DRD2 density in the striatum and with clinical disorders, particularly addiction. It was hypothesized that impulsivity represents an endophenotype underlying these associations with the TaqIA and that environmental stress would moderate the strength of the gene-behavior relationship. Methods: TaqIA genotyping was conducted on 72 healthy young adults who were randomly allocated to either an acute psychosocial stress or relaxation induction condition. Behavioral phenotypes of impulsivity were measured using a card-sorting index of reinforcement sensitivity and computerized response inhibition and delay discounting tasks. Results: Separate analyses of variance revealed associations between the A1 allele and two laboratory measures of impulsivity. The presence of the TaqIA allele (A1+) was associated with slower card-sorting in the presence of small financial reinforcers, but was overcome in a second administration after either a five-minute rest or psychosocial stress induction. A1+ participants also demonstrated significantly poorer response inhibition and faster response times on a computerized stop inhibition task, independent of acute stress exposure. Conclusion: These findings indicate the A1 allele is associated with an endophenotype comprising both a "rash impulsive" behavioral style and reinforcement-related learning deficits. These effects are independent of stress. in several forms of aggression and violence, sexual impul- Background The phenotypes of multiple psychiatric disorders involve sivity, binge eating, obesity, self-harm and suicidal behav- features of impulsivity including attention deficit hyperac- ior [2]. As such, the study of factors that may contribute to tivity disorder (ADHD), bipolar disorder, mania, bulimia impulsivity is fundamental to understanding and treating nervosa, several personality disorders, schizophrenia and maladaptive human behavior. substance dependence [1]. Impulsivity is also implicated Page 1 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:54 http://www.behavioralandbrainfunctions.com/content/4/1/54 Dopamine is integral to leading theories of an impulsive humans [29]. Further, recent PET scan findings suggest personality phenotype [3,4] and plays a crucial role in acute stress-induced striatal dopamine release may be brain reinforcement circuits [2,5]. Personality theories of greater in individuals at risk of psychosis. A significant impulsivity also consistently emphasize the role of genet- decrease in [ C]raclopride binding potential (indicative ics, reflecting evidence from twin studies of high heritabil- of dopamine release), particularly in the ventral striatum, ity on self-report measures, including sensation seeking was reported for seven healthy students identified as at (55% [6]), novelty seeking (40% [7]) and "rash/ risk for psychosis due to elevated scores for physical anhe- unplanned" impulsivity (15–40% [8]). Subsequently, donia/negative schizotypy. In contrast, no such effect was genes associated with brain dopaminergic activity have found for 10 controls and 9 healthy adults scoring highly been commonly studied candidates. The presence of the on perceptual aberrations/positive schizotypy [30]. No A1 allele of the TaqIA polymorphism (rs1800497) in the previous study has examined the combined influence of ANKK1 gene [9] (i.e., A1A1 and A1A2 genotypes) has specific polymorphisms related to brain dopamine activ- been associated with reduced D2 dopamine receptor ity and acute stress, as a gene-environment interaction, on (DRD2) density in key structures linked to brain rein- impulsivity. forcement, particularly in the striatum. This association has been confirmed by both in vitro [10,11] and in vivo We designed a study to examine the complexity of the positron emission tomography (PET) studies [12,13]. The ANKK1 gene-environment interaction on impulsive TaqIA had been historically described as residing in the behavior by testing acute stress as a plausible environmen- D2 dopamine receptor (DRD2) gene but has more tal factor in this relationship. To reduce the influence of recently been referred to as being within the ANKK1 [9]. potential confounds associated with psychopathology, we In addition to these biological associations, a strong body studied a community sample of young adults screened for of evidence suggests the involvement of the A1 allele in a psychiatric illness. Consistent with the multidimensional range of behavioral disorders characterized by impulsiv- nature of impulsivity [31] the laboratory paradigm incor- ity, including severe alcohol and other substance abuse, porated three separate measures of