Proc. Natl. Acad. Sci. USAVol. 93, pp. 10388-10392, September 1996Medical Sciences

Relationship between psychostimulant-induced "high" anddopamine transporter occupancy

(methylphenidate/positron-emission tomography/reinforcement/cocaine treatment)

N. D. VOLKOW*tt, G.-J. WANG*, J. S. FOWLER*, S. J. GATLEY*, Y.-S. DING*, J. LOGAN*, S. L. DEWEY*,R. HITZEMANNt, AND J. LIEBERMAN§*Medical and Chemistry Departments, Brookhaven National Laboratory, Upton, NY 11973; tDepartment of Psychiatry, State University of New York,Stony Brook, NY 11794; and §Hillside Hospital, Glen Oaks, NY 11004

Communicated by Alfred P. Wolf, Brookhaven National Laboratory, Upton, NY, June 19, 1996 (received for review February 8, 1996)

ABSTRACT The ability ofcocaine to inhibit the dopaminetransporter (DAT) appears to be crucial for its reinforcingproperties. The potential use of drugs that produce long-lasting inhibition of the DAT as a mean of preventing the"high" and reducing drug-seeking behavior has become amajor strategy in medication development. However, neitherthe relation between the high and DAT inhibition nor theability to block the high by prior DAT blockade have ever beendemonstrated. To evaluate if DAT could prevent the highinduced by methylphenidate (MP), a drug which like cocaineinhibits the DAT, we compared the responses in eight non-drug-abusing subjects between the first and the second of twoMP doses (0.375 mg/kg, i.v.) given 60 min apart. At 60 min thehigh from MP has returned to baseline, but 75-80%o of thedrug remains in brain. Positron-emission tomography and["C]d-threo-MP were used to estimate DAT occupancies atdifferent times after MP. DAT inhibition by MP did not blockor attenuate the high from a second dose ofMP given 60 minlater, despite a 80%o residual transporter occupancy from thefirst dose. Furthermore some subjects did not perceive a highafter single or repeated administration despite significantDAT blockade. These results indicate that DAT occupancy isnot sufficient to account for the high, and that for DATinhibitors to be therapeutically effective, occupancies >80%omay be required.

Cocaine addiction is one of the most devastating of thebehavioral diseases. Despite its seriousness, there are noeffective treatment medications. This has prompted a majoreffort in the development of pharmacological agents to treatcocaine addiction. One of the main strategies is the develop-ment of medications that would interfere with cocaine bindingto the dopamine transporter (DAT) and block its effects (1).This "cocaine substitute" strategy is based on the good cor-relation found between the affinities of cocaine and cocainelike drugs for the DAT and their reinforcing effects (2, 3) andthe fact that the "high" is associated with the fast uptake ofthese drugs in brain but not with their continuous presence (4).However, neither the relation between the high and acuteDAT inhibition nor the ability to block the high by long lastingDAT inhibitors has ever been demonstrated.

In this study we evaluated the relationship between DATblockade and the high using methylphenidate (MP) as thepharmacological challenge. MP was used because it has similarreinforcing properties to those of cocaine (5, 6) [its affinity forDAT is about twice that of cocaine (2)], its intravenousadministration induces a high indistinguishable from that ofcocaine (7), and it has longer pharmacokinetics than cocaine(half life in striatum >90 min versus 20 min for cocaine) whichallows its repeated administration while there is still significant

DAT blockade (4). We tested the ability to block or attenuatethe high by prior DAT blockade by comparing the responsesbetween the first and the second of two MP doses given 60 minapart. At 60 min the high from MP has returned to baseline,but the brain retains 75-80% of the peak drug concentration(4). Thus the two sequential dose strategy allowed us toevaluate the effects that DAT inhibition by the first dose hadon the perception of the high induced by the second dose. Wealso assessed the relation between DAT occupancy and thesubjective perception of the high after single and after twosequential doses of MP. Occupation of DAT by MP wasmeasured with positron-emission tomography (PET) using[11C]d-threo-MP (the labeled active isomer of MP) as a DATligand (8). Four scans, including a baseline, were obtained ineach subject to estimate MP-induced DAT occupancies at thetimes when the high induced after a single and after twosequential doses of MP occurs and to estimate DAT occupan-cies at 60 min after MP, which was the time selected to give thesecond of the two sequential MP doses.

