Obtained with Positron Emission Tomography

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Either scan protocol was preceded by intraperitoneal injection of carbidopa (typically2 mg/kg 1 hr before FD injection) to inhibit peripheral L-aromatic aminoacid ...

The Reproducibility of Stnatal Uptake Data Obtained with Positron Emission Tomography and fluorine- 18-L-6-Fluorodopa Tracer in Non-Human

Primates

Brian D. Pate, Barry J. Snow, Kellie A.Hewitt, K. Scott Morrison, Thomas J. Ruth, and Donald B. Caine TRJUMF and Department ofMedicine, University ofBritish Columbia, Vancouver,British Columbia, Canada

Cynomolgus and rhesus monkeys have been studied via PET with [18F]-L-6 fluorodopa tracer. Striatal fluorodopa uptake

rate constantshave been derived by graphicalanalysisof transaxial slice images centered on the sthata. The differ ences between pairs of values of the rate constant, obtained from two scans on the same monkey separated by two weeks

ual PET-FD measurements. The present work was under taken to explore this reproducibility. METhODS PET Scanning

PET-FDscanswereconductedwith a tomographbasedon the

or more,exhibiteda relativestandarddeviationof 34.4%. If the two scans were conductedone immediatelyafter the

whilethe axialresolutionvariedwith radiusbut averaged14mm.

other, with the position of the monkey undisturbed, the stand aid deviation was reduced to 14.0%. The utility of this tech

FD was synthesized by a published method (8). 3-O-Me-6FD was synthesized by the reaction described (9) for the synthesis of FD

nique was demonstratedby comparingthe effects on the scans of halothane and pentobarbital anesthesia and by the administration of NSD 1015, a peripheral and central inhibitor

exceptthat8 M HC1wasusedin thedeprotectionstepinsteadof HI. Malecynomolgusmonkeysweighingon average3 kgand male

of L-aromaticamino-aciddecarboxylase,between back-to

rhesus monkeys weighing about 17 kg were used. Most of the

back scans. With NSD 1015, the fluorodopa uptake constant was reducedby an averageof 76.0%.

subjects were normal, the exceptions having had a unilateral

PElT VI design (7). The in-plane resolution was 9 mm FWHM,

intracarotid infusion of MPTP. Scanning was conducted under

sodium pentobarbital or halothane anesthesia (see below).The anesthetizedanimals were positioned on a lucite tray, and their

J NucIMed 1991;32:1246-1251

heads were immobilized by strapping to the tray with adhesive tape.

Before PET scanning, each subject underwent MRI brain ositron emission tomography with [‘8F]L-6 fluorodopa tracer(PET-FD)

is a useful technique for the measurement

of striatal dopaminergic integrity in normal human sub jects (1), in patients suffering from idiopathic parkinson ism (2) or other forms of parkinsonism

(3), and in non

human primates (4,5). A quantitative measure of the uptake of FD into the striata may be obtained by means ofa graphicalanalysis ofthe temporal proffleofthe striatal image intensity and of the H) content of arterial blood (6). Data from successive PET-fl) scans may need to be compared, for example in longitudinal studies aimed at demonstrating a change in patients' dopaminergic integrity with time, or in experiments to show the effects of phar macological interventions. The significance of observed changes will depend on the reproducibilityof the individ ReceIved Jul. 20, 1990; revision accepted Dec. 5, 1990.

For reprints contact: B.D. Pate, Divisionof Neurology,Department of Medidne, Lkiiversityof British Columbia, 221 1 Wesbrook Mall, vancouver, BC, Canada V6T 1W5.

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imaging, by which the position ofthe striata was established with

respect to the plane of the lucite tray. Lateral and A-P x-ray imaging then recorded the orientation ofthe skull with respect to the tray plane, and repeated x-ray imaging allowed this orienta

tion to be re-establishedfor subsequentscanningsessions.A laser fiducialattached to the PET scannergantry allowedthe tray and the skull landmarks (and hence the striata) to be positioned (and repositioned) to within an estimated 1—2 mm error in a known

location in the PET imaging volume. The striata were always centered in the same “true― slice of the seven measured by the

