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International Journal of Neuropsychopharmacology (2013), 16, 1461–1471. f CINP 2013
doi:10.1017/S1461145712001678
ARTICLE
Acute NK1 receptor antagonist administration
affects reward incentive anticipation processing in
healthy volunteers
Kanako Saji1, Yumiko Ikeda2, Woochan Kim3, Yoshitoshi Shingai3, Amane Tateno3,
Hidehiko Takahashi4, Yoshiro Okubo3, Haruhisa Fukayama1 and Hidenori Suzuki2
1
Anesthesiology and Clinical Physiology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
Department of Pharmacology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
3
Department of Neuropsychiatry, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
4
Department of Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto, Japan
2
Abstract
The primary brain structures of reward processing are mainly situated in the mid-brain dopamine system. The
nucleus accumbens (NAc) receives dopaminergic projections from the ventral tegmental area and works as a key
brain region for the positive incentive value of rewards. Because neurokinin-1 (NK1) receptor, the cognate receptor for substance P (SP), is highly expressed in the NAc, we hypothesized that the SP/NK1 receptor system
might play a role in positive reward processing in the NAc in humans. Therefore, we conducted a functional
MRI (fMRI) study to assess the effects of an NK1 receptor antagonist on human reward processing through a
monetary incentive delay task that is known to elicit robust activation in the NAc especially during gain anticipation. Eighteen healthy adults participated in two series of an fMRI study, taking either a placebo or the NK1
receptor antagonist aprepitant. Behavioural measurements revealed that there was no significant difference in
reaction time, hit rate, or self-reported effort for incentive cues between the placebo and aprepitant treatments.
fMRI showed significant decrease in blood oxygenation-level-dependent signals in the NAc during gain anticipation with the aprepitant treatment compared to the placebo treatment. These results suggest that SP/NK1
receptor system is involved in processing of positive incentive anticipation and plays a role in accentuating
positive valence in association with the primary dopaminergic pathways in the reward circuit.
Received 8 May 2012 ; Reviewed 7 July 2012 ; Revised 26 November 2012 ; Accepted 20 December 2012 ;
First published online 13 February 2013
Key words : fMRI, monetary incentive delay task, NK1 receptor antagonist, nucleus accumbens, reward.
Introduction
The reward system is a collection of brain structures that
encourages humans to perform or repeat an action that
promotes survival. Recent studies have begun to identify
pathways underlying reward processing including motivation, learning and emotional reactions (Chau et al.,
2004). The primary brain structures of reward processing
are mainly situated in the mid-brain dopamine system :
the nigrostriatal system consisting of substantia nigra
pars compacta projections to the caudate nucleus and
putamen ; the mesolimbic system consisting of ventral
tegmental area (VTA) projections to the nucleus accumbens (NAc) and prefrontal cortex. The dopaminergic
projections from the VTA to the NAc are thought to
be associated with the incentive motivational value of
Address for correspondence : Professor H. Suzuki, Department of
Pharmacology, Graduate School of Medicine, Nippon Medical School,
1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
Tel. : +81 3 3822 2131 ext. 5277 Fax : +81 3 5814 1684
Email : [email protected]
rewards (Galtress and Kirkpatrick, 2010 ; Peters and
Büchel, 2011). This would indicate that the NAc works as
a key brain structure of reward processing (Knutson et al.,
2001a, b ; Cooper et al., 2009).
Mammalian tachykinins comprise a family of peptides
with a common carboxyl terminal amide motif
(Patacchini et al., 2004). Substance P (SP), a representative
family member, is mainly distributed throughout the
central nervous system and peripheral nervous system in
primates as well as rodents, serving as a neurotransmitter
through activation of its cognate receptor, tachykinin NK1
receptor (Otsuka and Yoshioka, 1993 ; Severini et al.,
2002). Our previous study on the rhesus monkey (Macaca
mulatta) brain showed that the caudate nucleus and putamen contain a markedly high concentration of NK1
mRNA (Nagano et al., 2006). Post-mortem human brain
studies also revealed that NK1 mRNA is highly expressed
in the caudate nucleus, putamen and NAc (Caberlotto
et al., 2003 ; Lai et al., 2008). Consistently, living human
brain studies using positron emission tomography
(PET) and isotope-labelled NK1 receptor ligands have
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K. Saji et al.
reported a similar distribution pattern of NK1 receptor
binding potential (Hargreaves, 2002 ; Nyman et al., 2007 ;
Okumura et al., 2008). As expected from such anatomical
distribution of NK1 receptors and the dopaminergic
pathways in the midbrain across species, it was reported
that SP increases the extracellular dopamine level in the
NAc (Boix et al., 1992 ; Krasnova et al., 2000) and that
SP-releasing neurons in the NAc can facilitate dopaminergic neurotransmission (Elliott et al., 1986) in rodents.
Furthermore, the importance of the SP/NK1 receptor
system for addiction-related behaviours has been revealed by studies using mice deleted of NK1 receptors.
Morphine, a most addictive substance, no longer appeared rewarding in NK1 knockout mice in the conditioned place preference test and drug self-administration
behaviours (Murtra et al., 2000 ; Ripley et al., 2002), both
of which tests are thought to involve neural circuits that
mediate positive reward processing (Commons, 2010).
Additionally, NK1 receptor antagonists are reported to
attenuate the reward-potentiating effects of morphine
in mice (Robinson et al., 2012). Based on these lines of
evidence, we hypothesized that the SP/NK1 receptor
system might play a role in positive reward processing in
the NAc in humans.
Functional magnetic resonance imaging (fMRI) offers
adequate spatial and temporal resolution to allow the
identification of neural correlates of higher brain functions (Horwits et al., 2000). A prototypical cued response
task called monetary incentive delay (MID) task was
developed to elicit anticipatory brain activation in the
context of fMRI (Knutson et al., 2000). The MID task trial
structure allows us to separately visualize brain activity
in response to incentive anticipation. Furthermore, separating gain and loss trials enables us to focus on the
brain activity of each incentive anticipation. In fact, a
meta-analysis of MID study clearly revealed that NAc
activation increases during gain anticipation relative to
loss anticipation in association with self-reported positive
arousal (Knutson and Greer, 2008). We therefore adopted
the MID task to investigate whether the SP/NK1 receptor
system might play a role in positive reward processing
in the NAc in humans, and we examined the effects of
the NK1 antagonist aprepitant on brain activation in the
NAc during gain anticipation.
