Bhr185 1133.1138

Cerebral Cortex May 2012;22:1133--1138doi:10.1093/cercor/bhr185Advance Access publication July 28, 2011 Modulation of Inhibition of Return by the Dopamine D2 Receptor Agonist BromocriptineDepends on Individual DAT1 Genotype Ariel Rokem1, Ayelet N. Landau2, William Prinzmetal2, Deanna L. Wallace1,2, Michael A. Silver1,3 and Mark D'Esposito1,2 1Helen Wills Neuroscience Institute, 2Department of Psychology and 3School of Optometry, University of California, Berkeley,Berkeley, CA 94720, USA.
Address correspondence to Ariel Rokem, 360 Minor Hall #2020, University of California, Berkeley, Berkeley, CA 94720-2020, USA.
Involuntary visual spatial attention is captured when a salient cue what extent these 2 phenomena depend on the same neural appears in the visual field. If a target appears soon after the cue, response times to targets at the cue location are faster relative to Here, we examined the role of the neurotransmitter other locations. However, after longer cue--target intervals, dopamine (DA) in both involuntary attention and IOR. DA is responses to targets at the cue location are slower, due to involved in a variety of cognitive functions, and 3 lines of inhibition of return (IOR). IOR depends on striatal dopamine (DA) evidence suggest that it also modulates IOR. First, patients with levels: It varies with different alleles of the DA transporter gene Parkinson's disease (PD), a disease characterized by reduced DAT1 and is reduced in patients with Parkinson's disease, a disease dopaminergic transmission in the striatum, have reduced IOR characterized by reduced striatal dopaminergic transmission. We magnitude, relative to healthy controls (Filoteo et al. 1997; examined the role of DA in involuntary attention and IOR by Yamaguchi and Kobayashi 1998; Possin et al. 2009). Second, administering the DA D2 receptor-specific agonist bromocriptine to even in healthy individuals, genetic differences in striatal DA healthy human subjects. There was no effect of either DAT1 transmission predict differences in IOR. In particular, the gene genotype or bromocriptine on involuntary attention, but participants DAT1 codes for a DA transporter which facilitates reuptake of with DAT1 alleles predicting higher striatal DA had a larger IOR.
DA in the striatum (Sesack et al. 1998), and this gene has Furthermore, bromocriptine increased the magnitude of IOR in different alleles that are associated with different levels of DA participants with low striatal DA but abolished the IOR in subjects clearance from synapses (Mill et al. 2002). Subjects with with high striatal DA. This inverted U-shaped pattern resembles a DAT1 allele that predicts higher levels of striatal DA have previously described relationships between DA levels and perfor- a larger IOR for short cue--target intervals (less than 750 ms), mance on cognitive tasks and suggests an involvement of striatal relative to subjects with a DAT1 allele that predicts lower levels DA in IOR that does not include a role in involuntary attention.
of striatal DA (Colzato et al. 2010). Finally, DA D2 receptors(DRD2) are enriched in the human striatum (Camps et al. 1989; Keywords: DAT1, dopamine, inhibition of return, striatum, visual attention Meador-Woodruff et al. 1996), and long-term cocaine use,which leads to reductions in DRD2 (Volkow et al. 1999),abolishes the IOR (Colzato and Hommel 2009).
Taken together, these results suggest that increased striatal DA transmission is associated with larger IOR. In order to When a salient event occurs in the visual field, involuntary delineate a causal role of striatal DA transmission in the IOR, visual spatial attention is captured at that location (Yantis and pharmacological methods can be used. A previous study has Jonides 1990). As a consequence, performance on discrimina- shown that the temporal extent of the IOR is increased in a dose- tion tasks is facilitated and response times (RTs) are faster dependent manner by the administration of d-amphetamine when a target appears in the cued location, relative to other (Fillmore et al. 2005), a drug that increases extracellular DA locations (Prinzmetal et al. 2005). This effect of cueing, due to levels. However, the actions of d-amphetamine are not specific to capture of involuntary attention, develops quickly but is a particular type of DA receptor. Moreover, d-amphetamine also transient (Posner and Cohen 1984). On the other hand, with increases levels of extracellular noradrenaline in the central longer delays between cue and target, involuntary attention nervous system (Heal et al. 2009).
dissipates before target presentation, and the opposite effect is In the present study, we administered the DRD2-specific observed: RTs are faster for targets presented at noncued agonist bromocriptine to a group of young healthy participants locations, relative to the cue location (Posner and Cohen and tested their performance in a cued visual discrimination 1984). This phenomenon is known as the inhibition of return task. Bromocriptine is used to treat PD (Radad et al. 2005), and (IOR; for a review, see Klein (2000)).