impulsivity, assessing obesity, pathological gambling and ADHD [14-16]. While reinforcer-cued approach, delay discounting and response A1 allele prevalence has been found to differ between eth- disinhibition respectively. These three dimensions are nic populations [17], raising the issue of population strat- supported by the results of factor analytic studies [32] and ification effects, research has shown that even across neuroimaging research linking these to differential brain diverse ethnic groups there are still robust associations of activation patterns in areas connected to mesolimbic the TaqIA with behavior [18]. Associations with addictive dopamine circuits. Reinforcement-related processing and disorders have led to the hypothesis that ANKK1 is a rein- delay discounting are linked to greater activation in the forcement gene and those with the A1 allele are more ventral striatum [33], while response inhibition is associ- likely to manifest brain reinforcement mechanism deficits ated with orbitofrontal circuit activity [34]. We directly than those without this allele [2,5]. Specifically, it is sug- examined the relationship between the A1 allele, labora- gested that in an effort to compensate for inherited tory-induced acute psychosocial stress and laboratory dopaminergic system deficiencies, individuals may seek measures of impulsive behavior. to stimulate the mesocorticolimbic circuits and experi- ence heightened reinforcement related to behaviors that Methods Participants increase brain dopamine levels (such as substance use), contributing to impulsive behavior. More direct evidence The study was approved by the Queensland University of in rats supports an association between reduced D2 recep- Technology Human Research Ethics Committee (Refer- tor availability in the ventral striatum and trait reinforcer- ence 3459H). All participants (44 females and 29 males) oriented impulsivity [19]. provided signed informed consent. Participants (M = 19.29 years, SD = 1.89) were recruited from technical col- In behavioral genetics, simple Mendelian genetic influ- lege campuses through advertising. Potential participants ences are rare, with most traits reflecting the interplay of were screened at initial contact via self-report for inclusion genes and environment [20]. In particular, the ANKK1 criteria: 17 to 25 years old, no history of head injury or conferred risk appears to be conveyed via an interaction of psychiatric disorder, no current gum disease and sufficient A1 allelic risk and environmental stress [21-25]. For exam- English language to complete the questionnaires. ple, in a sample of alcoholic patients, negative life events and a harm avoidant personality were associated with Of the 73 participants, 51 (69.9%) were Australian-born severity of alcohol dependence in those carrying the A1 and 51 (69.9%) were of Caucasian/European ethnicity, allele (A1+) but not in A1- patients [23]. Acute environ- with 6 (8.2%) reporting Polynesian ethnicity, 5 (6.8%) mental stress is associated with impulsive behavior [26- Asian ethnicity, 1 (1.4%) Aboriginal and/or Torres Strait 28] and can increase dopamine neurotransmission in Islander ethnicity and 9 (12.3%) reporting 'Other' ethnic- Page 2 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:54 http://www.behavioralandbrainfunctions.com/content/4/1/54 ity. On the highest level of education attained, 60 (82.2%) choice delay discounting task (choices paired with participants reported completing high school. Seven smaller, sooner-obtained point reinforcers vs. larger, (9.6%) participants reported a forensic history, typically longer delayed point reinforcers) named the Two Choice involving minor offences. Despite prior screening criteria, Impulsivity Paradigm (TCIP) [31] followed by a stop sig- 2 (2.7%) participants reported a history of head injury in nal task assessing the ability to withhold a prepotent the demographic questionnaire, and 8 (11.0%) reported a response, the GoStop task [31]. Due to the nature of the history/prior diagnosis of a psychiatric disorder. However, scoring of these tasks and the potential influence of carry- all participants were assessed as having normal cognitive over practice effects, they could only be administered function by the Trail Making Test [35] and an absence of post-induction. Table 1 provides further detail on these psychiatric symptoms according to the General Health behavioral measures of impulsivity. Questionnaire-28 [36]. On this basis, their data were retained and used in subsequent analyses. TaqIA Genotyping Buccal mucosa cells were collected using Cytosoft brushes Procedure (Medical