PETT VI camera. A single PET scan protocol incorporated one sequence of twelve 10-mm emission scans, starting immediately after injec

tion of 37 MBq of FD. The double-scan protocol, discussed below,consistedof two sequences;after the firstsequence,about 40 mm was required to reset the data acquisition system before the second ID injection and the second PET scan sequence. The

total time in the double-scanprotocol was thereforeabout 4 hr and 40 mm. Either scan protocol was preceded by intraperitoneal injection

of carbidopa (typically 2 mg/kg 1 hr before FD injection) to inhibit peripheral L-aromatic aminoacid decarboxylase (2). A

TheJournalof NuclearMedicine• Vol. 32 • No. 6 • June1991

transmissionscan with an externalring-sourceof germanium-68 PET-ID imagedata and the blood plasmaID concentrations measured in the second scan sequence contain the effects of

was then performed to permit correction ofthe subsequent emis sion data for self-absorption, transmission tioning.

sagittal section

and for confirmation reconstruction)

(through a

of the subject

posi

radioactivity residues from the first scan sequence. Two possibil

ities for analysisof the data from the secondscan sequencethen exist.

First, the changein striatal fluorodopauptake revealedby the BloodSamplingand Analysis Prior to starting the scan sequences,a venous catheter (ordi narily in the brachio-cephalicvein) was establishedfor the ID bolus injection and for pentobarbital anesthetic administration when employed. Similarly, a catheter was established (ordinarily in the anterior tibial artery) to collect blood samples. Twenty

analysis of images from the second scan sequence can be consid ered as the response to the changed blood input function follow ing the second fluorodopa injection. The second sets of image data and blood activity data are then analyzed without correction for residues from the first scan sequence (11).

Second, both the images and the blood ID concentrations bloodsampleswereacquiredduringeach2-hrscanningsequence. from the second scan sequence can be corrected for the residues

Of these, eight were taken during the first minute after ID

from the firstscan sequence and then analyzed on the same basis

injection;fivemore weretaken in the next 4 mm, and thereafter as those from the first sequence. the sampling interval increased, reaching 30 mm at the end of the scanning sequence. This sampling rate accurately delineated the variation with time of the blood ID concentration, and its

The procedures for making such corrections were defined in

the present work from singlescan sequencesthat were extended to 4 hr. It was found that image intensities during the period

integralas requiredin the analysis(6). The fractionofthe blood from 50 mm to 4 hr after ID injection decreased with time plasma radioactivity due to ID was determined as a function of time via absorption onto the alumina (10). The accuracy of the

exponentially (one component).

The striatal, cortical, and whole

slice intensities decayed with different half-lives. The differences techniquewasverifiedby comparisonwith HPLCanalysis,using were slight, however, as the decay was dominated by the 110-

authentic standards of ID and 3-OMe-6ID. It was shown that

mm radioactivitydecay half-lifeof ‘8F, and good analysiswas

over 90% ofthe plasma radioactivity was due to ID plus 3-OMe 6ID during the time course of these experiments. For a 3-kg cynomolgus monkey, the expected safe limit for a

possible without prior correction of the intensities for ‘8F decay.

Accordingly,a procedure was adopted in which the seven striatalregionalintensitiesobservedfrom 50 to 120mm after ID

singleblood withdrawalis 15 ml. (For the 17-kgrhesusmonkey, injection in the first scan sequence were fitted to a monoexpo it is 70 ml). The total volume

of blood removed

during the 4-hr

40-mm duration of the double-scan protocol was 20.4 ml. Con tinuous intravenous infusion of isotonic saline helped restore the

subject'sblood volume,and no evidenceof anemic distresswas observed during routine hemoglobin and hematocrit monitoring.

nential decay function by the least squares procedure. The cor responding effective decay half-life was used to calculate, on a pixel-by-pixel basis, the image intensity from the first ID injec tion that would have been presentat the time ofeach ofthe scans during the second scan sequence. This intensity was then applied,

againon a pixel-by-pixelbasis,as a subtractivecorrectionto yield Image Analysis:RadioactivityResidueCorrection the image intensities due to the second ID injection. Figure 1 Ellipticalregionsof interest(ROIs)were placedto encompass shows the variation with time of the striatal regional intensities the left and right striata on images obtained by summing the images recorded between 50 and 120 mm after ID injection. The images of the ID accumulated in the left and right striata were always distinct. The striatal ROIs were located to include as much as possible of the increased striatal image intensity over the adjacent background. Care was taken to minimize either the intensity