Materials and method
Participants
The study was approved by the ethics committee of
Nippon Medical School (approval number 222004).
Eighteen physically and psychiatrically healthy volunteers (eight non-pregnant females and 10 males,
mean age 29.6¡6.94 yr) participated in the study. All
subjects were right-handed according to the Edinburgh
Handedness Inventory (Oldfield, 1971). They were
not taking any medications such as contraceptives or
antiepileptics at the time of the experiment nor had a
history of psychiatric disorders or allergy to aprepitant.
Nor did they have any contraindications to fMRI including cardiac pacemaker, mechanical heart valve, metal
implants, potential pregnancy, tattoo or claustrophobia.
All subjects gave their written informed consent prior to
participation in the study.
Experimental design
The experiments were designed as a single-blind crossover trial. The participants took the NK1 antagonist
aprepitant (125 mg as an Emend 125 mg capsule formula,
Ono Pharmaceutical, Japan ; McCabe et al., 2009) or placebo (lactose capsule) in the first series and the other drug
(aprepitant or placebo) in the second series of the study,
with about a 1-wk interval. The order of drug administration was randomly allocated with equal probability.
The fMRI study started 4 h after drug administration, at
which time the peak level of aprepitant in plasma would
be expected (Majumdar et al., 2006). Previous PET studies
reported that 125 mg aprepitant occupies >90 % of NK1
receptors in the brain (Hargreaves, 2002 ; Bergström et al.,
2004). The participants took part in the fMRI scan during
the MID task.
The task was presented on a personal computer using
E-prime (version 2.0 ; Psychology Software Tools, USA)
and delivered to the participants through interchangeable prescriptive goggles suitable for use with MRI.
Behavioural responses were recorded using an MRIcompatible keypad and their accuracy and reaction times
were calculated by E-prime.
Subjective ratings
Before drug administration in each series of the fMRI
study, baseline mood and subjective states were assessed
by Beck Depression Inventory (BDI ; Beck et al., 1996 ;
Kojima and Furukawa, 2003), Dysfunctional Attitudes
Scale (DAS ; Tajima et al., 2007) and State-Trait Anxiety
Inventory (STAI ; Hidano et al., 2000). Transient subjective emotional states were also evaluated with visual
analogue scales (VAS emotion) for happiness, sadness,
anger, disgust, alertness and anxiety before and 1 h, 4 h
(just before MRI scanning) and 5 h (after MRI scanning)
after the drug administration. After scanning, the selfreported efforts for gain, loss and neutral cues were rated
by VAS (VAS effort, Beck et al., 2009) for assessing
the subjective eagerness of the participants to achieve
monetary incentives during the task.
Statistical analyses of behavioural data and
psychological measures
Values were expressed as mean¡S.D. The data of baseline
mood measured by BDI, DAS and STAI were analysed by
paired t test to compare the values between the placebo
and aprepitant treatments. Two-way repeated-measures
analysis of variance followed by Tukey’s post hoc test was
NK1 receptor antagonism in reward processing
1463
250 ms
2000–2500 ms
mean 213 ms
cue
1650 ms
delay
¥100
total
¥1200
target
1000 ms
feedback
ITI
All cues:
–¥100
–¥300
¥0
+¥100
+¥300
Fig. 1. Task structure for a representative trial in the monetary incentive delay task. The procedure is described in the text. All cues in
the task are shown : square with a horizontal line, ¥100 loss ; square with three horizontal lines, ¥300 loss ; triangle, no loss or gain ; circle
with a horizontal line, ¥100 gain ; circle with three horizontal lines, ¥300 gain. ITI, inter-trial interval.
used to compare values of reaction time, hit rate,
VAS effort and VAS emotion during a series of the fMRI
study between the placebo and aprepitant treatments.
Values of p<0.05 were considered to indicate statistical
significance.
Monetary incentive delay task
We used the MID task as described by Knutson et al.
(2001a) with slight modification to examine neural responses to monetary anticipation.
Before entering the scanner, participants completed
a 9-min practice version of the task. This practice task
minimized later learning effects and enabled us to estimate the duration of target presentation in individuals
for standardizing the task difficulty among all participants. Prior to executing the task, participants were also
informed that they would receive a gift voucher according to the amount of money they had earned during
the task. Participants’ monetary gain depended on their
performance in a simple reaction time task at the end of
each trial, which required pressing a button upon the
brief presentation of a visual target.
One MID task session consisted of 144 trials (mean
trial duration, 4.37 s) with 1-s inter-trial intervals, lasting
about 13 min (Fig. 1). In each trial, participants saw one
of five geometric figures (cue) for 250 ms, which indicated that they could either gain or avoid losing different amounts of money (¥100 or ¥300) if they pressed
the response button during the target presentation.
Participants were instructed to respond as fast as possible
during the target presentation. A cue signalled the
potential reward (total number of signals presented in
one session, n=48 ; denoted by circles in Fig. 1), potential
punishment (n=48 ; squares) or no monetary outcome
(n=48 ; triangles). Reward cues (circles) consisted of two
signals with the possibility of gaining ¥100 (n=24 ; circle
with one horizontal line) or ¥300 (n=24 ; circle with three
horizontal lines). Similarly, punishment cues (squares)
were further divided into two signals with the possibility
of losing ¥100 (n=24 ; square with one horizontal line)
or ¥300 (n=24 ; square with three horizontal lines). Trial
types were randomly ordered within each session.
Between cues and target, a variable delay (2000–2500 ms)
was inserted. Then a white target square was presented
with a variable length of time (160–260 ms ; target) urging
the participants to press a button. Feedback followed
the disappearance of the target for 1650 ms, notifying
whether the participant had won or lost money during
the preceding trial and the total amount of money they
had earned by that time point during the session. By
controlling the duration of the target presentation based
on the results of the practice, all the subjects successfully
pressed the button within the time-frame of the target
presentation in about 66 % of the trials.