Packing Corporation, California, USA). Mouth Participants were randomly allocated to either an experi- swabs were used to obtain DNA samples to avoid a selec- mental stress induction (preparation period for a video- tive exclusion of participants with blood and injection taped speech) or relaxation induction condition (listening phobias. These cells were spun and DNA was extracted to relaxing music), with each induction lasting five min- from leucocytes using standard techniques and subse- utes. This experimental manipulation consistently quently used as a template for determination of genotypes increases subjective feelings of stress and accompanying [47]. ANKK1 TaqIA genotyping was performed by restric- neuroendocrine and cardiovascular responses [37-39]. tion fragment length polymorphism (RFLP) analysis of The experiment was conducted individually in order to PCR products. A genomic sequence of 501 bp of the cod- maximize the effect of the psychosocial stressor and min- ing region of ANKK1 was amplified by PCR using the for- imize social support confounds [40]. Specifically, those in ward primer 5'-GCACGTGCCACCATACCC-3' and the the acute stress condition were told they were to spend the reverse primer 5'-TGCAGAGCAGTCAGGCTG-3'. A total next five minutes preparing a speech on their least favorite of 5–10 ng of genomic DNA was amplified in a PCR mas- body part which may be videotaped at the end of the test- ter mix containing 0.2 μM of forward primer and 0.2 μM ing session. These instructions are similar to those used of reverse primer, 1× PCR buffer, 1.5 mM MgCl , 200 μM successfully in previous research on the effect of alcohol dNTPs and 1 unit of Platinum Taq DNA Polymerase (Inv- on psychological stress [41,42] and the effect of psychoso- itrogen) in a 25 μL volume. Amplification conditions cial stress on decision-making performance [43]. A video were: Step 1: 94°C for 4 min, Step 2: 94°C for 30 s, Step camera was positioned on a tripod and visibly connected 3: 68°C for 30 s, Step 4: 72°C for 30 s, Steps 2–4 were to the power supply in full view of the participant. repeated by 40 cycles followed by 72°C for 3 min. Ampli- fied PCR fragments were digested with TaqI restriction A behavioral measure of reinforcement sensitivity, the enzyme (New England Biolabs) and digested fragments Card Arranging Reward Responsiveness Objective Test were visualized via agarose gel electrophoresis. (CARROT) [44], was administered before and after the induction. This is a simple card-sorting task that measures TaqIA genotyping identified 45 (61.6%) participants as over four trials the extent to which participants increase A2/A2 genotype (i.e., A1- allelic status), 24 (32.9%) as A1/ their speed of performance when reinforced via small A2 genotype and 4 (5.5%) as A1/A1 genotype (with the financial rewards compared with non-reinforcement trials latter two genotypes classified as A1+ allelic status). These (see Table 1 for further details). The CARROT has sound frequencies are in Hardy-Weinberg equilibrium, χ (N = validity as a behavioral measure of Gray's reinforcement 73) = 0.11, p > 0.05. Subsequent analyses were performed sensitivity, with scores correlating with self-reported comparing presence or absence of the A1 allele (A1+ vs. "reward sensitivity" in an Australian university sample A1-). The gender and ethnicity distribution for these two [45]. Measures of state anxiety (State Trait Anxiety Inven- genotypes are presented in Table 2. Chi-square analyses tory – State form, STAI-S) [46] and feelings of relaxation using Fisher's Exact Test showed no significant associa- or stress via a 100 mm Visual Analogue Scale (VAS) meas- tions of allelic status (A1+ vs. A1-) with gender (p = 0.33) ure were also administered pre and post. Participants were or with ethnicity (Caucasian vs. non-Caucasian, p = screened for psychopathology (General Health Question- 0.999). Further, there were no significant main or interac- naire-28) [36] and adequate cognitive function (Trail tive effects of gender or ethnicity (Caucasian vs. non-Cau- Making Test) [35]. After questionnaire completion partic- casian) with genotype on the baseline impulsivity ipants provided mouth swabs. Two computerized impul- measure tested, p > 0.05. sivity tasks were administered after the induction and second CARROT administration. These were a forced- Page 3 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:54 http://www.behavioralandbrainfunctions.com/content/4/1/54 Table 1: Procedure: Tests of behavioral impulsivity Test Description Dependent Variable CARROT [44] Participants complete four trials of sorting a pack of cards, each CARROT