METHODSSubjects. Subjects were nine normal healthy male volunteers

(25-35 years of age), who were screened for absence ofmedical, neurological, or psychiatric disease. Care was taken toexclude subjects with a past or present history of alcohol ordrug use (except for caffeine). Urine toxicology tests wereperformed to ensure absence of psychoactive drug use. Studieshad been approved by the Human Studies Review Committeeat the Brookhaven National Laboratory and have thereforebeen performed in accordance with the ethical standards laiddown in the Declaration of Helsinki. Informed consents wereobtained from all subjects after the nature of the procedureswere explained.

Behavioral and Cardiovascular Measures. The behavioraland cardiovascular effects induced by the administration ofMP (0.375 mg/kg, i.v.) were recorded in these subjects. Thesemeasures were obtained before and periodically after admin-istration of each dose ofMP. Behavioral effects were evaluatedby using analog scales that assessed the subjective perceptionof "high," "anxiety," and "restlessness" (defined as need tomove). The interviewer (G.-J.W.) asked the subjects to ratetheir subjective experience from 0 (felt nothing) to 100 (feltintensely). The scales were completed 5 min prior and everyminute for 20 min after each MP administration and then at5-min intervals thereafter. For comparison purposes, theindividual's responses were normalized to the subjects maxi-mal response and expressed as percent from this maximum.

Abbreviations: DAT, dopamine transporter(s); MP, methylphenidate,DV, distribution volume; PET, positron-emission tomography; DA,dopamine.tTo whom reprint requests should be addressed.

10388

The publication costs of this article were defrayed in part by page chargepayment. This article must therefore be hereby marked "advertisement" inaccordance with 18 U.S.C. §1734 solely to indicate this fact.

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Electrocardiographic recording, blood pressure, and pulserate were obtained every 15 min for 30 min prior to and at 2,4, 6, 8, 10, 15, 20, 30, 40, and 60 min after each dose of MP.The cardiovascular effects were quantified with respect to thevalues obtained before MP and then normalized with respectto the maximal change and expressed as percent of that value.

Scans. PET studies were carried out with a Siemens CTI 931tomograph (6 x 6 x 6.5 mm full-width half maximum, 15slices) using [11C]d-threo-MP. Eight of the subjects underwentfour scans done on different days: study 1 was done 7 min afterplacebo and was used as baseline; study 2 was done 7 min afterMP to estimate DAT occupancies when the high after a singledose occurs; study 3 was done 60 min after MP to estimateDAT occupancies at the time when the second MP dose wasto be given; and study 4 was done 7 min after the second of twosequential doses of MP given 60 min apart to estimate DATwhen the high from the second dose would occur. Subjectswere blind to the drug received, and the order of the scans wasvaried to optimize scheduling procedures. In addition, three ofthe subjects were scanned twice 60 min after MP administra-tion to assess reproducibility of the occupancy measures.Methods for positioning and repositioning of subjects in thetomograph, alignment, arterial and venous catetherization,transmission scans, blood sampling, and blood analysis havebeen published (8). Briefly, emission scans were started im-mediately after injection of 4-8 mCi (1 Ci = 37 GBq) of[11C]d-threo-MP (specific activity >0.4 Ci/,umol at time ofinjection). A series of 20 emission scans were obtained fromtime of injection up to 84 min (four 15-sec scans, two 30-secscans, four 1-min scans, four 2-min scans, five 10-min scans,and one 20-min scan). Arterial sampling was used to quantitatetotal carbon-11 and unchanged [11C]d-threo-MP in plasma andto measure the concentration of MP at 20 and 60 min aftereach dose, using procedures previously described (8). Wecompleted the four scans in six of the eight subjects evaluatedand test-retest scans in three subjects.Image Analysis. Regions of interest in striatum and cere-