in healthy young participants, it can increase performance on The physiological mechanisms underlying the IOR are only tasks requiring spatial working memory (reviewed in Mehta partially understood. Brain imaging studies suggest that IOR and Riedel (2006)). However, these findings are mixed, with involves frontal and posterior parietal cortical regions (Lepsien some studies failing to replicate increased spatial working and Pollmann 2002; Mayer et al. 2004). However, other results memory performance following bromocriptine administration implicate subcortical structures in IOR (Sapir et al. 1999; or replicating them only at lower doses. One possible Fecteau and Munoz 2005). Although physiological (Fecteau and explanation of these discrepancies is the inverted U-shaped Munoz 2005), neuropsychological (Sapir et al. 1999), and effect of DA transmission on cognitive functions that has been behavioral (Ro and Rafal 1999) studies suggest that involuntary observed in several different contexts (Cools and Robbins attention and IOR can occur independently, it is unclear to 2004; Seamans and Yang 2004; Cools and D'Esposito 2011), Ó The Author 2011. Published by Oxford University Press. All rights reserved.
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including following bromocriptine administration (Kimberg levels peak ca. 100 min after oral administration and remain et al. 1997; Cools et al. 2007, 2009). Based on the inverted U- significantly elevated for several hours; Price et al. (1978)). Subjects shaped effects of DA, we predicted that participants would first conducted a brief block of training (20 trials) to acquaint themwith the task, followed by 4 blocks of 80 trials each. They were respond to pharmacological activation of DRD2 in a non- instructed to fixate on a central point, and eye movements were monotonic fashion, depending on their genetic background.
monitored using a camera placed in front of their eyes. Auditory Specifically, we predicted that participants with low baseline feedback was provided at the end of a trial if fixation was not levels of striatal DA would show an increase in the magnitude maintained, and trials containing eye movements were excluded from of the IOR following bromocriptine administration, whereas further analysis. The proportion of trials in which eye movements bromocriptine would decrease IOR magnitude in participants occurred was low (ca. 0.3% of all trials) and did not differ between drugand placebo sessions (F with high baseline levels of striatal DA.
1,15 = 0.21, P = 0.65).
Materials and Methods Genetic TestingUsing the Oragene DNA Self-Collection Kit (DNA Genotek Inc., Ottawa,Ontario, Canada), we collected saliva samples from each subject, and the variable number of tandem repeats (VNTR) for the DAT1 gene was Twenty-one healthy adults (11 females; age: 19.9 ± 1.7) participated in determined by polymerase chain reaction, using primers designed the study. The experimental procedures were approved by the specifically for the 40-bp VNTR polymorphism in the 3 Committee for the Protection of Human Subjects at the University of region (Creative Genomics, Port Jefferson Station, NY). Of the 19 California, Berkeley, and all experiments were conducted with the subjects that completed the study, 10 were homozygous for the 10- written consent of each subject. Two subjects experienced adverse repeat allele of this gene (10R), 8 were heterozygous (one copy each of effects of the drug and did not complete the task.
the 10-repeat and 9-repeat alleles), and 1 was homozygous for the 9-repeat (9R) allele. Following Colzato et al. (2010), subjects carrying at least one copy of the 9R allele were grouped together and referred to Each trial began with a 200 ms cue: one of the peripheral rectangular collectively as 9R.
frames (Fig. 1) became black and thicker and, after a variable stimulusonset asynchrony (SOA), a target display appeared for 240 ms. The targetdisplay contained 12 Gabor patches (100% contrast, spatial frequency: 3 cycles/degree of visual angle; space constant: 1 degree of visual angle), 3 Correct responses were well above 90% in all conditions, and there was within each frame. The target (always the central of the 3 Gabor no main effect of the drug on the percentage of correct responses (F1,15 patches) was tilted ±45° away from vertical, and all other patches were = 0.97, P = 0.34). RTs from incorrect trials and trials with RTs faster than vertically oriented (Rokem et al. 2010). The tilted grating appeared in 100 ms or slower than 1500 ms were excluded from the analysis, as one of the 4 locations with equal probability (25% of the trials), were trials with RTs more than 3 standard deviations (SDs) away from independent of the cue location, and subjects were told that the cue did each participant's mean performance in a given condition (combination not contain any information about the subsequent target location.
of drug/SOA/target location for that subject).
Subjects reported the direction of tilt of the target by pressing one of 2buttons as quickly and accurately as they could. Auditory feedback onperformance was provided at the end of each trial. In different blocks, the SOA between cue and target appearance was either 40 or 600 ms.
