The effects of the dopamine D3 receptor antagonist GSK598809 on attentional bias to palatable food cues in overweight and obese subjects

The effects of the dopamine D3 receptorantagonist GSK598809 on attentional biasto palatable food cues in overweightand obese subjects

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, UK2 Brain Mapping Unit, Department of Psychiatry, University of Cambridge, UK3 School of Psychology, University of Southampton, UK4 Clinical Imaging Centre (CIC), Medicines Discovery & Development, GlaxoSmithKline R&D, London, UK5 Neurosciences CEDD, Medicines Discovery & Development, GlaxoSmithKline R&D, Verona, Italy

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

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

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 struc-

tures (i.e. schemas) (Williamson et al. 2004), food pre-

occupation (Cox & Klinger, 2004), expectancy (Tiffany,

1990) and incentive salience (Berridge & Robinson,

1998 ; Berridge et al. 2010). The latter theoretical view,

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.

International Journal of Neuropsychopharmacology, Page 1 of 13. f CINP 2011doi:10.1017/S1461145711001052

ARTICLE

which ascribes a key role to the mesolimbic dopamin-

ergic system, has been particularly influential.

The mesolimbic dopaminergic system plays a criti-

cal role in the reinforcing effects of natural rewards

like food (Bassareo andDi Chiara, 1997, 1999a, b ;Wang

et al. 2004; Wise, 2006). Dopamine has also been shown

to modulate hedonic and non-hedonic factors under-

lying 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), re-

straint and emotionality processes regulating food in-

take (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 func-

tioning, andmay 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 atten-

tional bias to drug cues (Cox et al. 2006; Field &

Cox, 2008). Furthermore, consistent with dopa-

minergic 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 formodulating behavioural aspects of food con-

sumption 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’, sug-

gesting a selective role for D3 receptors in the motiv-

ational 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 crav-

ing (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 food-

related 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 individ-

ual differences in eating style, namely restraint, modu-

lated 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 ap-

petitive 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, colour-

naming interference effects may reflect enhanced at-

tentional prioritizing of salient stimuli (attentional bias

2 P. J. Nathan et al.

towards salient cues) and/or cognitive effort to sup-

press 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. resol-

ution of processing conflicts. Thus, it is informative

to assess more than one type of attentional bias in

order to evaluate its generality across differentmethod-

ologies.

We hypothesized that, on both attentional tasks,

GSK598809 would attenuate attentional bias to re-

warding food-related cues. Specifically, we predicted

that overweight/obese individuals would show an

attentional bias towards food relative to control (non-

food-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 in-

clusive) 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 [mini-

mum one episode per week as assessed by the YBOCS-

BE questionnaire (Q6) (Goodman et al. 1989, McElroy

et al. 2007)] and emotional eating behaviour (by at-

taining 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 andHillingdon

Research Ethics Committee, UK.

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 atten-

tional 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 pic-

ture was paired with a photograph of another scene

matched as closely as possible for content (e.g. num-

ber, 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 re-

corded 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 pic-

tures 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 indi-

cate 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

D3 receptor antagonism and attentional bias 3

buffer trials. The critical trials were made up from

eight presentations of each of the 20 food-control pic-

ture 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 pres-

ented 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 par-

ticipants 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 food-

related 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 para-

digms 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 colour-

word 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 colour-

word 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 exper-

imental trial lasted 2.2 s and included the presentation

of a word for 1.9 s followed by a presentation of a fix-

ation 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 be-

haviour : cognitive restraint, uncontrolled eating, and

emotional eating (Karlsson et al. 2000; Stunkard &

Messick, 1988). Restrained eating or cognitive restraint

Visual Probe Task

Stimulus presentation500 ms or 2000 ms

Stimulus presentation500 ms or 2000 ms

Response – right button press

Response – left button press

Fixation 500 ms

Fixation 500 ms

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).


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 re-

straint 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), cardio-

vascular 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 sub-

tracting the mean reaction time (mRT) when the probe

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 devi-

ations (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 (colour-

unrelated) words was subtracted from the mRT

of correct responses to incongruent colour words).

Greater interference in the colour-word Stroop indi-

cates 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 atten-

tional bias to food. Correlational analyses were con-

ducted between the questionnaire measure of restraint

at screening (time 1) and the drug-effect contrast term

and overall attentional bias (averaged across all con-

ditions) 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).