MRI data acquisition
Imaging data were acquired with Intera Achieva
1.5T Nova (Phillips Electronics, The Netherlands).
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K. Saji et al.
High-resolution T1-weighted anatomical images were
acquired : repetition time (TR)=9.3 ms ; echo time (TE)=
4.6 ms ; flip angle=8x ; field of view (FOV)=250 mm ;
matrix=256r256 ; slice thickness=1.2 mm ; number of
slices=160. For the acquisition of functional images,
the following parameters were used : TR=2000 ms ; TE=
40 ms ; flip angle=90x ; FOV=256 mm ; matrix=64r64.
A total of 400 functional images were acquired from
each participant using a T2*-weighted gradient-echo
echo-planer imaging sequence sensitive to the blood
oxygenation-level-dependent (BOLD) contrast. Wholebrain coverage was obtained with a section thickness of
5 mm and 28 axial slices.
fMRI data analysis
fMRI data analyses focused on changes in BOLD activation occurring during the anticipatory period and were
conducted with SPM8 (Wellcome Department of Imaging
Neuroscience, UK, http://www.fil.ion.ucl.ac.uk/spm)
running with MATLAB (Mathworks, USA). The anatomical T1 image and the functional images were manually reoriented to the anterior commissure–posterior
commissure line. Slice-time correction was conducted to
adjust for time differences due to multi-slice imaging
acquisition. To correct for between-scan movements,
the functional images were realigned to the first image
of the session and again realigned to the mean image
created after the first realignment. The individual anatomical T1 image was then co-registered to the mean
functional image. The transformed anatomical image
was then segmented to create spatial normalization
parameters that were applied to functional images in
the next normalization step. The functional images were
spatially normalized to the standard space defined by
the Montreal Neurological Institute (MNI) template.
After normalization, all scans had a resolution of
2r2r2 mm. The functional images were spatially
smoothed with an isotropic Gaussian kernel (full width
at half maximum of 8 mm) to increase the signal:noise
ratio. For subject-level statistical analyses, the functional
images were analysed using the general linear model.
Haemodynamic responses to each stimulus were
modelled with a d function convolved with a synthetic
haemodynamic response function time-locked to the
onset time of the delay following the cue and with a
variable duration based on the delay time. Low frequency
noise was removed by applying a high-pass filter (cut-off
period, 128 s) to the fMRI time-series data of each voxel.
To analyse gain and loss anticipation, we contrasted
the BOLD activation of gain anticipation (both BOLD
activations during +¥100- and +¥300-presentations ;
indicated by circles) and loss anticipation (BOLD
activations during x¥100- and x¥300-presentations ;
squares) with that of neutral anticipation (triangles). The
statistical parametric map for each contrast (gain anticipation>neutral anticipation, loss anticipation>neutral
anticipation) of the t statistic was calculated on a
voxelrvoxel basis.
For group-level analyses, the one-sample t test was
used to determine group-level activation for each drug
effect. Then, a paired t test was used to assess the difference between the placebo and aprepitant administrations. The contrast images obtained from subject-level
statistical analyses were entered into the paired t test
analyses. All results on activation in the whole brain except the NAc were reported at p<0.001 uncorrected with
a minimum cluster size of 10 voxels. For anatomical location, peak voxels were converted from MNI to
Talairach coordinates (Talairach and Tournoux, 1988).
Based on previous fMRI reports using the MID task
and NK1 receptor expression in human brain (see
Introduction), we set the NAc as an a priori region of interest (ROI) for gain anticipation and loss anticipation,
respectively, and tested brain activity in the NAc by
using small-volume-corrections (Worsley et al., 1996) at
familywise error (FWE)-corrected p<0.05. According to
previous studies (van Duijvenvoorde et al., 2008 ; Demos
et al., 2012), we constructed the bilateral NAc ROI with a
sphere of 3 mm radius by use of the WFU PickAtlas
[Talairach coordinates left : (x8, 5, x7) ; right : (8, 5, x7)].
Results
Effects of drugs on baseline mood and subjective
emotional states
First, we assessed the baseline mood and subjective
emotional states by BDI, DAS and STAI before drug administration in each series of the fMRI study. None of
general mood, personality or subjective state before drug
administration was significantly different between the
two series of experiments (Table 1). There was no significant main effect of drug between the placebo and
aprepitant treatments in VAS emotion scores, nor was
any treatmentrtime interaction observed (Table 2).
These results showing no effects on emotional states after
a single administration of aprepitant were consistent with
those of a previous report (McCabe et al., 2009).
Effects of drugs on behavioural and affective reactions
We then investigated whether aprepitant caused any
changes in behavioural and affective reactions in response to cues in the subjects. No significant main effect
of drug between the placebo and aprepitant treatments
was observed. The subjects treated with the placebo succeeded in pressing the button during target presentation
in 71.99¡12.50 % of gain trials (hit rate for gain cues),
65.53¡16.04 % of loss trials (hit rate for loss cues)
and 53.93¡18.00 % of neutral trials (hit rate for neutral
cues, Table 1). With aprepitant they succeeded in
68.05¡11.85 % of gain anticipation trials, 64.20¡12.19 %
of loss trials and 51.71¡16.35 % of neutral anticipation
trials (Table 1). Mean reaction times of gain anticipation,
NK1 receptor antagonism in reward processing
1465
Table 1. Demographic and baseline rating of subjective mood and behavioural
characteristics
Placebo
Mean (s.d.)
Before drug treatment
BDI
DAS
STAI (state)
STAI (trait)
After drug treatment
Reaction time of gain trials (ms)1
Reaction time of neutral trials (ms)
Reaction time of loss trial (ms)
Hit rate of gain trials ( %)3
Hit rate of neutral trials ( %)
Hit rate of loss trials ( %)
VAS effort for gain cues3
VAS effort for neutral cues
VAS effort for loss cues
Aprepitant
Mean (s.d.)
