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Original Article |

Depressed Dopamine Activity in Caudate and Preliminary Evidence of Limbic Involvement in Adults With Attention-Deficit/Hyperactivity Disorder FREE

Nora D. Volkow, MD; Gene-Jack Wang, MD; Jeffrey Newcorn, MD; Frank Telang, MD; Mary V. Solanto, PhD; Joanna S. Fowler, PhD; Jean Logan, PhD; Yeming Ma, PhD; Kurt Schulz, PhD; Kith Pradhan, MS; Christopher Wong, MS; James M. Swanson, PhD
[+] Author Affiliations

Author Affiliations: National Institute on Drug Abuse, Bethesda, Maryland (Dr Volkow); Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, Bethesda (Drs Volkow, Telang, and Ma); Medical and Chemistry Departments, Brookhaven National Laboratory, Upton, New York (Drs Wang, Fowler, and Logan and Mr Wong); Department of Psychiatry, Mount Sinai Medical Center, New York, New York (Drs Newcorn, Solanto, and Schulz); Department of Applied Mathematics, State University of New York at Stony Brook (Mr Pradhan); and Child Development Center, University of California, Irvine (Dr Swanson).


Arch Gen Psychiatry. 2007;64(8):932-940. doi:10.1001/archpsyc.64.8.932.
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Published online

Context  Attention-deficit/hyperactivity disorder (ADHD) is the most prevalent psychiatric disorder of childhood. There is considerable evidence that brain dopamine is involved in ADHD, but it is unclear whether dopamine activity is enhanced or depressed.

Objective  To test the hypotheses that striatal dopamine activity is depressed in ADHD and that this contributes to symptoms of inattention.

Design  Clinical (ADHD adult) and comparison (healthy control) subjects were scanned with positron emission tomography and raclopride labeled with carbon 11 (D2/D3 receptor radioligand sensitive to competition with endogenous dopamine) after placebo and after intravenous methylphenidate hydrochloride (stimulant that increases extracellular dopamine by blocking dopamine transporters). The difference in [11C]raclopride's specific binding between placebo and methylphenidate was used as marker of dopamine release. Symptoms were quantified using the Conners Adult ADHD Rating Scales.

Setting  Outpatient setting.

Participants  Nineteen adults with ADHD who had never received medication and 24 healthy controls.

Results  With the placebo, D2/D3 receptor availability in left caudate was lower (P < .05) in subjects with ADHD than in controls. Methylphenidate induced smaller decrements in [11C]raclopride binding in left and right caudate (blunted DA increases) (P < .05) and higher scores on self-reports of “drug liking” in ADHD than in control subjects. The blunted response to methylphenidate in caudate was associated with symptoms of inattention (P < .05) and with higher self-reports of drug liking (P < .01). Exploratory analysis using statistical parametric mapping revealed that methylphenidate also decreased [11C]raclopride binding in hippocampus and amygdala and that these decrements were smaller in subjects with ADHD (P < .001).

Conclusions  This study reveals depressed dopamine activity in caudate and preliminary evidence in limbic regions in adults with ADHD that was associated with inattention and with enhanced reinforcing responses to intravenous methylphenidate. This suggests that dopamine dysfunction is involved with symptoms of inattention but may also contribute to substance abuse comorbidity in ADHD.

Figures in this Article

Attention-deficit/hyperactivity disorder (ADHD) is considered to be the most prevalent psychiatric disorder of childhood.1 Despite decades of research, the specific neurobiological mechanisms underlying this disorder still remain unclear. Genetic, clinical, and imaging studies point to a disruption of the brain dopamine (DA) system,2 which is corroborated by the clinical effectiveness of stimulant drugs (methylphenidate hydrochloride and amphetamine), which increase extracellular DA in brain.3

Brain imaging studies have provided evidence of differences in markers of DA neurotransmission in subjects with ADHD. However, the results have not always been consistent and do not clarify the abnormal direction of the differences in DA neurotransmission. For example, the studies measuring levels of dopamine transporters (DATs) cannot distinguish whether abnormalities reflect changes in DAT levels per terminal (up- or down-regulation) vs differences in terminal density. Uncertainty remains because DATs can up-regulate under conditions of high DA neurotransmission and down-regulate under conditions of low DA activity.4 The finding of DAT elevation in the striatum of subjects with ADHD (reviewed5) might suggest enhanced DA reuptake and weak DA signals or increased DA terminal density and hence enhanced dopaminergic activity. In addition, some studies have not replicated the finding of DAT elevation in subjects with ADHD68 and some report lower than normal DATs,7,8 which could be interpreted as down-regulation to compensate for depressed dopaminergic neurotransmission or as lower DA terminal density. Similarly, while the reduction in DA synthesis in prefrontal cortex reported in adults with ADHD9 is consistent with decreased DA activity, the increased level of DA synthesis in mesencephalon reported in children with ADHD10 is consistent with increased activity.