# 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).


Visual probe task

Rates of errors and outliers were low (mean percent-

ages 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 con-

dition appeared skewed due to a large positive score

for one participant ; so analyses were repeated without

this individual (similar results were obtained irrespec-

tive 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 inter-

action (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 atten-

tional bias for food cues relative to non-food cues.

The effect of GSK598809 on attentional bias corre-

lated significantly and negatively with TFEQ restraint

score (r=x0.45, p=0.02, two-tailed ; Fig. 3a), suggest-

ing 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

(a) Food Stroop (b) Colour word Stroop

Colour wordsPalatable food words

Non-palatable food words Neutral words matched forcolour words

Neutral words matched forpalatable 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.


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 drugrrestraint 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 pri-

mary hypothesis (corrected p values=uncorrected

pmultiplied by 2, as hypothesis-driven tests were con-

ducted for each group separately) : the low-restraint

group had a marginally significant attentional bias

towards food in the placebo condition (t14=2.46 ; un-

corrected 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).

80

100

(a) (b)

0.4

60

40

20

Att

entio

nal b

ias

plac

ebo-

drug

(ms)

00 5 10 15 20 25

–20

–40

0.3

0.2

0.1

–0.1

–0.2

–0.3

–0.4

–0.5

–0.6

00 5 10 15 20 25

Food

inte

rfer

ence

pal

cebo

-dru

g (m

s)

TEFQ restraint 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.

15

(a) (b)

0.1

0.08

0.06

0.04

0.02

0

–0.02

–0.04

Mae

n fo

od in

terf

eren

ce e

ffec

t (m

s)

–0.06

–0.08

10

5

0

Mea

n at

tent

iona

l bia

s (m

s)

–5

–10Low High

TFEQ restraint group

Low High

TFEQ restraint group

PlaceboGSK598809

PlaceboGSK598809

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.


Modified Stroop task

Mean percent of correct trials in the food Stroop task

was 87% (S.D.=17). Mean percent correct in the stan-

dard 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 incon-

gruent 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 sig-

nificantly 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 inter-

ference=18, S.D.=63, t23=1.4, p=0.17. Repeated-

measures 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 sig-

nificantly 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 sig-

nificance 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. One-

sample 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 inter-

ference 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, cor-

rected 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 posi-

tive 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 investi-

gating the efficacy of D3 receptor antagonists in experi-

mentalmodels of food reinforcement.We report for the

first time, the acute effects of theD3 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 atten-

tional bias, as evident from a significant negative cor-

relation between restraint and the effect of GSK598809

on attentional bias for each task.More specifically, low-

restrained 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 con-

dition. 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


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 mar-

ginally significant on the visual probe task. Together,

these findings provide additional support that antag-

onism of D3 receptors may attenuate attentional pro-

cessing of salient or rewarding cues. Given that obese

individuals have been shown to have greater atten-

tional 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 an-

tagonism 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, re-

spectively). 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 differen-

tiation 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 non-

food cues, indicating that attentional bias was directed

towards food cues in the low-restraint group, whereas

this food-directed attentional bias was no longer

evident after administration of GSK598809.

The lack of overall effect of GSK598809 on atten-

tional 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 neuro-

transmission 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 auto-

receptors 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 dopa-

mine 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 hypoth-

esis, 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 reinforce-

ment) (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 modi-

fied 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 atten-

tional bias to food-related cues. As discussed earlier

this may be related to high-restrained eaters adopting


cognitive control strategies to minimize their proces-

sing of salient food cues. This finding also seems

conceptually compatible with results of a recent eye-

tracking study which indicated that higher levels of

restrained eating were associated with reduced atten-

tional 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 (Perpina 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 sig-

nificant interaction effect of restraintrstimulus ex-

posure, which suggests caution in the interpretation

of these null results. Nevertheless, as discussed above,

for both tasks there was a significant inverse relation-

ship between TFEQ-restrained eating and drug-

induced 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 proof-

of-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 be-

haviour and hence these findings may not be general-

izible to the wider obese population. (5) It should be

highlighted that while restrained eating may be asso-

ciated 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 exper-

imental 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.


Statement of Interest

This study was funded and conducted by Glaxo-

SmithKline (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 compen-

sation 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.

References

Ahern AL, Field M, Yokum S, Bohon C, Stice E (2010).