from the contralateral

striatum

or that from ID uptake

from the firstand second scans ofa typical experiment, the fitted mono-exponential

function,

and the effect ofthe

resulting

image

intensitycorrection. Similarly,the 4-hr blood sampling revealedempiricallythat the variation of blood plasma ID content with time followed a function of the form y = [email protected]+ [email protected] parameters were accu rately estimated for each case by fitting such a function to the

into the adjacent temporalis muscle. Background ROIs were datafrombloodsamplesobtainedbetween10and 120mmafter placed on the left and right occipital cortices, also minimizing ID injection. The residue from the first ID injection, then inclusion of intensity from temporalis muscle. In the double-scan protocol, the images from the first and

calculated for later times (2—4 hr after first injection), was sub

tracted from resultsobtained from blood samplingfollowingthe second scan sequenceswere in spatial register.Thus, identical second ID injection (as shown in Fig. 2). ROls were placed on the first and second image sets from that In the images and in the data from blood measurements, the protocol. corrected values had a greater statistical uncertainty than the The image intensity in the striatal and cortical regions was also measured in scans following injection of 3-OMe-6ID (a major component in cortical PET-ID images). In these images, the

corticalintensitiesvaried with time in a way similar to those in PET-IDscans.Thestriatalregionsshowedan intensityindistin guishable from the cortical background; thus, the cortical regions were used to estimate the background variation in the striatal

uncorrected ones due to the subtraction process. The effect of

this increase in uncertainty on the results of the analysis is included in the reproducibility findings reported below. Since the image sets from the first and second scans of the double scan protocol were in exact register in the image plane (the subject having not been moved between the scans) and since the same quantity of ID (37 MBq) to within 1% was injected

ROlin ID scans.Thevariationsof PET-IDROIintensitieswith each time, the imageintensitiesin the secondset (afterthe above time were then analyzed

by the graphical

method

of Martin et al.

(6). When the double-scan protocol is employed with a scanning agent labeled with 110-mm ‘8F, as in the present case, both the

Reproducibility of Stnatal Uptake Data • Pate et al

correction) could be subtracted on a pixel-by-pixel basis from those in the first set to yield difference images. Further, ROIs placed on any of the images were in the correspondingposition when transferredto any of the others prior to graphicalanalysis.

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anesthesia to determine ifthis change affected the analysis results. The experimental protocol involved a ketamine/pentobarbital pre-anesthetic, followed by a first scan sequence under halothane.

During the interval between the two scans, the halothane was stopped and the monkey regained consciousness.It was then reanesthetizedwith pentobarbitalfor the secondscan sequence.

[email protected] 0.50

Decarboxylase Inhibition To illustratethe value ofthe double-scan technique for study ing pharmacologic manipulation of the dopaminergic pathways,

experimentswere conducted on three monkeys in which NSD 1015(an inhibitor of peripheraland central L-aromaticamino acid decarboxylase) was administered by intraperitoneal injection of a suspension in isotonic saline between the two scans. The

3 Time

dosesof inhibitoremployedand the timing ofthe injection(1 hr

(hours)

before the second ID injection) were chosen to produce a maxi mal enzyme inhibition after the time of the second ID injection FIGURE1. Correction ofmeasured striatalregional intensities (14—16). in the secondscan sequenceof the double-scanprotocol for the residuesfrom the first scan sequence.Squarepoints and contin RESULTS uous Iine=measuredstnatal AOl intensities following first and second FD injections (at 0 and 2.6 hr on the abscissa). Filled Single Scan Protocol square points=data used for fitting the monoexponentialdecay Figure 3 shows a MM image together with the corre function

(showed

extended

to 5 hr postinjection

as the dOtted

line).Crossesand broken Iine=correctedAOl regionalintensities forsecondscansequence.

sponding PET-FD image (with its ROl placement) and a 3-OMe-6FD image from the same cynomolgus monkey. Figure 4 shows images obtained in two separate single scan protocols conducted

Anesthesia PET scans on monkeys are ordinarily performed with the subjectanesthetized.It has been reported that sodium pentobar bital and halothane

alter dopamine

metabolism

in the rat (12,

13). Pentobarbital anesthetic has been used in PET-ID scanning on monkeys both in previous work (4) and initially in the present

studies, prior to a change to the less-invasivehalothane. The double-scanprotocol was used to compare ID uptake constants measuredwithpentobarbitalwiththosemeasuredwith halothane

