Blockade of Striatal Dopamine Transporters by Intravenous Methylphenidate Is Not Sufficient to Induce Self-Reports of High

Transcription

1 /99/ $03.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 288, No. 1 Copyright 1999 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 288:14 20, 1999 Blockade of Striatal Dopamine Transporters by Intravenous Methylphenidate Is Not Sufficient to Induce Self-Reports of High NORA D. VOLKOW, GENE-JACK WANG, JOANNA S. FOWLER, S. JOHN GATLEY, JEAN LOGAN, YU-SHIN DING, STEPHEN L. DEWEY, ROBERT HITZEMANN, ANDREW N. GIFFORD and NAOMI R. PAPPAS Brookhaven National Laboratory, Upton, New York (N.D.V., G.J.W., J.S.F., S.J.G., J.L., Y.S.D., S.L.D., A.N.G., N.P.); and Department of Psychiatry, State University of New York at Stony Brook, Stony Brook, New York (N.D.V., R.H.) Accepted for publication August 13, 1998 This paper is available online at ABSTRACT The reinforcing effects of cocaine and methylphenidate have been linked to their ability to block dopamine transporters (DAT). Using positron emission tomography (PET), we previously showed that intravenous cocaine induced a significant level of DAT blockade, which was associated with the intensity for self-reports of high in cocaine abusers. In this study, we measured DAT occupancies after intravenous methylphenidate and assessed whether they also were associated with the high. Occupation of DAT by intravenous MP was measured with PET using [ 11 C]cocaine, as a DAT ligand, in eight normal control subjects tested with different methylphenidate doses. The ratio of the distribution volume of [ 11 C]cocaine in striatum to that in cerebellum, which corresponds to B max /K d 1, was Received for publication May 13, This research was carried out at Brookhaven National Laboratory under support by the U.S. Department of Energy Office of Health and Environmental Research under Contract DE-ACO2 98CH10886 and by the National Institute on Drug Abuse Grant DA used as measure of DAT availability. In parallel, self-reports of high were measured. Methylphenidate produced a dose-dependent blockade of DAT with an estimated ED 50 of mg/kg. DAT occupancies were significantly correlated with the high (p.03). However, four of the eight subjects, despite having significant levels of DAT blockade, did not perceive the high. Methylphenidate is as effective as cocaine in blocking DAT in the human brain (cocaine ED mg/kg), and DAT blockade, as for cocaine, was also associated with the high. However, the fact that there were subjects who despite significant DAT blockade did not experience the high suggests that DAT blockade, although necessary, is not sufficient to produce the high. Methylphenidate (Ritalin) (MP), a drug used widely to treat children with attention deficit disorder (Carrey et al., 1996), blocks the dopamine transporters (DAT) (Ritz et al., 1987), which is an effect that has been linked to the reinforcing effects of cocaine as assessed by the good correlation between the affinity of drugs for the DAT and their reinforcing effects (Ritz et al., 1987). Methylphenidate (MP) has been shown to be self-administered by nonhuman primates in which it was shown to have equivalent reinforcing effects to those of cocaine (Johanson and Schuster, 1975; Bergman et al., 1989). When MP was administered intravenously to cocaine abusers, it induced a high that was reported to be almost indistinguishable from that induced by i.v. cocaine (Wang et al., 1997). MP has also been shown to be abused by humans, although its abuse is much less frequent than that of cocaine (NIDA-CEWG, 1995) and is predominantly restricted to the i.v. route of administration (Parran and Jasinski, 1991). Although the much less common use of MP than of cocaine could reflect market availability and drug trends, it also is possible that it reflects pharmacological differences between the two drugs, such as in vivo efficacy to block DAT and/or differences in pharmacokinetics (Volkow et al., 1995). Thus, the concern about the potential abuse liability of MP (Parran and Jasinski, 1991) emphasizes the need to understand better the variables affecting its reinforcing effects. With positron emission tomography (PET) and appropriate radiotracers, it is now possible to measure reproducibly the levels of DAT occupancy achieved by drugs that block the DAT in human subjects (Volkow et al., 1997a). Using this strategy, we have shown a significant correlation between the magnitude of cocaine-induced DAT blockade and the self-reports for the high in cocaine abusers (Volkow et al., 1997a). It was of interest to determine whether we could replicate the correlation between DAT blockade and the high in normal control subjects tested with MP. In this study, we used PET and [ 11 C]cocaine as a DAT ligand (Fowler et al., 1989) to assess the level of DAT occupancy achieved with different doses of i.v. MP in human ABBREVIATIONS: MP, methylphenidate; DA, dopamine; DAT, dopamine transporter; PET, positron emission tomography. 14

