Ctn.uoregon.edu

5990 • The Journal of Neuroscience, April 15, 2015 • 35(15):5990 –5997
Striatal D1- and D2-type Dopamine Receptors Are Linked to
Motor Response Inhibition in Human Subjects
Chelsea L. Robertson,1,5 Kenji Ishibashi,3,4 Mark A. Mandelkern,5,6 Amira K. Brown,3 Dara G. Ghahremani,3 Fred Sabb,3
Robert Bilder,3 Tyrone Cannon,2 Jacqueline Borg,2 and Edythe D. London1,3,4,5
Departments of 1Molecular and Medical Pharmacology, and 2Psychology, 3Department of Psychiatry and Biobehavioral Sciences, The Semel Institute for
Neuroscience and Human Behavior at UCLA, and 4Brain Research Institute, University of California, Los Angeles, Los Angeles, California 90024, 5Veterans
Administration Greater Los Angeles Healthcare System, Los Angeles, California 90073, and 6Department of Physics, University of California, Irvine, Irvine,
California 92697
Motor response inhibition is mediated by neural circuits involving dopaminergic transmission; however, the relative contributions of
dopaminergic signaling via D1- and D2-type receptors are unclear. Although evidence supports dissociable contributions of D1- and

D2-type receptors to response inhibition in rats and associations of D2-type receptors to response inhibition in humans, the relationship
between D1-type receptors and response inhibition has not been evaluated in humans. Here, we tested whether individual differences in
striatal D1- and D2-type receptors are related to response inhibition in human subjects, possibly in opposing ways. Thirty-one volunteers
participated. Response inhibition was indexed by stop-signal reaction time on the stop-signal task and commission errors on the
continuous performance task, and tested for association with striatal D1- and D2-type receptor availability [binding potential referred to

nondisplaceable uptake (BPND)], measured using positron emission tomography with [11C]NNC-112 and [18F]fallypride, respectively.
Stop-signal reaction time was negatively correlated with D1- and D2-type BPND in whole striatum, with significant relationships involving
the dorsal striatum, but not the ventral striatum, and no significant correlations involving the continuous performance task. The results
indicate that dopamine D1- and D2-type receptors are associated with response inhibition, and identify the dorsal striatum as an impor-

tant locus of dopaminergic control in stopping. Moreover, the similar contribution of both receptor subtypes suggests the importance of
a relative balance between phasic and tonic dopaminergic activity subserved by D1- and D2-type receptors, respectively, in support of

response inhibition. The results also suggest that the stop-signal task and the continuous performance task use different neurochemical
mechanisms subserving motor response inhibition.

Key words: dopamine; impulsivity; PET imaging
2013). Impaired inhibitory control can disrupt goal-directed be- Impulsive actions are premature, poorly conceived, or difficult to with negative consequences that contribute to psycholog- suppress (Dalley et al., 2008), and lack of inhibitory control over ical distress associated with these disorders. Clarifying the of attention deficit hyperactivity dis- mechanisms that mediate inhibitory control, therefore, ulti- order (ADHD) and substance use disorders (Bari and Robbins, mately may help to guide treatment for disorders characterizedby an impulsive phenotype.
Research findings have indicated a role for dopamine in im- Received Nov. 24, 2014; revised Feb. 10, 2015; accepted Feb. 24, 2015.
pulsive behavior. Syndromes such as ADHD (Vaidya et al., 1998; Author contributions: F.S., R.B., T.C., J.B., and E.D.L. designed research; C.L.R., K.I., and A.K.B. performed re- search; C.L.R., K.I., M.A.M., and D.G.G. analyzed data; C.L.R., M.A.M., and E.D.L. wrote the paper.
Bedard et al., 2003; Senderecka et al., 2012 This work was supported by the Consortium for Neuropsychiatric Phenomics (National Institutes of Health Road- map for Medical Research Grants UL1-DE019580, RL1MH083269, RL1DA024853, and PL1MH083271), The UCLA Training Program in Translational Neuroscience of Drug Abuse (Grant T32DA024635), and Endowments from the dysfunction. In addition, studies of genetic poly- Thomas P. and Katherine P. Pike Chair in Addiction Studies and the Marjorie Greene Trust.
The authors declare no competing financial interests.
morphisms (Colzato et al., 2010, 2013) and pharmacological manip- Correspondence should be addressed to Edythe D. London, Semel Institute, University of California, Los Angeles, ulations (; Eagle and Baunez, 2010) have 760 Westwood Plaza, C8-831, Los Angeles, CA 90024. E-mail: [email protected]
K. Ishibashi's present address: Tokyo Metropolitan 173-0022, Japan.
bition, an index of inhibitory control (Chamberlain et al., 2006; A.K. Brown's present address: Life Sciences Institute, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059.
Eagle and Baunez, 2010). For or F. Sabb's present address: Research Team for Neuroimaging, Lewis Center for Neuroimaging, University of Ore- improves response inhibition in gon, Eugene, OR 97403.
ADHD patients and healthy subjects, respectively (Tannock et al., R. Borg's present address: Department of Clinical Neuroscience, Karolinska Institute, 171 77 Stockholm, Sweden.
1989; de Wit et al., 2000; Aron et al., 2003), of T. Cannon's present address: Departments of Psychology and Psychiatry, Yale University, New Haven, CT 06520.
response inhibition Copyright 2015 the authors 0270-6474/15/355990-08$15.00/0 (Colzato et al., 2014; Ramdani et al., 2014).
Robertson et al. • Dopamine Receptors and Motor Response Inhibition J. Neurosci., April 15, 2015 • 35(15):5990 –5997 • 5991
Despite an evident role for dopamine, the relative contribu- They were instructed to respond quickly and accurately, and that stop- tions of dopamine signaling via dopamine D ping and going were equally important. The SSD was adjusted on a 1- and D2-like recep- tor subtypes are unclear. In rats, systemic administration of trial-by-trial basis according to performance; values were drawn from dopaminergic antagonists does not affect response inhibition two interleaved ladders to ensure equal performance levels across partic- (Eagle et al., 2007, 2008; Bari and Robbins, 2013). However, di- ipants, producing successful inhibition on !50% of stop trials. Partici- pants received task training before task initiation, consisting of eight trials (three of which were stop trials).
dorsal-medial striatum improves response inhibition, whereas During the CPT, participants viewed a series of go stimuli (alphabet infusion of the D2 receptor antagonist sulpiride has the opposite letters, go trials) and were instructed to respond with a key press. On effect. Similar infusions into the ventral striatum have no effect some trials (no-go trials, 10%), a no-go stimulus was presented (the letter (Eagle et al., 2011). Thus, the effects of dopamine receptor sub- "X") in lieu of the go stimulus, and participants were instructed to with- response inhibition appear to be regionally spe- hold responding. The task comprised 18 blocks presented at random, cific and possibly opposing. In addition, the administration of the each containing 20 trials at a fixed intertrial interval (ITI): 1000, 2000, or 4000 ms. Participants received task training before initiation, consisting 2-specific agonist cabergoline improves response inhibition (Nandam et al., 2013), and striatal D of 10 trials from the 2000 ms ITI type.