Studies of changes in striatal DA in response to methylphenidate offer another view of the DA system that may clarify the specificity of disorder-related disruption. Since methylphenidate is a DAT blocker and not a DA releaser drug, for an equivalent level of DAT blockade the magnitude of methylphenidate-induced DA increases will reflect the amount of spontaneous DA release.11 One positron emission tomographic (PET) study in adolescents with ADHD reported that methylphenidate-induced DA increases were associated with greater symptom severity,12 but without a control group this study left unresolved whether the DA responses were abnormal in subjects with ADHD. Here we investigate DA release in adults with ADHD using PET to measure their response to intravenous methylphenidate when compared with that of controls. Our working hypotheses are that subjects with ADHD have lower than normal DA release and that this contributes to symptoms of inattention.

We tested 19 subjects with ADHD who had never received medication and 24 healthy controls with PET and raclopride labeled with carbon 11 (DA D2/D3 receptor radioligand whose binding is sensitive to competition by endogenous DA)13 with and without an acute pharmacological challenge with intravenous methylphenidate. Differences in specific binding of [11C]raclopride with and without methylphenidate mostly reflect methylphenidate-induced changes in extracellular DA.14 In parallel we quantified clinical symptoms before the study using the Conners Adult ADHD Rating Scales (CAARS)15 and “drug liking” after intravenous administration of methylphenidate using self-reports of drug effects to assess the functional significance of methylphenidate-induced DA changes.

SUBJECTS

We completed studies in 19 subjects with ADHD who had never received medication (9 men, 10 women; mean ± SD age, 32 ± 7 years) and 24 adult healthy controls (18 men, 6 women; mean ± SD age, 30 ± 5 years). Note that these subjects are much older than those in a published study that evaluated DA release in adolescents with ADHD.12 Subjects with ADHD were recruited from a variety of sources, including clinical referrals to the ADHD program at Mount Sinai and advertisements. At least 2 clinicians (psychiatrist or neurologist and clinical psychologist) interviewed the patients to ensure that they met DSM-IV diagnostic criteria for ADHD as evidenced by the presence of at least 6 of 9 inattention symptoms (with or without 6 of 9 hyperactive/impulsive symptoms) as ascertained with a semistructured interview using DSM-IV criteria. In addition, evidence was required from each subject's history that some symptoms of ADHD started during childhood (before age 7 years) even when the diagnosis was not made until adulthood. Subjects were excluded if they had a prior history of more than 1 month of medication treatment for ADHD and excluded if this short treatment occurred within the 2 years prior to the study. They were also excluded if they had a present or past history of substance abuse or addiction (except nicotine). Smoking status was assessed with self-reports, and in our final sample only 1 of the controls and 1 of the subjects with ADHD were smokers. Exclusion criteria also included present or past history of psychiatric disease (axis I or II diagnosis other than ADHD) or neurological disease, medical conditions that may alter cerebral function (ie, cardiovascular, endocrinological, oncological, or autoimmune diseases), current use of prescribed or over-the-counter medications, and/or head trauma with loss of consciousness of more than 30 minutes. All subjects had Hamilton Anxiety16 and Hamilton Depression17 scores lower than 19. Controls were recruited from advertisements in the local newspapers; exclusion criteria other than allowance for ADHD were the same as for subjects with ADHD. Urine drug screens were obtained on all subjects the day of the PET study to check for psychoactive drug use. Written informed consent was obtained after complete description of the study to the subjects.

CLINICAL SCALES

We measured clinical symptoms using the CAARS long version,15 which provides self-assessment of ADHD symptoms on a scale of 1 (not at all) to 4 (very much). The CAARS was completed in all subjects with ADHD (CAARS for 1 subject with ADHD was lost) and in 20 of the controls. Mean ± SD averages on the 8 CAARS scales for subjects with ADHD and controls, respectively, were as follows: section A, inattention/memory problems, 25 ± 5 and 5 ± 3; B, hyperactivity/restlessness, 22 ± 8 and 6 ± 4; C, impulsivity/emotional lability, 17 ± 8 and 4 ± 4; D, problems with self-concept, 10 ± 5 and 3 ± 3; E, DSM-IV inattentive symptoms, 21 ± 3 and 2 ± 3; F, DSM-IV hyperactive-impulsive symptoms, 15 ± 6 and 3 ± 3; G, DSM-IV symptom total, 35 ± 6 and 5 ± 5; and section H, ADHD index, 21 ± 5 and 4 ± 3.