2 1999 DAT Occupancy by Intravenous Methylphenidate in Human Brain 15 brain. The reinforcing effects of cocaine, which in humans are generally accompanied by self-reports of euphoria or high (Nestler, 1992), were assessed by asking participants to respond verbally to the self-reports of high. The self-reports for the high have been reported to be reliable and consistent across studies, and there is no other known measure that is better in predicting self-administration of drugs in humans (Fischman and Foltin, 1991). The results obtained with i.v. MP were compared with those we had previously reported for i.v. cocaine (Volkow et al., 1997a). Materials and Methods Subjects. Eight healthy control subjects (five men and three women; age, 32 7 years) were studied. Subjects with past and present histories of alcohol or drugs use (except for caffeine and cigarettes) were excluded from the studies. Prescan urinalysis ensured absence of psychoactive drug use. Subjects were instructed to discontinue any over-the-counter medication 1 week before the scan. Written informed consent was obtained in all subjects following the guidelines set by the Institutional Review Board at Brookhaven National Laboratory. Scan. PET studies were carried out with a Siemens CTI 931 tomograph ( mm full-width half-maximum, 15 slices) using [ 11 C]cocaine as a DAT ligand (Fowler et al., 1989). Methods for positioning and repositioning of subjects in the tomograph, alignment, arterial and venous catheterization, transmission scans, blood sampling, and blood analysis have been published (Fowler et al., 1989). Briefly, emission scans were started immediately after injection of 4 to 8 mci of [ 11 C]cocaine (specific activity 0.2 Ci/ mol at time of injection). A series of 20 emission scans were obtained from time of injection up to 54 min. Arterial sampling was used to quantify total carbon-11 and unchanged [ 11 C]cocaine in plasma as described (Fowler et al., 1989). Each subject was scanned four times with [ 11 C]cocaine over a 3-day period: one after placebo (baseline scan) and three times after different i.v. doses of MP (0.05, 0.1, 0.25, and 0.5 mg/kg). A different dose was used for each scan. The [ 11 C]cocaine scans were performed 5 to 8 min after placebo (3 ml of saline) or 5 to 8 min after one of the MP doses. The placebo scan was done on the first day and was followed 2 h later by a second scan done after MP. On the 2nd and 3rd days of scanning, only one scan was performed using a different MP dose each day. Subjects were blind to the drug received, and the doses used were randomly assigned so that each dose was tested on six different subjects. Table 1 summarizes the doses of MP received by the subjects. The design of this study assumed that the intra- and intersubject variability in the DAT occupancy measures were equivalent. Venous blood was drawn for quantification of plasma concentration of MP before and at 27 and 47 min after MP using capillary GC/Mass spectrometry (Srinivas et al., 1991). Behavioral Measures. The subjective effects of MP were assessed by asking participants to orally respond to the following mood descriptors: high, rush, anxious, and restless every 5 min starting 15 min before placebo or MP, then every minute for 20 min, and then every 5 min for a total of 75 min. High was defined as TABLE 1 Doses of MP received by the different subjects Subject Placebo x x x x 2 x x x x 3 x x x x 4 x x x x 5 x x x x 6 x x x x 7 x x x x 8 x x x x euphoria, rush as the sensation of the drug in the body, and restlessness as the desire to move. To simulate an analog rating scale, participants were instructed to respond to each descriptor using a whole number between 0 (no effects) and 10 (maximal effects) (Wang et al., 1997). Effects of MP on heart rate and blood pressure were continuously monitored throughout the study. Image Analyses. Regions of interest in striatum and cerebellum were drawn directly on an averaged emission image (images obtained between 10 and 54 min) as previously described (Fowler et al., 1989). 