Reproducibility of Repeated Measures of Endogenous Dopamine Competition with [11C]Raclopride in the Human Brain in Response to Methylphenidate

Gene-Jack Wang, Nora D. Volkow, Joanna S. Fowler, Jean Logan, Naomi R. Pappas, Christopher T. Wong, Robert J. Hitzemann and Noelwah Netusil

Medical and Chemistry Departments, Brookhaven National Laboratory, Upton; Departments ofRadiology and Psychiatry, State University ofNew York Stony Brook; and Psychiatry Seri'ice, Veterans Affairs Medical Center@Northport, New York

The measureof changes in synaptic dopamine(DA) concentra easures of dopamine (DA) D2 receptors using PET tion in response to the psychostimulantdrug methylphenidate and [@C]raclopride have been used to assess neuropsychiat (MP) has been used as an indicatorof responsivenessof the DA ric disorders such as schizophrenia (1—4), Parkinson's system.The purposeofthis studywasto assessthe reproducibil disease (5—11),Huntington's disease (12), Wilson's disease ity of thesemeasures.Methods:Sevenhealthysubjectswere scanned with PET and [11C]raclopridetwice in the same day: 7 (13), manganese intoxication (14, 15), cocaine abuse (16), mmafter placeboor methylphenidate(0.5 mg/kg)administration. alcoholism (17,18) and opiate dependence (19), as well as In parallel we also measured the physiologic and behavioral during aging (20—23).These measures have also been responsesto placeboand to methylphenidate.The same proce performed to assess the progress ofdisease (24,25), which is dureswere repeated1—2wk laterto assesstest-retestreproduc feasible because repeated measures of [“C]raclopridebind ibility. Results: Measures of plasma to brain transfer constant (Ki), striataldistributionvolume (DV@) and DA D2 receptor ing in the human brain are highly reproducible (26—29). availability(Bmax/Kd),for the placeboconditionwere similarfor [“Ciraclopride-PEThas also been used to assess levels of the first (El) and second (E2)evaluations(Bmax/Kd,El : 2.77 ± DA D2 receptor occupancies by different doses of typical 0.44; E2: 2.97 ±0.44). MP administration did notchange , but and atypical antipsychotics and to assess the relation be @ itsignificantly decreasedDV@(El: —25.9%±8.7%, P 0.0002; tween levels of occupancy and therapeutic effectiveness and E2: —20.7%±11.7%,P 0.007)andBmaxlKd(El: —18.4%± @ 8.7%,P 0.002;E2: —13.4%±9.2%,P 0.008),andthe side effects (30). Because raclopnde is sensitive to competi magnitudeof these changes,though lower for E2, did not differ tion with endogenous DA (31), due to its relatively low @ significantly.MP increased pulse rate (El : +64% ±43%, P affinity for DA D2 receptor, [“Ciraclopride has also been 0.002; E2: +69% ±33%, P 0.001), systolicpressure used to assess relative changes in synaptic DA induced by (El : +37% ±19%, P 0.0006;E2: +29% ±15%, P 0.0009), psychostimulant drugs. Drug-induced changes in [@C]raclo selfreportsfordrugeffects(0: nothingto 10:extreme)of “rush― (El: +8 ±3, P 0.0004; E2: +6 ±4, P 0.01) and “high―pride striatal binding are interpreted as reflecting changes (El: +8 ±3, P 0.0001, E2: +8 ±3, P 0.0003), anxiety induced by DA occupancy of D2 receptors secondary to the (El:+5 ±4,P 0.02;E2:+4 ±4,P = 0.1)andrestlessnesschanges in DA synaptic concentration (32—34).This mea (El: +4 ±4, P 0.04; E2: +4 ±5, p = 0.1). The magnitude sure has been used as an indication of the responsivity of the of the cardiovascular and behavioral effects did not differ be DA system to pharmacologic challenge. With this strategy, a tweenEl andE2.Conclusion:MP-inducedchangesin stnatal DVandinBmaxlKd,aswellasthebehavioralandcardiovascular recent study showed decreased DA responsivity in cocaine effects,were reproduciblewith repeatedadministration. abusers when compared with controls, consistent with Key Words:[11C]raclopride;methylphenidate;pharmacologicdecreased DA release during cocaine detoxification (16). In challenge;PET@reproducibility contrast, studies in schizophrenic patients have documented J NucIMed1999;40:1285—1291 an enhanced DA response to psychostimulants when corn pared with healthy controls (4,35). Furthermore, in these studies the magnitude of the increase in DA concentration induced by the psychostimulant was significantly correlated with the increase in positive psychotic symptoms; corrobo rating the importance of DA in this disorder. Because this Received Oct. 5, 1998; revision accepted Feb. 4, 1999. strategy may be useful in monitoring disease progression Forcorrespondenceor reprintscontact:Gene-JackWang,MD,Medical Department,BrookhavenNationalLaboratory,Upton,NY11973. and/or response to treatment, it is important to evaluate the

