Results

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
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 lt0.30
  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

• Results
• Statistical Analysis
• Pearsons 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 a 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 VNTR on 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 VNTR alleles. DRD2
  genotype seems to have an emphasized effect in
  those with at least one long DRD4 allele. Those
  with both DRD2Taq1 and DRD4 VNTR risk 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