2-type receptor availability is capacity for response inhibition and corre- Analysis of neurobehavioral data. SST data were analyzed using the sponding neural activation during inhibition in humans (Ghah- same methods as in a prior study of a separate sample (Ghahremani et al.,2012). The median and SD of reaction time on go remani et al., 2012). Nonetheless, human all-correct go trials [go trial reaction times (GoRTs)]. The average in response inhibition and direct com- SSD was calculated using all-successful stop trials. The stop-signal reac- parisons of D1- vs D2-type receptor contributions to motor re- tion time (SSRT) was estimated by subtracting each participant's average sponse inhibition have not been performed.
SSD from his/her median GoRT (Band et al., 2003). The percentage of We used positron emission tomography (PET) with inhibition on stop trials was of successful stop trials [11C]NNC-112 and [18F]fallypride as radioligands for dopamine to all stop trials presented. As recommended (Congdon et al., 2012), participant data meeting the following 1- and D2-type receptors, respectively (Mukherjee et al., 1995; Ekelund et al., 2007), to examine the ysis: (1) "25% or #75% inhibition on stop trials (n $ 3); (2) "60% receptor availability [binding potential re- correct responding on go trials (n $ 0); (3) #10% direction errors on go ferred to nondisplaceable uptake (BP trials (n $ 0); and (4) SSRT estimate that was negative or "50 ms (n $ 1, ND)] with measures from computer failure). SST data from 27 participants were subject to analysis, prototypical assessments of motor response inhibition—the as follows: 22 participants with D stop-signal task (SST) and continuous performance task (CPT) 1-type dopamine receptor availability (Logan et al., 1984; Tannock et al., 1989; Aron et al., 2014). We 1-type BPND); 24 participants with D2-type BPND; and 19 participants with both. Performance data from the CPT were used to calculate the mean and SD of the GoRT on all go trials. The commission error (CE) was calcu- not the ventral striatum, would be linked to response inhibition lated as the number of failed no-go trials (response to a no-go stimulus).
task performance, and that D1- and D2-type receptor contribu- PET scanning. D1-type BPND was assayed using [11C]NNC-112, a tions would be dissociable in this region, reflecting opposing high-affinity ligand for D1-type receptors (Andersen et al., 1992; Ekelund et al., 2007) in 26 subjects (14 a different day using [ 18F]fallypride, a high-affinity radioli-gand for D Materials and Methods
2-type receptors (Mukherjee et al., 1995) in 27 subjects (14 females). PET scanning Gemini Tru Flight Research participants. All study procedures were approved by the Univer- PET/CT scanner in 3D mode (FWHM $ 5.0 mm % 4.8 mm; 90 slices; sity of California, Los Angeles (UCLA) Institutional Review Board.
voxel size, 2 mm 3). A CT transmission scan was performed to obtain data Thirty-one healthy volunteers (16 females; mean age, 30.68 years; SD, 8.3 for measured attenuation correction. After a bolus injection of years), who were participating in the UCLA Consortium for Neuropsy- [ 11C]NNC-112 (!15 mCi &5%; specific activity, !1 Ci/"mol), dy- chiatric Phenomics (CNP; www.phenomics.ucla.edu), completed exten- namic emission data were acquired for 90 min. For [18F]fallypride (!5 sive response inhibition mCi &5%, specific activity ! 1 Ci/"mol), data were acquired in two and MRI scanning (Bilder et al., 2009). CNP participants who expressed scanning blocks of 80 min each, with a short break between blocks. Data interest in being studies were offered flyers or were reconstructed using the 3D row action maximum likelihood algo- were called via telephone, and were invited to participate in this study rithm. Scatter and random corrections were applied.
involving PET scanning. On average, PET scanning occurred !17 PET image processing. Reconstructed [ 11C]NNC-112 PET data (1 months after participation in the CNP study. Participants received a min % 90 frames) were averaged into 23 frames, consisting of 4 1 min complete description of this study and provided written informed con- frames, 3 2 min frames, and 16 5 min frames. Reconstructed [ 18F]fally- sent. Health screening was performed using the Structured Clinical In- pride PET data (2 blocks; 1 min % 80 frames) were combined into 16 terview for the Diagnostic and Statistical Manual of Mental Disorders, 4th frames, each consisting of an average of 10 min. PET images were motion edition, and a physical examination. Participants were excluded if they corrected (Jenkinson et al., 2002) then coregistered to the corresponding met the following criteria: current axis I psychiatric diagnoses other than MRI (). Volume of interest (VOI)-based time nicotine dependence; use of psychotropic medications or substances, kinetic modeling using PMOD version except marijuana or alcohol; CNS, cardiovascular, or systematic disease; 3.1. Time–activity curves were fit using the simplified reference tissue or HIV-seropositive status, hepatic disease, or pregnancy. On all test model (SRTM; Lammertsma and Hume, 1996). The cerebellum was se- days, negative urine samples for recent drug use and pregnancy (women) lected as the ; Abi-Dargham et al., 2000; were required.
