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International Journal of Neuropsychopharmacology (2012), 15, 149–161. f CINP 2011
doi:10.1017/S1461145711001052
ARTICLE
The effects of the dopamine D3 receptor
antagonist GSK598809 on attentional bias
to palatable food cues in overweight
and obese subjects
THEMATIC SECTION
Eating Disorders and
Obesity
Pradeep J. Nathan1,2*, Barry V. O’Neill1*, Karin Mogg3*, Brendan P. Bradley3*,
John Beaver4, Massimo Bani5, Emilio Merlo-Pich5, Paul C. Fletcher2, Bridget Swirski1#,
Annelize Koch1, Chris M. Dodds1* and Edward T. Bullmore1,2
1
Clinical Unit Cambridge, Medicines Discovery & Development, GlaxoSmithKline R&D, Cambridge, UK
Brain Mapping Unit, Department of Psychiatry, University of Cambridge, UK
3
School of Psychology, University of Southampton, UK
4
Clinical Imaging Centre (CIC), Medicines Discovery & Development, GlaxoSmithKline R&D, London, UK
5
Neurosciences CEDD, Medicines Discovery & Development, GlaxoSmithKline R&D, Verona, Italy
2
Abstract
The mesolimbic dopamine system plays a critical role in the reinforcing effects of rewards. Evidence from
pre-clinical studies suggests that D3 receptor antagonists may attenuate the motivational impact of
rewarding cues. In this study we examined the acute effects of the D3 receptor antagonist GSK598809 on
attentional bias to rewarding food cues in overweight to obese individuals (n=26, BMI mean=32.7¡3.7,
range 27–40 kg/m2) who reported binge and emotional eating. We also determined whether individual
differences in restrained eating style modulated the effects of GSK598809 on attentional bias. The study
utilized a randomized, double-blind, placebo-controlled cross-over design with each participant tested
following acute administration of placebo and GSK598809 (175 mg). Attentional bias was assessed by the
visual probe task and modified Stroop task using food-related words. Overall GSK598809 had no effects
on attentional bias in either the visual probe or food Stroop tasks. However, the effect of GSK598809 on
both visual probe and food Stroop attentional bias scores was inversely correlated with a measure
of eating restraint allowing the identification of two subpopulations, low- and high-restrained eaters.
Low-restrained eaters had a significant attentional bias towards food cues in both tasks under placebo,
and this was attenuated by GSK598809. In contrast, high-restrained eaters showed no attentional bias to
food cues following either placebo or GSK598809. These findings suggest that excessive attentional bias to
food cues generated by individual differences in eating traits can be modulated by D3 receptor antagonists,
warranting further investigation with measures of eating behaviour and weight loss.
Received 24 February 2011 ; Reviewed 13 April 2011 ; Revised 2 June 2011 ; Accepted 9 June 2011 ;
First published online 12 July 2011
Key words : Attentional bias, D3 receptor, food, Stroop, visual probe task.
Introduction
Over-consumption of food is one of the leading factors
contributing to the significant rise in the incidence
Address for correspondence : Professor P. J. Nathan, GSK Clinical
Unit Cambridge, Addenbrooke’s Centre for Clinical Investigations,
Cambridge Biomedical Campus, Cambridge CB2 2GG, UK.
Tel. : +44 1223 296081 Fax : +44 1223 296108
Email : [email protected]
* These authors contributed equally to this work.
# This paper is dedicated to Bridget Swirski, who sadly passed away
during the preparation of this manuscript.
of obesity (Hedley et al. 2004). Obese individuals are
more motivated to eat and find food (particularly
palatable food) more reinforcing than do non-obese
controls (Johnson, 1974 ; Saelens & Epstein, 1996). A
number of cognitive theories may explain enhanced
responsivity to food-related information in obese
individuals, including maladaptive knowledge structures (i.e. schemas) (Williamson et al. 2004), food preoccupation (Cox & Klinger, 2004), expectancy (Tiffany,
1990) and incentive salience (Berridge & Robinson,
1998 ; Berridge et al. 2010). The latter theoretical view,
150
P. J. Nathan et al.
which ascribes a key role to the mesolimbic dopaminergic system, has been particularly influential.
The mesolimbic dopaminergic system plays a critical role in the reinforcing effects of natural rewards
like food (Bassareo and Di Chiara, 1997, 1999a, b ; Wang
et al. 2004 ; Wise, 2006). Dopamine has also been shown
to modulate hedonic and non-hedonic factors underlying motivation for food intake in animals (Swanson
et al. 1997 ; Szczypka et al. 2001 ; Taber & Fibiger, 1997),
while human imaging studies have linked changes
in dopamine to motivational (Volkow et al. 2002), restraint and emotionality processes regulating food intake (Volkow et al. 2003). In particular, high-restrained
eaters (i.e. individuals that intentionally restrict their
intake of food and calories due to concern with weight
and shape) show greater changes in dopamine in
the dorsal striatum in response to food stimulation
(Volkow et al. 2003) and these authors suggested that
higher restraint in this group could reflect a preventive
adaptation strategy to minimize their exposure to
salient food cues (Volkow et al. 2003). This is consistent
with theories that cognitive restraint may influence
consumption of food (Herman & Mack, 1975) and with
evidence that high-restrained eaters are more attuned
to food cues in the environment, attempting to avoid
these in order to control their body weight (Green &
Rogers, 1993 ; Green et al. 1997).