score of reinforcement sensitivity, calculated by card with five digits, into three corresponding trays. The first trial subtracting the mean of the number of cards sorted in T2 (T1) involves sorting 60 cards while being timed, with this time and T4 from the number of cards sorted in T3. CARROT = used as the time limit for subsequent trials. In trial two (T2), the T3 - ((T2+T4)/2). participant sorts a pack of 100 cards until told to stop. The third trial (T3) involves sorting 100 cards again with the time restriction of the previous trial, but with a small monetary reward offered for every five cards correctly sorted. A 20 cent coin is placed in front of the participant as the fifth card is sorted into the correct trays. The fourth trial (T4) is identical to T2 and controls for fatigue or practice effects on response speed. After T4, the participant is given the money earned during T3. TCIP [31] A forced-choice, reinforcement-directed computerized task, 1. Proportion of more immediate reinforcer choices modeled on delay discounting and delay of gratification tasks. (higher = more impulsive) Participants press a mouse button to select one of two shapes (a 2. Reaction times when making these more immediate square and a circle), each associated with either a short delay (in reinforcer choices (faster = more impulsive). this case, 5 seconds) followed by a small reinforcer (in this case, 5 points) or a longer delay (15 seconds) followed by a larger reinforcer (15 points). For this experiment, the parameters were set to include 10 training trials followed by 40 session trials using the "Reward Feedback" option. Pairing of shapes with immediate/ delayed conditions was counterbalanced within each experimental induction group. Reinforcement contingencies were not made explicit, with participants implicitly learning the relationship between the number of reward points displayed on the screen and each preceding geometric shape choice. GoStop [31] Like other stop response inhibition procedures, participants are 1. Percent inhibited responses (proportion of Stop trials required to attend to a series of visual stimuli, respond when a where no response occurs) (lower = more impulsive). target "go" signal appears, and withhold responding when a "stop" 2. Stop Latency (time in ms between the Stop Signal onset signal or non-target stimulus appears. In the GoStop, the stimuli and response) (quicker = more impulsive). are a series of five-digit numbers presented in black font one at a time on the screen. The "go" signal is a number that matches the previous number identically and is also presented in black. The "stop" signal is a matching number that changes color from black to red font some time after the stimulus onset. In addition to No- Stop (only the "go" signal) and Stop trials, at least half of the trials are Novel trials, with randomly generated non-matching numbers presented in black. For this experiment, the parameters were the default option of two blocks, seven stop trials (default is 10), 28 non-stop trials (default is 40), and 56 novel trials (minimum of one Novel stimulus following every Stop and No-Stop Trial). Stop Interval settings (ms from stimulus onset, SOA) were set as default (four intervals of 50 ms, 150 ms, 250 ms, and 350 ms, quasi- randomized throughout the session). Stimuli were presented for 500 ms each followed by 600 ms blackout between stimuli presentations. CARROT, Card Arranging Reward Responsiveness Objective Test; TCIP, Two Choice Impulsivity Paradigm. Data Analyses Results This experimental design was mixed (Time: pre, post × Experimental manipulation checks Genotype: A1A1 and A1A2 vs. A2A2 genotypes × Induc- Manipulation checks via paired t-tests on pre- and post- tion: stress, rest), with time as repeated measures for the induction STAI-S scores confirmed the validity of the CARROT only (and for manipulation checks involving the induction. Those exposed to the stress induction reported STAI and VAS measures). A square root transformation significantly more anxiety after exposure (M = 40.67, SD corrected a significant positive skew on TCIP mean choice = 12.17) than at baseline (M = 36.78, SD = 10.75), t(35) latency for immediate reinforcers. Separate analyses of = -2.50, p = 0.017. Those exposed to the relaxation induc- variance were conducted for each dependent variable of tion significantly reduced their anxiety scores from base- each task. While only pertinent results are reported, the line (M = 37.35, SD = 11.72) to post-induction (M = full results of all analyses are available from the author. 