BEHAVIORAL MEASURES

Behavioral effects of intravenous methylphenidate were evaluated using analog scales that assessed self-reports of “high,” tiredness, alertness, anxiety, “feel drug,” and restlessness from 0 (felt nothing) to 10 (felt intensely).18 These self-reports of drug effects have been shown to be reliable and consistent across studies and to predict administration of drugs in human subjects.19 Subjective ratings were recorded 5 minutes before placebo or methylphenidate and then 27 and 47 minutes after administration. At the end of the study, subjects were asked to rate drug liking and drug disliking (0-10).

SCANS

Positron emission tomographic studies were done with a Siemens HR+ tomograph (Siemens Medical Solutions, Knoxville, Tennessee) in 3-dimensional mode (resolution, 4.5 × 4.5 × 4.5 mm, full-width half-maximum). Each subject underwent 2 scans with [11C]raclopride: 1 after intravenous placebo (3 mL of saline) and 1 after intravenous methylphenidate (0.5 mg/kg). The study was a single-blind design (subjects were blind to the drugs received). Dynamic scans were started immediately after injection of 4 to 10 mCi of [11C]raclopride (specific activity, 0.5-1.5 Ci/μM at end of bombardment). Dynamic scans were obtained for a total of 60 minutes as previously described.14 Arterial blood was obtained throughout the procedure to measure the concentration of unchanged [11C]raclopride in plasma.20

IMAGE ANALYSIS AND STATISTICS

Regions of interest (ROIs) were obtained directly from the [11C]raclopride images as previously described.14 Briefly, we identified and selected the ROIs on summed images (dynamic images taken from 10-54 minutes) that were resliced along the intercommisural plane (anterior commissural to posterior commissural line). The caudate, putamen, and cerebellum were measured on 4, 3, and 2 planes, respectively, and right and left regions were delineated. These regions were then projected to the dynamic scans to obtain concentrations of carbon 11 vs time, which were used to calculate the K1 (transport constant from plasma to tissue) and the distribution volumes (DV) using a graphical analysis technique for reversible systems.21 We computed the ratio of the DV in caudate and putamen to that in the cerebellum to obtain the DV ratio (DVR). The DVR, which corresponds to Bmax′/Kd′ + 1 (Kd′ and Bmax′ are the effective in vivo constants in the presence of endogenous neurotransmitter and nonspecific binding), was used as an estimate of D2/D3 receptor availability.21 The effect of methylphenidate on [11C]raclopride binding was quantified as percentage change in Bmax′/Kd′ from placebo.

Differences in baseline D2/D3 receptor availability between the groups were assessed with unpaired t tests (2-tailed). Differences in the response to methylphenidate between groups were assessed with analyses of variance with 1 between-subject factor (control vs ADHD) and 1 within-subject factor (placebo vs methylphenidate). Post hoc t tests were used to determine which of the conditions differed. Pearson product moment correlations were used to assess the association between the measures in methylphenidate-induced changes in DA and the CAARS. These correlations were done separately for the controls and for the subjects with ADHD and with all the subjects included. We also measured the correlations between methylphenidate-induced DA changes and the behavioral effects significantly affected by methylphenidate. To test the 2 main hypotheses of the study (that methylphenidate-induced DA changes would be smaller in the ADHD group than in the control group and that placebo-methylphenidate differences would be associated with inattention), we set significance at P < .05; for the exploratory analysis (correlations of DA changes with behavioral measures), we set significance at P < .01.

For exploratory analyses of areas other than striatum affected by methylphenidate, we used statistical parametric mapping (SPM)22 since this allows for the assessment of differences in areas without the need to preselect the regions. The SPM analysis was performed on the DVR images (obtained by computing the DV in each pixel and then dividing it by the DV in cerebellum). The DVR images were spatially normalized using the Montreal Neurological Institute template provided in the SPM 99 package and subsequently smoothed with a 16-mm isotropic Gaussian kernel. Paired t tests were performed separately for the controls and the subjects with ADHD to identify the areas where there were significant differences between the DVR images obtained after placebo from those after methylphenidate. Significance was set at P < .001 (uncorrected, cluster-size threshold > 100 voxels), and the statistical maps were overlaid on a magnetic resonance imaging structural image. The cluster sizes (number of pixels) that differed significantly between placebo and methylphenidate at the threshold level of P < .001 were expressed as percentage of the volume of the pertinent anatomical region (ie, caudate, putamen, amygdala, hippocampus) as defined from the Talairach Daemon.23 Comparisons of the differences in the percentage of the regional volume changed by methylphenidate between controls and ADHD were assessed using bootstrap resampling.24 For this purpose, we performed random sampling with replacement of the same number of images involved in the SPM comparison for 1000 times to obtain the bootstrap duplicate used for SPM comparisons. The resampling method does not require the use of a parametric model where the large number of voxels per image (N = ~ 50 000) renders the usual normal assumption inappropriate for the N-dimensional joint distribution of the image that was treated as an N-dimensional vector.25