A key role of the dopamine system is to mediate
the attribution of incentive salience to stimuli that are
associated with reward (Berridge & Robinson, 1998 ;
Berridge et al. 2010). Attribution of high-incentive
salience to a stimulus makes it attractive and ‘ attention
grabbing ’ (Berridge et al. 2010). Thus, attentional biases
for food cues provide an objective cognitive index
which has been linked to dopaminergic system functioning, and may underlie individual differences in the
motivational salience of food cues and proneness to
overeat and obesity. In support of this theoretical
view linking attention biases and over-consumption
of rewards, there is considerable evidence indicating
that drug-dependent individuals show greater attentional bias to drug cues (Cox et al. 2006 ; Field &
Cox, 2008). Furthermore, consistent with dopaminergic models of overeating and obesity, a number
of studies have shown enhanced attentional biases to
food cues in obese and overweight individuals (Braet
& Crombez, 2003 ; Castellanos et al. 2009 ; Nijs et al.
2010 ; Werthmann et al. in press). However, some have
failed to find such biases (Phelan et al. 2011 ; Pothos
et al. 2009) and variation in results across studies may
arise as a function of methodological variables (Pothos
et al. 2009) and/or influences of eating style (Graham
et al. 2011). Although the relationship between body
mass index (BMI) and attentional bias may not be
a simple linear one (Pothos et al. 2009), attentional
biases for food cues have not only been associated
with obesity (Braet & Crombez, 2003 ; Castellanos et al.
2009 ; Nijs et al. 2010), but have also been shown to
predict change in BMI over a 1-yr period (Calitri et al.
2010).
Dopamine receptors are potential therapeutic
targets for modulating behavioural aspects of food consumption in conditions such as obesity. The dopamine
D3 receptor has recently been explored as potential
drug target for the treatment of addiction (Heidbreder
et al. 2005). In animals, D3 antagonists have been
shown to reduce cue-controlled ‘drug seeking ’, suggesting a selective role for D3 receptors in the motivational impact of drug-related cues (Di Ciano et al.
2003 ; Heidbreder et al. 2005 ; Pilla et al. 1999). Similarly,
selective antagonism of D3 receptors has been shown
to reduce food intake and responses for food in obese
Zucker rats (Thanos et al. 2008). Clinical studies in
human addict populations have also shown that
mixed D2/D3 antagonists attenuate cue-induced craving (Gawin et al. 1989) and reduce attentional biases
on a modified Stroop task with drug-relevant stimuli
(Ersche et al. 2010 ; Franken et al. 2004).
GSK598809 is a selective D3 receptor antagonist in
development for treatment of disorders of compulsive
consumption including obesity (Searle et al. 2010). In
this study, we examined for the first time, the acute
effects of GSK598809 on attentional bias to foodrelated cues in overweight to obese individuals who
reported binge and emotional eating. This stratified
sample was selected to ensure the obese population
had characteristic overeating behaviours.
Attentional bias was tested with two commonly
used tasks, the modified (food) Stroop task and the
visual probe task. We also explored whether individual differences in eating style, namely restraint, modulated the effects of GSK598809 on attentional bias,
given research noted earlier indicating that restraint
influences dopamine response to food cues (Volkow
et al. 2003). The modified Stroop and visual probe
(or dot probe) tasks have relative advantages and
disadvantages as measures of attentional bias. The
modified Stroop task provides a robust index of the
personal motivational salience of aversive and appetitive stimuli (Cox et al. 2006 ; Williams et al. 1996)
and has been shown to be predictive of weight gain in
non-obese individuals (Calitri et al. 2010). However,
the modified Stroop index may reflect more than one
underlying cognitive mechanism. For example, colournaming interference effects may reflect enhanced attentional prioritizing of salient stimuli (attentional bias
D3 receptor antagonism and attentional bias
towards salient cues) and/or cognitive effort to suppress processing of them (‘avoidance ’ of salient cues)
(de Ruiter & Brosschot, 1994). In contrast, the visual
probe task enables a more fine-grained analysis of
the direction of attentional bias, because it allows for
the differentiation between attention directed towards
or away from a particular type of information
(MacLeod et al. 1986). The modified Stroop and the
visual probe tasks also tap biases in different aspects
of attentional processes, i.e. visual orienting vs. resolution of processing conflicts. Thus, it is informative
to assess more than one type of attentional bias in
order to evaluate its generality across different methodologies.
We hypothesized that, on both attentional tasks,
GSK598809 would attenuate attentional bias to rewarding food-related cues. Specifically, we predicted
that overweight/obese individuals would show an
attentional bias towards food relative to control (nonfood-related) cues in the placebo condition, but not in
the GSK598809 condition. We also explored whether
the effect of GSK598809 on attentional bias to food
cues was modified by eating style, namely restrained
eating.