Relation of dietary restraint scores to cognitive biases

and reward sensitivity. Appetite 55, 61–68.

Bassareo V, Di Chiara G (1997). Modulation of

feeding-induced activation of mesolimbic dopamine

transmission by appetitive stimuli and its relation to

motivational state. European Journal of Neuroscience 11,

4389–4397.

Bassareo V, Di Chiara G (1999a). Differential responsiveness

of dopamine transmission to food-stimuli in nucleus

accumbens shell/core compartments. Neuroscience 89,

637–641.

Bassareo V, Di Chiara G (1999b). Modulation of

feeding-induced activation of mesolimbic dopamine

transmission by appetitive stimuli and its relation to

motivational state. European Journal of Neuroscience 11,

4389–4397.

Berridge KC, Ho C, Jocelyn JM, DiFeliceantonio AG (2010).

The tempted brain eats : pleasure and desire circuits in

obesity and eating disorders. Brain Research 1350, 43–64.

Berridge KC, Robinson TE (1998). What is the role of

dopamine in reward : hedonic impact, reward learning,

or incentive salience? Brain Research Reviews 28, 309–369.

Bradley BP, Mogg K, Falla SJ, Hamilton LR (1998).

Attentional bias for threatening facial expressions in

anxiety : manipulation of stimulus duration. Cognition and

Emotion 12, 737–753.

Bradley BP, Mogg K, Wright T, Field M (2003). Attentional

bias in drug dependence: vigilance for cigarette-related

cues in smokers. Psychology of Addictive Behaviors 17, 66–72.

Braet C, Crombez G (2003). Cognitive interference due to

food cues in childhood obesity. Journal of Clinical Child &

Adolescent Psychology 32, 32–39.

Brignell C, Griffiths T, Bradley BP, Mogg K (2009).

Attentional and approach biases for pictorial food cues.

Influence of external eating Appetite 52, 299–306.

Calitri R, Pothos EM, Tapper K, Brunstrom JM, et al. (2010).

cognitive biases to healthy and unhealthy food words

predict change in BMI. Obesity 18, 2282–2287.

Castellanos EH, Charboneau E, Dietrich MS, Park S, et al.

(2009). Obese adults have visual attention bias for food cue

images : evidence for altered reward system function.

International Journal of Obesity 33, 1063–1073.

Collo G, Zanetti S, Missale C, Spano P (2008). Dopamine D3

receptor-preferring agonists increase dendrite arborization

of mesencephalic dopaminergic neurons via extracellular

signal-regulated kinase phosphorylation. European Journal

of Neuroscience 28, 1231–1240.

Cox WM, Fadardi JS, Pothos EM (2006). The

addiction-Stroop test : theoretical considerations and

procedural recommendations. Psychological Bulletin 132,

443–476.

Cox WM, Klinger E (2004). A motivational model of alcohol

use : determinants of use and change. In : Cox WM,

Klinger E (Eds), Handbook of Motivational Counseling :

Concepts, Approaches, and Assessment (pp. 121–138).

Chichester, UK: Wiley.

de Lauzon B, RomonM, Deschamps V, Lafay L, et al. (2004).

The Three-Factor Eating Questionnaire-R18 is able to

distinguish among different eating patterns in a general

population. Journal of Nutrition 134, 2372–2380.

de Ruiter C, Brosschot JF (1994). The emotional Stroop

interference effect in anxiety : attentional bias or

cognitive avoidance? Behaviour Research and Therapy 32,

315–319.

Di Ciano P, Underwood RJ, Hagan JJ, Everitt BJ (2003).

Attenuation of cue-controlled cocaine-seeking by a

selective D3 dopamine receptor antagonist SB-277011-A.

Neuropsychopharmacology 28, 329–338.

Ersche KD, Bullmore ET, Craig KJ, Shabbir SS, et al. (2010).

Influence of compulsivity of drug abuse on dopaminergic

modulation of attentional bias in stimulant dependence.

Archives of General Psychiatry 67, 632–644.

Field M, Cox WM (2008). Attentional bias in addictive

behaviours : a review of its development, causes, and

consequences. Drug and Alcohol Dependence 97, 1–20.

Franken IHA, Hendriks VM, Stam CJ, Van den Brink W

(2004). A role for dopamine in the processing of drug

cues in heroin dependent patients. European

Neuropsychopharmacology 14, 503–508.