DOPAMINE D2/D3 RECEPTORS AT BASELINE (PLACEBO)

At baseline, there were no differences in K1 between controls and subjects with ADHD in cerebellum, caudate, or putamen (Table 1). In contrast, D2/D3 receptors' availability (Bmax′/Kd′) was significantly lower in subjects with ADHD than in controls in left caudate (t41 = 2.12, P < .04) and showed a trend in right caudate (t = 1.87, P < .07) but did not differ in putamen (Table 1).

Table Graphic Jump LocationTable 1. Measures for K1, Distribution Volume, and Bmax′/Kd′ for Controls and Subjects With ADHD a
EFFECTS OF METHYLPHENIDATE ON [11C]RACLOPRIDE BINDING

The analysis of variance on the K1 measures revealed that neither the drug nor the interaction effects were significant in caudate, putamen, or cerebellum, which indicates that methylphenidate did not change the radiotracer delivery into the tissue and that there were no differences in the responses between controls and subjects with ADHD (Table 1).

The analysis of variance on the Bmax′/Kd′ measures revealed a significant drug effect in left and right caudate (F1,41 = 53, P < .001) and in left and right putamen (F = 182, P < .001), which indicates that Bmax′/Kd′ was significantly reduced by methylphenidate in both groups (Figure 1 and Table 1). The interaction effect was significant for the left caudate (F1,41 = 4.5, P < .04) and for the right caudate (F = 4.9, P < .04), which indicates that the responses in these regions differed between groups. Post hoc t test revealed that the responses to methylphenidate were significantly smaller in subjects with ADHD than in controls in left caudate (t1,41 = 2.1, P < .04) and right caudate (t = 2.2, P < .04).

Place holder to copy figure label and caption
Figure 1.

Effects of methylphenidate hydrochloride on brain dopamine. A, Distribution volume ratio images for raclopride labeled with carbon 11 at the level of striatum and the cerebellum in a control and a subject with attention-deficit/hyperactivity disorder (ADHD) after placebo and after methylphenidate. Note the decrease in specific binding (distribution volume ratios) with methylphenidate and the attenuated response to methylphenidate in the subject with ADHD when compared with the control. B, Histogram for percentage change in Bmax′/Kd′ (D2 receptor availability) between placebo and methylphenidate for the caudate (average of left and right) and putamen (average of left and right) for controls and subjects with ADHD. * Indicates repeated factorial analysis of variance significant interaction effect (P < .05).

Graphic Jump Location

To control for potential confounds, we did separate analyses of variance. One used the DV in occipital cortex as the normalization region for the DVR since the cerebellum has been found to be abnormal in subjects with ADHD, and the other excluded smokers in the event that nicotine could affect the methylphenidate responses. Both yielded the same results. The normalization with occipital cortex showed a significant interaction effect in left caudate (F1,41 = 5.3, P < .03) and right caudate (F = 5.1, P < .02), and post hoc t test corroborated the smaller decrements in subjects with ADHD (t = 2.3, P < .03). The analysis without the smokers also showed a significant interaction effect in left and right caudate (F1,39 > 5.2, P < .05) with post hoc t test showing that reductions were smaller in subjects with ADHD (t = 2.0, P < .05). These analyses indicate that neither the cerebellum nor the smokers accounted for the group differences.

Exploratory analysis with SPM—to assess whether there were regions other than the striatum where specific [11C]raclopride binding was reduced by methylphenidate—revealed significant (P < .001) decrements not only in caudate and putamen but also in hippocampus and amygdala both in controls and in subjects with ADHD (Figure 2). The SPM comparison on the difference image (placebo − methylphenidate) between controls and subjects with ADHD was not significant. However, the comparison of volume differences in the regions where methylphenidate significantly reduced Bmax′/Kd′ (threshold level of P < .001) revealed a group difference: these volumes were significantly larger for controls than for subjects with ADHD in left and right caudate, left amygdala, and left and right hippocampus (P < .001) (Figure 2).