2.82 (2.63)
82.22 (12.49)
36.28 (6.68)
39.78 (8.13)
3.56 (3.07)
84.83 (13.21)
36.94 (5.30)
38.33 (6.71)
192.16 (29.38)
215.45 (29.70)
198.17 (24.89)
71.99 (12.50)
53.93 (18.00)
65.53 (16.04)
8.53 (1.49)
6.05 (3.15)
8.39 (1.48)4
203.32 (24.14)
226.85 (33.50)
202.54 (17.84)2
68.05 (11.85)
51.71 (16.35)
64.20 (12.19)2
8.58 (1.30)
6.03 (3.04)
7.98 (1.86)2
BDI, Beck Depression Inventory ; DAS, Dysfunctional Attitudes Scale ; STAI, State-Trait
Anxiety Inventory ; VAS, visual analogue scale.
1
p<0.05 between gain cues and neutral cues in both placebo and aprepitant treatments.
2
p<0.05 between loss cues and neutral cues in the aprepitant treatment.
3
p<0.01 between gain cues and neutral cues in both placebo and aprepitant treatments.
4
p<0.01 between loss cue and neutral cue in the placebo treatment.
Table 2. VAS emotion scores
Before
Time-course
1h
4h
5h
Mean (s.e.)
Placebo
Happiness
Sadness
Anger
Disgust
Alertness
Anxiety
5.91 (0.45)
1.14 (0.27)
1.48 (0.35)
1.26 (0.30)
1.33 (0.33)
1.53 (0.37)
5.49 (0.47)
0.84 (0.29)
0.82 (0.28)
0.86 (0.28)
0.83 (0.31)
1.31 (0.33)
4.94 (0.61)
0.91 (0.27)
0.84 (0.25)
0.83 (0.26)
0.84 (0.25)
1.58 (0.48)
4.64 (0.56)
0.93 (0.31)
0.78 (0.30)
1.04 (0.30)
0.78 (0.30)
0.95 (0.31)
Aprepitant
Happiness
Sadness
Anger
Disgust
Alertness
Anxiety
6.30 (0.47)
1.76 (0.38)
2.15 (0.41)
1.95 (0.43)
1.79 (0.33)
2.45 (0.34)
5.99 (0.53)
0.94 (0.25)
0.76 (0.25)
0.90 (0.27)
0.92 (0.28)
1.11 (0.28)
5.31 (0.55)
0.81 (0.28)
0.76 (0.28)
0.78 (0.28)
0.80 (0.26)
0.99 (0.26)
4.91 (0.59)
0.94 (0.29)
0.69 (0.21)
0.79 (0.22)
0.74 (0.22)
0.82 (0.23)
VAS, visual analogue scale.
Time-course represents before and 1 h, 4 h [just before magnetic
resonance image (MRI) scanning] and 5 h (after MRI scanning)
after drug administration.
loss anticipation and neutral anticipation trials were
192.16¡29.38 ms, 198.17¡24.89 ms and 215.45¡29.70 ms
with placebo, and 203.32¡24.14 ms, 202.54¡17.84 ms
and 226.85¡33.50 ms with aprepitant, respectively,
indicating no significant difference between the two
treatments (Table 1). Although there were no differences
in reaction time, hit rate and VAS effort scores for gain
cues, loss cues nor neutral cues between the placebo and
aprepitant treatments (Table 1), all these values for both
gain and loss cues were higher than those for neutral cues
(p<0.001, Table 1). The post hoc test further revealed
that both treatments displayed a higher hit rate and VAS
effort score for both gain and loss cues than those for
neutral cues (p<0.05, Table 1).
To evaluate the effects of aprepitant on general attention, the reaction time and accuracy of the task in the
attention network task (Fan et al., 2005) were examined
in both placebo and aprepitant treatments. There
were no significant differences in both reaction time and
accuracy between the two treatments (reaction time,
540.22¡86.13 ms and 540.61¡83.30 ms in placebo and
aprepitant treatments, respectively ; accuracy of task,
96.81¡3.14 % and 97.79¡1.77 % in placebo and aprepitant treatments, respectively).
Effects of drugs on BOLD activities in fMRI
Table 3 and Fig. 2 show the regions more activated
during anticipation to gain cues than to neutral cues in
the different medication conditions. Consistent with
previous studies (Knutson et al., 2001a, b), the placebo
treatment showed a significant increase in BOLD signal
in the bilateral NAc (p<0.05 FWE-corrected for the NAc
ROI). Other activated areas during gain anticipation
in the placebo treatment were observed in the bilateral
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K. Saji et al.
Table 3. Significant differences in activation in response to gain anticipation vs. neutral anticipation
Talairach coordinates
Contrast
Region
BA
gain anticipation > neutral anticipation
Placebo
Nucleus accumbens
Putamen
Caudate
Thalamus
Insula
Red Nucleus
Cingulate gyrus
Superior frontal gyrus
Middle frontal gyrus
Precentral gyrus
Cuneus
Calcarine sulcus
Lingual gyrus
13
24/32
24/32
6/9
9
8
6
6
18
18
17/18/37
19
Cerebellum
Aprepitant
Putamen
Caudate
Thalamus
Substantia nigra
Red nucleus
Insula
Cingulate gyrus
Medial frontal gyrus
Middle frontal gyrus
Inferior frontal gyrus
Precentral gyrus
Postcentral gyrus
Cuneus
Inferior parietal lobule
13
31
24/31
6
6/10
44/45
44/45
4
6
1
17
40
40
Claustrum
Lingual gyrus
18
18
L
R
L
R
R
R
L
L
R
L
R
L
L
R
L
R
R
L
L
R
L
R
L
R
R
L
R
L
R
R
L
L
R
R
L
L
R
L
R
L
R
L
R
L
R
L
R
x
y
z
t value
x8
10
x14
20
6
10
x26
x6
10
x8
12
16
x53
36
x42
40
8
x26
x20
12
x2
14
x14
18
10
x4
10
x8
8
8
x30
x4
16
10
x38
x53
34
x26
55
x44
18
x61
57
x32
22
x16
22
7
7
9
4
10
x19
27
x27
x20
19
19
7
7
7
1
x2
x83
x62
x86
x65
x54
x48
9
11
16
x19
x10
x18
x16
x26
25
x25
x19
6
x4
13
30
x9
5
x26
x69
x29
x30
4
23
x78
x60
x5
x5
x6
0
7
10
x3
x5
x4
40
36
59
27
33
28
41
17
10
x1
14
x31
x19
x6
x4
x1
3
4
x8
x11
x7
1
45
40
49
46
20
17
48
16
33
15
33
27
2
1
x3
1
3.83*
3.73*
4.31
5.40
5.16
4.37
4.11
7.11
5.96
5.46
5.40
5.48
5.01
4.60
4.45
4.07
4.17
4.81
5.72
4.65
5.66
4.95
5.74
5.12
4.09
4.86
4.86
4.20
6.00
6.16
7.93
4.97
5.62
7.55
6.96
6.01
4.34
7.46
5.24
4.39
4.57
5.78
5.03
5.94
4.88
5.46
4.42
BA : Brodmann area ; L, left ; R, right.