Materials and methods
Participants
Twenty-six otherwise healthy, overweight and obese
participants (15 males, 11 females) aged between
18 and 45 yr (mean age=35.1¡7.1 yr) and BMI
o27 kg/m2 (mean=32.7¡3.7, range 27–40 kg/m2 inclusive) were recruited for this study. All participants
had no history of psychiatric disorders, neurological
disorders or eating disorders (including binge-eating
disorder), substance abuse and significant weight
loss (or gain) (defined as a change of o5 % of their
body weight in the past 30 days) based on a physical
examination and a clinical and psychiatric interview
by a medical physician. Additionally, participants
were only included if they reported current history
(over the last 2 wk) of binge-eating behaviour [minimum one episode per week as assessed by the YBOCSBE questionnaire (Q6) (Goodman et al. 1989, McElroy
et al. 2007)] and emotional eating behaviour (by attaining a score of o3 in at least one of the questions
of the emotional eating scale (Q3, Q6, Q10) of
the Three-Factor Eating Questionnaire (TFEQ-R18)
(de Lauzon et al. 2004). All participants gave written
informed consent for participation in the study,
which was approved by the Hounslow and Hillingdon
Research Ethics Committee, UK.
151
Procedure
The study utilized a randomized, counterbalanced,
double-blind, placebo-controlled, two-way cross-over
design, where each participant was tested under two
acute treatment conditions, separated by at least a 7-d
washout period. The two treatment conditions were ;
GSK598809 (175 mg capsule) and placebo. The dose
of GSK598809 was selected because it has been shown
to be associated with >90 % D2/3 receptor occupancy
(Searle et al. 2010). Subjects attended the study on day
1. Dosing, and behavioural assessments and were
conducted on day 1. Safety and tolerability were
assessed on days 1, 3 and 4. Subjects were required to
fast for approximately 15 h prior to testing. The attentional bias tasks were performed approximately 4–5 h
post-dose [to coincide with the approximate time of
peak plasma concentration (Tmax) of GSK598809] and
between 15 and 16 h following fasting.
Attentional bias tasks
Visual probe task
The main pictorial stimuli consisted of 20 colour
photographs of food similar to those used by Brignell
et al. (2009) and Hepworth et al. (2010). Each food picture was paired with a photograph of another scene
matched as closely as possible for content (e.g. number, colour and shape of items), but lacking any food
cues (see Fig. 1 for examples). These stimuli were used
as the main experimental and control stimuli for this
task. An additional 20 picture pairs (unrelated to food)
were used as fillers, and an additional 12 food-control
picture pairs were used for practice and buffer trials.
The computer tasks were presented on a computer
using Presentation software and responses were recorded using a two-button response box.
The design was similar to that used by Bradley et al.
(1998, 2003) and Hepworth et al. (2010). Each trial
commenced with a fixation cross displayed for 500 ms
in the centre of the screen followed by a pair of pictures presented side by side for either 500 or 2000 ms
(Fig. 1). A probe was then presented in the position of
one of the preceding pictures until the participant gave
a manual response. The probe was a single black dot
($). Participants pressed one of two buttons to indicate the location of the probe. They were instructed
to look at the fixation cross at the start of each trial.
The duration of the inter-trial interval (ITI) varied
randomly between 500 and 1500 ms. There were 12
practice trials, and two blocks of 120 trials (160 critical
trials and 80 filler trials in total), with a short break
between the blocks. Each block was preceded by two
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P. J. Nathan et al.
Visual Probe Task
Fixation 500 ms
Stimulus presentation
500 ms or 2000 ms
Response – right button press
Fixation 500 ms
Stimulus presentation
500 ms or 2000 ms
Response – left button press
Fig. 1. In the visual probe task, a fixation cross was displayed for 500 ms in the centre of the screen followed by a pair of pictures
presented side by side for either 500 or 2000 ms. A probe (a single black dot) was then presented in the position of one of the
pictures until the participant gave a manual response on a two-button response box to indicate the location of the probe. There
were an equal number of trials in each condition, as a function of picture duration, location of the food picture and probe
location. The stimuli were largely those used in Brignell et al. (2009).
buffer trials. The critical trials were made up from
eight presentations of each of the 20 food-control picture pairs. There were an equal number of trials in each
condition, as a function of picture duration, location of
the food picture and probe location. The 20 filler pairs
were presented four times each. All trials were presented in a new random order for each participant.
When presented on the screen, each picture was 9 cm
high by 12 cm wide, the distance between their inner
edges was 6 cm and the distance between the two
probe positions was 18 cm (visual angle of 11x as participants were seated 100 cm from the screen).
Modified (food) Stroop task
The food Stroop task was adapted from a modified
version of the Stroop task used to probe addiction
(Cox et al. 2006) and further modified to include foodrelated words. Participants were asked to colour-name
words, presented on a computer screen, as quickly
and accurately as possible, while ignoring the word’s
meaning (see Fig. 2). Two different block-design paradigms were used : a food Stroop paradigm to measure
attentional bias for food-related cues and a standard
colour-word Stroop paradigm to measure cognitive
(interference) control.