REPEATED MEASURES OF DoP@tm@E RELEASE •Wang et al. 1285 reproducibility of this measurement under test-retest condi CardiovascularAssessment tions. Electrocardiographic recording, blood pressure and pulse rate This study assesses the reproducibility of measurement of were obtained every 15mm for 30 mm before injection of saline or endogenous DA competition in human brain with [@C]raclo MP and then at 2, 4, 6, 8, 10, 15, 20, 30, 40 and 67 mm after pride using methylphenidate (MP) as the pharmacological administration. agent in seven subjects who were tested twice, 1—2wk apart. BehavioralandCognitiveEvaluation MP is a psychostimulant drug that raises synaptic DA Before placebo or MP and at 27 and 67 mm after placebo or MP concentration by blocking DA transporters and is used for administration, subjects were asked to evaluate on an analog scale the treatment of attention deficit hyperactivity disorder rated from 0 (felt nothing) to 10 (felt extremely) their subjective (36—38). perception of alertness, annoyance, depression, distrustful thought (perception that others are trying to cause harm), happiness, hunger, mood (defined as a contrast between being depressed and MATERIALSAND METHODS being happy), sexual desire, stimulation, talkativeness, tiredness, desire to use MP and loss of control over MP use. The subjective Subjects experiences of rush, high (defined as euphoria), anxiety and Seven healthy subjects (two women, five men; mean age 31.4 ± restlessness (defined as the need to move) were also recorded every 7.9 y, agerange24—42y) withoutmedicalor neuropsychiatricminute for 20 mm, as well as 25, 30, 45 and 67 mm after drug illnesses were selected for the study. Subjects with past and present injection. usage of alcohol or drugs (except for caffeine and cigarettes) were ImageAnalysis excluded from the studies. Prescan urinalysis ensured absence of For images obtained with the CTI-931 PET scanner, regions of psychoactive drug use. Subjects were instructed to discontinue any interest (ROIs) in striatum and cerebellum were drawn direcfly on over-the-counter medication 1 wk before the scan. Informed an averaged emission image (summation of images obtained consent was obtained from each participant after the nature of the between 10—60mm) as described previously (19). ROIs for experiment was fully explained. Studies were approved by the striatum were obtained bilaterally from the planes where they were Investigational Review Board at Brookhaven National Laboratory. best identified (two slices). Right and left cerebellar regions (two slices) were obtained in the two planes 1.0 and 1.7 cm above the ExperImentalDesign canthomeatal line. Images obtained with the Siemens HR@scanner Two sets of identical studies were performed 1—2wk apart in were resliced parallel to the line between the anterior and the each subject. Each set consisted of two PET scans performed on the posterior commissures (AC-PC line). To increase the signal on each same day with [“C]raclopride.In the first scan, subjects were plane, we summed contiguous planes, which gave images with a injected with a placebo (3 mL saline solution) given 7 mm before 4.8mmFWHMratherthanthe2.4mmFWHMfromtheoriginal [@C]raclopride.In the second scan, subjects were injected with MP planes. ROIs in striatum and cerebellum were