31.24, SD = 8.15), t(36) = 4.59, p < 0.001. Further tests Page 4 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:54 http://www.behavioralandbrainfunctions.com/content/4/1/54 Table 2: ANKK1 TaqIA A1 allele classification frequencies (% of Correlations between impulsivity measures total) by self-reported gender and ethnicity Table 3 presents the intercorrelations between the three laboratory paradigms used to measure impulsivity, Subgroup A1+ A1- namely the CARROT, TCIP and GoStop task variables. As shown, correlations between the three paradigms are all Gender Male 9 (12.3%) 20 (27.4%) low, supporting their relative independence. Female 19 (26.0%) 25 (34.2%) Total 28 (38.4%) 45 (61.6%) Reinforcement sensitivity: CARROT scores Ethnicity A Genotype × Induction × Time split-plot ANOVA Aboriginal and/or Torres Strait Islander 1 (1.4%) 0 (0%) revealed a multivariate two-way interaction between time Caucasian/European 20 (27.8%) 31 (43.1%) and genotype on CARROT scores, F(1,69) = 5.41, p = Polynesian 1 (1.4%) 5 (6.9%) 0.023, η = 0.073. Further comparisons revealed that at Asian 3 (4.2%) 2 (2.8%) Other 3 (4.2%) 6 (8.3%) baseline, A1+ participants were slower in card sorting Total 28 (38.9%) 44 (61.1%) under reinforcement conditions versus non-reinforce- ment conditions, compared with A1- participants, F(1,71) A1+ participants have at least one A1 allele and A1- participants are 2 = 6.98, p = 0.010, η = 0.089. These CARROT scores homozygous for A2. improved for A1+ participants after exposure to either induction (F(1,71) = 16.02, p < 0.001, η = 0.184), but revealed no baseline differences between the two induc- not for A1- participants (F(1,71) = .62, p = 0.43, η = tion groups, t(71) = 0.22, p = 0.83, and no effect of TaqIA 0.009) (Figure 1). There were no interactive or main genotype on anxiety scores at baseline or over time (p > effects of the stress manipulation (p > 0.05). 0.05). These test results were replicated using the VAS Delay discounting: TCIP measures measure of stress, further supporting the validity of the stress manipulation. Separate Genotype × Induction between-groups ANOVAs were conducted for TCIP measures, proportion of smaller Tobacco smoking status confound check sooner 'immediate' reinforcer choices made and square A self-report measure of tobacco smoking showed 27 root transformed mean response latencies for 'immediate' (37.0%) of the sample were current smokers. A chi-square reinforcer selections (Table 4). There were no significant analysis of smoking status by TaqIA allelic status by induc- effects of allelic status or the stress manipulation (p > tion condition using Fisher's exact Test showed no signif- 0.05). icant association of smoking status with allelic status for either the rest induction (p = 0.9999) or stress induction (p = 0.50) groups. Table 3: Intercorrelations between laboratory measures of impulsivity 1 2 3 4 5 6 7 8 9 101112 1. CARROT1 - -.02 .10 .08 .04 -.13 -.01 .03 -.02 .13 .10 .02 2. CARROT2 - .01 .00 .04 -.05 -.08 .05 -.14 .17 .05 -.01 3. TCIP PrChIm - -.68** .07 -.01 .09 .04 .07 .00 .05 -.05 4. TCIP MChLIm - -.07 .09 .04 .05 .11 -.16 -.06 .08 5. GS St50Inpc - .71** .39** .28* .39** .51** .46** .74** 6. GS St150Inpc - .54** .37** .36** .34** .32** .67** 7. GS St250Inpc - .58** .31* .20 .14 .52** 8. GS St350Inpc - .19 .07 .11 .28* 9. GS St50StL - .42** .44** .60** 10. GS St150StL - .62** .68** 11. GS St250StL -.68** 12. GS St350StL - Note. CARROT = Card Arranging Reward Responsiveness Objective Test score – first (1) and second administration (2); TCIP = Two Choice Impulsivity Paradigm, PrChIm = Proportion of Immediate Choices made, MChLIm = Mean choice latency (ms) to choose the option paired with an 'immediate' reinforcer, from presentation of stimuli to response; GS = GoStop task, St[50]Inpc = % inhibition at [50], [150], [250], and [350] ms SOAs; St[50]StL = response latency on Stop trials at [50], [150], [250], and [350] ms SOAs. ** Correlation is significant at the 0.01 level (2-tailed). * Correlation is significant at the 0.05 level (2-tailed). Page 5 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:54 http://www.behavioralandbrainfunctions.com/content/4/1/54 -1 -2 -3 -4 -5 Pre-Induction Post-Induction CARROT administration session A1+ Rest (n=11) A1+ Stress (n=17) A1- Rest (n=26) A1- Stress (n=19) Figure 1 Reward sensitivity (CARROT scores) pre- and post-induction (rest vs. stress) by ANKK1 TaqIA allelic status (A1+ vs. A1-) Reward sensitivity (CARROT scores) pre- and post-induction (rest vs. stress) by ANKK1 TaqIA allelic status (A1+ vs. A1-). Error bars display ± 2 SEM. Table 4: TCIP Delay Discounting by ANKK1 TaqIA genotype and induction condition (Rest A1+ n = 11, A1- n = 