U)

on the same monkey. Table 1

shows the results calculated from 16 such measurement sequences, two each from eight monkeys. The second scans followed the first ones by 2 wk or more, and therefore involved repeated positioning of the monkey within the tomograph. Uptake values are shown separately for the left and right striata, although these data are correlated (the average left-right differences in unlesioned animals being 3.3% ±8.8% sd.). For the left and right sides separately,the averagepercent difference between the con stants derived from the first and second scans was calcu lated together with its standard deviation, as seen at the bottom of Table 1. The average of the standard deviations from left and right was 34.4%. Double-Scan Protocol

a

C)

Figure 5 shows images summed from those obtained between 50 and 120 mm after FD injection in the firstand second scan sequences of the double-scan protocol and their difference.

a

0 0

FIGURE 3. Sliceimages, summedfrom images meas

ured between50 and 120

CYNON

MONKEY -

mm afterFD injection, and

centered on the striata of a

cynomolgusmonkey. Top FIGURE2. Correction of measured bloodplasmaFDactivity left:MRIscan.Topnght:PET in the second half of the double-scanprotocol for the residues scan with FD tracer. In this from the first half. Square points and continuousline=measured and all subsequentfigures, blood plasmaFD activity followingfirst and second FD injections the numbers on the color

(at 0 and2.5 hr on the abscissa).Filledsquares=datausedfor scale are measuredevents fittingthepolynomial function,ShOWn extendedto 5 hr poslinjec (counts)per pixel. Bottom: tion as the dotted line.Crossesand broken line=correctedbiood

plasmaFDactivityfor secondscansequence.

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PET scan with 3-OMe-FD tracer.

[email protected] PETOLGIJS 3-ONE-PDI•..

[email protected]

The Journalof NuclearMedicine• Vol. 32 • No. 6 • June1991

@

[email protected] HORNALSINGLE FIGURE

4. PET-FD im

FIGURE5. Summed back to-backPET-FDscanimages ofa normalcynomolgus mon

j0, HORNALDOUBLE

agesfrom a normalcynomol gus monkeyand the stnatal uptake constants derived from themby graphicalanaly sis.Thetwo scansweresap

aratedbyseveralweeks.The

________________________

0

208

imagesare displayedon a common intensity scale and are the summationof images measured between 50 and 120 mmafterFD injection.

experiments.

0.183

0.181

0

U5

age.

I..e.eø7—0.011

iN

administered between the scans and from the difference

Tables 2 and 3 show the striatal ID uptake constants obtained in 10 double-scan

key. Top left: first scan im

age.Top right:secondscan image.Bottom:differenceim

image. Table 4 shows the results from similar experiments

In Table 2, the

data from the second of the two scans have not been corrected for radioactivity residues from the first scan sequence, whereas in Table 3 they have been corrected. The percent difference in constants from the two scans is calculated separately for the left and right striata for each

monkey, as are the averages and standard deviations of these quantities.

on this and two other subjects without residuecorrections. DISCUSSION We have shown that back-to-back PET scanning can reduce scan-to-scan variability in monkeys to a standard BEFORE HSO 1B15 AFTER

Effect of Change in Anesthetic

Striataluptake data values obtained with the halothane and pentobarbital anesthetic regimes are shown in Table

FIGURE 6. Summedback to-back PET-FDscanimages of a cynomolgusmonkey.

4. The change in anesthetic did not produce a significant

change in the striataluptake constants.

0

138

0

132

0 013

-0

002

Left:normal.Right:afteri.p.

NSD 1015 Figure 6 shows the images and uptake constants ob tamed (after the above corrections) from the first and second scan sequences on one monkey with NSD 1015

in 0

123

0

13?

administrationof NSD 1015 (centraldecarboxylaseinhib itor). Bottom: difference im age.