Ishibashi et al., 2013). A Neurobehavioral tasks. The SST (Logan et al., 1984) and CPT (Tannock the reference region tissue), estimated from high- et al., 1989) were administered activity regions (caudate and putamen), was computed. Time–activity Software Tools). During the SST, participants viewed a series of curves were then refit using SRTM2 (Wu and Carson, 2002), applying the go stimuli (left/right arrows) and were instructed to respond with corre- computed k2' values to all VOIs. subtracting 1.0 sponding left or right key presses, respectively (go trials). On some trials from the product of R1 (ratio of radiotracer delivery in the target region (stop trials, 25%), an audible tone (stop-signal) was presented after a tissue relative to that of the reference region tissue) and k2'/k2a.
short delay [stop-signal delay (SSD)] following the go stimulus. Partici- MRI scanning and volumes of interest. MRI scanning was performed on pants were instructed to withhold their responses upon hearing the tone.
a Siemens Trio scanner (MPRAGE: repetition time, 1.9 s; echo time, 2.26 5992 • J. Neurosci., April 15, 2015 • 35(15):5990 –5997
Robertson et al. • Dopamine Receptors and Motor Response Inhibition ms; voxel size, 1 mm 3; 176 slices), and processed using the FMRIB Soft- Table 1. Performance variables for the stop-signal task and the continuous
ware Library (FSL; http://www.fmrib.ox.ac.uk/fsl/index.html; Oxford Selected VOIs included the whole striatum and functional striatal sub- divisions: limbic striatum, associative striatum, and sensory–motor stria- Stop-signal task (n $ 27) tum. A VOI for the whole striatum was created by combining anatomically defined VOIs for the caudate, putamen, and nucleus ac- cumbens using the FSL software package (Patenaude et al., 2011). Func- tional subdivisions of the striatum () and the Correct go responding (%) midbrain region (Zald et al., 2010) previously.
Inhibition on stop-trials (%) The manually in standard space and trans- Continuous performance task (n $ 31) formed to each subject's MRI.
Data analysis and statistical analysis. Striatal VOIs were selected a pri- ori on the basis of evidence that dopaminergic transmission in these regions is important for inhibitory control (Lee et al., 2009; Buckholtz et Commission errors al., 2010; Ghahremani et al., 2012). subdivisions were tested post hoc if a sig- Table 2. D
nificant relationship was found using the whole-striatum VOI. Relation- 1-type and D2-type BPND in the striatum and within-region correlations
Region of interest ND, SST, and CPT were conducted analyzed using SPSS version 22 (IBM Corp.). Analyses reported here were conducted using measurements from bilateral VOIs. These correlations were nearly iden- tical to those examined using measurements from left and right VOIs Associative striatum separately. Exploratory investigations of D1- and D2-type BPND with SST Sensory motor striatum and CPT performance included a voxelwise analysis of correlations be- Data are reported as the mean (SD).
tween cortical BPND and SSRT, GoRT, or CE, and VOI-based analysis *p $ 0.028: n $ 26, 14 females; n $ 27, 14 females; n $ 22, 12 females.
using measurements of midbrain BPND.
Relationships of regional D1-type and D2-type BPND. Within-region correlations of D1- and D2-type BPND were performed for all striatal samples (Boehler et al., 2010; Ghahremani et al., 2012). On the VOIs by Pearson correlation analysis. Of the 31 participants included inthe study, 22 (12 female) underwent PET scans for the determination of 13 CEs (of 36 no-go trials). Mean GoRT values were similar to 1- and D2-type BPND, and their data were used for this analysis.
Dopamine receptor BP those reported previously (Steele et al., 2013).
ND, and performance on the SST and CPT. Rela- tionships of striatal BPND with SSRT were tested using partial correlation analysis controlling for age and sex. Similar analyses were performed Dopamine receptor BPND
Overall, BPND values for both receptor subtypes were higher in The Hotelling–Williams test (Van Sickle, 2003) was used to test for the dorsal than in ventral regions of the striatum. D1- and D2-type equality of the correlations dorsal striatum BPND versus SSRT and ventral striatum BP ND values were approximately equal in the associative and sen- ND. For this test, BPND values of the sory motor striatum, while D associative and sensory motor regions were combined to create a BP 2-type BPND was higher in the sen- sory motor than the associative striatum (Table 2; see Fig. 4).
value for the dorsal striatum, and compared with the BPND value of the ventral striatum.
D1-type receptor BPND and D2-type BPno To examine the contributions of both receptor subtypes (BP correlation in the associative or limbic striatal subdivisions, but SSRT, a stepwise regression analysis was used. To determine the effect of were significantly positively correlated in the sensory motor stria- tum (r $ 0.469, p $ 0.028).
2-type BPND to a model with D1-type BPND, the variables en- tered into the first step of the regression were age, sex, and D1-type BPND; D2-type BPND was included in the second step. Next, the reverse relation- Dopamine receptor BPND and response inhibition on the SST
ship was tested to determine the effect of adding D1-type BPND to a SSRT was negatively correlated with D1-type BPND in the whole model using D2-type BPND, with D1-type BPND included in the second striatum, controlling for the effects of age and sex (r $ (0.624, step instead.
p $ 0.003; (Figs. 1, 3; Table 3). Post hoc evaluations of data from The relationships of receptor BPND with CEs, the outcome variable striatum revealed significant rela- reflecting response inhibition in the CPT, and GoRTs were assessed usingpartial correlation analysis, controlling for sex and age.
tionships in the dorsal regions (associative striatum: r $ (0.548, To estimate effects of time lapse between neuroimaging and neurobe- p $ 0.012; sensory motor striatum: r $ (0.527, p $ 0.017), but havioral procedures (average elapsed time, 17 months), the stability of not in the ventral region (limbic striatum: r $ (0.342, p $ neurobehavioral task performance over time was evaluated. For this 0.139). A difference in correlations between SSRT and D1-type analysis, a subset of participants (n $ 10) was invited to return for retest- BPND in the dorsal versus ventral region of striatum was detected ing of SST and CPT performance after an average elapsed time of 40 using the Hotelling–Williams test at a trend level (p $ 0.083). To months. Reliability assessments were assessed using the intraclass corre- determine the specificity of the association to the stopping pro- lation coefficient (ICC).
cess, correlations between GoRT and D1-type BPND were exam- 1-type BPND in the whole striatum showed a trend toward a negative correlation with GoRT (r $ (0.425, p $ 0.062). We therefore conducted a post hoc analysis of the functional sub- On the stop-signal task, participants performed at a level of 99% divisions and found that the correlation involving D1-type correct on go trials and inhibited their responses on approxi- BPND in the ventral striatum reached a trend level ( p $ 0.082), mately half of the stop trials [mean (SD), 52% (0.056)], indicat- but the Hotelling–Williams test indicated no difference in ing that the adaptive staircase procedure for equating stop-trial dorsal versus ventral correlations.
performance across participants was successful (Table 1). SSRT SSRT was negatively correlated with D2-type BPND in the values were similar to those observed in prior separate whole striatum, controlling for the effects of age and sex (r $





Robertson et al. • Dopamine Receptors and Motor Response Inhibition J. Neurosci., April 15, 2015 • 35(15):5990 –5997 • 5993
striatum. Table insert displays partial correlation coefficients, p values, and R 2 values for therelationship between whole striatum and associative striatum D1-type BPND and SSRT, control- ling for age and sex.