drawn directly on the (0.5 mg/kg) given 7 mm before [@C]raclopride.The subjects were averaged emission images (summation of images obtained between unaware of the drug received. MP concentration in plasma was 10—60mm). ROIs for striatum (three slices) were obtained measured before and 27 and 67 mm after MP administration with bilaterally from the planes where they were best identified. Right high-performance liquid chromatography (HPLC) performed at the and left cerebellar regions (three slices) were obtained in the three National Psychopharmacology Laboratory. planes 1.0 and 1.7 cm below the AC-PC lines. These regions were then projected into the dynamic images to generate time-activity PET Scanning curves for striatum and cerebellum. Values for the striatal and cerebellar regions were computed by using the weighted average For five of the subjects (subjects 1—5),PET scans were from the different slices where the regions were obtained. The performed with a CTI-931 (Computer Technologies, Inc., Knox time-activity curves for tissue concentration, along with the ville, TN) tomograph (resolution 6 X 6 X 6.5 mm full width at half time-activity curves for unchanged tracer in plasma, were used to maximum [FWHMJ, 15 slices). Procedures for subjects' position calculate the distribution volume (DV) and the blood-to-tissue ing, scanning protocol and arterial blood sampling for the CTI-931 transport constant (Kl) in striatum and cerebellum using a graphi were described previously (27). For two of the subjects (subjects 6 cal analyses technique for reversible systems (39). The D2receptor and 7), PET scans were performed with a Siemens HR@tomograph availability was quantified with the ratio of the DV in striatum to (resolution 3 X 3 X 3 mm FWHM, 63 slices). To ensure accurate that in cerebellum, which corresponds to Bmax'IKd' + 1 (39). repositioning of subjects for the repeated scans, an individually molded headholder was made for each subject. The head of the StatisticalAnalysis subject was then positioned in the gantry with the aid of two Comparison for measures of KI, DV and BmaxlKd at placebo orthogonal laser lines, one placed at the corner of the canthus and between the first and the second evaluation and between the the other parallel to the saginal plane. Scanning protocol and placebo and the MP condition were evaluated with repeated arterial blood sampling procedures were the same for the scans analysis of variance (ANOVA). Comparisons of MP-induced performed with the Siemens HR@PET and with the CTI-93l PET. changes in BmaxlKd (placebo-MP) between the first and the Briefly, a series of 20 emission scans (scans were taken every second evaluation were tested with repeated ANOVA. Comparison minute for the first 10 mm and then ten 5-mm scans were taken for between the plasma MP concentration, the cardiovascular and the the next 50 mm) were obtained from the time of injection up to 60 behavioral effects were tested with repeated ANOVA. For the mm after intravenous injection of 148—296MBq (4—8mCi) behavioral measures for which we obtained a complete time [“C]raclopride.Quantitation of [“C]raclopridein plasma was response (high, rush, anxiety and restlessness), we compared performed as described previously (27). MP-induced changes (placebo-MP) in peak effects as well as in the

