Results Statistical Analysis:

1. Impulsivity and Risk Taking as Dopamine Gene Endophenotypes Dan T.A. Eisenberg, James MacKillop, Meera Modi, Joshua Beauchemin, David Dang, J. Koji Lum, Stephen A. Lisman, David S. Wilson State University of New York at Binghamton Subjective value of $100 Subjective value of $100 Figure 2. DRD2 by DRD4 discounting. Subjective value of $100 with delays ranging from 1 to 300 weeks. Points show the median points of indifference of the four DRD2xDRD4 groups given in legend. Hyperbolic curves are derived from the median k values for each of the four DRD2xDRD4 groups shown in the legend. Figure 1. DRD2 discounting. Subjective value of $100 with delays ranging from 1 to 300 weeks. Squares show the median points of indifference for A1+; diamonds show the median points of indifference for A1- subjects. The hyperbolic curves derived from the median k values of A1+ (continuous line) and A1- groups (dotted line) are given. Table 1. Pearson’s Correlations Between All Psychological Scales Figure 3. DDT median k values by genotype; ** p<.01. Introduction Background: Alcoholism has been demonstrated to be substantially influenced by genetics (Crabbe, 2002) and is associated with both impulsivity and risk taking (Butler, 2004). Dopamine (DA) D2 and D4 receptor genes are implicated in addictive behavior, novelty seeking, and impulsivity on self-report measures, albeit with considerable ambiguity (Noble, 2003; Hutchinson, 2002; Kluger, 2002). Behavioral measures of impulsivity may clarify the influences of functional polymorphisms by avoiding the biases of self-report and providing more genetically proximate assays of behavior as potential endophenotypes. Of particular promise, delay discounting, or the extent to which an individual devalues a reward based on its delay in time, is a behavioral index of impulsivity (Ainslie, 1978, 2004) that is typically assessed using a behavioral assessment termed the delay discounting task. Excessive delay discounting is common across forms of substance misuse (for a review, see Bickel & Johnson, 2001) and appears to be mediated by neural substrates that are rich in D2 and D4 receptors (Cardinal et al., 2004; McClure, 2004), making it a promising candidate for expression of DA D2 and D4 receptor gene polymorphisms. Objective: To examine the relationship between polymorphisms of the D2 and D4 genes, specifically DRD2 TaqIA and DRD4 48bp VNTR, and impulsivity assessed using a delay discounting task and traditional self-report measures. Hypothesis: Minor alleles of DRD2 Taq1 (i.e., DRD2-A1) and DRD4 48bp VNTR (i.e., DRD4-Long) were predicted to be associated with greater impulsivity across measures and these effects are predicted to be most prominent on the behavioral delay discounting task. • Methods • Participants: • Participants were 195 undergraduates (60% female; 46% European ancestry; 20.6 years-old mean age, SD = 1.6) recruited via the Human Subject Pool system at Binghamton University. The pool is run by the Department of Psychology and is made up of students who are encouraged to serve as lab subjects for course credit. • Measures: • Delay-Discounting Task (DDT; Green et al., 1994) is a behavioral measure of impulsivity that involves posing participants with a series of choices between an immediate reward and a larger magnitude delayed reward, defining impulsivity as the degree to which participants are willing to give up the magnitude of a reward in favor of its immediacy. Specifically, participants completed a computer task (DeVona, 2005) that repeatedly asked: “Would you rather have $X today, or $100 in Y time period?” systematically varying both the amount of money offered immediately and the length of time before receiving the delayed reward. The amount to be received today (X) varied over 29 reward amounts ranging from $100 - $0.10. There were seven delay periods (Y) ranging from one week to 25 years. The points of indifference at which subjects switched from preferring immediate to delayed rewards were employed in a hyperbolic regression (Mazur, 1987). In this a value proportionate to the degree of delay discounting is derived for each subject, the ‘k’ value. The k value is normalized with a base-10 logarithmic transformation. Those participants with k values with R2 values <0.30 or with erratic responses were excluded from the analysis (Reynolds & Shiffbauer, 2004). • Barratt Impulsivity Scale version 11 (BIS; Patton, Stanford et al. 1995) provides an overall measure of impulsivity and three relevant subscores: Attentional Impulsiveness, Motor Impulsiveness and Non-Planning Impulsiveness. • Eysenck Impulsivity Questionnaire (EIQ; Eysenck and Eysenck, 1978) yields two relevant