Figure 3. A, B, Voxelwise effect size maps depicting the partial correlation coefficient (r)
between individual SSRT and D1-type (A) and D2-type (B) receptor BPND in the striatum, con-
trolling for the effects of age and sex.
Figure 4. Scatter plot depicting the relationship between D2-type BPND and D1-type
BPND in the whole striatum; z-scores of BPND were used for presentation purposes. Table striatum. Table insert displays partial correlation coefficients, p values, and R 2 values for the insert displays correlation coefficients, p values, and R 2 values for the correlations in the relationship between whole striatum and associative striatum D2-type BPND and SSRT, control- whole and associative striatum.
ling for age and sex.
associative striatum was present at trend level when controlling (0.478, p $ 0.021; Figs. 2, 3; Table 3). Post hoc tests involving for D2-type BPND (r $ (0.473, p $ 0.064). SSRT was negatively functional showed significant nega- correlated with D2-type BPND in associative striatum when con- tive correlations in the associative striatum (r $ (0.544, p $ trolling for D1-type BPND (r $ (0.599, p $ 0.014).
0.007) and sensory motor striatum (r $ (0.419, p $ 0.046), but To examine the effect of both receptor BPND measures on not in the limbic striatum (r $ (0.308, p $ 0.153; Table 3). The SSRT, a stepwise regression was used to determine the effect of Hotelling–Williams test of equality of that adding additional BPND measures to a model of SST performance the relationships of SSRT and D2-type BPND in the dorsal versus using only one BPND measure. A model using age, sex and D1- ventral regions of striatum differed significantly from one an- type BPND to predict SST performance was improved by adding other (p $ 0.039), suggesting that the correlation of D2-type D2-type BPND to the model (D1: F(3,18) $ 2.937, p $ 0.067; D1 BPND with SSRT was specific to the dorsal striatum.
) D2: F(4,18) $ 3.776, p $ 0.028). In the reverse analysis, adding Since BPND for each receptor subtype in the dorsal striatum D1-type BPND to a model of SST performance using D2-type was negatively correlated with SSRT, we tested the correlations BPND also improved the model (D2: F(3,18) $ 2.176, p $ 0.133; D1 between BPND for each receptor subtype and SSRT, controlling ) D2: F(4,18) $ 3.776, p $ 0.028). The model including both for the effects of age, sex, and BPND for the other receptor sub- receptors showed the effects of both D1- and D2-type BPND (D1: type. A negative correlation of SSRT with D1-type BPND in the t $ (2.506, p $ 0.025; D2: t $ (2.082, p $ 0.056).
5994 • J. Neurosci., April 15, 2015 • 35(15):5990 –5997
Robertson et al. • Dopamine Receptors and Motor Response Inhibition Table 3. Relationships of dopamine receptor binding potential (BPND) and stop-
receptors are activated at high dopamine concentrations during signal task performance variables
phasic increases in extracellular dopamine (Dreyer et al., 2010).
D1- and D2-type receptor signaling can as shown by the observation that coadministration of D Region of interest type dopamine receptor agonists, at doses that are behaviorally inactive when administered alone, increases locomotor behavior in rats (Vermeulen et al., 1994). Such an interaction between Associative striatum pathways may govern the perfor- Sensory motor striatum mance on the SST.
The results obtained here align with a model of striatal motor control of response inhibition in which D1- and D2-type recep- tors support competing processes via the modulation of stria- tonigral and striatopallidal pathways (Logan et al., 1984; Mink, Associative striatum 1996; Frank, 2005; Frank et al., Sensory motor striatum facilitate the "go" process Partial correlation coefficients for the relationships between dopamine receptor availability (BP 2-expressing striatopallidal neurons facilitate the "stop" ND ) and stop-signal task performance variables, controlling for the effects of sex and age. Significant relationships are highlighted in process (Alexander and Crutcher, 1990; Surmeier et al., 2007; ND and SSRT is consistent with this Dopamine receptor BP
model and corroborates findings from other human studies ND and response inhibition assessed by
showing that the administration of the D2-type receptor agonist, Tests of the correlations between dopamine receptor subtype cabergoline, enhances stopping ability (Nandam et al., 2013), and findings from neuroimaging results ND and CE or GoRT on the CPT showed no statistically signif- icant relationships. Furthermore, CE was not correlated with re- BPND is correlated with SSRT and inhibition-related striatal neu- sponse inhibition capacity (SSRT) on the SST. Although GoRT ral activity (Ghahremani et al., 2012).
on the SST and GoRT on the CPT showed a significant associa- contributions of D1- tion (r $ 0.419, p $ 0.024), GoRT on the CPT did not show any and D2-mediated dopamine signaling to cognitive function and significant relationship with either D behavior. For example, individual differences in the ability to 1- or D2-type BPND in any region tested.
learn from positive and negative feedback are related to D1- and 1- nor D2-type BPND in the cortex showed a signif- 2-type BPND values, respectively (Cox et al., 2015). A theory of icant correlation with SSRT, GoRT, or CE in a voxelwise analysis, prefrontal dopamine function between D1- using a liberal threshold (p " 0.05, uncorrected). Analysis of D 2-type receptor-mediated signaling in modulating fronto- striatal function (Durstewitz and Seamans, 2008). Moreover, a 2-type BPND in the midbrain showed no significant correla- tions with SSRT, GoRT, or CE.
new model of posit thatD1 receptor activation prepares a set of possible responses, then Repeated measures of neurobehaviorial task performance
D2 receptor activation functions in selecting the final response Task performance variables showed a high degree of test–retest (Keeler et al., 2014). The present findings are consistent with such reliability over an average elapsed time of 40 months. The average suggesting that there is cooperative sig- percentage change in CE and SSRT was small (8% and 7%, re- naling between D1- and D2-type receptor-mediated pathways spectively), and intraclass correlations were moderately high (CE: during stopping.