* p<0.05 FWE-corrected for nucleus accumbens.
All other results p<0.001 uncorrected.
putamen, right caudate, right thalamus, bilateral red
nucleus, bilateral cingulate gyrus, left superior frontal
gyrus, bilateral middle frontal gyrus, bilateral precentral
gyrus, right cuneus, left calcarine sulcus, bilateral
lingual gyrus and cerebellum (p<0.001 uncorrected).
Particularly, the activations of the NAc, putamen and
NK1 receptor antagonism in reward processing
(a)
1467
(b)
L
R
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
y=7
y=7
Fig. 2. Neural responses to gain anticipation in the bilateral nucleus accumbens. (a) Brain activation in the bilateral nucleus accumbens
during gain anticipation vs. neutral anticipation in the placebo treatment. Familywise error-corrected p<0.05 for small-volume
corrections [Talairach coordinates left (L) : (x8, 7, x5) ; right (R) : (10, 7, x5)]. (b) No activation in the nucleus accumbens during gain
anticipation vs. neutral anticipation in the aprepitant treatment. Colour bar indicates t statistics.
Placebo > Aprepitant
L
R
3.0
2.5
2.0
1.5
1.0
0.5
0
y=5
Fig. 3. Effects of aprepitant on neural responses to gain
anticipation. Group-level analyses between the placebo and
aprepitant treatments for gain anticipation vs. neutral
anticipation contrast show that aprepitant reduces activation in
the left nucleus accumbens (circled). Familywise error-corrected
p<0.05 for small-volume corrections [Talairach coordinates left
(L) : (x6, 5, x7)]. Colour bar indicates t statistics. R, right.
caudate, critical regions for gain anticipation, were consistent with previous results (Juckel et al., 2006 ; Knutson
et al., 2008 ; Beck et al., 2009). Conversely, the aprepitant
treatment did not show significant increases in BOLD
signal in the NAc during gain anticipation (p<0.05
FWE-corrected for the NAc ROI). Activated areas during
gain anticipation in the aprepitant treatment were observed in the bilateral putamen, right caudate, bilateral
thalamus, bilateral substantia nigra, right red nucleus,
left insula, bilateral cingulate gyrus, right medial frontal
gyrus, left middle frontal gyrus, bilateral inferior frontal
gyrus, bilateral precentral gyrus, left postcentral
gyrus, right cuneus, bilateral inferior parietal lobule,
bilateral claustrum and bilateral lingual gyrus (p<0.001
uncorrected).
Group-level analyses revealed that aprepitant
showed a significant decrease in BOLD signal in the left
NAc during gain anticipation as compared with
the placebo (p<0.05 FWE-corrected for the NAc ROI ;
Table 4 and Fig. 3). Other brain areas showed no difference in BOLD response during gain anticipation between
the placebo and aprepitant treatments (p<0.001 uncorrected). Additionally, although the NAc, and several
other brain regions, were activated during loss anticipation in the placebo and aprepitant treatments, the
BOLD signal in the NAc during loss anticipation was
unchanged between the two treatments (Supplementary
Table 1). The linearity of the haemodynamic response
in the NAc during gain anticipation associated with an
increase in the reward value was confirmed using parametric modulation (Büchel et al., 1998) and analysis of
parametric estimates under placebo, not under aprepitant
treatment (data not shown).
Discussion
This study investigated the acute effects of a single dose
of the NK1 receptor antagonist aprepitant on gain anticipation in the MID task in healthy volunteers. The BOLD
signal in the NAc was increased during gain anticipation
in the MID task with the placebo treatment and was significantly reduced with the aprepitant treatment without
affecting subjective mood or behavioural changes. These
results clearly support our hypothesis that the SP/NK1
receptor system might play a role in positive reward
processing in the NAc in humans.
In animal studies, reward anticipation is accompanied
by dopamine release in the NAc (Schultz, 1997, 1998 ;
Roitman et al., 2004). Consistently, pharmacological MRI
studies have shown that the NAc dopamine release
1468
K. Saji et al.
Table 4. Comparison of aprepitant vs. placebo in response to gain anticipation vs. neutral anticipation in NAc
Talairach coordinates
Contrast
gain anticipation>neutral anticipation
Placebo>Aprepitant
L
x
y
z
t value
x6
5
x7
3.01*
NAc, Nucleus accumbens, L, left.
* p<0.05 family-wise error corrected for NAc.
increases the BOLD signal in the NAc in humans
(Knutson and Gibbs, 2007). In addition, an fMRI study
combined with PET measures also demonstrated that the
ventral striatal BOLD response to reward anticipation
correlates positively with dopamine release during a reward task in humans (Schott et al., 2008). Because the
NAc receives dopaminergic neurons from the VTA involved in the reward system, it is probable that the MID
task activates the dopaminergic pathway from the VTA
to the NAc (Knutson and Gibbs, 2007). Since aprepitant
reduced the activation of the NAc during gain anticipation in the present study, it may modulate dopamine
release by acting on NK1 receptors located along this
pathway. Rodent studies showed that SP increases extracellular dopamine levels in the NAc (Boix et al., 1992 ;
Krasnova et al., 2000) and that SP-releasing neurons in
the NAc can facilitate dopaminergic neurotransmission
(Elliott et al., 1986). An immunocytochemical study
showed that terminals with SP-like immunoreactivity
form axoaxonic contact with dopaminergic terminals in
the NAc (Pickel et al., 1988). Therefore, aprepitant might
decrease dopamine release through NK1 receptors located on pre-synaptic dopaminergic terminals in the
NAc. In addition, aprepitant may also have effects on
dopaminergic neural activity within the VTA. Injection of
SP into the VTA increases the cell-firing rate of neurons
(Korotkova et al., 2006) and dopamine release in the
forebrain area including the NAc (Cador et al., 1989).