1286 THE Joui@i@ OF NUCLEARMEDICINE •Vol. 40 •No. 8 •August 1999 TABLEI Subject Data, Kl , DV in Cerebellum and Striatum, Stnatal [11CjRaclopndeBinding (Bmaxlkd) After Placebo in First and SecondEvaluationsas Well as PercentageChangeof Bmaxlkd

Cerebellum Striatum Subject Age change no.Bmax/Kd1 (y) Sex Evaluation Ki DV Kl DVStnatalBmax/KdPercentage 25 M 2.5212.677—6.6%21 0.060 0.686 0.144 2.5662.8532 0.077 0.666 0.152 31 M 1.7912.354—15.7%21 0.075 0.534 0.113 .8352.7233 0.055 0.493 0.118 1 24 M 2.0062.878+6.9%21 0.071 0.517 0.116 1.9542.6814 0.075 0.531 0.135 32 M 2.0803.280—10.5%21 0.053 0.486 0.111 .7553.6245 0.071 0.380 0.107 1 42 M 2.0882.442—13.7%21 0.058 0.607 0.128 1.7612.7766 0.061 0.466 0.113 42 F 2.2812.344—9.4%2I 0.053 0.682 0.102 .7082.5647 0.056 0.479 0.101 1 24 F .8553.404—5.5%21 0.065 0.421 0.115 1 2.0853.591K1 0.069 0.454 0.111

(mUg).Percentage= plasmatobraintransferconstant(mLfminlg);DV= distributionvolume changeofBmax/Kdis(firstevaluationminussecondevaluation)minusfirstevaluationtimeS100.

area under the curve (AUC) for the time points between 0 and 20 2.77 ±0.44; E2: 2.97 ±0.44; Table 1). Administration of mm after drug administration between the first and the second MP did not change the plasma-to-brain transfer constant evaluations. For the measures for which we obtained only three (K!) in striatumor cerebellum;however,MPsignificantly time points (baseline, MP 27 and MP 67 mm), we compared the decreased the DV in cerebellum (DVth; El: —14.3% ±7%, three measurements between the first and the second evaluations P 0.005;E2: —12% ±9.8%, P 0.03), in StriatUm(DV,@; using a 2 within (experiment and drug) repeated ANOVA design. For the cardiovascular effects, we averaged the measurements El: —25.9%±8.7%,P 0.0002;E2: —20.7%±11.7%, @ obtained between baseline and 20 mm after MP administration, P 0.007)andBmax/Kd estimatesin striatum(El: - 18.4%± which was the period when we observed peak effects, and then 8.7%, P 0.002; E2: —13.4% ±9.2%; P 0.008) in the first compared MP-induced changes in these measurements (placebo and in the second eva1uation@(Table 2). The magnitude of MP)betweenthefirstandthesecondevaluations. MP-induced decrements in striatal DV and in Bmax/Kd did not differ between the first and second evaluations (DVrh: RESULTS P = 0.7;DV@ P = 0.41;BrnaxlKd:P = 0.11;Fig. 1). Measurements of BrnaxlKd after placebo did not differ The concentration of MP in plasma did not differ signifi between the first (El) and second (E2) evaluations (El: cantly for both evaluations and corresponded to 122 ±23.4

TABLE2 PercentageChangeAfterMethylphenidateInjection(Methylphenidate-Placebo/Placebo)of Kl , DV of Stnatumand Cerebellumas Well as Striatal[11C]RaclopndeBinding(BmaxlKd)in Firstand SecondEvaluations

evaluationSubjectCerebellumStnatumStnatalCerebellumStriatumStnatalno.K1FirstevaluationSecond

DVBmax/Kd1—35.0 DVKl DVBmax/KdK1DVKI —32.7—11.02+8.0 —12.0—44.8 —14.9—4.7—18.2—26.7—15.8 —36.7—29.83—12.7—9.0+25.0 —28.8—31.1+27.3—19.1—18.7 —13.7—1.04+32.1 —3.9—33.8 —13.4—13.4+1.3—13.2—7.8 —15.1—14.35+20.7—19.3—13.1 —34.9—25.3—25.4—4.5—22.5 —10.5—6.66+69.8 —12.2—12.1 —24.4—19.7+9.8—5.8—16.9 —7.4—12.47+7.7 —26.3+20.7 —33.4—13.9+30.4+1.7+4.0 —28.7—18.6Mean+12.9—17.8—10.0 —31.3—21.0+29.0—16.5+5.0 —20.7—13.4SD33.3—14.3—9.7 —25.9—18.4+7.8—12.0—10.4 11.79.2K1 7.425.7 8.78.722.99.811.1

= plasmato braintransferconstant(mL/min/g);DV= distnbutionvolume(mUg).