TABLE I Reproducibility of Striatal Uptake Constants in Rhesus andCynomolqus Monkeys Single-Scan ProtocolStriatal —SpeciesSubjectSide(mI.st,iatum'

(scan2 1, % of

uptakeconst.Difference mean)1st .min1)scan

ARhesusCL

scan

2ndscanL 0.341

—0.3CynomolgusFL

A0.329

0.343

0.342+3.6

—10.3CynomolgusHL

A0.173

0.194

+32.6CynomolgusHL

A0.184

0.205

+30.2CynomolgusIL

A0.208

0.183

—53.4CynomolgusXL

A0.239

0.243

0.164 0.175—2.3 0.284 0.285+42.7 0.275 0.248+27.7 0.405 0.420—51.6

—12.2CynomolgusXL

A0.163

0.131

0.172 0.116+5.4

—5.5CynomolgusZL

A0.163

0.131

0.125—24.1

A0.144

0.170

0.259 +54.3Means: 0.297+57.1

0.128

Standarddeviations: Averagestandarddeviation:+7.31

Reproducibility of Stnatal Uptake Data • Pate at al

+4.4 33.6

35.3

34.4%

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TABLE 2 Reproducibility of Stnatal Uptake Constants in Rhesus and Cynomolgus Monkeys Double-ScanProtocol—Without text)Striatal ResidueCorrection(see

—Species(ml.sttiatum'

uptakeconst.

mean)Subject ARhesusC

.min') Side

Difference (scan2 scan1, % of

1st scan

2ndscan

L +11.6

L

0.315

0.354

—14.8RhesusE

A

0.189

0.163

L

0.280

0.210

—2.7CynomolgusG

A

0.267

0.260

L A

0.239 0.236

0.206 0.202

—14.8

—15.5CynomolgusH

—28.6

L

0.208

0.207

—0.5

A L A L

0.183 0.275 0.248 0.184

0.260 0.232 0.166

—5.6

—4.4CynomolgusH

A

0.163

0.156

L

0.249

0.207

—27.5CynomolgusI

A

0.240

0.182

L A L A L A

0.405 0.420 0.242 0.121 0.215 0.207

0.357 0.415 0.204

—12.6

0.170 +3.3Means: 0.214

—23.3

—46.9

—11.9 11.6

—10.8 16.3

0.198CynomolgusH —6.6CynomolgusH

—1.2CynomolgusI 0.075CynomolgusZ

Standarddeviations:

+7.9

—10.3

—18.4

—17.0

Average standard deviation:

14.0%

TABLE 3 Reproducibility of Stnatal Uptake Constants in Rhesus and Cynomolgus Monkeys text)SpeciesStnatal Double-ScanProtocol—With ResidueCorrection(see uptakeconst. (ml-stnatium' .min')

mean)Subject ARhesusC

Side

1st scan

2nd scan

L +26.4

L

0.315

0.411

—4.9RhesusE

A

0.189

0.180

+11.4CynomolgusG

L A L

0.280 0.267 0.239

0.183 0.283 0.185

—26.9CynomolgusH

A

0.236

0.180

L

0.208

0.181

—4.5CynomolgusH

A L A L A L

0.183 0.275 0.248 0.184 0.163 0.249

0.175 0.236 0.212 0.149 0.142 0.189

A

0.240

0.164

—15.7CynomolgusH —13.8CynomolgusH —37.6CynomolgusI

—18.9CynomolgusI —58.8CynomolgusZ

L A L A —40.9A L

0.405 0.420 0.242 0.121 0.215 , 0.207

—41.9 —25.5

—13.9 —15.3 —21.0 —27.4

0.298 —30.4 0.349 0.192 —23.0 0.066 0.142 0.186 —10.7Means:

Standarddeviations: Averagestandarddeviation:

1250

Difference(scan2 — scan1, % of

—21 .3 19.2

—18.0 19.5 19.4%

The Journalof NuclearMedicine• Vol. 32 • No. 6 • June1991

TABLE 4

Effectsof AnestheticProcedureand DecarboxylaseInhibitorAdministration Double-ScanProtocol—Without ResidueCorrection text)Stnatal (see const.SpeciesDose

uptake striatum1.min')Difference

(mg/ Agent scanCyno.Halothane,

kg, p.)Side(ml. thenPentobarbitalL

+4.8Cyno.NSD

1015

2nd

(%of 1st

0.269 A0.260

0.293

0.307+3.4

A0.078

0.074

0.029—66.7

A0.138

0.132

A0.276

0.284

80L

—60.8Cyno.NSD

1015 —89.4RhesusNSD 1015

st scan scan)1

0.026

77L 36L

0.027 0.014—80.4 0.043 0.073—84.4

—74.3

deviation of 14.0%, down from 34.4% with separate scans.