subscales: Impulsiveness, and Venturesomeness. • Sensation Seeking Scale – Form A (SSS; Zuckerman, 1979) provides an overall measure of sensation seeking proneness and three relevant lower order factors: Experience Seeking, Boredom Susceptibility and Thrill and Adventure Seeking. • Zimbardo Time Perspective Inventory (ZTPI; Zimbardo and Boyd, 1999) yields three relevant factors: Future Orientation, Present Hedonistic, and Present Fatalistic. • Genotyping: • DNA was collected with buccal swabs and typed for two polymorphisms: • DRD2/TaqIA Single Nucleotide Polymorphism (GSFL Research Group 2003). • - Participants were dichotomized by possession of at least one A1 allele (A1+) versus no A1 alleles (A1-) (Erblich et al., 2004, 2005). • - 29.7% of participants were A1+, distributed in the sample population in Hardy-Weinberg equilibrium (p = 1.0). • DRD4/48bp Variable Number of Tandem Repeats (Boor et. al., 2002) • - Participants were dichotomized based on possession of at least one allele greater than 6 repeats (L+) versus those without any short alleles (L-) (Hutchison et al., 2002, 2003, 2004). • - The sample population had 16.5% 7R alleles, 68.6% 4R alleles and 10.1% 2R alleles in Hardy-Weinberg equilibrium (p =0.38). • Results • Statistical Analysis: • Pearson’s product-moment correlations were calculated between the indices of impulsivity. Each index of impulsivity was examined as a dependent variable in a Factorial 2 (A1+/A1-) X 2 (L+/L-) analysis of variance (ANOVA). Only significant main or interaction effects are reported (critical α = 0.05). • Findings: • Correlations between the psychometric scale variables are examined in Table 1. While the DDT impulsivity value is significantly correlated with some of the other psychometrics, it is less often than the other psychometrics are related to each other and a Principal Components Analysis loads k values highly on a somewhat distinct factor from the other scales (not shown). • There was a main effect of DRD2Taq1 on DDT k values (F1,164= 7.648, p = .006). As shown in Figure 1 and Figure 3, those of A1+ genotypes exhibit steeper discounting functions (i.e., are more impulsive). • There was an interaction effect between DRD2Taq1 and DRD4 VNTRon k value (F1,164= 7.634, p =.006). As illustrated in Figure 2 and Figure 3, DRD2 variation seems to have little effect on those with only short DRD4 VNTRalleles. DRD2 genotype seems to have an emphasized effect in those with at least one long DRD4 allele. Those with both DRD2Taq1and DRD4 VNTRrisk alleles have much higher impulsivity than other groups. • While a post-hoc analysis of the k values of all three DRD2Taq1 genotypes (A2/A2, A1/A2 and A1/A1) by both Scheffe ANOVA and dummy coded linear regression yields non significant results the trend is for A1 alleles to increase delay-discounting in an additive fashion (Figure 3). • For all other self-report measures, there were no significant DRD2Taq1 and/or DRD4 48bp VNTR effects. Discussion and Conclusion - The results of this study revealed negligible influences of polymorphisms of DRD2Taq1 and DRD4 48bp VNTR genotypes on an array of self-report measures of impulsivity but both a main effect of DRD2/TaqIA polymorphism and an interaction effect between the two polymorphisms on the behavioral index of impulsivity. Further examination revealed that the main effect was largely a result of the interaction effect, which reflected substantially greater impulsivity in individuals with both A1+ and 7+ genotypes. - This is the first study to examine a behavioral index of impulsivity as an endophenotype and supports the notion that behavioral assays may offer substantial advantages over self-report measures of behavior. The endophenotype approach to understanding the genetics of addictive behavior may generally benefit by focusing on objective behavioral indices. - These findings also underscore the potential importance of examining multiple polymorphisms concurrently in endophenotype research. If this study had only examined DRD2Taq1 or DRD4 VNTR, the results would have spuriously suggested a specific effect of DRD2 status or no effect at all, overlooking the interactive effect. - Replication of these findings and concurrent examination of impulsivity and dopamine genotypes in alcoholics is clearly warranted. Moreover, it will be important to trace the molecular pathways that underlie the relationships observed. - From a clinical perspective, these findings suggest that genotype-by-treatment approaches may need to consider the interactive effects of multiple genes as treatment targets. For More Information Contact Dan Eisenberg at ___ or James MacKillop at___ - email addressed deleted because of Evil Internet spam-bots