25; Acute Stress A1+ n = 17, A1- n = 18) Proportion Impulsive Choices Mean Immediate Choice Latency (ms) Induction Condition and Allele MSD M SD Rest A1+ 0.34 0.22 2500.73 1094.28 A1- 0.39 0.28 2515.80 1283.48 Stress A1+ 0.36 0.20 2220.12 900.13 A1- 0.46 0.30 2223.33 804.80 Means based on untransformed raw latencies. Page 6 of 9 (page number not for citation purposes) CARROT score Behavioral and Brain Functions 2008, 4:54 http://www.behavioralandbrainfunctions.com/content/4/1/54 Inhibitory control: GoStop measures Discussion We examined the interaction and main effects of the A1 Our study has, for the first time, examined several behav- allele and stress exposure via separate mixed-design ANO- ioral measures of impulsivity in combination with molec- VAs for the two indices of rash impulsiveness, poorer stop ular genetic risk and acute psychosocial stress. We have inhibition and faster mean response latencies when shown that the TaqIA A1 allele is associated with preclini- responding to the stop signal. Mean latency data at 50 ms cal behavioral risk in two dimensions of impulsivity, one SOA (stimulus onset asynchrony) contained 21% missing characterized by impaired performance sensitive to rein- data (15 participants successfully inhibited the prepotent forcers in the environment (though quickly overcome response 100% of the time) and was thus excluded from with repeated exposure) and the other by an accelerated analysis. For both measures, main effects of TaqIA geno- and disinhibited approach style in the absence of incen- type emerged, with A1+ participants demonstrating tive cues. This shared genetic risk was not associated with poorer stop inhibition (F(1,68) = 4.22, p = 0.04, η = acute stress and may represent indirect evidence of a com- 0.058) and quicker mean latencies on stop trials (F(1,66) mon etiology involving altered brain dopaminergic activ- = 9.45, p = 0.003, η = 0.125) than A1- participants across ity, consistent with reward deficiency theory [2,5]. all SOAs (Figure 2). Again, there were no interactive or main effects of the stress manipulation (p > 0.05). There Similar reinforcement-related performance deficits associ- were consistent effects of SOA on both response inhibi- ated with A1+ allelic status have been previously reversed tion (F(4,66) = 90.52, p < 0.001, η = 0.80) and mean under the influence of the dopamine agonist, bromocrip- stop response latency (F(2,65) = 288.69, p < 0.0001, η = tine [48]. While an acute stressor can increase dopamine 0.90), with poorer stop inhibition and faster incorrect neurotransmission in humans [29], our study has shown responses as SOA increased. a baseline performance deficit and subsequent improve- ment for A1+ participants regardless of acute stress. These results may reflect the importance of dopaminergic activ- ity in the reinforcement pathways for initial CARROT per- formance and an increased sensitivity of those with A1+ A1- deficiencies conferred by the A1 allele to repeated cue exposure. The second finding of poorer response inhibi- tion by A1+ participants has been shown in Spanish alco- hol 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 endopheno- type, rather than as a confound with alcoholism. The combined rash impulsive profile shown on this task by 50 150 250 350 A1+ young adults is also similar to that shown previously SOA (ms) for adults diagnosed with ADHD, a disorder characterized 220 by impulsivity [50]. We suggest the A1 allele confers a greater need for practice to overcome inherent reinforcement-related learning def- icits associated with fewer dopamine receptors in key brain reinforcement sites. Once sensitized, the general acceleration of approach behavior may be associated with 40 reduced inhibitory control observed in A1+ participants. Slower baseline approach in the presence of financial reinforcers could alternatively reflect an attentional bias 150 250 350 towards reinforcement cues in the environment, thus SOA (ms) indicating heightened reinforcement sensitivity in these individuals. This alternative is consistent with reward defi- ciency [2,5]. ( sto a stop Figure 2 A s a ) p func Stop signal trial inh tion of stimulus onse s (m ibi s)tio ofn AN (%KK1 Taq ) and (B) t asy IA alle mean r nchro lic gro esny (S pon ups se la OA, (A1+ vs ten ms cy on ) o . A1- f the ), (A) Stop inhibition (%) and (B) mean response The absence of TaqIA effects on implicit delay discounting latency on stop trials (ms) of ANKK1 TaqIA allelic contrasts with the impulsive profile suggested by effects groups (A1+ vs. A1-), as a function of stimulus onset asynchrony (SOA, ms) of the stop signal. on the other