Gawin FH, Allen D, Humblestone B (1989). Outpatient

treatment of crack cocaine smoking with flupentixol

decanoate – a preliminary-report. Archives of General

Psychiatry 46, 322–325.

Goodman WK, Price LH, Rasmussen SA, Mazure C, et al.

(1989). The Yale-Brown Obsessive Compulsive Scale. I.

Development, use, and reliability. Archives of General

Psychiatry 46, 1006–1011.

Graham R, Hoover A, Ceballos NA, Komogortsev O (2011).

Body mass index moderates gaze orienting biases and

pupil diameter to high and low calorie food images.

Appetite 56, 577–586.

Green MW, Elliman NA, Rogers PJ (1997). Impaired

cognitive processing in dieters : failure of attention focus

or resource capacity limitation? British Journal of Health

Psychology 2, 259–267.

Green MW, Rogers PJ (1993). Selective attention to food and

body shape words in dieters and restrained nondieters.

International Journal of Eating Disorders 14, 515–517.

Hedley AA, Ogden CL, Johnson CL, Carroll MD, et al.

(2004). Prevalence of overweight and obesity among


US children, adolescents, and adults, 1999–2002. Journal of

the American Medical Association 291, 2847–2850.

Heidbreder CA, Gardner EL, Xi ZX, Thanos PK, et al. (2005).

The role of central dopamine D3 receptors in drug

addiction : a review of pharmacological evidence.

Brain Research. Brain Research Reviews 49, 77–105.

Hepworth R, Mogg K, Brignell C, Bradley BP (2010).

Negative mood increases selective attention to food cues

and subjective appetite. Appetite 54, 134–142.

Herman CP, Mack D (1975). Restrained and unrestrained

eating. Journal of Personality 43, 647–660.

Hou R, Mogg K, Bradley BP, Moss-Morris R, et al. (2011).

External eating, impulsivity and attentional bias to

food cues. Appetite 56, 424–427.

Johnson WG (1974). Effect of cue prominence and

subject weight on human food-directed performance.

Journal of Personality and Social Psychology 29, 843–848.

Karlsson J, Persson LO, Sjostrom L, Sullivan M (2000).

Psychometric properties and factor structure of the

Three Factor Eating Questionnaire (TFEQ) in obese

men and women. Results from the Swedish Obese

Subjects (SOS) study. International Journal of Obesity 24,

1715–1725.

MacLeod C, Mathews A, Tata P (1986). Attentional bias in

emotional disorders. Journal of Abnormal Psychology 95,

15–20.

McElroy SL, Guerdjikova A, Kotwal R, Welge JA, et al.

(2007). Atomoxetine in the treatment of binge-eating

disorder : a randomized placebo-controlled trial. Journal of

Clinical Psychiatry 68, 390–395.

McQuade JA, Benoit SC, XuM,Woods SC, Seeley RJ (2004).

High-fat diet induced adiposity in mice with targeted

disruption of the dopamine-3 receptor gene. Behavioral

Brain Research 151, 313–319.

Nijs IM, Muris P, Euser AS, Franken IH (2010). Differences

in attention to food and food intake between

overweight/obese and normal-weight females under

conditions of hunger and satiety. Appetite 54, 243–254.

Overduin J, Jansen A, Louwerse E (1995). Stroop interference

and food intake. International Journal of Eating Disorders 18,

277–285.

Patton JH, Stanford MS, Barratt ES (1995). Factor structure

of the Barratt impulsiveness scale. Journal of Clinical

Psychology 51, 768–774.

Perpina C, Hemsley D, Treasure J, de Silva P (1993). Is the

selective information processing of food and body words

specific to patients with eating disorders? International

Journal of Eating Disorders 14, 359–366.

Phelan S, Hassenstab J, McCaffery JM, Sweet L, et al. (2011).

Cognitive interference from food cues in weight loss

maintainers, normal weight, and obese individuals.

Obesity 19, 69–73.

Pilla M, Perachon S, Sautel F, Garrido F, et al. (1999).

Selective inhibition of cocaine-seeking behaviour by a

partial dopamine D3 receptor agonist. Nature 400, 371–375.

Pothos EM, Tapper K, Calitri R (2009). Cognitive and

behavioral correlates of BMI among male and female

undergraduate students. Appetite 52, 797–800.