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 with the timeactivity curves for unchanged tracer in plasma were used to calculate the distribution volume in striatum and cerebellum using the Logan Plot graphic analysis technique for reversible systems (Logan et al., 1990). The ratio of the distribution volume in striatum to that in cerebellum, which corresponds to B max /K d 1 and is insensitive to changes in cerebral blood flow, was our measure of DAT availability (Logan et al., 1994). DAT occupancies were calculated as [(B max / K d placebo B max /K dmp )/B max /K d placebo ] 100. Data Analyses. Differences in DAT occupancy and in the behavioral and cardiovascular measures after placebo and after the different doses of MP were tested with ANOVA. For the behavioral measures, we averaged the scores obtained between 2 and 7 min after placebo or MP, and for the cardiovascular measures, we averaged the scores between 5 and 30 min because these were the time periods when peak effects for these measures occurred. Post hoc t tests then were performed to determine the doses for which the behavioral and cardiovascular effects were significant. Pearson s product moment correlations analyses were calculated for the estimates of DAT occupancy and the behavioral and cardiovascular changes (MP placebo) and between DAT occupancy and the concentration of MP in plasma. To obtain the ED 50 for MP (dose required to occupy 50% of DAT), the percent occupancy was linearized by plotting lnp/(100 P) versus ln dose (mg/kg) where P is the percent DAT occupancy; the linear regression enabled the determination of the ED 50, which corresponds to the 0 value on the x-axis (Keen and MacDermot, 1993). The ED 50 for MP was compared with the ED 50 for cocaine, which was obtained using the previously published data on DAT occupancies for i.v. cocaine in cocaine abusers (Volkow et al., 1997a). Results MP decreased [ 11 C]cocaine binding in striatum but not in cerebellum in a dose-dependent manner (Fig. 1). B max /K d measures were significantly reduced by all doses of MP, and the estimated DAT occupancies corresponded to 35 5% for mg/kg, 62 13% for 0.1 mg/kg, 67 3% for 0.25 mg/kg, and 78 11% for 0.5 mg/kg (Fig. 2A). The estimated ED 50 (dose required to block 50% of the DAT) was mg/kg (Fig. 2B). The estimated ED 50 for i.v. cocaine calculated using previously published data was 0.13 mg/kg. The plasma concentration for MP is shown in Table 2. DAT occupancies were significantly correlated with MP plasma concentration at 27 and 47 min after its administration (r 0.72, df 22, p.0001) (Fig. 3). MP significantly increased self-reports of high (F 4.3, df 4, 31, p.008) and of rush (F 3.2, df 4, 31, p.03), but its effects on anxiety or restlessness did not reach significance (Table 3). Post hoc t tests revealed that the effects on high and rush were significant for the 0.25 and 0.5 mg/kg doses. Selfreports of high and rush were significantly correlated with DAT blockade (r 0.46, df 23, p.05) (Fig. 4). However, individual analysis of the data revealed that four of the eight

3 16 Volkow et al. Vol. 288 Fig. 1. Distribution volume images of [ 11 C]cocaine obtained at the level of the striatum (left) and the cerebellum (right) for one of the subjects tested at baseline (placebo) and with and 0.1 mg/kg i.v. MP doses. MP dosedependently decreased the binding of [ 11 C]cocaine in striatum but not in cerebellum. subjects did not report a high after MP despite having DAT occupancies of greater than 60%. MP induced a significant dose related increase in heart rate (F 6.6, df 4, 31, p.0007), systolic (F 4.9, df 4, 31, p.004), and diastolic blood pressure (F 3.9, df 4, 31, p.01) (Table 2). Post hoc t tests revealed that the effects on heart rate were significant for the 0.1, 0.25, and 0.5 mg/kg doses (p.05), and for systolic and diastolic blood pressure, they were significant for the 0.25 and 0.5 mg/kg doses (p.05). Levels of DAT blockade were significantly correlated with MP-induced (MP placebo) increases in heart rate (r 0.49, df 23, p.02) and in systolic blood pressure (r 0.51, df 23, p.01) but not with diastolic blood pressure (r 0.26, df 23, p 0.22) (Fig. 5). Discussion These results corroborate an association between DAT occupancy and self-reports of high in non-drug-abusing subjects given i.v. MP. However, the correlation was weaker than that we had obtained for i.v. cocaine in cocaine abusers; in this study, DAT blockade accounted only for 21% of the variance, whereas in the study done in cocaine abusers, DAT blockade accounted for 31% (Volkow et al., 1997a). Moreover,