REPEATED MEASURES OF Do@@ur@ RELEASE •Wang et al. 1287 Baseline Methyiphenidate @ ,4@

FIGURE1. Distributionvolumeimagesof [11C]raclopridePET studies in healthy sub Study 1 ject at level of basal ganglia (right images) andcerebellum(leftimages)forfirstevalua tion(studyI) withplacebo(baseline),first @ evaluationwith methyiphenidate,second e@.$ ‘,s @ evaluation (study 2) wIth placebo and sac : • . . . -- mI/gm ond evaluation with methylphenidate. Im ages for bothevaluationsare scaledwith

respect to maximum value obtained on . Study 2 placebo condition of first evaluation and presentedusingrainbowscaleinwhichred representshighestvalue (2 mUg) and dark [C-I 1]raclopride violet representslowestvalue.

A B

120 120 ililihli:@:i I I @II@1T@_I_II I 80 80 I [email protected] I 1. 40 40 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70

‘@‘ 180 ‘@% 180 I ?IwII4J@@---1 I @r@IIIII@@II I .@140

@ ••@s.•a@s*_,@—•---- S a ‘_:;;:;_@ _ - - C,, rLL1s'-1-w@L1:Ij I I 1U@LL1@±@-LLI I I I 100 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70

@I1@I@Ij------I 100 ;III@@@@I 1': 80 @ @W@1ItT—r .LaIIIIIllI I I 60 I 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70 Time(minutes) Time (minutes) FIGURE2. Averagedmeasuresof bloodpressureandpulseratebeforeandafterintravenousinjectionof placebo(•)and methylphenidate(0) infirst(A)andsecond(B)evaluations.

1288 THE Joui@i@ OF NUCLEARMEDICINE •Vol. 40 •No. 8 •August 1999 @ 0@ @I@I-I----:@_ ,@ 1@

A B 12 8 ,@ 4@ p.see.@e..@-4=------= @ 0•@±?_?y,,@,ti1 I I °@ @ .—.4.@, I -4 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70

12 12

.@ 4. - - - ,p .. -. @ 0@ .....e.... a a - —a -4 0•10 20 3040 50 60 70 0 10 20 30 40 50 60 70 12 12 8 I I I 0 “@!,@::i@1. -4 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70

1',. 12 @ ;;I@I@@i@i:;@--- -@I ,@ 4, ,eee@ee..._. -. -. @ .tt?@t't?tt11 I ! 0 “@.....i . S • -4 , , 1@1@1@@@@@I@ , —4. 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70 Time (minutes) Time (minutes)

FIGURE3. Self-reportsofdrugeffects(0 = nothingto 10 = extreme)forrush,high,anxietyandrestlessnessbeforeandafter intravenousInjectionofplacebo(S) andmethylphenidate(0) inthefirst(A)andsecond(B)evaluations.

@ and 135.9 ±23.1 ng/rnL at 27 mm and to 71.6 ±14.6 and pressure ([SP] El: +37% ±19%, P 0.0006; E2: +29% ± 79.9 ±19.3 ng/rnL at 67 mm after MP administration. 15%, P 0.0009) and diastolic blood pressure ([DP] El: MP significantly increased pulse rate ([PR] El: +64% ± +38% ±17%, P 0.0002; E2: +34% ±21%, P 0.0008) 43%, P :S 0.002; E2: +69% ±33%, P 0.001), systolic (Fig. 2). The magnitude ofthe cardiovascular effects did not

TABLE3 PublishedReportsof PercentageChange of Stnatum-to-CerebellumRatiofor [11C]Raclopnde Uptake for Test-Retest Studies

changes change (range)NordstromReferenceAge (meany)Age (rangey)SexPercentage (mean)Percentage 12.0%Volkowatal.(26)27.319—366M, 4F1 .2%10.8% to + +6.7%Schlosseratal.(27)—21—465M0.4%—8.1% to 12.2%Breieret al. (28)48.124-755M, 3F—0.3%—12.7% to + +6%Wangat al. (29)32.55M, 1F1 .9%—4% to atal.(reportedhere)31 .424—425M, 2F—5.6%—11 .0%to +5.2%