The two trial types were administered in a block
design consisting of two blocks : food Stroop and colourword Stroop, which differed from each other in the type
of words presented. Each block consisted of 64 trials.
The food Stroop block presented a list of 16 palatable
food-related target words, a list of 16 non-palatable
food-related target words and two lists of 16 neutral
words (matched for length and frequency). The colourword Stroop block consisted of 16 words including
eight colour-incongruent colour words (e.g. the word
blue written in green ink) and eight congruent colour
words (e.g. the word red written in red ink), each
matched with 16 colour-unrelated words. Each experimental trial lasted 2.2 s and included the presentation
of a word for 1.9 s followed by a presentation of a fixation for 0.3 s, which was then immediately followed
by the next trial.
Eating style
TFEQ-R18
The TFEQ-R18 measures three aspects of eating behaviour : cognitive restraint, uncontrolled eating, and
emotional eating (Karlsson et al. 2000 ; Stunkard &
Messick, 1988). Restrained eating or cognitive restraint
D3 receptor antagonism and attentional bias
measures dietary restraint, i.e. the conscious restriction
of food intake in order to control body weight or to
promote weight loss. The primary reason for including
the TFEQ-R18 was to explore the relationship between
restrained eating and drug effects on attentional bias
and the results reported here focus on this measure,
given previous literature, discussed earlier, linking restraint with dopamine response to food cues (Volkow
et al. 2003). However, additional measures of eating
style were included for further exploratory analyses,
which are described in Supplementary Tables S1 and
S2 (available online)#.
Safety and tolerability assessments
Safety and tolerability were assessed and included
spontaneously reported adverse effects (AEs), cardiovascular variables, movement disorder, temperature
and respiratory rate.
Data preparation and statistical analysis
For the visual probe task, attentional bias scores were
calculated for each participant, session and stimulus
exposure duration. These were calculated by subtracting the mean reaction time (mRT) when the probe
# In addition to TFEQ restraint, several supplementary measures were
included in order to explore their relationships with (i) the drug effect
on attentional bias, and (ii) overall attentional bias, in the present
sample. These supplementary measures included the TFEQ emotional
and disinhibited eating scales and the Dutch Eating Behaviour
Questionnaire (DEBQ) which comprises 33 items assessing three
dimensions of eating behaviour : external eating, emotional eating,
and restrained eating (Van Strien et al. 1986). The DEBQ emotional
and restrained eating scales are conceptually similar to the TFEQ but
reflect different approaches to the assessment of eating style.
The DEBQ also measures external eating (eating in response to
food-related cues such as the sight or smell of palatable food, e.g.
‘ If food tastes good to you, do you eat more than usual? ’). Another
supplementary measure was the Barratt Impulsiveness Scale (BIS ;
Patton, 1995), which is a 30-item self-report measure of impulsivity
which refers to behaviour that is performed with little or inadequate
forethought. The BIS impulsivity has been shown to be correlated
with attentional bias in healthy subjects (Hou et al. 2011).
See Supplementary Table S1 for correlational results from the
supplementary exploratory analyses. None of these results were
significant following Bonferroni correction for multiple tests (critical p
is 0.004 for each experimental task). However, it is of interest to note
that the overall attentional bias from the visual probe task (averaged
across conditions) correlated positively with DEBQ external eating
(r=0.41, p=0.043 ; two-tailed, p value unadjusted for multiple tests).
This correlation is consistent with previous research which also found
that DEBQ external eating positively correlated with attentional
bias on the visual probe task (r=0.42, p<0.01), in a sample of
55 participants who were predominantly normal weight or
overweight (Brignell et al. 2009).
153
replaced the food cue from the mRT when the probe
replaced the non-food cue. Positive values indicate an
attentional bias towards food. Before the calculation
of bias scores, reaction times were excluded if they
occurred on error trials or if they were outliers
(i.e. f200 ms, o2000 ms, and/or >3 standard deviations (S.D.) above each participant’s mRT in each
session ; Hepworth et al. 2010).
For the food Stroop and colour-word Stroop task,
attentional bias scores for food-related cues was
measured by comparing the time taken to name the
colour of food-related words and the time taken for
matched neutral words. An interference score was
calculated by subtracting each participant’s mRT for
correct responses to neutral words from their mRT for
correct responses to target (i.e. food words). Greater
colour naming interference for food-related words is
interpreted as greater attentional bias to food-related
words. For the colour-word Stroop, the interference
score was similarly derived for the colour words
(i.e. mRT of correct responses to neutral (colourunrelated) words was subtracted from the mRT
of correct responses to incongruent colour words).
Greater interference in the colour-word Stroop indicates less cognitive control or conflict monitoring.
A 2r2 analysis of variance (ANOVA) model was
fitted for attentional bias scores with drug (GSK598809,
placebo) and stimulus duration (500 ms, 2000 ms)
as within-subjects independent variables. An ANOVA
was also performed for the Stroop interference scores
and error data with drug (GSK598809, placebo) as a
within-subjects independent variable.