two behavioral measures. This may reflect a distinction between implicit and explicit awareness of Page 7 of 9 (page number not for citation purposes) M ean S top Latency (m s) Stop Inhibition (%) Behavioral and Brain Functions 2008, 4:54 http://www.behavioralandbrainfunctions.com/content/4/1/54 sive, addictive, and compulsive behaviors. J Psychoactive Drugs reinforcers, given a contrasting recent report of an associ- 2000, 32 Suppl:i-iv. ation between the A1 allele and an explicit delay discount- 3. Gray JA, McNaughton N: The Neuropsychology of Anxiety: An Enquiry ing paradigm in an unselected university sample [51]. into the Functions of the Septo-hippocampal System 2nd edition. New York: Oxford University Press; 2000. Future research should further examine a comparison 4. Cloninger CR, Svrakic DM, Przybeck TR: A psychobiological between explicit and implicit cognitive processes with the model of temperament and character. Arch Gen Psychiatry 1993, 50:975-990. A1 allele. 5. Noble EP: Addiction and its reward process through polymor- phisms of the D2 dopamine receptor gene: a review. Eur Psy- The absence of an effect of the acute psychosocial stressor chiatry 2000, 15:79-89. 6. 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New Jersey: Erl- iological and neuroendocrine stress measurement in baum; 1983:1-27. 9. Neville MJ, Johnstone EC, Walton RT: Identification and charac- future research is important. Future research should also terization of ANKK1: a novel kinase gene closely linked to investigate other plausible environmental moderators DRD2 on chromosome band 11q23.1. Hum Mutat 2004, 23:540-545. and mediators of this relationship, including chronic 10. Noble EP, Blum K, Ritchie T, Montgomery A, Sheridan PJ: Allelic stress. association of the D2 dopamine receptor gene with receptor binding characteristics in alcoholism. Arch Gen Psychiatry 1991, 48:648-654. Conclusion 11. Thompson J, Thomas N, Singleton A, Piggott M, Lloyd S, Perry EK, Our findings have helped elucidate the nature of an Morris CM, Perry RH, Ferrier IN, Court JA: D2 dopamine recep- impulsivity endophenotype associated with the A1 allele tor gene (DRD2) TaqI A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with of the ANKK1 TaqIA polymorphism that is differentially the A1 allele. Pharmacogenetics 1997, 7:479-484. related to a rash impulsive behavioral style and reinforce- 12. Pohjalainen T, Rinne JO, Nagren K, Lehikoinen P, Anttila K, Syvalahti EKG, Hietala J: The A1 allele of the human D2 dopamine ment-related performance deficits. This phenotype is receptor gene predicts low D2 receptor availability in unaffected by acute stress exposure. healthy volunteers. Mol Psychiatry 1998, 3:256-260. 13. Jonsson EG, Nothen MM, Grunhage F, Farde L, Nakashima Y, Prop- ping P, Sedvall GC: Polymorphisms in the dopamine D2 recep- Competing interests tor gene and their relationships to striatal dopamine The authors declare that they have no competing interests. receptor density of healthy volunteers. Mol Psychiatry 1999, 4:290-296. 14. Noble EP: D2 dopamine receptor gene in psychiatric and neu- Authors' contributions rologic disorders and its phenotypes. Am J Med Genet 2003, MW participated in the design of the study and coordina- 116:103-125. 15. Bobb AJ, Castellanos FX, Addington AM, Rapoport JL: Molecular tion, carried out the experiments, performed the statistical genetic studies of ADHD: 1991 to 2004. Am J Med Genet 2006, analyses and drafted the manuscript as part of a PhD the- 141:551-565. sis. CM participated in the design and coordinated the 16. Sery O, Drtilkova I, Theiner P, Pitelova R, Staif R, Znojil V, Lochman J, Didden W: Polymorphism of DRD2 gene and ADHD. Neuro DNA extraction and genotyping. BL participated in the Endocrinol Lett 2006, 27(1-2):236-240. design. BL and CM were PhD co-supervisors. RY partici- 17. Barr CL, Kidd KK: Population frequencies of the A1 allele at pated in the design and coordination, helped to draft the the dopamine D2 receptor locus. Biol Psychiatry 1993, 34:204-209. manuscript and was primary PhD supervisor. All authors 18. Young RM, Lawford BR, Nutting A, Noble EP: Advances in molec- read and approved the final manuscript. ular genetics and the prevention and treatment of substance misuse: implications of association studies of the A1 allele of the D2 dopamine receptor gene. Addict Behav 2004, Acknowledgements 29:1275-1294. Supported by an Australian Postgraduate Award (MW) and Institute of 19. Dalley JW, Fryer TD, Brichard L, Robinson ESJ, Theobald DEH, Laane Health and Biomedical Innovation Postgraduate Award (MW). 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