4 1999 DAT Occupancy by Intravenous Methylphenidate in Human Brain 17 Fig. 2. A, Relationship between DAT occupancy by MP and doses of MP (mg/kg). B, Linearized plots used to calculate the dose of MP required to occupy 50% DAT (dose ED 50 ), which corresponded to mg/kg (P percent dopamine transporter occupancy). TABLE 2 Plasma concentration of MP at different times after its administration for the various doses MP Dose 27 min 47 min mg/kg ng/ml Fig. 3. A, Correlation between DAT occupancy and plasma concentration of MP at 27 min after its administration. (r 0.72, df 22, p.001). B, Correlation between DAT occupancy and plasma concentration of MP at 47 min (r 0.72, df 22, p.001) after its administration. with MP, only four of the eight subjects who showed DAT occupancies of greater than 60% reported a high, whereas all of the cocaine abusers in whom cocaine induced 60% blockade reported a high. The differences between the two studies could reflect differences in response to psychostimulant-induced high between controls and cocaine abusers and/or differences between MP and cocaine. Cocaine abusers may be sensitized to the high induced by cocaine and therefore may have been more likely to experience it after DAT blockade. Future studies evaluating the relation between the high and DAT blockade induced by MP in cocaine abusers will allow us to determine whether they are more sensitive to DAT blockade than controls. However, these results differ from those we had previously reported with a fixed dose of i.v. MP (0.5 mg/kg) in which we were unable to show a correlation between DAT blockade and the high in nonabusing control subjects (Volkow et al., 1996a). The range of DAT occupancies in that study was limited (70 83%) and that is why we believe we did not find an association with the high. In fact we also fail to observe a correlation between DAT blockade and high in the current study if we limit the analysis to the 71 to 87% range of DAT occupancies (r 0.36, df 6, p.43). However, the failure to observe an association between DAT blockade and the high when the occupancies are limited to a very narrow range highlights the fact that variables other than DAT blockade are required to explain why in subjects with equivalent levels of DAT blockade, some experience the high and others do not. Because DAT blockade by MP or by cocaine is the triggering event that leads to increases in synaptic DA and subsequent DA receptor stimulation, the variability could reflect these postsynaptic responses. In fact, blockade of D 2 receptors decreases or abolishes the reinforcing effects of cocaine in laboratory animals (De Wit and Wise, 1977; Woolverton, 1986). Therefore, the variability in the response to MP among control subjects and the differences between the current study and the one in cocaine abusers could reflect in part differences in responses mediated by DA stimulation of D 2 and/or D 1 receptors. That this may be the case is supported by studies showing that in control subjects, MP-induced changes in regional brain glucose metabolism are dependent in part on the availability of striatal D 2 receptors (Volkow et al., 1997b). Furthermore, cocaine abusers, compared with control subjects, have fewer striatal D 2 receptors (Volkow et al., 1990, 1993) and show a blunted response to MP-induced decreases in the binding of [ 11 C]raclopride to D 2 receptors, a measure that reflects occupancy of D 2 receptors by endogenous DA (Volkow et al., 1997c). Future studies evaluating the relation between MP-induced levels of D 2 receptor occupancy by DA and the high will allow us to determine whether this is a better predictor of behavioral responses than levels of DAT blockade. The variability in the behavioral responses could also reflect differences in transduction responses (Nestler, 1992). It is also possible that neurotransmitters other than DA may participate in the high. Cocaine, but not MP, blocks the serotonin transporter, and both drugs block the norepinephrine transporter (Gatley et al., 1996). The facts that i.v. MP has been shown to elicit a high similar to that of cocaine (Wang et al., 1997), that cocaine and MP show similar rates of self-administration in nonhuman primates (Johanson and Schuster, 1975; Bergman et al., 1989), and that MP substitutes for cocaine in discrimination studies (Wood and Emmett-Oglesby 1988) suggest that serotonin transporter blockade does not play a prominent role in the acute reinforcing effects of these drugs. However, chronic administration of cocaine may lead to different adaptation changes in the serotonin system than after chronic MP, which could affect the motivational drive for drug self-administration (Richardson and Roberts, 1991; Roberts et al., 1994), leading to differences in the addiction liability of these two drugs. The involvement of norepinephrine transporter blockade in the reinforcing effects of these two drugs is also unclear because although noradrenergic blockade does not affect cocaine selfadministration (De Wit and Wise, 1977), it does affect its discriminative properties (Spealman, 1995; Kleven and Koek, 1997). Corelease of peptides and/or hormones such as cortisol could also modulate the reinforcing effects of cocaine and/or MP (Goeders, 1997). The contribution of variables other than DAT blockade in the reinforcing effects of cocaine are upheld by recent studies showing that DAT knockout