Place holder to copy figure label and caption
Figure 2.

Brain areas where methylphenidate hydrochloride increased dopamine. A, Location of the regions where statistical parametric mapping analysis revealed significant decrements (P < .001) in distribution volume ratio (measure for dopamine increases) after methylphenidate in controls and in subjects with attention-deficit/hyperactivity disorder (ADHD). Note that methylphenidate not only reduced binding in striatum but also in amygdala and hippocampus and that the volume of decrements is larger for controls than for subjects with ADHD. * Highlights planes where decrements were smaller in subjects with ADHD than controls. B, Histogram showing the percentage volume of a given region where methylphenidate significantly decreased the distribution volume ratio in controls and in subjects with ADHD. † Indicates bootstrap comparisons where values differed significantly between groups (P < .001). Note that the volume of decrements is larger for controls than for subjects with ADHD.

Graphic Jump Location
PLASMA CONCENTRATIONS AND BEHAVIORAL RESPONSES TO METHYLPHENIDATE

Mean ± SD plasma concentrations did not differ between controls and subjects with ADHD at 10 minutes (117 ± 27 vs 113 ± 31 ng/mL, respectively), 25 minutes (84 ± 16 vs 83 ± 22 ng/mL), 40 minutes (64 ± 11 vs 62 ± 21 ng/mL), or 60 minutes (46 ± 10 vs 46 ± 16 ng/mL).

In both groups of subjects, methylphenidate significantly increased self-reports of alertness, anxiety, high, restlessness, feel drug, drug liking, and drug disliking and decreased tiredness (Table 2). The interaction effect was significant for alertness, tiredness, drug liking, and drug disliking. Post hoc t tests revealed that methylphenidate effects were significantly larger in subjects with ADHD than in controls for alertness (t41 = 3.5, P < .001), tiredness (t = 2.1, P < .03), and drug liking (t = 2.5, P < .02) and significantly smaller for drug disliking (t = 2.0, P < .05) (Table 2).

Table Graphic Jump LocationTable 2. Behavioral Effects of Intravenous Methylphenidate in Controls and Subjects With ADHD
CORRELATION BETWEEN DA MEASURES AND ADHD SYMPTOMS (CAARS)

The correlation between the baseline measures of D2/D3 receptor availability and the CAARS were not significant in either controls or subjects with ADHD. In contrast, methylphenidate-induced changes in DA (percentage change in Bmax"/Kd") in the subjects with ADHD were negatively correlated with the scores on CAARS section E (DSM-IV inattentive symptoms) in left caudate (r = −0.49, P < .04), right caudate (r = −0.56, P < .02), left putamen (r = −0.61, P < .008), and right putamen (r = −0.71, P < .001) and on CAARS section A (inattention/memory problems) in left caudate (r = −0.51, P < .04) and showed a trend in right caudate (r = −0.41, P < .09), left putamen (r = −0.45, P < .06), and right putamen (r = −0.45, P < .06). The smaller the DA changes, the greater the symptoms of inattention (Figure 3). These correlations were not significant in control subjects, but this may be due to the restricted ratings range of the CAARS in normal subjects. The analyses were also performed with all subjects (controls and ADHD) and resulted in a similar pattern of significant effects: the correlations were for the CAARS A and the left and right caudate (r = −0.31, P < .05) and for the CAARS E and the right caudate (r = −0.34, P < .04) and left caudate (r = 0.30, P < .06). The correlations in putamen were not significant.

Place holder to copy figure label and caption
Figure 3.

Regression slopes between changes in dopamine (DA) in caudate and in putamen and scores on Conners Adult ADHD Rating Scales (CAARS) section E (DSM-IV symptoms of inattention) in subjects with attention-deficit/hyperactivity disorder (ADHD). Correlations correspond for left caudate (r = −0.49, P < .04), right caudate (r = −0.56, P < .02), left putamen (r = −0.61, P < .008), and right putamen (r = −0.71, P < .001).

Graphic Jump Location
CORRELATION BETWEEN METHYLPHENIDATE-INDUCED DA CHANGES AND ITS BEHAVIORAL EFFECTS

The pattern of correlations obtained for all subjects showed that methylphenidate-induced self-reports of drug liking were negatively correlated with DA changes in left caudate (r = −0.39, P < .01) and showed a trend in right caudate (r = −0.37, P < .02). Methylphenidate-induced self-reports of feel drug showed significant positive correlations in left caudate (r = −0.43, P < .005), left putamen (r = −0.41, P < .007), and right putamen (r = −0.46, P < .003) and showed a trend in right caudate (r = −0.35, P < .05). The pattern of correlations was the same when done separately for subjects with ADHD or for controls except that the correlations only showed a trend for significant effects (P > .04 and P < .08). The correlations with the other behavioral measures were not significant.