Since NK1 receptors are located in somata and dendrites
of VTA neurons projecting to the NAc (Lessard et al.,
2009), aprepitant may act on these VTA neurons, resulting in a decrease in dopamine release in the NAc.
Furthermore, NK1 receptors are prominently located on
cholinergic neurons in the NAc (Kaneko et al., 1993 ;
Pickel et al., 2000 ; Commons, 2010), which are suggested
to modulate activity of dopaminergic neurons (Mark et
al., 2011). In rats, conditioned taste preference releases
dopamine in the NAc, whereas conditioned taste aversion results in a decrease in extracellular dopamine and
an increase in extracellular acetylcholine in the NAc
(Hoebel et al., 2007). It is noteworthy that intraperitoneal
administration of SP reportedly decreases extracellular
acetylcholine in the NAc (Boix et al., 1994).
An important finding of the present study is that only
the NAc activation during gain anticipation is sensitive to
the aprepitant treatment despite the NAc being activated
during loss anticipation with the placebo treatment. In an
fMRI study with the MID task, anticipation of monetary
gain proportionally increased NAc activation, while
magnitude-proportional activations were not observed in
anticipation of monetary loss (Knutson et al., 2001a).
Taken together, anticipation of positive incentive (reward), but not anticipation of negative incentive (punishment), is suggested to recruit a distinct brain circuit
including the activated SP/NK1 receptor system. It has
been clearly shown that the NAc activation separately
represents valence and salience (Cooper and Knutson,
2008). In this context, the SP/NK1 receptor system may
play a role in accentuating positive valence in association
with the primary dopaminergic pathways in the reward
circuit.
In the present study, we recruited participants of both
genders. A previous study using the MID task reported
that the BOLD signal in the NAc showed no difference
between males and females (Spreckelmeyer et al., 2009).
Conversely, a PET report showed a gender difference
in NK1 receptor binding potential in several regions,
females showing lower NK1 receptor binding potential
values than males in the putamen and caudate
(Nyman et al., 2007). Although the gender difference in
NK1 receptor expression in the NAc is unclear, we
cannot exclude the possibility that the gender difference
may have affected the present results. Further clarification of gender differences in the involvement of the
SP/NK1 receptor system in reward processing will be
needed.
Abnormality in the brain reward circuitry has been
reported in patients with several psychiatric disorders
including substance-use disorders, schizophrenia and
major depressive disorder (Chau et al., 2004). The
SP/NK1 receptor system is also thought to be involved in
substance dependence including drug addiction and alcoholism (Chahl, 2006 ; George et al., 2008). As revealed in
the present study, the use of pharmacological fMRI can
provide non-invasive detection and visualization of drug
effects in the living human brain, thereby facilitating
our understanding of distinct neuronal substrates pertinent to complex cognitive functions such as reward.
Therefore, future application of the present study paradigm for patients with psychiatric disorders would
NK1 receptor antagonism in reward processing
promote our understanding of the pathophysiological
roles of the SP/NK1 receptor system and the development of therapeutics against some discrete symptoms in
such disorders.
Limitations of the study
To observe carefully whether the participants suffered
from unexpected adverse drug effects, the present
study was designed in a single-blind manner. No subjective judgement intervened in the fMRI experiments.
However, the process of data analysis might affect the
interpretation of the results, since it was not conducted in
a blind manner. Additionally, the neural effect was very
weak in the NAc in the present study. The weak NAc
activation may reflect that BOLD activation occurred in a
small part of NAc in our present task, although we could
not identify the specific subregions. Further refinement of
the task design with the use of high-resolution MRI might
provide clearer results in future studies.
Acknowledgements
We thank Koji Nagaya, Koji Kanaya, Masaya Suda,
Megumi Takei and Minoru Sakurai (Clinical Imaging
Centre for Healthcare, Nippon Medical School) for their
assistance in performing MRI examinations. We also
thank Chieko Kishi for help as clinical research coordinator and Dr Gerz for his English editing of our manuscript. This study was supported by a grant-in-aid for
encouragement of young scientists (B ; 24791237 to Y. I.)
and a grant-in-aid for challenging exploratory research
(22659212 to Y. O.) from the Japan Society for the
Promotion of Science, and a grant (S0801035 to H.S.) from
the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
Statement of Interest
Dr Okubo has received grants or speaker’s honoraria
from Dainippon Sumitomo Pharma, GlaxoSmithKline,
Janssen Pharmaceutical, Ohtuka, Pfizer, Eli Lilly,
Astellas, Yoshitomo and Meiji within the past 3 yr.
Supplementary material
For supplementary material accompanying this paper,
visit http://dx.doi.org/10.1017/S1461145712001678.
References
Beck A, Schlagenhauf F, Wüstenberg T, Hein J, Kienast T,
Kahnt T, Schmack K, Hägele C, Knutson B, Heinz A, Wrase J
(2009) Ventral striatal activation during reward anticipation
correlates with impulsivity in alcoholics. Biol Psychiatry
66 :734–742.
Beck AT, Steer RA, Brown GK (1996) Manual for the Beck
Depression Inventory, 2nd edn. Texas : Pearson.
1469
Bergström M, Hargreaves RJ, Burns HD, Goldberg MR,
Sciberras D, Reines SA, Petty KJ, Ögren M, Antoni G,
Långström B, Eskola O, Scheinin M, Solin O, Majumdar AK,
Constanzer ML, Battisti WP, Bradstreet TE, Gargano C,
Hietala J (2004) Human positron emission tomography
studies of brain neurokinin 1 receptor occupancy by
aprepitant. Biol Psychiatry 55 :1007–1012.
Boix F, Mattioli R, Adams F, Huston JP, Schwarting RKW (1992)
Effects of substance P on extracellular dopamine in
neostriatum and nucleus accumbens. Eur J Pharmacol
216 :103–107.