5 18 Volkow et al. Vol. 288 TABLE 3 Behavioral and cardiovascular measures after placebo or after the various MP doses Significance (p) corresponds to ANOVA (df 4, 31). Superscript letters correspond to post hoc t tests showing significant differences from placebo. Placebo p Behavioral High a 5 4 b.008 Rush a 4 4 a.03 Restless NS Anxiety NS Cardiovascular Heart rate c 87 9 c a.0007 Systolic c d.004 Diastolic a 83 4 d.01 a p.05, b p.01, c p.005, d p.001. Fig. 4. A, Relationship between DAT occupancy and self-report of high (r 0.46, df 23, p.05). The numbers in the scattergram identify the subjects (see Table 1) who experienced a high and the subjects who did not experience a high but had DAT occupancies of 60%. B, Relationship between DAT occupancy and self-report of rush (r 0.46, df 23, p.05). mice self-administer cocaine and exhibit conditioned place preference (Rocha et al., 1998; Sora et al., 1998). The differences in the ED 50 between cocaine and MP (0.13 and mg/kg, respectively) are compatible with differences in their affinities for DAT (K i for inhibition of DA uptake correspond to 640 and 390 nm, respectively) (Ritz et al., 1987). The similar efficacy of MP and cocaine to block DAT in the human brain after their i.v. administration could explain the similar reinforcing effects reported for these two drugs (Johanson and Schuster, 1975; Bergman et al., 1989). Although to our knowledge no microdialysis study has compared DA changes induced by MP and by cocaine, review of separate studies indicates similar increases after their i.v. administration, that is, MP (2 10 mg/kg) increased DA 300 to 900% (Aoyama et al., 1996) and cocaine (1 2 mg/kg) 280 to 700% (Hurd and Ungerstedt, 1989; Moghaddam and Bunney, 1989). However, when comparing cocaine and MP, it is important to realize that MP is a racemic mixture 50% is an active enantiomer (d-threo-mp) and 50% is an inactive enantiomer (l-threo-mp) (Patrick et al., 1987), whereas cocaine is the enantiomerically pure ( )-cocaine. Thus, in this study, the DAT blockade is likely due to d-threo-mp because l-threo-mp shows no binding to DAT, nor does it increase DA (Ding et al., 1997). Future comparisons between cocaine and d-threo-mp may be more pertinent to the pharmacological characterization of these two drugs. In analyzing the implications of the similar in vivo efficacy for DAT blockade by cocaine and MP, regarding the abuse potential of MP, it is important to emphasize that the similarities were observed after i.v. administration, which is not the route of administration used therapeutically. Because the rapidity of drug effects is an important variable in the reinforcing effects of drugs of abuse (Balster and Schuster, 1973), the results with i.v. MP, which leads to very fast uptake in brain, cannot be extrapolated to what happens when MP is taken orally, which results in a much slower brain uptake (Volkow et al., 1998). In fact, when given for therapeutic purposes, oral MP has not been associated with euphoric responses or with a high (Klein et al., 1997). Also, although cocaine and MP have similar efficacies at the DAT, they have different pharmacokinetics. In the human brain, the uptake of cocaine is slightly faster than that of MP (4 6 versus 8 10 min) and the rate of clearance is significantly faster for cocaine (20 min) than for MP ( 90 min) (Volkow et al., 1995). Because we had shown that the high was associated only with the initial fast uptake of the drug in brain and not with its continuous presence, we have postulated that the slow clearance of MP from brain may interfere with its frequent repeated administration because it would lead to saturation of DAT (Volkow et al., 1995). Also, the longer half-life of MP than that of cocaine is likely to lead to more Fig. 5. Relationship among DAT occupancy and MP-induced (MP Placebo) increases in heart rate (r 0.49, df 23, p.02), systolic blood pressure (r 0.51, df 23, p.01), and diastolic blood pressure (r 0.26, df 23, p 0.22).