bellum were drawn directly on an averaged emission image(images obtained between 15 to 84 min) as described (8).These regions were then projected into the dynamic images to

generate time activity curves for striatum and for cerebellum.These time activity curves for tissue concentration along withthe time activity curves for unchanged tracer in plasma wereused to calculate the distribution volume (DV) in striatum (ST)and cerebellum (CB) using a graphical analyses technique forreversible system (Logan Plots) (9). The ratio of the DV instriatum to that in cerebellum (DVST/DVCB) was used asmodel parameter. This ratio corresponds to (Bm.a,/Kd) + 1 andis insensitive to changes in cerebral blood flow (10). Theconcentration of MP in plasma was quantified using capillaryGC/mass spectrometry for samples taken 27 and 60 min afterthe first MP dose, and for samples taken 27 and 67 min afterthe second dose (87 and 127 min after the first dose).

Differences in DAT occupancy at baseline and at 7 and 60min after MP administration and between baseline measuresand the behavioral and the cardiovascular effects of MP weretested with paired t tests. Pearson product moment correlationanalysis was done between the estimates of DAT occupancyobtained for the different studies and their corresponding highmeasures. We also measured the correlation between theestimates ofDAT occupancies at 60 min and the high after thesecond of the two sequential doses of MP to assess if DAToccupancies at the time that MP was given would predict theresponse to the high.

RESULTSMP pretreatment significantly reduced the binding of ['1C]d-threo-MP at 7 and at 60 min after a single dose (Fig. 1) and at7 min after the second of two sequential doses (P < 0.0001).The estimates for BmjxcaKd were reduced from a baseline valueof (mean ± SD) 1.81 ± 0.3 to a values of 0.29 ± 0.2 at 7 minand of 0.36 ± 0.1 at 60 min after a single injection of MP anda value of 0.13 ± 0.1 at 7 min after the second of the twosequential doses (Table 1). This corresponds to a DAT occu-pancy by MP of 84 ± 7% at 7 min and of 80 ± 7% at 60 minafter a single dose and of 93 ± 6% at 7 min after the secondof two sequential doses. Estimates of occupancy for the threesubjects that were scanned twice 60 min after MP adminis-tration were highly reproducible and corresponded for the first

FIG. 1. Brain images obtained with [11CJd-threo-MP in a subject tested after placebo (baseline) and 7 min and 60 min after MP administration(0.375 mg/kg, i.v). MP inhibited the binding of [11C]d-threo-MP in striatum and significant inhibition was still present 60 min after MPadministration.

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Table 1. Values for Bmax/Kd and plasma MP concentration

Bmax/Kd Plasma MP concentration study 4 (ng/ml)Subject Study 1 Study 2 Study 3 Study 4 27 min 60 min 87 min 127 min

1 1.97 0.48 0.47 0.29 92 61 149 832 1.79 0.19 0.25 91 58 141 923* 1.65 0.34 0.31/0.36 0.21 85 54 127 784 2.08 0.34 0.65 0.04 112 81 189 1245 1.50 0.26 0.40 0.00 138 118 238 1606* 2.20 0.21/0.30 145 70 114 767 1.36 0.12 0.16 0.13 90 66 150 1018 1.98 0.14 0.45 0.14 86 62 133 859* 1.72 0.35/0.37