ICC $ 0.913, p $ 0.001, n $ 10; SSRT: ICC $ 0.738, p $ 0.029, The effect of D2-type BPND on SSRT appears to be specific to n $ 10). Adding the time interval between neuroimaging and stopping a motor response, as indicated by the lack of correlation neurocognitive tests as a covariate in statistical analyses did not with GoRT. In contrast, the relationship between D1-type BPND change the results.
and SSRT may reflect a general motor effect. This view is sup-ported by the trend-level correlation found with GoRT on the SST, and by literature showing consistently that the activation This study extends evidence for a contribution of striatal dopa- of D1 receptors enhances motor activity (Kreitzer and Berke, minergic function to motor response inhibition in humans 2011). D1-type BPND, however, was not T (Ghahremani et al., 2012; Bari and Robbins, 2013; Nandam et al., The anatomical specificity of the correlations between SSRT receptors in the dorsal striatum. D1 and D2 receptors and BPND corroborate findings from rodent studies (Eagle and are localized to striatonigral and striatopallidal neurons, respec- Robbins, 2003a; Eagle et al., 2011). These studies tively, with minimal colocalization (Hersch et al., 1995). Dopa- dorsal striatum, but not the mine regulates striatal activation 1 receptor ventral striatum, is necessary for SST performance. Specifically, activation, which enhances the function of striatonigral neurons, neither excitotoxic lesions nor direct antagonist infusions into and via D2-receptor activation, which suppresses the function of the nucleus accumbens affected SST performance in rats (Eagle striatopallidal neurons (Creese et al., 1983; Surmeier et al., 2007; and Robbins, 2003a,b; Eagle et al., 2011). Moreover, this performance was also ob- activation of either subtype de- served in humans in whom D2-type BPND and fMRI activation pends on the intrasynaptic dopamine concentration and the during stopping was found in dorsal striatum, but not in ventral respective affinities of the receptors for the neurotransmitter. D2- striatum (Ghahremani et al., 2012). Last, although D2-type BPND type receptors, which have higher affinity than D1-type receptors in the with self-reports of impul- for dopamine, mediate tonic dopaminergic signaling. D1-type sivity and novelty seeking (Zald et al., 2008; Buckholtz et al., Robertson et al. • Dopamine Receptors and Motor Response Inhibition J. Neurosci., April 15, 2015 • 35(15):5990 –5997 • 5995
2010), there were no significant relationships between behavioral in D1- and D2-type BPND with aging, a decrease of only !8% with measures and D2-type BPND in the midbrain. This every decade of life. In addition, the test–retest reliability of the difference between findings may reflect differences between what SST and CPT performance variables is well established, showing is measured by self-reports of impulsivity compared with neuro- high reliability over several weeks (Soreni et al., 2009; Weafer et cognitive tasks (Reynolds et al., 2006, 2008; Fields et al., 2009).
al., 2013; but also see Wo¨ ciated with dopamine receptor availability suggests that the tasks average elapsed time of 40 months between assessments. Adding tap into different neurochemical mechanisms subserving motor the time interval between neuroimaging and neurocognitive tests response inhibition. Whereas the SST measures the ability to as a covariate in statistical analyses did not change the results, cancel a motor response that has been initiated, the CPT mea- suggesting that the time-related influences on the relationships sures action restraint (i.e., not going). Brain-imaging studies have between dopamine receptor BPND and task performance re- shown that these tasks engage overlapping, but distinct, neural ported here are likely to be minimal.
circuits (Rubia et al., 2001; Zheng et al., 2008; Swick et al., 2011,; In summary, we present direct evidence for associations of striatal D1- and D2-type receptor availability with capacity for they would be governed by the same neu- response inhibition on the SST in humans. These relationships rotransmitter systems and would show comparable relationships were specific to the dorsal striatum, identifying this region as an with neurochemical markers (Jentsch et al., 2014). Our findings, important locus for differential dopaminergic control of motor however, support a stopping response inhibition. The results support the notion that the bal- (SST) and not going (CPT) as separate constructs (Robinson et ance between D1- and D2-type receptor-mediated signaling is al., 2009; Swick et al., 2011) that are subserved important for motor response inhibition. The findings represent et al., 2008; Robinson et al., 2009).
an important advance as the understanding of dopaminergic sig- naling in the human brain has implications for the development process (SSRT) is likely influenced by dopaminergic signaling, of specific agents, possibly D1 targeted, to treat patients with neu- the ability to withhold a response (CPT) is not (Eagle and Baunez, ropsychiatric disorders that are characterized by an impulsive 2010). Different cognitive requirements, phenotype, such as observed in ADHD and addictive disorders.
or working memory, may influence overall task perfor-mance and links to dopamine markers. Such differences may also explain the lack of correlation between scores on the CPT and Abi-Dargham A, Martinez D, Mawlawi O, Simpson N, Hwang DR, Slifstein M, Anjilvel S, Pidcock J, Guo NN, Lombardo I, Mann JJ, Van Heertum R, SST in both rodents and human subjects (Broos et al., 2012).
Foged C, Halldin C, Laruelle M (2000) Measurement of striatal and ex- Finally, while dopamine receptors were trastriatal dopamine D1 receptor binding potential with [11C]NNC 112 study, contributions of other neurotransmitter systems cannot be in humans: validation and reproducibility. J Cereb Blood Flow Metab overlooked, as there is substantial evidence for a role of norad- 20:225–243. CrossRef Medline renergic and other transmitter systems in the striatal control of Alexander Functional architecture of basal ganglia response inhibition (Zheng et al., 1999; Eagle et al., 2011; Bari and circuits: neural substrates of parallel processing. Trends Neurosci 13:266 –271. CrossRef Medline Robbins, 2013).
FC, Hohlweg R, Hansen LB, Guddal E, Braestrup C, has limitations. Among them are its correlative Nielsen EB (1992) NNC-112, NNC-687 and NNC-756, new selective design, which cannot inform on causal relationships between and highly potent dopamine D1 receptor antagonists. Eur J Pharmacol dopamine receptor subtype signaling and motor response inhi- 219:45–52. CrossRef Medline bition, and the relatively small sample size. Another is the imper- Aron AR, BJ, Robbins TW (2003) Methylphenidate fect selectivity of the radioligands used. [11C]NNC-112 has an improves response inhibition in adults with attention-deficit/hyperactiv- !10-fold higher in vivo affinity for D ity disorder. Biol Psychiatry 54:1465–1468. CrossRef Medline 1-type over 5HT2A recep- Aron AR, Robbins TW, Poldrack RA right infe- tors (Slifstein et al., 2007), and pharmacological blocking studies rior frontal cortex: one decade on. Trends Cogn Sci 18:177–185. CrossRef (that !5% of the [11C]NNC-112 sig- 5HT2A binding. Although contam- van der Molen MW, Logan GD (2003) Horse-race model simu- lations of the stop-signal procedure. Acta Psychol (Amst) 112:105–142.