6 1999 DAT Occupancy by Intravenous Methylphenidate in Human Brain 19 side effects, which may eventually interfere with its administration. This study showed a correlation between DAT blockade and MP-induced changes in heart rate and in systolic but not in diastolic blood pressure. This association suggests that the cardiovascular effects of MP are in part mediated by central effects modulated by DA. This is in agreement with studies showing that the cardiovascular effects for stimulant drugs such as cocaine and amphetamine can be antagonized by administration of DA D 2 receptor blockers (Tella, 1996). Failure to observe any correspondence between diastolic blood pressure and DAT blockade suggests that other factors, such as noradrenergic blockade, are involved in this response. We found a similar dissociation in a study that evaluated the temporal course of MP-induced cardiovascular changes, which showed that although the temporal course of the increases in heart rate and systolic pressure corresponded well with the pharmacokinetics of [ 11 C]MP in striatum, those for diastolic blood pressure did not (Volkow et al., 1996b). However, it is also possible that the association between DAT blockade and changes in heart rate and systolic blood pressure reflect a spurious and not a causal association. Limitations of this study include the inaccuracies posed by differences in nonspecific binding of [ 11 C]cocaine between striatum and cerebellum and the use of the placebo scan as the measure that reflected no occupancy. The error introduced by differences in nonspecific binding between striatum and cerebellum has been estimated to be on the order of 10% (Volkow et al., 1995b), and that introduced by the competition of endogenous DA with [ 11 C]cocaine for binding to the DAT has been estimated to be less than 5% (Gatley et al., 1995). Another limitation for the study is that measurements were made in the dorsal striatum and not in the nucleus accumbens, the structure in the striatum associated with drug reinforcement in laboratory animals (Pettit et al., 1984; Pontieri et al., 1996); however, DAT occupancy by MP should not differ appreciably between these brain regions (Izenwasser et al., 1990). This study measures for the first time the levels of DAT blockade achieved after i.v. MP and shows that i.v. MP has a comparable efficacy to that of i.v. cocaine in blocking DAT in vivo in the human brain. This study also corroborates our previous findings in cocaine abusers of an association between DAT blockade and self-reports of high in controls subjects. However, the fact that there were subjects who despite significant DAT blockade did not experience the high after MP suggests that although DAT blockade may be necessary for the high, it is not sufficient, and additional factor or factors are required for the high. Acknowledgments We thank D. Schlyer and R. Carciello for Cyclotron operations; A. Levy and D. Warner for PET operations; C. Wong for data management; R. Ferrieri, C. Shea, R. MacGregor, and P. King for radiotracer preparation and analysis; P. Cerveny and N. Netusil for patient care; and T. Cooper for plasma analyses of MP. References Aoyama TN, Kotaki HN, Sawada YN and Iga T (1996) Pharmacokinetics and pharmacodynamics of methylphenidate enantiomers in rats. Psychopharmacology (Berl) 127: Balster RL and Schuster CR (1973) Fixed-interval schedule of cocaine reinforcement: effects of dose and infusion duration. J Exp Anal Behav 20: Bergman J, Madras B, Johnson SE and Spealman RD (1989) Effects of cocaine and related drugs in nonhuman primates. III: Self-administration by squirrel monkeys. J Pharmacol Exp Ther 251: Carrey NJ, Wiggins DM and Milin RP (1996) Pharmacological treatment of psychiatric disorders in children and adolescents: Focus on guidelines for the primary care practitioner. Drugs 51: De Wit H and Wise RA (1977) Blockade of cocaine reinforcement in rats with the dopamine receptor blocker pimozide, but not with the noradrenergic blockers phentolamine or