Meant SD 1.8 ± 0.3 0.3 ± 0.1 0.4 ± 0.1 0.1 ± 0.01 104 ± 24 71 ± 20 155 ± 40 100 ± 28Data are for individual values for Bmax/Kd {distribution volume ratios for [11C]d-threo-MP in striatum to that in cerebellum (DVST/DVCB) - 1}

and for plasma methylphenidate concentration at different times after methylphenidate administration. Study 1 corresponds to the scan done afterplacebo (baseline), Study 2 corresponds to the scan done 7 min after MP, Study 3 to the scan done 60 min after MP, and study 4 to the scan done7 min after the second of two MP doses given 60 min apart. Plasma concentrations for study 4 are given for the measures taken at 27 and 60 minafter the first dose (just prior to the second dose), and at 27 and 67 min after the second dose (87 and 127 min from the first dose).*These subjects were scanned twice 60 min after administration of MP to assess test-retest reproducibility of occupancy measures.

and second measurements, respectively, to 81% and 78% forsubject 3; 90% and 86% for subject 6; and 80% and 78% forsubject 9.MP induced a "high" and increased "anxiety" and "rest-

lessness" all the times it was administered in most of thesubjects. The individual's reports of the high for the threedifferent studies are shown in Table 2. The behavioral re-sponses to MP, including those for the high, were significantwhether the drug was given as a single injection or whether itwas given in the sequential pattern. MP increased heart rate(61 ± 18% from baseline) and systolic (35 ± 7% from baseline)and diastolic blood pressure (20 ± 9% from baseline) in allsubjects, including the subjects (subjects 2, 5, and 8) whoreported minimal perception of high to the two sequential MPdoses (study 4) (Table 2). Also, two of these three subjects(subjects 2 and 5) reported significant behavioral effects withMP despite a minimal perception of the high (data not shown).The peak responses for the subjective behavioral measures,

including the high did not differ for the responses recordedwith the two sequential doses (Fig. 2). In fact the subjectiveperception of the high after the second dose of MP was of asimilar magnitude to that experienced after the first dose, inspite of the very different starting DAT occupancies (0 and80%, respectively) (Fig. 2). The only cardiovascular effectwhich was found to be significantly lower in the second than inthe first sequential dose was diastolic blood pressure (paired ttest; P < 0.05) (Fig. 2).There was no relation between the level of DAT occupancy

and the subjective perception of the high for the data obtainedduring study 2 and study 3. However there was a significantnegative correlation for study 4 (r = 0.91, df 5, P < 0.02) (Fig.

3). When two sequential doses were given, the one subject whodid not experience any high had 100% DAT occupancy(subject 5) and another who experienced a minimal high had93% DAT occupancy (subject 8). The correlation between theestimates of DAT occupancies at 60 min, a measure that wasfound to be highly reproducible in a given subject, and the highafter the second of the two sequential doses of MP was notsignificant (r = 0.14, df 7, P > 0.7). Fig. 4 shows the individualvalues for the occupation of the DAT measures (obtainedduring studies 2, 3, and 4) along with the subjective scores ofthe high measures obtained in study 4 (two sequential doses).

DISCUSSIONIn contrast to the predictions of the "cocaine substitute"concept, in this study we were unable to block the high by priorDAT blockade. Therefore, these results do not support the useof long-lasting DAT blocker drugs as an interventional strat-egy to block cocaine's reinforcing effects. The failure toprevent the high by preblocking the DAT might be explainedby the relationship between DAT occupancy and concentra-tion of dopamine (DA) in the synapse or the relationshipbetween synaptic DA and activity of reward pathways. Theserelationships are currently unknown. However, one couldpredict that if there is an excess of DAT, then a significantpercentage may need to be initially inhibited to modify DAconcentration, after which, additional inhibition would resultin proportionally larger changes in DA. Therefore the possi-bility cannot be excluded that changes in occupancy between0-84% and 80-93% could induce similar changes in DAconcentration and/or activation of reward pathways. This