REPEATED MEASURES OF DOPAMINE RELEASE •Wang et al. 1289 differ between the first and second evaluations (PR: P = subjects. Although this study included men and women, the 0.95; SP:P = 0.1; DP: P = 0.2). sample size was too small to assess gender differences in DA MP increased the subjective perception of rush responses to psychostimulants. Further studies are required (El:+7±3,PO.0004;E2:+5±4,P0.Ol)andhigh to assess whether there are differences in DA responses to (El: +7 ±2,P0.0001;E2: +7 ±3,PS0.0003), anxiety psychostimulants throughout the menstrual cycle. (El: +5 ±4, P 0.02; E2: +4 ±4, P = 0.1) and rest Although not significant, the changes in DA responsivity lessness (El: +4 ±4, P 0.04; E2: +4 ±5, P = 0.1) in the second evaluation tended to be smaller than those (Fig. 3). The peak effects for these behavioral changes did during the first evaluation. A possible explanation could be not differ between evaluations. However, a comparison of that the novelty component, which has been shown to affect the AUC revealed that, although MP-induced effects in high drug responses (40,41), accounts for the differences between and restlessness were comparable for both evaluations, they the first and second evaluations. Further studies are required were significantly lower for the second than for the first to evaluate the effects of novelty in psychostimulant induced evaluation for self-reports of rush (El: 112 ±27; E2: 75 ± DAchanges. 34; F = 6; df 1.13; P < 0.05) and of anxiety (El: 75 ±55; Finally, this study also replicates previous studies (Table E2: 30 ±51; F 16; df 1.13; P < 0.007). 3) that have shown that measures of DA D2 receptor In addition, MP decreased tiredness (drug effect F = 5.3; availability under baseline conditions as assessed with [“C] df 2.12; P 0.02), increased talkativeness (drug effect F = raclopride are highly reproducible (26—29). @ 13; df 2.12; P 0.001) and made subjects feel more @ stimulated (F 15; df 2.12; P 0.0005) (data not shown). CONCLUSION None of the drug by experiment effects were significant, This study demonstrates that measures of striatal DA indicating that these behavioral effects did not differ be changes induced by MP with [“C]racloprideand PET are tween the first and the second evaluations. reproducible. It also showed high reproducibility for most of the behavioral and cardiovascular effects of MP under the DISCUSSION PETexperimentalconditions. This study shows that decreases in striatal [@C]raclopride binding induced by acute MP administration are reproduc ACKNOWLEDGMENTS ible in a given subject when tested at a 1- to 2-wk interval. This study was supported by the U.S. Department of They also show that the behavioral and cardiovascular Energy (DE-ACO2-98CH108886, National Institute on effects induced by MP (except for rush and anxiety) were Drug Abuse (NIDA) (DA 06891-02), National Institute on also highly reproducible. Alcohol Abuse and Alcoholism (AA 09481—04) and After initial MP administration, the subjects reported NIDA/VA Medications Development Research Unit. We significant increase in rush, high, anxiety and restlessness. thank D. Alexoff, R. Carciello, P. Cervany, R. Ferrieri, P. They also reported feeling stimulated, talkative and less King, A. Levy, R. MacGregor, L. Malachowsky, C. Red tired. These behavioral effects are compatible with those vanly, D. Rodgers, D. Schlyer, C. Shea, M. Taylor and D. previously reported after intravenous administration of MP Warner for their participation in various aspects of this (33). study. The only behavioral effects that differed between evalua tions were the changes in anxiety and rush, which were REFERENCES lower in the second than in the first evaluation. The decrease I. Farde L, Wiesel FA, Halidin C, Sedvall G. 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