phenoxybenzamine. Can J Psychol 31: Ding Y-D, Fowler JS, Volkow ND, Dewey SL, Wang G-J, Gatley J, Logan J and Pappas N (1997) Chiral drugs: Comparison of the pharmacokinetics of [ 11 C]d-threo and l-threo methylphenidate in the human and baboon brain. Psychopharmacology 131: Fischman MW and Foltin RW (1991) Utility of subjective-effects measurements in assessing abuse liability of drugs in humans. Br J Addict 86: Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, MacGregor R, Hitzemann R, Logan J, Bendriem B, Gatley SJ and Christman D (1989) Mapping cocainebinding sites in human and baboon brain in vivo. Synapse 4: Gatley SJ, Volkow ND, Fowler JS, Dewey SL and Logan J (1995) Sensitivity of striatal [ 11 C]cocaine binding to decreases in synaptic dopamine. Synapse 20: Gatley SJ, Pan D, Chen R, Chaturvedi G and Ding YS (1996) Affinities of methylphenidate derivatives for dopamine, norepinephrine and serotonin transporters. Life Sci 58: Goeders NE (1997) A neuroendocrine role in cocaine reinforcement. Psychoneuroendocrinology 22: Hurd YL and Ungerstedt U (1989) Cocaine: An in vivo microdialysis evaluation of its acute actions on dopamine transmission in rat striatum. Synapse 3: Izenwasser S, Werling LL and Cox B (1990) Comparison of the effects of cocaine and other inhibitors of dopamine uptake in rat striatum, nucleus accumbens, olfactory tubercle, and medial prefrontal cortex. Brain Res 520: Johanson CE and Schuster CR (1975) A choice procedure for drug reinforcers: Cocaine and methylphenidate in the rhesus monkey. J Pharmacol Exp Ther 193: Keen M and MacDermot J (1993) Analysis of Receptors by Radioligand Binding (Wharton J and Polak JM eds) pp 50 51, Oxford Science Publications, Oxford. Klein RG, Abikoff H, Klass E, Ganeles D, Seese LM and Pollack S (1997) Clinical efficacy of methylphenidate in conduct disorder with and without attention deficit hyperactivity disorder. Arch Gen Psychiatry 54: Kleven MS and Koek W (1997) Discriminative stimulus properties of cocaine: Enhancement by -adrenergic receptor antagonists. Psychopharmacology (Berl) 131: Logan J, Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, MacGregor RR, Hitzemann R, Bendriem B, Gatley SJ and Christman DR (1990) Graphical analysis of reversible radioligand binding from time activity measurements applied to [N- 11 C-methyl]-( )cocaine PET studies in human subjects. J Cereb Blood Flow Metab 10: Logan J, Volkow ND, Fowler JS, Wang G-J, Dewey SL, MacGregor RR, Schlyer DJ, Gatley SJ, Pappas N, King P, Hitzemann R and Vitkun S (1994) Effects of blood flow on [ 11 C] raclopride binding in the brain: Model simulations and kinetic analysis of PET data. J Cereb Blood Flow Metab 14: Moghaddam B and Bunney BS (1989) Differential effect of cocaine on extracellular dopamine levels in rat medial prefrontal cortex and nucleus accumbens: Comparison to amphetamine. Synapse 4: National Institute on Drug Abuse, Community Epidemiology Work Group (CEWG) (1995) Epidemiologic Trends in Drug Abuse. Washington DC, DHHS Publication no. (NIH) 95:3988. Nestler EJ (1992) Molecular mechanisms of drug addiction. J Neurosci 12: Parran TV and Jasinski DR (1991) Intravenous methylphenidate abuse: Prototype for prescription drug abuse. Arch Intern Med 151: Patrick KS, Caldwell RW, Ferris RM and Breese GR (1987) Pharmacology of the enantiomers of threo-methylphenidate. J Pharmacol Exp Ther 241: Pettit HO, Ettenberg A, Bloom FE and Koob GF (1984) Destruction of dopamine in the nucleus accumbens selectively attenuates cocaine but not heroine selfadministration in rats. Psychopharmacology 84: Pontieri FE, Tanda G, Orzi F and Di Chiara G (1996) Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 382: Richardson NR and Roberts DCS (1991) Fluoxetine pretreatment reduces breaking points on a progressive ratio schedule reinforced by intravenous cocaine selfadministration in ther rat. Life Sci 49: Ritz MC, Lamb RJ, Goldberg SR and Kuhar MJ (1987) Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science 237: Roberts DC, Loh EA and Vickers