Table 2. Behavioral (high) and cardiovascular responses to MP

High Heart rate Blood pressure

Subject 2 3 4.1 4.2 4.0 4.1 4.2 4.0 4.1 4.2

1 90 85 90 100 68 113 115 78/119 77/159 72/1542 95 15 20 30 67 128 91 77/116 95/168 86/1643 80 60 60 80 68 97 103 77/115 100/166 102/1634 30 20 50 36 58 105 88 80/126 98/177 98/1775 70 40 0 0 77 108 113 81/131 95/171 84/1706 60 60 40 40 87 140 126 87/134 103/175 102/1577 70 90 30 60 60 91 85 73/120 90/161 91/1718 37 15 10 20 66 101 92 70/126 86/166 86/165Subjective perception of the high at the time of maximal response for the various studies (2-4) when MP was administered and peak cardiovascular

responses to the two sequential doses of MP (study 4). Measurements correspond to the study when MP was given to assess occupation at 7 min(study 2); at 60 min (study 3); and after two sequential doses (study 4). For study 4, two doses were given and hence two responses for the highwere recorded (studies 4.1 and 4.2). Cardiovascular responses are reported only for study 4 and correspond to baseline (4.0), peak from first dose(4.1), and peak from second dose (4.2).

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Behavioral Measures

Cardiovascular Measures

ITMr (Miu.)

FIG. 2. Time course for the behavioral and the cardiovasculareffects for the two sequential doses of MP (average of eight subjects).Values are expressed as percent change from maximum along with thestandard errors for the measurements. Peak responses for thesesubjective behavioral measures, including the high did not differ forthe two sequential doses. The only cardiovascular effect that was foundto be significantly lower in the second than in the first dose wasdiastolic blood pressure (paired t test; P < 0.05). Black bars in the xaxis denote time points where measures were significantly higher thanbaseline (paired t test; P < 0.01).

possibility is therapeutically relevant because it implies thatalmost total DAT occupation may be required for medicationsto be effective in preventing cocaine's effects. Inducing partialoccupancy of DAT with a "therapeutic" medication mighteven enhance the high experienced after self-administration ofcocaine. For MP, a 0.375 mg/kg i.v. dose induced 84% DAToccupancy whereas a 0.5 mg/kg i.v. dose induced 91% occu-pancy (4), which indicates that very high doses may be requiredto achieve nearly complete DAT occupancy. Insufficient DAToccupancy could explain why mazindol is ineffective in mod-ifying the high from cocaine (11) as well as accounting for itslack of therapeutic efficacy in cocaine addicts (12) and why theuse of MP to treat cocaine abusers increased cocaine cravingand consumption (13).

In this respect it is interesting to note that while thecorrelations between DAT occupancy and high were notsignificant for studies 2 and 3, where the average occupancieswere 84% and 80%, respectively, they were negatively corre-lated in study 4 were the average occupancies were 93%.Though the latter finding is on a very small sample (n = 6), onecould still argue that there is a threshold DAT occupancy(=90%) after which higher occupancies will not induce a high.

STUDY 2100 . -

*0

60. 0

40 . 040~~~~

20

0 20 40 60 80 100DAT Occp0c

STUDY 3 STUDY 4. . .. . . . ..

100 100

80. 80

60 .0 60

40 . 40

20 20

0[ 010 20 40 60 80 100 0 20 40 60 80 100

DAT Ocuncy DAT Oc0ancy

FIG. 3. Relation between DAT occupancy and the subjectiveperception of the high for the three studies when MP was adminis-tered. Correlations were not significant for study 2 (r = 0.26, df 7, P >0.5) (occupancy measured 7 min after MP) and for study 3 (r = 0.36,df 8, P > 0.3) (occupancy measured 60 min after MP) but showed anegative correlation for study 4 (r = 0.90, df 5, P < 0.02) (occupancymeasured 7 min after the last of two sequential doses of MP). For study4 the values for the high are those reported after the last of the twosequential doses.

100 ub9 6

seo

40. 40.