1 receptor signal with 5HT2A binding is minor in the striatum, it should be acknowledged. [18F]Fallypride has nearly equal affinity for D 2 and D3 dopamine receptors in vivo pulsivity, attention and monitoring behaviour in rats performing the stop-signal (Slifstein et al., 2004) and cannot distinguish between them; how- task: possible relevance to ADHD. Psychopharmacology (Berl) 230:89–111.
in the dorsal striatum are almost exclu- sively D2 receptors with very low D3 expression (Murray et al., A, Logan GD, Hogg-Johnson S, Schachar R, Tannock R (2003) Selective inhibition in children with attention-deficit hyperactiv- ND measurements in the dorsal - ity disorder off and on stimulant medication. J Abnorm Child Psychol 2 receptor availability, and those in the ventral stria- tum are likely a combination of signals from D 31:315–327. CrossRef Medline 2 and D3 receptors.
Bilder RM, London ED, Jentsch JD, Parker DS, Poldrack [18F]Fallypride also binds to both isoforms of the D2 receptor RA, Evans C, Freimer NB (2009) Phenomics: the systematic study of phe- (D2S and D2L); therefore, BPND measurements using [18F]fally- notypes on a genome-wide scale. Neuroscience 164:30–42. CrossRef pride do not distinguish between presynaptic and postsynaptic D2 receptors.
Appelbaum LG, Krebs RM, Hopf JM, Woldorff MG (2010) Another limitation is the time interval between the behavioral Pinning down response inhibition in the brain— conjunction analyses of and PET assessments, which was 17 months on average. Of rele- the stop-signal task. Neuroimage 52:1621–1632. CrossRef Medline vance is the low test–retest variation in BP Broos N, Schmaal L, Wiskerke J, Kostelijk L, L, Ham J, de Geus EJ, Schoffelmeer AN, van den Brink W, Veltman DJ, de made using [11C]NNC-112 or [18F]fallypride, which has been Vries TJ, Pattij T, Goudriaan AE (2012) The relationship between im- determined in previous studies to be 5–10% (Abi-Dargham et al., pulsive choice and impulsive action: a cross-species translational study.
2000; Fujita et al., 2006; Dunn et al., 2013 PLoS One 7:e36781. CrossRef Medline 5996 • J. Neurosci., April 15, 2015 • 35(15):5990 –5997
Robertson et al. • Dopamine Receptors and Motor Response Inhibition Buckholtz JW, Treadway MT, Cowan RL, Woodward ND, Li R, Ansari MS, Fields S, Collins C, Leraas K, Reynolds B (2009) Dimensions of impulsive Baldwin RM, Schwartzman AN, Shelby ES, Smith CE, Kessler RM, Zald behavior in adolescent smokers and nonsmokers. Exp Clin Psychophar- DH (2010) Dopaminergic network differences in human impulsivity.
macol 17:302–311. CrossRef Medline Science 329:532. CrossRef Medline Fillmore MT, Rush inhibitory control of behavior in Chamberlain SR, AD, Clark L, Robbins TW, Sahakian BJ chronic cocaine users. Drug Alcohol Depend 66:265–273. CrossRef (2006) Neurochemical modulation of response inhibition and probabi- listic learning in humans. Science 311:861– 863. CrossRef Medline (2005) Dynamic dopamine modulation in the basal ganglia: a Colzato LS, van den Wildenberg WP, Van der (2010) neurocomputational account of cognitive deficits in medicated and non- Genetic markers of striatal dopamine predict individual differences in medicated Parkinsonism. J Cogn Neurosci 17:51–72. CrossRef Medline dysfunctional, but not functional impulsivity. Neuroscience 170:782– Frank MJ, Santamaria A, O'Reilly RC, Willcutt E 788. CrossRef Medline tational models of dopamine and noradrenaline dysfunction in atten- WP, Hommel B (2013) The genetic impact tion deficit/hyperactivity disorder. Neuropsychopharmacology 32: (C957T-DRD2) on inhibitory control is magnified by aging. Neuropsy- 1583–1599. CrossRef Medline chologia 51:1377–1381. CrossRef Medline Fujita M, Brown A, Sangare J, Ryu Y, Sprague K, Colzato LS, Jongkees Wildenberg WP, Hommel B Berman K, Pike V, Innis R (2006) Test retest reproducibility and influ- (2014) Eating to stop: tyrosine supplementation enhances inhibitory ence of dopamine levels on [18F]fallypride PET quantification. J Nucl control but not response execution. Neuropsychologia 62:398 – 402.
Med 47 [Suppl 1]:282P.
Gerfen CR, Surmeier DJ (2011) Modulation of striatal projection systems JA, Cohen JR, Galvan A, Canli T, Poldrack RA (2012) by dopamine. Annu Rev Neurosci 34:441– 466. CrossRef Medline Measurement and reliability of response inhibition. Front Psychol 3:37.
Ghahremani DG, Lee B, Robertson CL, Shetler N, Brown AK, Monterosso JR, Aron AR, Mandelkern MA, Poldrack RA, Larcher K, Fellows LK, Clark CA, Leyton M, Dagher A London ED (2012) Striatal dopamine D2/D3 receptors mediate response (2015) Striatal D1 and D2 signaling differentially predict learning from inhibition and related activity in frontostriatal neural circuitry in humans.
positive and negative outcomes. Neuroimage 109:95–101. CrossRef J Neurosci 32:7316 –7324. CrossRef Medline Hall H, Sedvall G, C, Farde L (1994) Distri- DR, Hamblin MW, Leff SE (1983) The classification of do- bution of D1- and D2-dopamine receptors, and dopamine and its metab- pamine receptors: relationship to radioligand binding. Annu Rev Neuro- olites in the human brain. Neuropsychopharmacology 11:245–256.