In order to measure behavioral effects of the allocation of SOA blocks were interleaved, and the order was counterbalanced involuntary attention and the IOR, we measured RT in a visual between subjects, such that all combinations of order of SOA and orderof drug administration were approximately equally represented.
discrimination task. In each trial, a cue appeared with equalprobability in one of 4 locations in the visual field (Fig. 1). Thelocation of the cue was not predictive of subsequent target location, which was also randomly selected on each trial. The A crossover design was employed: each subject received placebo priorto one experimental session and 1.25 mg bromocriptine prior to the effects of cueing were assessed by comparing RTs from trials in other. Drug administration was double blind. Testing was conducted which the target appeared in the cue location (25% of trials) approximately 3--4 h after bromocriptine administration (drug plasma with RTs from trials in which targets appeared in other Figure 1. Visual cueing task. At the beginning of each trial, one of the 4 peripheral rectangular frames became black and thicker. Following a SOA of either 40 or 600 ms, thetarget appeared in one of the 4 locations (25% probability at each location). The target was a Gabor patch oriented ±45° relative to vertical. Subjects indicated target orientationas quickly and accurately as they could by pressing one of 2 buttons.
Rokem et al.

locations (75% of trials). Separate sets of blocks with differentcue-to-target SOAs were used to assess involuntary attentionand IOR. In half of the blocks, a 40 ms SOA was used, consistentwith the SOA required for allocation of involuntary attention(Posner and Cohen 1984). In the other half of the blocks, a 600ms SOA was used, consistent with the time course of the IOR(Posner and Cohen 1984). To test the effects of the DRD2agonist bromocriptine, we employed a placebo-controlled,double blind crossover design in which each subject partici-pated in 2 sessions: one with a placebo and the other aftertaking a pill containing bromocriptine.
In order to assess the effects of cueing, SOA and bromocrip- tine, we conducted a mixed-model analysis of variance(ANOVA) on mean RTs, with target location (cued vs. other),SOA (short vs. long), and drug (bromocriptine vs. placebo) as within-subject factors. In addition, DAT1 genotype (10R, or lowstriatal DA, vs. 9R, or high striatal DA) was also entered asa between-subjects factor in the ANOVA to test the effects ofindividual differences in baseline striatal DA levels. Finally, toaccount for effects of learning between the 2 sessions, order ofdrug administration (bromocriptine first vs. placebo first) was also entered as a between-subjects factor.
We did not find a main effect of bromocriptine on RT (F1,15 = 0.01, P = 0.9), suggesting that the drug did not have an overall Figure 2. Short SOA blocks. (A) Average RTs for 40 ms SOA blocks. RTs are shown effect on motor response or arousal. In addition, there was no main for trials in which the target appeared in the cue location (25% of trials, left) and for effect of DAT1 genotype on RT (F trials in which the target appeared in one of the other locations (75% of trials, right).
1,15 = 1.41, P = 0.25), suggesting (B) The cueing effect is defined for each subject as the mean RT of trials in which the that overall task performance was not determined by baseline target appeared in the cue location minus the mean RT of trials in which the target striatal DA levels. However, there was a significant interaction of appeared in one of the other locations. Cueing effects are shown separately for 10R the effects of drug and order of drug administration (F1,15 = 23.23, (left) and 9R subjects (right) and for placebo (white) and bromocriptine (gray) P < 0.01). Specifically, if participants were administered placebo in sessions. The negative values indicate a reduction in RT for trials in which the target the first session and bromocriptine in the second session, they appeared in the cue location, reflecting capture of involuntary attention. Thisinvoluntary attention effect was not affected by either bromocriptine administration or were faster in the bromocriptine session. If they were adminis- DAT1 genotype. Error bars are standard error of the mean within group/condition.
tered bromocriptine and then placebo, they were faster in theplacebo session. This suggests that participants' performance computed within-subject cueing effects in order to eliminate improved through their experience with the task and that they variability due to overall RT differences between subjects. The were generally faster in the second testing session, regardless of average cueing effect, defined as the difference in RT between whether bromocriptine or placebo was administered in this trials in which the target was in the cue location and trials in session. We controlled for this order effect by counterbalancing which the target appeared in one of the other locations, was the order of drug and placebo sessions between subjects.
significantly less than zero (–15 ms, within-subject 2-tailed t- Collapsing across both SOA conditions and drug and placebo test: t18 = 2.38, P < 0.05) and was negative for 14 of the 19 sessions, we found no main effect of target location (cued vs.