Boix F, Pfister M, Huston JP, Schwarting RKW (1994) Substance
P decreases extracellular concentrations of acetylcholine in
neostriatum and nucleus accumbens in vivo : possible
relevance for the central processing of reward and aversion.
Behav Brain Res 63 :213–219.
Büchel C, Holmes AP, Rees G, Friston KJ (1998) Characterizing
stimulus-response functions using nonlinear regressors in
parametric fMRI experiments. Neuroimage 8 :140–148.
Caberlotto L, Hurd YL, Murdock P, Wahlin JP, Melotto S,
Corsi M, Carletti R (2003) Neurokinin 1 receptor and relative
abundance of the short and long isoforms in the human brain.
Eur J Neurosci 17 :1736–1746.
Cador M, Rivet JM, Kelley AE, Le Moal M, Stinus L (1989)
Substance P, neurotensin and enkephalin injections into the
ventral tegmental area : comparative study on dopamine
turnover in several forebrain structures. Brain Res
486 :357–363.
Chahl LA (2006) Tachykinins and neuropsychiatric disorders.
Curr Drug Targets 7 :993–1003.
Chau DT, Roth RM, Green AI (2004) The neural circuitry of
reward and its relevance to psychiatric disorders. Curr
Psychiatry Rep 6 :391–399.
Commons KG (2010) Neuronal pathways linking substance P to
drug addiction and stress. Brain Res 1314 :175–182.
Cooper JC, Hollon NG, Wimmer GE, Knutson B (2009)
Available alternative incentives modulate anticipatory
nucleus accumbens activation. Soc Cogn Affect Neurosci
4 :409–416.
Cooper JC, Knutson B (2008) Valence and salience contribute to
nucleus accumbens activation. Neuroimage 39 :538–547.
Demos KE, Heatherton TF, Kelley WM (2012) Individual
differences in nucleus accumbens activity to food and sexual
images predict weight gain and sexual behavior. J Neurosci
32 :5549–5552.
Elliott PJ, Nemeroff CB, Kilts CD (1986) Evidence for a tonic
facilitatory influence of substance P on dopamine release in
the nucleus accumbens. Brain Res 385 :379–382.
Fan J, McCandliss BD, Fossella J, Flombaum JI, Posner MI (2005)
The activation of attentional networks. Neuroimage
26 :471–479.
Galtress T, Kirkpatrick K (2010) The role of the nucleus
accumbens core in impulsive choice, timing, and reward
processing. Behav Neurosci 124 :26–43.
George DT, Gilman J, Hersh J, Thorsell A, Herion D, Geyer C,
Peng X, Kielbasa W, Rawlings R, Brandt JE, Gehlert DR,
Tauscher JT, Hunt SP, Hommer D, Heilig M (2008)
Neurokinin 1 receptor antagonism as a possible therapy for
alcoholism. Science 319 :1536–1539.
Hargreaves R (2002) Imaging substance P receptors (NK1) in
the living human brain using positron emission tomography.
J Clin Psychiatry 63 :18–24.
1470
K. Saji et al.
Hidano T, Fukuhara M, Iwawaki M, Soga S, Spielberger CD
(2000) State-trait anxiety inventory – form JYZ. Tokyo :
Jitsumukyoiku Shuppan.
Hoebel BG, Avena NM, Rada P (2007) Accumbens dopamineacetylcholine balance in approach and avoidance. Curr Opin
Pharmacol 7 :617–627.
Horwitz B, Friston KJ, Taylor JG (2000) Neural modeling and
functional brain imaging : an overview. Neural Netw
13 :829–846.
Juckel G, Schlagenhauf F, Koslowski M, Wüstenberg T,
Villringer A, Knutson B, Wrase J, Heinz A (2006) Dysfunction
of ventral striatal reward prediction in schizophrenia.
Neuroimage 29 :409–416.
Kaneko T, Shigemoto R, Nakanishi S, Mizuno N (1993) Substance
P receptor-immunoreactive neurons in the rat neostriatum are
segregated into somatostatinergic and cholinergic aspiny
neurons. Brain Res 631 :297–303.
Knutson B, Adams CM, Fong GW, Hommer D (2001a)
Anticipation of increasing monetary reward selectively
recruits nucleus accumbens. J Neurosci 21 :RC159.
Knutson B, Bhanji JP, Cooney RE, Atlas LY, Gotlib IH (2008)
Neural responses to monetary incentives in major depression.
Biol Psychiatry 63 :686–692.
Knutson B, Fong GW, Adams CM, Varner JL, Hommer D (2001b)
Dissociation of reward anticipation and outcome with eventrelated fMRI. Neuroreport 12 :3683–3687.
Knutson B, Gibbs SEB (2007) Linking nucleus accumbens
dopamine and blood oxygenation. Psychopharmacology
191 :813–822.
Knutson B, Greer SM (2008) Anticipatory affect : neural correlates
and consequences for choice. Philos Trans R Soc Lond B Biol
Sci 363 :3771–3786.
Knutson B, Westdorp A, Kaiser E, Hommer D (2000) FMRI
visualization of brain activity during a monetary incentive
delay task. Neuroimage 12 :20–27.
Kojima M, Furukawa TA (2003) Japanese manual of the Beck
Depression Inventory, 2nd edn. Tokyo : Nihon Bunka
Kagakusha.
Korotkova TM, Brown RE, Sergeeva OA, Ponomarenko AA,
Haas HL (2006) Effects of arousal- and feeding-related
neuropeptides on dopaminergic and GABAergic neurons in
the ventral tegmental area of the rat. Eur J Neurosci
23 :2677–2685.
Krasnova IN, Bychkov ER, Lioudyno VI, Zubareva OE,
Dambinova SA (2000) Intracerebroventricular administration
of substance P increases dopamine content in the brain
of 6-hydroxydopamine-lesioned rats. Neuroscience
95 :113–117.
Lai JP, Cnaan A, Zhao H, Douglas SD (2008) Detection of fulllength and truncated neurokinin-1 receptor mRNA expression
in human brain regions. J Neurosci Methods 168 :127–133.