For the correlational analyses, the effect of
GSK598809 on attentional bias for the visual probe and
modified Stroop tasks was summarized by a contrast
term formed by subtracting the bias score in the
GSK598809 condition from the bias score in the placebo
condition. Positive values indicate larger attentional
bias to food in the placebo than drug condition ; i.e.
reflecting the predicted effect of drug reducing attentional bias to food. Correlational analyses were conducted between the questionnaire measure of restraint
at screening (time 1) and the drug-effect contrast term
and overall attentional bias (averaged across all conditions) for the visual probe and modified Stroop
tasks.
Results
Safety and tolerability assessments
The safety and tolerability data are reported in the
Supplementary material (available online).
154
P. J. Nathan et al.
(a) Food Stroop
(b) Colour word Stroop
Palatable food words
Colour words
Non-palatable food words
Neutral words matched for
colour words
Neutral words matched for
palatable food words
Fig. 2. In the Stroop task, participants were shown a series of words on the computer screen, which were presented one at a
time. The participants’ task was to name the ink colour of each word presented, as quickly and accurately as possible, while
ignoring the word’s meaning. Participants made their responses by pressing a button on a four-button box that was allocated to
one of the four ink colours (red, blue, yellow, green). The words presented in the task fell into two broad categories : food-related
words (food Stroop) and colour words (colour-word Stroop). (a) The food Stroop consisted of two target word lists, one for
palatable food words and for non-palatable food words. For both lists there were neutral control words that were matched in
terms of length and frequency. (b) The colour-word Stroop involved colour words which included incongruent colour words
(e.g. to word blue written in green ink) and congruent colour words (e.g. the word red written in red ink). These colour words
were complemented with a list of matched neutral words. (c) The order of the words within a list and the order of the conditions
were counterbalanced across participants.
Visual probe task
Rates of errors and outliers were low (mean percentages of trials with errors and outliers were 0.6 and
1.6 %, respectively) and mRT was 436 ms, with no
significant differences in error or outlier rate, or overall
mRT between GSK598809 and placebo conditions
(F1,25<1). One-sample Kolmogorov–Smirnov tests
indicated that the distributions of the bias scores did
not differ significantly from normality. However,
attentional bias scores from the 2000-ms placebo condition appeared skewed due to a large positive score
for one participant ; so analyses were repeated without
this individual (similar results were obtained irrespective of whether or not this participant was included).
Repeated-measures ANOVA of attentional bias
scores showed no overall main effects of drug or
stimulus duration, or drugrstimulus duration interaction (F1,25<1). (There were no significant main or
interactive effects of session order on attentional bias.)
A one-sample t test showed that, across all participants
and conditions, the mean attentional bias score did not
differ significantly from zero (mean bias=2.6 ms,
S.D.=7.9, t25=1.7, p=0.10) ; i.e. no significant attentional bias for food cues relative to non-food cues.
The effect of GSK598809 on attentional bias correlated significantly and negatively with TFEQ restraint
score (r=x0.45, p=0.02, two-tailed ; Fig. 3a), suggesting that the effect of GSK598809 on attentional bias
was greater in individuals with lower restraint. The
overall attentional bias score was not significantly
correlated with TFEQ restraint (r=x0.09, p=0.67).
The correlation between restraint and the drug
effect on attentional bias remained significant after
Bonferroni correction of the threshold for significance
for the two bias measures from this task at p<0.05/
2=0.025.
The correlational finding indicated that the effect
of GSK598809 on attentional bias for food cues was
significantly influenced by individual differences in
D3 receptor antagonism and attentional bias
(b)
Attentional bias placebo-drug (ms)
100
80
60
40
20
0
0
5
10
15
20
–20
–40
TEFQ restraint
25
Food interference palcebo-drug (ms)
(a)
155
0.4
0.3
0.2
0.1
0
–0.1 0
5
10
15
20
25
–0.2
–0.3
–0.4
–0.5
–0.6
TEFQ restraint
Fig. 3. Correlations (Pearson’s r) between TFEQ restraint and effect of drug on attentional bias in the (a) visual probe task and
(b) modified Stroop task.
Mean attentional bias (ms)
15
Placebo
GSK598809
10
5
0
–5
–10
(b)
Maen food interference effect (ms)
(a)
0.1
Placebo
GSK598809
0.08
0.06
0.04
0.02
0
–0.02
–0.04
–0.06
–0.08
Low
High
TFEQ restraint group
Low
High
TFEQ restraint group
Fig. 4. (a) Visual probe task : mean attentional bias scores as a function of restraint group and drug condition. (b) food Stroop
task : food interference effect as a function of restrained eating and drug condition. Error bars reflect S.E.M.
restraint. However, this analysis does not indicate the
precise nature of this interaction effect of GSK598809
and restraint on attentional bias. Thus, to clarify
the correlational results, the sample was divided into
low- and high-restraint groups (TFEQ restraint scores :
mean=12.5, median=11.5, S.D.=3.7, range 7–20,
n=26 ; low-restraint group : TFEQ restraint scores
f12, n=15 ; high-restraint group : TFEQ restraint
scores >12, n=11). An independent-sample t test
showed no significant difference in mean BMI between
the low- and high-restraint groups (low restraint=
32.3, high restraint=33.1 ; t24=x0.52, p=0.6). The
categorization of low- vs. high-restrained eating using
a cut-off of 12 is consistent with previous studies
(Yeomans et al. 2004, 2008). A 2r2r2 ANOVA model
was fitted to attentional bias scores, with drug
(GSK598809, placebo) and stimulus duration (500 ms,
2000 ms) as within-subjects independent variables,
and restraint group (high, low) as a between-subjects
independent variable. There was a significant drugr
restraint interaction (F1,24=4.45, p<0.05) (see Fig. 4a),
which corresponds to findings from the correlational
analysis.