subjects in the placebo sessions. In the bromocriptine sessions, other, F1,15 = 2.95, P = 0.1). However, there was a main effect of subjects were also faster to respond to targets presented at the SOA (F1,15 = 6.60, P < 0.05): subjects were faster in 600 ms cued location than other locations (cue location: 278 ms, SD compared with 40 ms SOA blocks. This reflects the fact that 104, other locations: 300 ms, SD 106, Fig. 2A), again resulting in subjects have more time to prepare their response in long SOA a significant cueing effect due to involuntary attention (–22 ms, trials. In addition, there was a significant interaction of target within-subject 2-tailed t-test: t18 = 2.92, P < 0.01). There was no location and SOA (F1,15 = 14.37, P < 0.01), indicating that, as significant difference between the cueing effect observed in predicted, the cue had opposite effects in the 2 SOA the placebo sessions and the cueing effect in the bromocrip- conditions. Specifically, RTs were faster for trials in which the tine sessions (within-subject 2-tailed t-test: t18 = 0.88, P = 0.39).
cue and target location were the same for the short SOA Additionally, involuntary attention cueing effects were not condition (involuntary attention), but they were slower for significantly different for 9R and 10R subjects in either placebo these trials in the long SOA condition (IOR). Therefore, we will (9R: –17 ms, 10R: –13 ms, t17 = 0.3, P = 0.76) or bromocriptine separately examine the effects observed in each SOA condition.
(9R: –24 ms, 10R: –20 ms, t17 = 0.57, P = 0.58, Fig. 2B) sessions. Weconclude that differences in DA transmission in the striatum, Short SOA: Involuntary Attention Is Unaffected by Striatal resulting either from individual genetic differences or from bromocriptine administration, do not affect involuntary attention.
In 40 ms SOA trials, capture of involuntary attention occurredat the cue location, and RTs (placebo sessions, combining bothgenotype groups) were faster when the target appeared in this Long SOA: IOR Depends on Bromocriptine Administration cued location versus other locations (cue: 282 ms, SD 103; and Baseline Levels of Striatal DA other: 297 ms SD 99, Fig. 2A). As there is substantial between- In 600 ms SOA blocks (placebo sessions, combining both subject variance in mean RT in these measurements, we genotype groups), RTs were slower when the target appeared Cerebral Cortex May 2012, V 22 N 5 1135

(placebo: 21 ms, bromocriptine: –15 ms, within-subject 2-tailedt-test: t8 = 2.88, P < 0.05, Fig. 3B).
To summarize the results, although an involuntary attention cueing effect was observed with a short SOA, we did not findany effects of either bromocriptine administration or DAT1genotype on involuntary attention. In addition, we replicatedprevious results (Colzato et al. 2010) showing that for an SOAof 600 ms, IOR is larger for 9R (higher striatal DA) subjects thanfor 10R (lower striatal DA) subjects. Moreover, bromocriptineadministration had differential effects on IOR, depending onDAT1 genotype: bromocriptine increased IOR in 10R subjectsand abolished it in 9R subjects.
The neurotransmitter DA is involved in a variety of cognitivefunctions through its activity in multiple brain areas, includingthe prefrontal cortex (PFC) and striatum (Cools and Robbins2004; Cools and D'Esposito 2009). In this study, we focused onthe role of DA transmission in the striatum in modulating visual discrimination performance following a nonpredictive cue.
This type of cue leads to capture of involuntary attention for Figure 3. Long SOA blocks. (A) Average RTs for 600 ms SOA blocks. RTs are shown short cue-to-target SOAs and causes IOR for longer SOAs for the cue location (left) and other locations (right) for sessions in which placebo (Posner and Cohen 1984).
(white) or bromocriptine (gray) was administered. (B) Cueing effects. Data are plottedseparately for 10R (left) and 9R subjects (right) for sessions in which placebo (white) We manipulated striatal DA transmission by administering or bromocriptine (gray) was administered. Positive values indicate IOR. In placebo the DRD2 receptor--specific agonist bromocriptine to healthy sessions, 9R subjects had greater IOR than 10R subjects. Bromocriptine increased participants. DRD2 levels are much higher in striatum than in IOR in 10R participants and abolished IOR in 9R participants. Error bars are standard other parts of the human brain, including PFC, where DRD1 is error of the mean within group/condition.
more abundant (Camps et al. 1989; Meador-Woodruff et al.