Saelens BE, Epstein LH (1996). Reinforcing value of food in

obese and non-obese women. Appetite 27, 41–50.

Schwarz AJ, Gozzi A, Reese T, Heidbreder CA, et al. (2007).

Pharmacological modulation of functional connectivity :

the correlation structure underlying the phMRI response to

d-amphetamine modified by selective dopamine D3

receptor antagonist SB277011A. Magnetic Resonance

Imaging 25, 811–820.

Searle G, Beaver JD, Comley RA, Bani M, et al. (2010).

Imaging dopamine D3 receptors in the human brain

with positron emission tomography, [11C]PHNO, and

a selective D3 receptor antagonist. Biological Psychiatry 68,

392–399.

Stewart SH, Samoluk SB (1997). Effects of short-term food

deprivation and chronic dietary restraint on the selective

processing of appetitive-related cues. International Journal

of Eating Disorders 21, 129–135.

Stunkard AJ, Messick S (1988). Eating Inventory Manual.

San Antonio, Texas : The Psychological Corporation,

Harcourt Brace & Company.

Swanson CJ, Heath S, Stratford TR, Kelley AE (1997).

Differential behavioural responses to dopaminergic

stimulation of nucleus accumbens subregions in the rat.

Pharmacology Biochemistry and Behaviour 58, 933–945.

Szczypka MS, Kwok K, Brot MD, Marck BT, et al. (2001).

Dopamine production in the caudate putamen restores

feeding in dopamine-deficient mice. Neuron 30, 819–828.

Taber MT, Fibiger HC (1997). Feeding-evoked dopamine

release in the nucleus, accumbens : regulation by

glutamatergic mechanisms. Neuroscience 76, 1105–1012.

Thanos PK, Michaelides M, Ho CW, Wang GJ, et al.

(2008). The effects of two highly selective dopamine D(3)

receptor antagonists (SB-277011A and NGB-2904) on

food self-administration in a rodent model of obesity.

Pharmacology Biochemistry and Behaviour 89, 499–507.

Tiffany ST (1990). A cognitive model of drug urges and

drug-use behavior : role of automatic and nonautomatic

processes. Psychological Review 97, 147–168.

van Strien T, Frijters JE, Bergers GP, Defares PB (1986).

The Dutch Eating Behaviour Questionnaire (DEBQ) for

assessment of emotional, external and restrained eating

behaviour. International Journal of Eating Disorders 5,

295–313.

Volkow ND, Wang GJ, Fowler JS, Logan J, et al. (2002).

‘Nonhedonic’ food motivation in humans involves

dopamine in the dorsal striatum and methylphenidate

amplifies this effect. Synapse 44, 175–180.

Volkow ND, Wang GJ, Maynard L, Jayne M, et al. (2003).

Brain dopamine is associated with eating behaviors in

humans. International Journal of Eating Disorders 33,

136–142.

Wang GJ, Volkow ND, Thanos PK, Fowler JS (2004).

Similarity between obesity and drug addiction as assessed

by neurofunctional imaging: a concept review. Journal of

Addictive Disorders 23, 39–53.

Werthmann J, Roefs A, Nederkoorn C, Mogg K, et al.

(in press). Can(not) take my eyes off it : attention bias for

food in overweight participants. Health Psychology.


Williams JMG, Mathews A, MacLeod C (1996). The

emotional Stroop task and psychopathology.

Psychological Bulletin 120, 3–24.

Williamson DA, White MA, York-Crowe E, Stewart TM

(2004). Cognitive-behavioral theories of eating disorders.

Behaviour Modification 28, 711–738.

Wise RA (2006). Role of brain dopamine in food reward

and reinforcement. Philosophical Transactions of the Royal

Society B : Biological Sciences 361, 1149–1158.

Yeomans MR, Leitch M, Mobini S (2008). Impulsivity is

associated with the disinhibition but not restraint factor

from the Three Factor Eating Questionnaire. Appetite 50,

469–476.

Yeomans MR, Tovey HM, Tinley EM, Haynes CJ. (2004).

Effects of manipulated palatability on appetite depend on

restraint and disinhibition scores from the Three-Factor

Eating Questionnaire. International Journal of Obesity 28,

144–151.


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The effects of the dopamine D3 receptor antagonist GSK598809 on attentional bias to palatable food cues in overweight and obese subjects