MedicalResearchCouncil of Canada and by the DystoniaMcd

This improved reproducibility allows better assessment of

ical Research Foundation.

the effects of pharmacologic agents on the dopaminergic REFERENCES system. 1. Garnett ES, Firnau G, Nahmias C. Dopamine visualized in the basal The poor reproducibility observed with the single-scan ganglia ofliving man. Nature 1983;305:137—138. technique is believed to result largely from the 1—2-mm 2. Martin WRW, Stoessi AJ, Adam Mi, ci al. Positron emission tomography in Parkinson's disease: glucose and dopa metabolism. In: Yahr MD, repositioning error, which is exacerbated by the large par Bergmann KJ, eds. Parkinson ‘s disease. Advances in neurology. New York: tial volume factors resulting from small monkey striata. Raven Press; 1986:95—98. Other contributions may come from fluctuations in tom 3. CaIne DB, Langston JW, Martin WRW, et al. Positron emission tomog

ograph performance, variations in specific activity of H) tracer, or altered biologic factors. The double-scan protocol substantially reduces these sources of variability. Table 2 shows an average 11.4% reduction in striatal

uptake constant during a double-scan protocol. This is smaller than the average standard deviation of the data shown in Table 2 and much less than the variability of the

data from the single-scan protocol in Table 1. The origin of this reduction

is not evident.

It was shown in trial

experiments that repeating the carbidopa injection prior to the second scan did not remove this effect; neither did varying the carbidopa quantity injected between 2 and 8 mg/kg. No difference was observed when fresh H) prepa rations (of closely similar specific activity) were used for each of the injections in the double-scan protocol or when aliquots drawn from the same original stock were used (in which case the specific activity of the second quantity injected would be reduced by more than a factor of 2). Further studies are needed to elucidate this point. The highly significant reduction in striatal H) uptake reported in Table 4 indicates that H) is a substrate for aromatic amino-acid decarboxylase and that H) decarbox ylation is a necessary process for the generation of the

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striatal intensities seen in PET-H) images. ACKNOWLEDGMENTS

14. 15.

The authors acknowledgethe valuable contribution to this work by Dr. M.J. Adam, C. Schofield, S. Jivan of the UBC/ TRIUMF PET group, by the operating team of the TRIUMF CP42 cyclotron, and by Dr. J. Love and the personnel of the UBC Animal Care Centre. This work was supported by the

Reproducibility of Stnatal Uptake Data • Pate et al

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1986;27: 1462—1466. Boyes BE, Cumming P, Martin WRW, McGeer EG. Determination of plasma [‘8F1-6-fluorodopa during positron emission tomography: elimina tion and metabolism in carbidopa-treated subjects. Life Sci l986;39:2243— 2252. Huang SC, Bahn MM, Barrio JR, et al. A double-injection technique for in vivo measurement of dopamine D-2 receptor density in monkeys with 3-(2'.['8F]Fluoroethyl) spiperone and dynamic positron emission tomog raphy. J Cereb Blood Flow Metab 1989;9:850—858. Ford APDW, Marsden CA. Influence of anaesthetics on rat striatal dopa mine metabolism in vivo. Brain Res 1986;379:l62—l66. Stahle L, Collin A-K, Ungerstedt U. Effects of halothane anaesthesia on extracellular levels ofdopamine, dihydroxyphenylacetic acid. homovanillic acid and 5-hydroxyindolacetic acid in rat striatum: a microdialysis study. Arch Pharmacol 1990;342:l36—140. Modigh K. Effects of L-Tryptophan on motor activity in mice. Psycho pharmacologia 1973:30:123—134. Bartholini 0, Pletscher A. Effect ofvarious decarboxylase inhibitors on the cerebral metabolism of dihydroxyphenylalanine. J Pharm [email protected] 1969:21:323—324. Carlsson A. Davis JN, Kehr W. Lindquist M. Mack CV. Simultaneous measurement of tyrosine and tryptophan hydroxylase activities in brain in vivo using an inhibitor of the aromatic amino acid decarboxylase. Arc/i Phar,nacol 1972:275:153—168.

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