in the cue location compared with one of the other locations 1996). A non-monotonic effect of DA transmission levels on (cue: 267 ms, SD 101; other: 257 ms, SD 89, Fig. 3A). This cognitive functions has been identified in many different resulted in a significant mean positive cueing effect of 13 ms contexts (Cools and Robbins 2004; Seamans and Yang 2004), (within-subject 2-tailed t-test: t18 = 2.76, P < 0.05), indicating IOR and the effects of bromocriptine on a variety of measures can (Posner and Cohen 1984). This positive cueing effect was found be described by an inverted U-shaped function of DA levels in 13 of 19 subjects in the placebo sessions. Differences in striatal (Cools and D'Esposito 2011). Thus, bromocriptine benefits DA transmission, as indicated by subjects' DAT1 genotype, have performance on cognitive tasks in subjects with low memory previously been found to predict differences in IOR for SOAs less spans (who have lower baseline striatal DA; Cools et al. (2008)), than 750 ms (Colzato et al. 2010). We also found a significant while subjects with high memory spans are impaired on these difference of DAT1 genotype on the magnitude of the IOR in the tasks following bromocriptine administration (Kimberg et al.
placebo sessions, with 9R participants (higher striatal DA) having 1997). Similarly, bromocriptine reduces the behavioral costs of a greater IOR (9R: 21 ms, 10R: 5 ms, between-subject one-tailed task switching and their neural correlates in the striatum in t-test: t17 = 2.02, P < 0.05).
high-impulsive but not in low-impulsive subjects (Cools et al.
In the bromocriptine session, the RT in 600 ms SOA blocks 2007), and impulsivity is a personality trait that is linked to low- for all subjects was not significantly different for cue versus binding availability of striatal DA D2/D3 receptors (Dalley et al.
other target locations (cue: 266 ms, SD 84; other: 267 ms, SD 2007). In addition, an inverted U-shaped curve accounts for the 98; cueing effect: 1 ms, within-subject 2-tailed t-test: t18 = 0.1, differential effects of bromocriptine on reversal learning as P = 0.93, Fig. 3A). However, when the cueing effects were a function of baseline striatal DA synthesis capacity, as separately analyzed for the 2 DAT1 genotypes, significant measured using positron emission tomography (Cools et al.
differences were found, indicating that bromocriptine had 2009). These findings suggest that cognitive functions are most different effects on IOR, depending on DAT1 genotype (drug efficiently performed at intermediate levels of striatal DA by target location by DAT1 interaction: F1,15 = 4.85, P < 0.05; activation and that higher or lower levels of DA transmission at drug by target location by SOA by DAT1 interaction: F1,15 = striatal synapses may lead to suboptimal performance.
4.85, P < 0.05). Specifically, the 10R subjects (lower striatal In order to examine individual differences in drug effects as DA) showed a numerically higher IOR in bromocriptine a function of baseline striatal DA levels, we determined the compared with placebo sessions, although this was not genotype of DAT1, a DA transporter that is enriched in the statistically significant (placebo: 5 ms, bromocriptine: 12 ms, striatum (Sesack et al. 1998), in every subject. Replicating within-subject 2-tailed t-test: t9 = 1.25, P = 0.24, Fig. 3B). On the previous results (Colzato et al. 2010), we found that carriers of other hand, participants with the 9R allele of DAT1 (higher the 9R allele (higher striatal DA) have a larger IOR in 600 ms striatal DA) exhibited larger IOR than 10R subjects under SOA blocks. In addition, we found a differential effect of placebo (see above) as well as a significant decrease in the bromocriptine, resulting in reduced IOR in 9R subjects and magnitude of IOR following bromocriptine administration increased IOR in 10R subjects. These results are consistent Rokem et al.
with an inverted U-shaped function of the effects of striatal DA involuntary attention and the IOR rely on different neural transmission on IOR magnitude.
Brain imaging studies suggest that IOR involves regions of the frontal and posterior parietal cerebral cortex (Lepsien andPollmann 2002; Mayer et al. 2004), but the pattern of deficits in a human patient with a focal midbrain lesion (Sapir et al. 1999), as National Institutes of Health (R01-DA20600 to M.D. and NEI well as electrophysiological evidence from non-human primates CORE grant EY003176).
(Dorris et al. 2002; Fecteau and Munoz 2005), suggest that theIOR is also mediated by the superior colliculus (SC), a brainstem structure involved in oculomotor control and in allocation of Jon Kelvey and Alexandra Carstensen helped collect the data. Conflict visual spatial attention (Cavanaugh and Wurtz 2004). Furthermore, of Interest: None declared.
functional imaging studies have shown that bromocriptinemodulates striatal and prefrontal cortical activity (Cools et al.
2007) as well as the functional connectivity between these Camps M, Corte´s R, Gueye B, Probst A, Palacios JM. 1989. Dopamine regions (Wallace et al. 2011). Therefore, despite the systemic receptors in human brain: autoradiographic distribution of D2 sites.
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