G (1994) Lesions of central serotonin systems affect responding on a progressive ratio schedule reinforced either by intravenous cocaine or by food. Pharmacol Biochem Behav 49: Rocha BA, Fumagalli F, Gainetdinov RR, Jones SR, Ator R, Giros B, Miller GW and Caron MG (1998) Cocaine self-administration in dopamine-transporter knockout mice. Nat Neurosci 1: Spealman RD (1995) Noradrenergic involvement in the discriminative stimulus effects of cocaine in squirrel monkeys. J Pharmacol Exp Ther 275: Srinivas NR, Hubbard JW, Quinn D, Korchinski ED and Midha K (1991) Extensive and enantioselective presystemic metabolism of dl-threo-methylphenidate in humans. Prog Neuropsychopharmacol Biol Psychiatry 15: Sora I, Wichems C, Takahashi N, Li XF, Zeng Z, Revay R, Lesch KP, Murphy DL and Uhl GR (1998) Cocaine reward models: conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice. Proc Natl Acad Sci USA 95:

7 20 Volkow et al. Vol. 288 Tella SR (1996) Possible novel pharmacodynamic action of cocaine: Cardiovascular and behavioral evidence. Pharmacol Biochem Behav 54: Volkow ND, Ding Y-S, Fowler JS, Wang G-J, Logan J, Gatley SJ, Dewey SL, Ashby C, Lieberman J, Hitzemann R and Wolf AP (1995) Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in human brain. Arch Gen Psychiatry 52: Volkow ND, Fowler JS, Logan J, Gatley JS, Dewey SL, MacGregor RR, Schlyer DJ, Pappas N, King P and Wolf AP (1995b) Carbon-11-cocaine binding compared at sub-pharmacological and pharmacological doses: A PET study. J Nucl Med 36: Volkow ND, Fowler JS, Wang G-J, Hitzemann R, Logan J, Schlyer D, Dewey S and Wolf AP (1993) Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse 14: Volkow ND, Fowler JS, Wolf AP, Shlyer D, Shiue Chy, Albert R, Dewey SL, Logan J, Bendriem B, Christman D, Hitzemann R and Henn F (1990) Effects of chronic cocaine abuse on postsynaptic dopamine receptors. Am J Psychiatry 147:7l Volkow ND, Wang G-J, Fischman MW, Foltin RW, Fowler JS, Abumrad NN, Vitkun S, Logan J, Gatley SJ, Pappas N, Hitzemann R and Shea K (1997a) Relationship between subjective effects of cocaine and dopamine transporter occupancy. Nature 386: Volkow ND, Wang G-J, Fowler JS, Gatley SJ, Ding Y-S, Logan J, Dewey SL, Hitzemann R and Lieberman J (1996a) Relationship between psychostimulant induced high and dopamine transporter occupancy. Proc Nat Acad Sci USA 93: Volkow ND, Wang G-J, Fowler JS, Gatley JS, Logan J, Ding Y-S, Hitzemann R and Pappas N (1998) Therapeutic doses of oral methylphenidate induce significant levels of dopamine transporter occupancies in the human brain. Am J Psychiatry 155: Volkow ND, Wang G-J, Fowler JS, Logan J, Angrist B, Hitzemann RJ, Lieberman J and Pappas NS (1997b) Effects of methylphenidate on regional brain glucose metabolism in humans: Relationship to dopamine D2 receptors. Am J Psychiatry 154: Volkow ND, Wang G-J, Fowler JS, Logan J, Gatley SJ, Hitzemann R, Chen AD and Pappas N (1997c) Decreased striatal dopaminergic responsivity in detoxified cocaine abusers. Nature 386: Volkow ND, Wang G-J, Gatley SJ, Fowler JS, Ding Y-S, Hitzemann R, Logan J, Wong C and Lieberman J (1996b) Temporal relationships between the pharmacokinetics of methylphenidate in the human brain and its behavioral and cardiovascular effects. Psychopharmacology (Berl) 123: Wang G-J, Volkow ND, Hitzemann RJ, Wong C, Angrist B, Burr G, Pascani K, Pappas N, Lu A, Cooper T and Lieberman JA (1997) Behavioral and cardiovascular effects of intravenous methylphenidate in normal subjects and cocaine abusers. Eur Addict Res 3: Wood DM and Emmett-Oglesby MW (1988) Substitution and cross-tolerance profiles of anorectic drugs in rats trained to detect the discriminative stimulus properties of cocaine. Psychopharmacology (Berl) 95: Woolverton WL (1986) Effects of a D1 and a D2 dopamine antagonist on the selfadministration of cocaine and piribedil by rhesus monkeys. Pharmacol Biochem Behav 24: Send reprint requests to: Nora D. Volkow, M.D., Medical Department, Build. 490, Brookhaven National Laboratory, Upton, NY volkow@bnl.gov.