DECREASED DA RELEASE

Herein we report that adult subjects with ADHD had lower methylphenidate-induced changes in DA in caudate compared with controls and that the blunted responses were associated with symptoms of inattention and with more positive subjective responses to intravenous methylphenidate. The exploratory analysis also revealed preliminary evidence of lower than normal DA changes in limbic regions (amygdala and hippocampus). Since methylphenidate is a DAT blocker and not a DA releaser, for a given level of DAT blockade the DA changes reflect the amount of spontaneous DA released.11 Inasmuch as the concentration of methylphenidate in plasma, which did not differ between groups, predicts the levels of DAT blockade,26,27 the blunted response to methylphenidate suggests that subjects with ADHD have lower DA release than controls.

The mechanisms resulting in reduced DA release in ADHD are unclear, but we consider 2 possibilities. The reduced release could reflect either a primary effect due to disruption in DA cells (ie, DA synthesis, DAT, DA autoreceptors) or a secondary effect from disruption of circuits that regulate DA release (ie, cortical-striatal glutamate pathways). Indeed in adults subjects with ADHD, there is evidence of decreased DA synthesis and metabolism in the prefrontal cortex.9 As discussed earlier, there is also evidence of disruption in DAT levels in subjects with ADHD, although the findings are inconsistent (reviewed5) and difficult to interpret because DAT levels are a function of both the density of DA terminals and the number of DATs per terminal. Decreased DA release could also reflect prefrontal pathology, which has been consistently documented in ADHD (reviewed28,29) since frontal-striatal glutamatergic circuits regulate striatal DA release.30,31 However, prefrontal pathology in ADHD could also indicate improper dopaminergic regulation of frontal regions.32 The findings of reduced DA release in subjects with ADHD are consistent with the notion that the ability of stimulant medications to enhance extracellular DA underlies their therapeutic effects in ADHD.

DOPAMINERGIC DISRUPTION IN CAUDATE AND INATTENTION IN ADHD

Baseline D2/D3 receptor availability (Bmax′/Kd′) on left caudate was also significantly lower in subjects with ADHD than in controls. Since measures of D2/D3 receptor availability are influenced by extracellular DA, low Bmax′/Kd′ could reflect either increased DA release or low D2/D3 receptor levels.33 The observations that subjects with ADHD had reduced DA release discounts the former and supports the latter possibility that lower Bmax"/Kd" measures at baseline are due to lower than normal D2/D3 receptor levels in subjects with ADHD. This finding is opposite to results in patients with schizophrenia who show increases in baseline D2 receptors and in DA release.34 Although a prior study reported increases in striatal D2/D3 receptor availability in children with ADHD when compared with young adults,35 the differences could reflect the normal decreases in D2 receptors that occur with age.36 The reduction in D2/D3 receptors in caudate at baseline coupled with the reduced DA release in this region corroborate findings from prior studies identifying the caudate as a key area involved in ADHD.37,38 The association between the DA response in caudate and symptoms of inattention implicates the caudate in attentional process and is consistent with reports that caudate lesions result in attention deficits.39 Future studies should investigate the significance of the caudate DA changes in cognitive symptoms in ADHD.

Our findings differ from those previously reported in adolescents with ADHD in whom methylphenidate-induced striatal DA increases correlated positively with inattention and impulsivity.12 This discrepancy could be related to age of subjects (adolescents vs adults) since the DA system undergoes major developmental changes from childhood/adolescence to adulthood40 and the response to stimulant drugs changes as a function of developmental stage.41 Moreover, the clinical symptomatology in ADHD also changes during this developmental transition,1 and thus it is conceivable that DA's involvement in ADHD could also differ.42 Indeed, the failure to show a correlation with hyperactivity and impulsivity in our study could reflect the restricted range of symptoms in adults with ADHD since these symptoms decline with age more than the symptoms of inattention, which predominate in adults with ADHD.43 The route of administration used for methylphenidate by these 2 studies (0.3 mg/kg orally vs 0.5 mg/kg intravenously) is also likely to have contributed to the differences in the findings. Oral methylphenidate gets into the brain slowly (peaking 60-90 minutes after administration), inducing a slow and progressive increase in DA that is not rewarding, while intravenous methylphenidate gets into the brain very rapidly (peaking < 15 minutes), inducing a large and abrupt DA increase that is perceived as very reinforcing.44