Lessard A, Savard M, Gobeil Jr. F, Pierce JP, Pickel VM (2009)
The neurokinin-3 (NK3) and the neurokinin-1 (NK1) receptors
are differentially targeted to mesocortical and mesolimbic
projection neurons and to neuronal nuclei in the rat ventral
tegmental area. Synapse 63 :484–501.
McCabe C, Cowen PJ, Harmer CJ (2009) NK1 receptor
antagonism and the neural processing of emotional
information in healthy volunteers. Int J
Neuropsychopharmacol 12 :1261–1274.
Majumdar AK, Howard L, Goldberg MR, Hickey L,
Constanzer M, Rothenberg PL, Crumley TM, Panebianco D,
Bradstreet TE, Bergman AJ, Waldman SA, Greenberg HE,
Butler K, Knops A, De Lepeleire I, Michiels N, Petty KJ (2006)
Pharmacokinetics of aprepitant after single and multiple oral
doses in healthy volunteers. J Clin Pharmacol 46 :291–300.
Mark GP, Shabani S, Dobbs LK, Hansen ST (2011) Cholinergic
modulation of mesolimbic dopamine function and reward.
Physiol Behav 104 :76–81.
Murtra P, Sheasby AM, Hunt SP, De Felipe C (2000) Rewarding
effects of opiates are absent in mice lacking the receptor for
substance P. Nature 405 :180–183.
Nagano M, Saitow F, Haneda E, Konishi S, Hayashi M, Suzuki H
(2006) Distribution and pharmacological characterization of
primate NK-1 and NK-3 tachykinin receptors in the central
nervous system of the rhesus monkey. Br J Pharmacol
147 :316–323.
Nyman MJ, Eskola O, Kajander J, Vahlberg T, Sanabria S,
Burns D, Hargreaves R, Solin O, Hietala J (2007) Gender and
age affect NK1 receptors in the human brain – a positron
emission tomography study with [18F]SPA-RQ. Int J
Neuropsychopharmacol 10 :219–229.
Okumura M, Arakawa R, Ito H, Seki C, Takahashi H, Takano H,
Haneda E, Nakao R, Suzuki H, Suzuki K, Okubo Y, Suhara T
(2008) Quantitative analysis of NK1 receptor in the human
brain using PET with 18F-FE-SPA-RQ. J Nucl Med
49 :1749–1755.
Oldfield RC (1971) The assessment and analysis of handedness :
the Edinburgh inventory. Neuropsychologia 9 :97–113.
Otsuka M, Yoshioka K (1993) Neurotransmitter functions of
mammalian tachykinins. Physiol Rev 73 :229–308.
Patacchini R, Lecci A, Holzer P, Maggi CA (2004) Newly
discovered tachykinins raise new questions about their
peripheral roles and the tachykinin nomenclature. Trends
Pharmacol Sci 25 :1–3.
Peters J, Büchel C (2011) The neural mechanism of inter-temporal
decision-making : understanding variability. Trends Cogn Sci
15 :227–239.
Pickel VM, Douglas J, Chan J, Gamp PD, Bunnett NW (2000)
Neurokinin 1 receptor distribution in cholinergic neurons and
targets of substance P terminals in the rat neucleus
accumbens. J Comp Neurol 423 :500–511.
Pickel VM, Joh TH, Chan J (1988) Substance P in the rat nucleus
accumbens : ultrastructural localization in axon terminals and
their relation to dopaminergic afferents. Brain Res
444 :247–264.
Ripley TL, Gadd CA, De Felipe C, Hunt SP, Stephens DN
(2002) Lack of self-administration and behavioural
sensitisation to morphine, but not cocaine, in
mice lacking NK1 receptors. Neuropharmacology
43 :1258–1268.
Robinson JE, Fish EW, Krouse MC, Thorsell A, Heilig M,
Malanga CJ (2012) Potentiation of brain stimulation reward by
morphine effects of neurokinin-1 receptor antagonism.
Psychopharmacology 220 :215–224.
Roitman MF, Stuber GD, Phillips PE, Wightman RM, Carelli RM
(2004) Dopamine operates as a subsecond modulator of food
seeking. J Neurosci 24 :1265–1271.
Schott BH, Minuzzi L, Krebs RM, Elmenhorst D, Lang M,
Winz OH, Seidenbecher CI, Coenen HH, Heinze HJ, Zilles K,
Düzel E, Bauer A (2008) Mesolimbic functional magnetic
resonance imaging activations during reward anticipation
correlate with reward-related ventral striatal dopamine
release. J Neurosci 28 :14311–14319.
NK1 receptor antagonism in reward processing
Schultz W (1997) Dopamine neurons and their role in reward
mechanisms. Curr Opin Neurobiol 7 :191–197.
Schultz W (1998) Predictive reward signal of dopamine neurons.
J Neurophysiol 80 :1–27.
Severini C, Improta G, Falconieri-Erspamer G, Salvadori S,
Erspamer V (2002) The tachykinin peptide family. Pharmacol
Rev 54 :285–322.
Spreckelmeyer KN, Krach S, Kohls G, Rademacher L, Irmak A,
Konrad K, Kircher T, Gründer G (2009) Anticipation of
monetary and social reward differently activates mesolimbic
brain structures in men and women. Soc Cogn Affect Neurosci
4 :158–165.
Tajima M, Akiyama T, Numa H, Kawamura Y, Okada Y,
Sakai Y, Miyake Y, Ono Y, Power MJ (2007) Reliability
and validity of the Japanese version of 24-item
1471
Dysfunctional Attitude Scale. Acta Neuropsychiatr
19 :362–367.
Talairach J, Tournoux P (1988) Co-planar stereotaxic atlas of the
human brain : 3-dimensional proportional system – an
approach to cerebral imaging. New York : Thieme Medical
Publishers.
van Duijvenvoorde ACK, Zanolie K, Rombouts SARB,
Raijmakers MEJ, Crone EA (2008) Evaluating the negative or
valuing the positive? Neural mechanisms supporting
feedback-based learning across development. J Neurosci
28 :9495–9503.
Worsley KJ, Marrett S, Neelin P, Vandal AC, Friston KJ,
Evans AC (1996) A unified statistical approach for
determining significant signals in images of cerebral
activation. Hum Brain Mapp 4 :58–73.