283% 100%

0 0120 180 00 60 120 180

FIG. 4. Individual response to the subjective perception of the high(rated from 0 to 100) after the two sequential MP doses. Theindividual's DAT occupancies (estimated as percent change frombaseline Bmax/Kd) at 7 min (study 2) and at 60 min after the first MPdose (study 3) and at 7 min after the second dose (study 4) are includedat their corresponding time points. In contrast to the large intersubjectvariability in the perception of the high (range after 7 min of the firstdose, 0-90), the rates of DAT occupancies were much less variable(range after 7 min of the first dose, 75-93%). This dissociation ishighlighted in subject 5 who did not perceive the high despite 83%DAT occupancy after the first of the two doses and 100% DAToccupancy after the second dose. For the rest of the subjects, exceptfor subject 4, the second dose of MP elicited a similar or higherresponse than the first dose.

However, this is unlikely since the subjects who had a minimalor no high during the sequential dose design had the sameresponse for the first than for the second of the two sequentialdoses when their DAT occupancies were lower. In thesesubjects the cardiovascular responses to MP were as robust asthose in subjects who perceived the high replicating ourprevious findings of a dissociation between the behavioral andthe cardiovascular effects of MP (14). Future studies arerequired to determine if DAT occupancies >90% will blockthe high and to assess the cardiovascular responses at theselevels of DAT occupancies.Another possible explanation for our findings is that mech-

anisms other than DAT blockade are involved in the subjectiveperception of the high. This is supported by the lack ofcorrelation between the individual's level of DAT occupancyand their perception of the high for studies 2 and 3 and thenegative correlation for study 4, and by the temporal dissoci-ation observed between the short lasting high and the longlasting occupancy of the DAT (14). This dissociation cannot beexplained as acute tolerance (15), since the high was elicited bya second dose given while DAT were still inhibited by the priordose. Furthermore the fact that some drugs with higher affinityfor the DAT than cocaine, such as mazindol (16), are not

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perceived as pleasurable by humans (17) and that DA antag-onists do not block cocaine-induced high (18) suggest thatother neurotransmitters, in addition to DA, may be involved inthe high.Though the PET measures for this study were made in the

dorsal striatum and not in the nucleus accumbens, the struc-ture associated with drug reinforcing properties (19), DAToccupancy by MP should not differ significantly between thesetwo brain regions (20). Also, we evaluated the response to MPand not to cocaine; and though both drugs have similarreinforcing properties (5) it is cocaine which is the target oftherapeutic interventions. Thus, further studies should be donewith cocaine in cocaine addicts. Our results lead us to bringinto question the feasibility of using DAT inhibitors to blockthe high. However, it is possible that these drugs could bebeneficial in treating cocaine addiction by affecting variablessuch as craving, drug seeking behavior, and dysphoria (21).The results from this study also need to be considered in lightof the limitations imposed by the subjectiveness of the quan-tification of behavioral states and the imprecision of termssuch as "high" and "euphoria."

In summary, this study did not find a relationship betweenDAT blockade and the high, except for the negative correla-tion when DAT occupancies were close to 100%. This wouldsuggest that other neurotransmitters, in addition to DA, arevery likely to be involved in the reinforcing properties ofpsychostimulant drugs in humans and that DAT blockadeslarger than 80% may be required to prevent the high fromcocaine. However, toxicity at these doses may limit this ap-proach. Furthermore insufficient DAT blockade may enhancecocaine effects. The possible involvement of neurotransmittersother than DA in psychostimulants-induced high should beevaluated. This may lead to identification of alternative targetsfor development of medications able to prevent cocaine'seffects.

We thank David Schlyer, Robert Carciello, and Babe Barrett forCyclotron operations; Alex Levy, Naome Pappas, and Donald Warnerfor PET operations; Christopher Wong for data management; ColleenShea, Payton King, and Robert MacGregor for radiotracer prepara-tion and analysis; Thomas P Cooper for MP plasma analysis; KathyPascani for subject recruitment; Noelwah Netusil for patient care; andCarol Redvanly for scheduling and organization. We also thank thevolunteers for their participation. This study was supported by the U.S.Department of Energy under Contract DE-ACO2-76CH00016 and theNational Institute of Drug Abuse Grant 09490-01.

