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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 1462 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). 1464 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 1466 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. 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