One-sample t tests showed that only the results of
the low-restraint group were consistent with the primary hypothesis (corrected p values=uncorrected
p multiplied by 2, as hypothesis-driven tests were conducted for each group separately) : the low-restraint
group had a marginally significant attentional bias
towards food in the placebo condition (t14=2.46 ; uncorrected p=0.027, corrected p=0.054), but not in the
GSK598809 condition (t14=0.45 ; uncorrected p=0.66,
corrected p=1). The high-restraint group showed no
bias in either placebo (t10=1.23 ; uncorrected p=0.25,
corrected p=0.49) or GSK598809 conditions (t10=1.57 ;
uncorrected p=0.15, corrected p=0.29) (Fig. 4a).
156
P. J. Nathan et al.
Modified Stroop task
Mean percent of correct trials in the food Stroop task
was 87 % (S.D.=17). Mean percent correct in the standard Stroop task was 84 % (S.D.=19). Two subjects
performed with an accuracy level greater than 2 S.D.
below the mean and their data was excluded from
further analyses. Mean overall RT for the standard
Stroop task was 875 ms (S.D.=169). Mean overall RT
for the food Stroop task was 874 ms (S.D.=169). Two
variables were calculated from RT scores ; food Stroop
interference effect (calculated by subtracting mRT to
neutral food words from mRT to palatable food
words) and the standard Stroop incongruency effect
(i.e. interference) (calculated by subtracting mRT to
colour-unrelated neutral words from mRT to incongruent colour words). These variables were calculated
for the GSK598809 and placebo conditions separately.
One-sample Kolmogorov–Smirnov tests indicated that
the distributions of these variables did not differ significantly from normality.
One-sample t tests on the standard and food Stroop
interference scores in the placebo condition showed
that there was the standard interference effect in the
standard Stroop (mean interference=172 ms, S.D.=86,
t23=9.7, p<0.001), but no significant interference effect
of food cues in the modified Stroop (mean interference=18, S.D.=63, t23=1.4, p=0.17. Repeatedmeasures ANOVA showed no overall effect of
GSK598809 on either the food interference effect or
standard Stroop incongruency effect (F1,23<1.2) (there
were no significant main or interactive effects of
session order on the Stroop effects). The effect of
GSK598809 on food interference effect correlated significantly and negatively with TFEQ restraint (r=
x0.47, p=0.02 ; Fig. 3b), suggesting that the effect of
GSK598809 on the food interference effect was greater
in individuals with lower restraint scores. The overall
food interference effect also correlated significantly
and negatively with TFEQ restraint score (r=x0.56,
p=0.004). These correlations between restraint and the
two attentional bias measures remained significant
after Bonferroni correction of the threshold for significance for the two bias measures from this task at
p<0.05/2=0.025.
To clarify the correlational results concerning the
GSK598809 effect on the food interference effect, the
sample was divided into low- and high-restraint
groups (as described above for analysis of the visual
probe task). A 2r2 ANOVA was fitted to the food
interference scores, with drug (GSK598809, placebo) as
a within-subjects independent variable and restraint
group (high, low) as a between-subjects independent
variable. There was a significant drugrrestraint
interaction (F1,22=6.7, p<0.05), which corresponds
to the findings from the correlational analysis. Onesample t tests (corrected p values are unadjusted
p values multiplied by 2, as hypothesis-driven tests
were conducted for each group) showed that the
low-restraint group had a significant food interference effect in the placebo condition (t12=4.56 ;
uncorrected p=0.001, corrected p=0.002), but not in
the GSK598809 condition (t12=x0.85 ; uncorrected
p=0.41, corrected p=0.82). The high-restraint group
showed no food interference effect in either placebo
(t10=x0.77 ; uncorrected p=0.46, corrected p=0.92),
or GSK598809 (t10=0.78 ; uncorrected p=0.46, corrected p=0.92), conditions (Fig. 4b).
Correlations between the effects of GSK598809 on
visual probe and modified Stroop tasks
Correlational analysis revealed that there was a positive correlation between GSK598809 effects on the food
Stroop and attentional bias (r=0.43, p<0.05), but not
between GSK598809 effects on the standard Stroop
and attentional bias (r=0.33, p=0.12).