sci 6:43–71. CrossRef Medline Dalley JW, D, Robbins TW (2008) Neurobehavioral Gutekunst CA, Rees HD, Heilman CJ, Yung KK, Bolam mechanisms of impulsivity: fronto-striatal systems and functional neuro- JP, Ince E, Yi H, Levey AI (1995) Electron microscopic analysis of D1 and chemistry. Pharmacol Biochem Behav 90:250 –260. CrossRef Medline D2 dopamine receptor proteins in the dorsal striatum and their synaptic de Wit H, Crean J, Richards JB (2000) Effects of etha- relationships with motor corticostriatal afferents. J Neurosci 15:5222– nol on a measure of behavioral inhibition in humans. Behav Neurosci 114:830 – 837. CrossRef Medline CL, Mandelkern MA, Morgan AT, London ED Dreyer JK, JD (2010) Influence of phasic (2013) The simplified reference tissue model with 18F-fallypride posi- and tonic dopamine release on receptor activation. J Neurosci 30:14273– tron emission tomography: choice of reference region. Mol Imaging 12: 14283. CrossRef Medline 1536 – 0121. CrossRef Medline Dunn C, Marsden P, Baker S, Cleij M, Kapur S, Kessler R, Jenkinson global optimisation method for robust af- Howard R, Reeves SJ (2013) Establishing test-retest reliability of an fine registration of brain images. Med Image Anal 5:143–156. CrossRef adapted [(18)F]fallypride imaging protocol in older people. J Cereb Blood Flow Metab 33:1098 –1103. CrossRef Medline M, Bannister P, Brady M, Smith S (2002) Improved optimization Durstewitz D, Seamans JK theory of prefrontal cortex for the robust and accurate linear registration and motion correction of dopamine function with relevance to catechol-o-methyltransferase geno- brain images. Neuroimage 17:825– 841. CrossRef Medline types and schizophrenia. Biol Psychiatry 64:739 –749. CrossRef Medline Jentsch JD, Ashenhurst JR, Cervantes AS, Penning- Eagle DM, Baunez C (2010) Is there an ton ZT (2014) Dissecting impulsivity and its relationships to drug ad- in the rat? Evidence from anatomical and pharmacological studies of dictions. Ann N Y Acad Sci 1327:1–26. CrossRef Medline behavioral inhibition. Neurosci Biobehav Rev 34:50 –72. CrossRef Keeler JF, Pretsell DO, Robbins TW of do- pamine D1 vs. D2 receptors: a "prepare and select" model of the striatal Robbins TW (2003a) Lesions of the medial prefrontal cortex or direct vs. indirect pathways. Neuroscience 282C:156 –175. CrossRef nucleus accumbens core do not impair inhibitory control in rats perform- ing a stop-signal reaction time task. Behav Brain Res 146:131–144.
Berke JD (2011) Investigating striatal function through cell- type-specific manipulations. Neuroscience 198:19 –26. CrossRef Medline TW (2003b) Inhibitory control in rats performing a Lammertsma AA, Hume SP (1996) Simplified stop-signal reaction-time task: effects of lesions of the medial striatum PET receptor studies. Neuroimage 4:153–158. CrossRef Medline and d-amphetamine. Behav Neurosci 117:1302–1317. CrossRef Medline Lane SD, Moeller FG, Steinberg JL, Buzby Perfor- Eagle DM, Tufft MR, Goodchild HL, Robbins TW mance of cocaine dependent individuals and controls on a response inhi- fects of modafinil and methylphenidate on stop-signal reaction time task bition task with varying levels of difficulty. Am J Drug Alcohol Abuse performance in the rat, and interactions with the dopamine receptor 33:717–726. CrossRef Medline antagonist cis-flupenthixol. Psychopharmacology (Berl) 192:193–206.
Lee B, Farahi J, Nacca A, Monterosso JR, Mumford JA, Bokarius AV, Dahlbom M, Mukherjee J, Bilder RM, Brody AL, Man- Robbins TW (2008) The neuropsychopharmacology of delkern MA (2009) Striatal dopamine D2/D3 receptor availability is re- action inhibition: cross-species translation of the stop-signal and go/ duced in methamphetamine dependence and is linked to impulsivity.
no-go tasks. Psychopharmacology (Berl) 199:439 – 456. CrossRef Medline J Neurosci 29:14734 –14740. CrossRef Medline Eagle DM, Wong JC, Allan ME, Mar AC, Theobald DE, Logan GD, Cowan WB, Davis ability to inhibit simple and Contrasting roles for dopamine D1 and D2 receptor subtypes in the dor- choice reaction time responses: a model and a method. J Exp Psychol somedial striatum but not the nucleus accumbens core during behavioral Hum Percept Perform 10:276 –291. CrossRef Medline inhibition in the stop-signal task in rats. J Neurosci 31:7349 –7356.
Mawlawi O, Martinez D, Slifstein R, Hwang DR, Huang Y, Simpson N, Ngo K, Van Heertum R, Laruelle M (2001) Im- Narendran R, Guillin O, Belani H, Guo NN, Hwang Y, aging human mesolimbic dopamine transmission with positron emission Hwang DR, Abi-Dargham A, Laruelle M (2007) In vivo DA D(1) recep- tomography: I. Accuracy and precision of D(2) receptor parameter mea- tor selectivity of NNC 112 and SCH 23390. Mol Imaging Biol 9:117–125.
surements in ventral striatum. J Cereb Blood Flow Metab 21:1034 –1057.
Robertson et al. • Dopamine Receptors and Motor Response Inhibition J. Neurosci., April 15, 2015 • 35(15):5990 –5997 • 5997
Mink JW (1996) The basal ganglia: focused selection and inhibition of com- continuous performance tasks: test–retest reliability of two inhibition peting motor programs. Prog Neurobiol 50:381– 425. CrossRef Medline measures in ADHD children. J Atten Disord 13:137–143. CrossRef Monterosso JR, Aron AR, Cordova X, Xu J, London in response inhibition associated with chronic methamphetamine abuse.
Aharoni E, Munro GE, Calhoun VD, Nyalakanti P, Stevens MC, Drug Alcohol Depend 79:273–277. CrossRef Medline Pearlson G, Kiehl KA (2013) A large scale (N $ 102) functional neuro- imaging study of response inhibition in a Go/NoGo task. Behav Brain Res 256:529 –536. CrossRef Medline fluoropropyl)-2, 3-dimethoxybenzamide as an improved dopamine D-2 recep- Surmeier DJ, Z, Shen W (2007) D1 and D2 dopamine- tor tracer. Nucl Med Biol 22:283–296. CrossRef Medline receptor modulation of striatal glutamatergic signaling in striatal medium Murray AM, Ryoo HL, Gurevich Localization of dopa- spiny neurons. Trends Neurosci 30:228 –235. CrossRef Medline mine D3 receptors to mesolimbic and D2 receptors to mesostriatal re- Swick D, Ashley V, Turken U (2011) Are stopping gions of human forebrain. Proc Natl Acad Sci U S A 91:11271–11275.
and not going identical? Quantitative meta-analysis of two response inhi- bition tasks. Neuroimage 56:1655–1665. CrossRef Medline R, Wagner J, Dean AJ, Messer C, Honeysett A, Nathan PJ, Tannock R, Schachar RJ, Carr RP, Effects of Bellgrove MA (2013) Dopamine D(2) receptor modulation of human methylphenidate on inhibitory control in hyperactive children. J Abnorm response inhibition and error awareness. J Cogn Neurosci 25:649 – 656.