ENHANCED REINFORCING EFFECTS OF INTRAVENOUS METHYLPHENIDATE IN ADHD

Here we also document that subjects with ADHD reported more intense reinforcing effects (drug liking) after intravenous methylphenidate than controls. The reinforcing responses to methylphenidate were negatively correlated with the DA increases, suggesting that decreased dopaminergic activity may also be involved in modulating the magnitude of the reinforcing effects of methylphenidate. This association could contribute to the higher vulnerability for substance abuse comorbidity in adult subjects with ADHD.45 Indeed substance abusers show blunted DA responses to intravenous methylphenidate or amphetamine administration.46,47 The finding would also be consistent with clinical studies indicating a protective effect of treatment with stimulants on development of substance abuse in individuals with ADHD48 since stimulant treatment will increase DA tone.

It is important to emphasize that the behavioral effects (drug liking) of intravenous methylphenidate as used in this study are quite different from those of oral methylphenidate as used when given in the treatment of ADHD where reinforcing effects are not observed. This is due, as discussed here, to differences in pharmacokinetics but also to differences on the doses used, which in this study led to much higher plasma methylphenidate concentrations than those achieved therapeutically (reviewed44). Thus the present report of methylphenidate-induced drug liking does not have a parallel in the therapeutic effects of oral methylphenidate and should not detract from its use. Elsewhere44 a more detailed discussion on the differences in use and abuse of methylphenidate that depend on route of administration has been presented with a discussion of why the clinical use in the treatment of ADHD is associated with oral administration and the abuse is associated with intravenous administration.

DOPAMINE RELEASE IN AMYGDALA AND HIPPOCAMPUS

In this study, we also provide preliminary evidence of disrupted DA release in hippocampus and amygdala. Although these regions have been much less investigated in ADHD than the striatum and the prefrontal cortex, recent studies have shown volumetric changes in the hippocampus (larger in ADHD) and the amygdala (smaller in ADHD) of children with ADHD.49 Similarly, functional imaging studies have reported inadequate activation of the hippocampus during a decision task in adults with ADHD.50 Inasmuch as DA release in amygdala and hippocampus has been associated with performance on working memory and attention in healthy controls,51 the preliminary findings of a blunted release in ADHD could also contribute to their impairments in these tasks.52

LIMITATIONS

First, although changes in [11C]raclopride binding are related to extracellular DA, the precise relationship with extracellular DA is not understood.33,53 The poor temporal resolution of PET allowed us to detect DA changes only over a 20- to 30-minute period, reflecting mostly tonic DA activity, and thus we could not assess if there are abnormalities in phasic DA activity in ADHD. Also we cannot rule out the possibility that the blunted DA responses to methylphenidate in subjects with ADHD could reflect higher baseline DA tone that would interfere with further increase by methylphenidate via activation of autoreceptors.

Second, the [11C]raclopride method is best suited to detect DA release in regions of high D2/D3 receptor density such as striatum and thus is much less sensitive to detect differences in extrastriatal regions. Although we were able to document robust effects of intravenous methylphenidate on amygdala and hippocampus and significant differences on the effects of methylphenidate between controls and subjects with ADHD on volume sizes in these regions, the SPM between group comparisons on the delta images (methylphenidate − placebo) was nonsignificant. This is likely to reflect the low statistical power in the SPM comparisons of the delta images, which are noisy and have large standard deviations (approximately the square root of 2 times the standard deviations of the nonsubtracted images). The failure to document significant group differences on the SPM comparisons on the delta images leads us to interpret the findings in hippocampus and amygdala as preliminary and in need of replication.

Here we detected lower D2/D3 receptor availability and decreased DA release in caudate, which is a brain region where prior studies have documented reduced volume in subjects with ADHD.5456 Even though decreased caudate volume could result in an underestimation of D2/D3 receptor availability measures because of a reduced recovery coefficient,57 this is unlikely to be the case since the K1 measures in caudate did not differ between groups.

Finally in this study, we did not obtain magnetic resonance imaging structural images and the ROIs were obtained directly from the [11C]raclopride images. Since measures of D2/D3 receptor availability obtained using ROIs selected directly from [11C]raclopride images are almost identical to those obtained when the ROIs were selected from the subject's magnetic resonance images,58 it is unlikely that this limitation influenced our findings. However, we cannot rule out the possibility that in subjects with ADHD who may have smaller caudates, the 2 methods may have yielded different results.