Discussion
The dopamine D3 receptor has recently been explored
as potential drug target for the treatment of disorders
of compulsive consumption including obesity. Until
now, there has not been any study in humans investigating the efficacy of D3 receptor antagonists in experimental models of food reinforcement. We report for the
first time, the acute effects of the D3 receptor antagonist,
GSK598809, on attentional bias to food-related cues in a
cohort of overweight/obese binge and emotional
eaters, using two commonly used tasks of attentional
bias, the food Stroop task and the visual probe task.
Overall, GSK598809 had no effect on attentional bias to
food cues. However, individual differences in eating
styles impacted on the effect of GSK598809 on attentional bias, as evident from a significant negative correlation between restraint and the effect of GSK598809
on attentional bias for each task. More specifically, lowrestrained eaters showed an attentional bias to food
cues in the placebo condition (this bias was significant
in the food Stroop task and marginally significant in
the visual probe task), but not in the GSK598809 condition. The high-restraint group showed no significant
attentional bias in either condition.
Dopamine and attentional bias
Dopamine has been shown modulate attentional
bias through activation of D2/D3 receptors. Studies
D3 receptor antagonism and attentional bias
conducted in human addict populations have also
shown that D2/D3 antagonists can reduce attentional
biases on a Stroop task with drug-relevant stimuli
(Ersche et al. 2010 ; Franken et al. 2004). In the current
study, low-restrained eaters showed an attentional
bias towards food cues in the placebo, but not the
GSK598809 treatment condition. This pattern of results
was significant on the modified Stroop task and marginally significant on the visual probe task. Together,
these findings provide additional support that antagonism of D3 receptors may attenuate attentional processing of salient or rewarding cues. Given that obese
individuals have been shown to have greater attentional bias to food cues (Braet & Crombez, 2003 ;
Castellanos et al. 2009 ; Nijs et al. 2010) and food-related
cognitive biases have been shown to predict changes
in BMI (Calitri et al. 2010), it is possible that D3 receptor
antagonists may have efficacy in reducing behavioural
aspects of food intake, such as bingeing or overeating
in a subgroup of obese individuals by modulating
cognitive processing (i.e. attentional bias) and food
cue-induced craving, possibly leading to weight loss.
These hypotheses require testing in future studies.
Modulation of attention bias by GSK598809 depends
on restrained eating
The attenuating effect of GSK598809 on attentional
bias was greater in overweight/obese individuals who
had lower levels of restrained eating. These findings
suggest that, in low-restrained eaters, D3 receptor antagonism with GSK598809 reduces selective attention
allocated to rewarding food cues, which is manifest
in both visual orienting and resolution of processing
conflict (on visual probe and food Stroop tasks, respectively). Interestingly, no significant correlation
between restraint eating and interference scores in
the standard Stroop was found (data not reported),
suggesting that the effects of the drug on attentional
bias are not due to a general attenuation of cognitive
interference, but rather, to interference (or conflict)
caused by the salient food-related cues. Previously it
has been argued that the interference effect in the
Stroop task may reflect either a bias towards or away
from food words (de Ruiter & Brosschot, 1994). In
contrast, the visual probe task allows for the differentiation between attention directed towards or away
from a particular type of information (MacLeod et al.
1986). In the current study, reaction times in the visual
probe task were faster when the probe replaced the
food cues (in the placebo condition) relative to nonfood cues, indicating that attentional bias was directed
towards food cues in the low-restraint group, whereas
157
this food-directed attentional bias was no longer
evident after administration of GSK598809.
The lack of overall effect of GSK598809 on attentional bias seems likely to be explained by the fact that
the high-restraint group did not show an attentional
bias to food cues during placebo treatment. It has been
suggested that restrained eaters are more attuned to
food cues in the environment and attempt to avoid
these in order to control their body weight (Green &
Rogers, 1993 ; Green et al. 1997). The lack of attentional
bias to food cues in the high-restrained eaters and the
inability of GSK598809 to modulate attentional bias
in this group may be related to high-restrained eaters
adopting cognitive control strategies that suppress
processing of food cues in an attempt to counteract the
high saliency that food cues may have for them. This
is consistent with the evidence that high-restrained
eaters show greater changes in dopamine neurotransmission in the dorsal striatum to food stimulation
(Volkow et al. 2003), possibly reflecting a preventive
adaptation strategy to minimize their exposure to
salient food cues (Volkow et al. 2003). Conversely,
low-restrained eaters could be characterized by low
dopamine release in dorsal striatum. Interestingly,
preclinical studies indicate that D3 antagonists can
act as pro-dopaminergic agents by blocking D3 autoreceptors expressed in mesencephalic dopaminergic
neurons that project to the nucleus accumbens and
striatum, increasing the release of dopamine (Collo
et al. 2008 ; Schwarz et al. 2007). According to this
interpretation, in low-restrained eaters GSK586809
would produce a generalized activation of the dopamine release non-contingent to the food cue, resulting
in the attenuation of the salience of the cue and of the
cue-induced attentional bias. Consistent with hypothesis, the D3 selective antagonist SB-277011A has been
shown to reduce food intake and responses for food in
an operant task (i.e. fixed ratio schedule of reinforcement) (Thanos et al. 2008) and D3 receptor-deficient
mice have been shown to become obese when fed a
high fat diet (McQuade et al. 2004), providing a link
between D3 receptors and obesity.