Child Psychol 17:473– 491. CrossRef Medline Vaidya CJ, Austin G, Desmond JE, Glover GH, SM, Kennedy DN, Jenkinson M (2011) A Bayesian Gabrieli JD (1998) Selective effects of methylphenidate in attention def- model of shape and appearance for subcortical brain segmentation. Neu- icit hyperactivity disorder: a functional magnetic resonance study. Proc roimage 56:907–922. CrossRef Medline Natl Acad Sci U S A 95:14494 –14499. CrossRef Medline Ramdani C, C, Dagher A, Hasbroucq T Van Sickle J (2003) Analyzing and watershed (2014) Dopamine precursors depletion impairs impulse control in attributes. JAWRA 39:717–726. CrossRef healthy volunteers. Psychopharmacology (Berl) 232:477– 487. CrossRef Vermeulen RJ, Drukarch B, Goosen C, Wolters EC, Stoof JC (1994) The dopamine D1 agonist SKF 81297 and the dopamine D2 ago- B, Ortengren A, Richards JB, de Wit H (2006) Dimensions of nist LY 171555 act synergistically to stimulate motor behavior of 1-methyl- impulsive behavior: personality and behavioral measures. Pers Individ Dif 40:305–315. CrossRef Mov Disord 9:664–672. CrossRef Medline Reynolds B, M (2008) Dimensions of impulsive behavior Weafer J, Baggott MJ, Test-retest reliability of behavioral in adolescents: laboratory behavioral assessments. Exp Clin Psychophar- measures of impulsive choice, impulsive action, and inattention. Exp Clin macol 16:124 –131. CrossRef Medline Psychopharmacol 21:475– 481. CrossRef Medline Robinson ES, Eagle Theobald DE, Mar AC, Murphy ER, Wo¨stmann NM, Aichert DS, HJ, Ettinger U (2013) Robbins TW, Dalley JW (2009) Behavioural characterisation of high Reliability and plasticity of response inhibition and interference control.
impulsivity on the 5-choice serial reaction time task: specific deficits in Brain Cogn 81:82–94. CrossRef Medline "waiting" versus "stopping." Behav Brain Res 196:310 –316. CrossRef Wu Y, Carson RE in the simplified reference tissue model for neuroreceptor functional imaging. J Cereb Blood Flow Metab Russell T, Overmeyer S, Brammer MJ, Bullmore ET, Sharma T, 22:1440 –1452. CrossRef Medline Simmons A, Williams SC, Giampietro V, Andrew CM, Taylor E (2001) Zald DH, RM, Ansari MS, Li R, Shelby ES, Mapping motor inhibition: conjunctive brain activations across different Smith CE, McHugo M, Kessler RM (2008) Midbrain dopamine receptor versions of go/no-go and stop tasks. Neuroimage 13:250 –261. CrossRef availability is inversely associated with novelty-seeking traits in humans.
J Neurosci 28:14372–14378. CrossRef Medline M, Grabowska A, Szewczyk J, Gerc K, Chmylak R (2012) Re- Zald DH, Woodward ND, P, Ansari MS, Baldwin RM, sponse inhibition of children with ADHD in the stop-signal task: an Cowan RL, Smith CE, Hakyemez H, Li R, Kessler RM (2010) The inter- event-related potential study. Int J Psychophysiol 85:93–105. CrossRef relationship of dopamine D2-like receptor availability in striatal and ex- trastriatal brain regions in healthy humans: a principal component Hwang DR, Huang Y, Guo N, Sudo Y, Narendran R, Talbot P, analysis of [18F]fallypride binding. Neuroimage 51:53– 62. CrossRef Laruelle M (2004) In vivo affinity of [18F]fallypride for striatal and ex- trastriatal dopamine D2 receptors in nonhuman primates. Psychophar- Oka T, Bokura H, Yamaguchi S (2008) The key locus of common macology (Berl) 175:274 –286. CrossRef Medline response inhibition network for no-go and stop signals. J Cogn Neurosci Slifstein M, Kegeles LS, Xu X, Laruelle M, Abi- 20:1434 –1442. CrossRef Medline Dargham A (2007) [11C]NNC 112 selectivity for dopamine D1 and se- Zheng P, WX (1999) Opposite modulation of rotonin 5-HT(2A) receptors: a PET study in healthy human subjects.
cortical N-methyl-D-aspartate receptor-mediated responses by low and J Cereb Blood Flow Metab 27:1733–1741. CrossRef Medline high concentrations of dopamine. Neuroscience 91:527–535. CrossRef Soreni N, Crosbie J, Ickowicz A, Schachar R and Conners'

Source: http://ctn.uoregon.edu/wp-content/uploads/2015/12/Robertson-2015-Striatal-D1-and-D2-type-Dopamine-Receptors-Are-Linked-to-Motor-Response-Inhibition-in-Human-Subjects.pdf

cran.ism.ac.jp

Package ‘openintro' February 20, 2015 Title OpenIntro data sets and supplemental functions Author David M Diez, Christopher D Barr, and Mine Cetinkaya-Rundel Maintainer David M Diez <[email protected]> Description This package is a supplement to OpenIntro Statistics, which is a free textbook available at openintro.org (at costpaperbacks are also available for under $10 on Amazon). Thepackage contains data sets used in the textbook along withcustom plotting functions for reproducing book figures. Notethat many functions and examples include color transparency.Some plotting elements may not show up properly (or at all) insome Windows versions.

Microsoft word - 502-509 _219_.doc

Fernando de Souza Costa and Ricardo Vieira Preliminary Analysis of Hybrid Fernando de Souza Costa Rockets for Launching Nanosats into [email protected] 12630-000 Cachoeira Paulista, SP, Brazil This work determines the preliminary mass distribution of hybrid rockets using 98% H2O2 and solid paraffin mixed with aluminum as propellants. An iterative process is used to