1. Rothman, R. B. (1990) Life Sci. 46, 17-21.2. Ritz, M. C., Lamb, R. J., Goldberg, S. R. & Kuhar, M. J. (1987)

Science 237, 1219-1223.3. Madras, B. K, Fahey, M. A., Bergman, J., Canfield, D. R. &

Spealman, R. D. (1989) J. Pharmacol. Exp. Ther. 251, 131-141.4. Volkow, N. D., Ding, U., Fowler, J. S., Wang, G. J., Logan, J.,

Gatley, J. S., Dewey, S. L., Ashby, C., Lieberman, J., Hitzemann,R. & Wolf, A. P. (1995) Arch. Gen. Psychiatiy 52, 456-463.

5. Johanson C. E. & Schuster, C. R. (1975)J. Pharmacol. Exp. Ther.193, 676.

6. Bergman, J., Madras, B. K., Johnson, S. E. & Spealman, R. D.(1989) J. Pharmacol. Exp. Ther. 251, 150.

7. Wang, G.-J., Volkow, N. D., Hitzemann, R., Wong, C., Angrist,B., Burr, G., Pascani, K., Pappas, N., Lu, A., Cooper, T. &Lieberman, J. (1996) Eur. Addiction Res., in press.

8. Volkow, N. D., Ding, Y.-S., Fowler, J. S., Wang, G.-J., Logan, J.,Gatley, S. J., Schlyer, D. J. & Pappas, N. (1995)J. Nucl. Med. 36,2162-2168.

9. Logan, J., Fowler, J. S., Volkow, N. D., Wolf, A. P., Dewey, S. L.,Schlyer, D. J., MacGregor, R., Hitzemann, R., Bendriem, B.,Gatley, J. & Christman, D. R. (1990) J. Cereb. Blood Flow Metab.10, 740-747.

10. Logan, J., Volkow, N. D., Fowler, J. S., Wang, G.-J, Dewey, S. L.,MacGregor, R., Schlyer, D., Gatley, S. J., Pappas, N., King, P.,Hitzemann, R. & Vitkun, S. (1994) J. Cereb. Blood Flow Metab.14, 995-1010.

11. Preston, K L., Sullivan, J. T., Berger, P. & Bigelow, G. E. (1993)J. Pharmacol. Exp. Ther. 267, 296-307.

12. Stine, S. M., Krystal, J. H., Koster, T. R. & Charney, D. (1995)Drug Alcohol Depend. 39, 245-252.

13. Gawin, F. & Kleber, H. (1985) Am. J. Drug. Alcohol Abuse 11,193-197.

14. Volkow, N. D., Wang, G.-J., Gatley, S. J., Fowler, J. S., DingY.-S., Hitzemann, R., Logan, J., Wong, C. & Lieberman, J. (1996)Psychopharmacology 123, 26-33.

15. Foltin, R. & Fischman, M. W. (1991) J. Pharmacol. Exp. Ther.257, 247-261.

16. Seeman, P. (1993) Receptor Tables (S. Z. Research, Toronto),Vol. 2.

17. Chait, L. D., Uhlenhuth, E. H. & Johanson, C. E. (1987)J. Phar-macol. Exp. Ther. 242, 777-783.

18. Gawin, F. H. (1986) Psychopharmacology 90, 142-143.19. Pettit, H. O., Ettenberg, A., Bloom, F. E. & Koob, G. F, (1984)

Psychopharmacology 84, 167-173.20. Izenwasser, S., Werling, L. L. & Cox, B. M. (1990) Brain Res. 520,

303-309.21. Johanson, C. E. & Fischman, M. W. (1989) Pharmacol. Rev. 41,

3-52.

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