Restraint and attentional bias
The overall attentional bias measured using the modified Stroop task (i.e. food interference effect averaged
across treatment conditions) was negatively correlated
with TFEQ-restrained eating suggesting that, at least
in this population of overweight to obese participants,
high-restraint eating was associated with lower attentional bias to food-related cues. As discussed earlier
this may be related to high-restrained eaters adopting
158
P. J. Nathan et al.
cognitive control strategies to minimize their processing of salient food cues. This finding also seems
conceptually compatible with results of a recent eyetracking study which indicated that higher levels of
restrained eating were associated with reduced attentional bias in visual orienting to high-calorie sweet
foods in overweight individuals, which the authors
suggested may have been due to such foods having
reduced reward value for overweight restrained eaters
(Graham et al. 2011). However, some other studies
using the modified Stroop task have shown that
restrained eaters may show greater attentional bias
to food cues, although these studies were performed
in healthy-weight subjects (Green & Rogers, 1993 ;
Overduin et al. 1995 ; Stewart & Samoluk, 1997) or
patients with anorexia and bulimia with high drive
for thinness (Perpiñá et al. 1993) and hence the latter
findings cannot be directly compared to our findings
in a overweight and obese population. If restrained
eating is associated with a controlled strategy aimed at
minimizing processing of food cues, it could be argued
that this should be more evident in the longer than
shorter stimulus exposure condition of the visual
probe task (which would be manifest in an interaction
effect of restraintrstimulus exposure on attentional
bias). The overall attentional bias score measured
using the visual probe task was not associated with
restrained eating, which is consistent with a previous
study (Ahern et al. 2010) and there was also no significant interaction effect of restraintrstimulus exposure, which suggests caution in the interpretation
of these null results. Nevertheless, as discussed above,
for both tasks there was a significant inverse relationship between TFEQ-restrained eating and druginduced changes in attentional bias indicating that
the effect of D3 receptor antagonism on attentional bias
may be dependent on individual trait difference in
cognitive/motivational processes, with attenuation of
bias observed only in the low-restrained eating group.
Methodological considerations
There are some methodological factors in the
study that should be highlighted. (1) The effects of
GSK598809 were observed under conditions of hunger
(i.e. 15–16 h of fasting) when increases in food craving
and appetitive behaviours are expected. Previous
studies have found that both obese and normal-weight
individuals show an attentional bias to food cues in a
state of hunger compared to satiety (Castellanos et al.
2009 ; Nijs et al. 2010) consistent with our findings
in low-restraint overweight/obese individuals (in
the placebo condition). However, differential effects of
hunger vs. satiety on attentional bias may depend on
the specific bias measure (Nijs et al. 2010) and, given
that the effects of GSK598809 were only tested in the
state of hunger, our findings cannot be extended to
conditions of satiety. (2) We report the acute effects of
GSK598809 on attentional bias to salient food cues.
It is unknown if these effects translate to a reduction
in reinforcing effects of foods and ultimately a decrease
in food intake. The findings generated from this study
provide encouraging evidence in support of a proofof-concept study in patients with obesity exploring
the chronic effects of GSK598809 on food-related
attentional bias, food intake and weight loss. (3) This
study only examined the effects of a single dose of
GSK598809 on attentional bias. While one could argue
that there may be dose-related effects, the dose used in
this study (175 mg) has been shown to occupy more
than 90 % of D3 receptors (Searle et al. 2010), and hence
it is unlikely that higher doses would impact further
on attentional bias (i.e. D3 receptor mediated). (4) This
study recruited a highly stratified group of obese
patients who reported binge and emotional eating behaviour and hence these findings may not be generalizible to the wider obese population. (5) It should be
highlighted that while restrained eating may be associated with impaired dopamine neurotransmission
(Volkow et al. 2003), the exact mechanisms of action
of D3 antagonists in humans (including the role of D3
receptors) are unknown.
In summary, the current study provides evidence
that the D3 receptor antagonist, GSK598809, has a
moderating effect on attentional bias to food-related
cues in overweight and obese individuals, which is
dependent on individual differences in eating styles,
with a stronger drug effect observed in those with
lower restrained eating. These findings highlight that
individual differences in eating style can modulate the
effects of D3 receptor antagonism on responses to food
cues and warrant further attention in future experimental studies investigating the effects D3 receptor
antagonists on measures of eating behaviour and body
weight.
Note
Supplementary material accompanies this paper on
the Journal’s website (http://journals.cambridge.org/
pnp).
Acknowledgements
The authors acknowledge the contributions made by
the GSK598809 project team.
D3 receptor antagonism and attentional bias
Statement of Interest
This study was funded and conducted by GlaxoSmithKline (GSK) Pharmaceuticals (ClinicalTrials.gov
identifier : NCT01039454). All authors except K.M.,
B.B. and P.C.F. are employees of GSK and hold shares
in the company. B.B. and K.M.’s primary employer,
the University of Southampton, received compensation from GSK for their work on this project.
B.B. and K.M. have received consultancy fees from
GSK for their contribution to other research.
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