These results provide evidence of depressed DA activity in ADHD. Moreover, the significant association between the blunted changes in DA in caudate and the severity of clinical symptoms suggests that reduced dopaminergic input into the caudate may underlie the symptoms of inattentiveness in adult subjects with ADHD. In addition, preliminary evidence of DA abnormalities in hippocampus and amygdala corroborates the involvement of the limbic system in the pathophysiology of ADHD.

Correspondence: Nora D. Volkow, MD, National Institute on Drug Abuse, 6001 Executive Blvd, Room 5274, Bethesda, MD 20892 (nvolkow@nida.nih.gov).

Submitted for Publication: August 28, 2006; final revision received November 27, 2006; accepted January 19, 2007.

Financial Disclosure: None reported.

Funding/Support: This research was supported in part by the Intramural Research Program of the National Institutes of Health (National Institute on Alcoholism and Alcohol Abuse), by contract DE-AC01-76CH00016 from the Department of Energy (Office of Health and Environmental Research), and by grant MH66961-02 from the National Institute of Mental Health.

Additional Contributions: David Schlyer, PhD, and Michael Schueller, PhD, managed cyclotron operations; David Alexoff, PhD, and Paul Vaska, PhD, provided quality control of PET measures; Colleen Shea, MS, and Youwen Xu, MS, radiotracer synthesis; Pauline Carter, RN, nursing care; Tim Wigal, PhD, and Scott Kollins, PhD, assistance with subject recruitment; Karen Apelskog, BS, protocol coordination; and Linda Thomas, MS, editorial assistance.

 National Institutes of Health Consensus Development Conference Statement: diagnosis and treatment of attention-deficit/hyperactivity disorder (ADHD). J Am Acad Child Adolesc Psychiatry 2000;39 (2) 182- 193
PubMed Link to Article
Sagvolden  TJohansen  EBAase  HRussell  VA A dynamic developmental theory of attention-deficit/hyperactivity disorder (ADHD) predominantly hyperactive/impulsive and combined subtypes. Behav Brain Sci 2005;28 (3) 397- 419
PubMed Link to Article
Kuczenski  RSegal  DS Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: comparison with amphetamine. J Neurochem 1997;68 (5) 2032- 2037
PubMed Link to Article
Zahniser  NRDoolen  S Chronic and acute regulation of Na+/Cl− -dependent neurotransmitter transporters: drugs, substrates, presynaptic receptors, and signaling systems. Pharmacol Ther 2001;92 (1) 21- 55
PubMed Link to Article
Spencer  TJBiederman  JMadras  BKFaraone  SVDougherty  DDBonab  AAFischman  AJ In vivo neuroreceptor imaging in attention-deficit/hyperactivity disorder: a focus on the dopamine transporter. Biol Psychiatry 2005;57 (11) 1293- 1300
PubMed Link to Article
van Dyck  CHQuinlan  DMCretella  LMStaley  JKMalison  RTBaldwin  RMSeibyl  JPInnis  RB Unaltered dopamine transporter availability in adult attention deficit hyperactivity disorder. Am J Psychiatry 2002;159 (2) 309- 312
PubMed Link to Article
Volkow  NDWang  GJNewcorn  JFowler  JSTelang  FSolanto  MVLogan  JWong  CMa  YSwanson  JMSchultz  KPradhan  K Brain dopamine transporter levels in treatment and drug naive adults with ADHD. Neuroimage 2007;34 (3) 1182- 1190
PubMed Link to Article
Hesse  SBallaschkle  OBarthel  Hvon Cramon  DSabri  O The striatal dopamine transporter availability is reduced in adults with attention-deficit/hyperactivity disorder [abstract]. J Nucl Med 2006;47142
Ernst  MZametkin  AJMatochik  JAJons  PHCohen  RM DOPA decarboxylase activity in attention deficit hyperactivity disorder adults: a [fluorine-18]fluorodopa positron emission tomographic study. J Neurosci 1998;18 (15) 5901- 5907
PubMed
Ernst  MZametkin  AJMatochik  JAPascualvaca  DJons  PHCohen  RM High midbrain [18F]DOPA accumulation in children with attention deficit hyperactivity disorder. Am J Psychiatry 1999;156 (8) 1209- 1215
PubMed
Volkow  NDWang  GJFowler  JSLogan  JFranceschi  DMaynard  LDing  YSGatley  SJGifford  AZhu  WSwanson  JM Relationship between blockade of dopamine transporters by oral methylphenidate and the increases in extracellular dopamine: therapeutic implications. Synapse 2002;43 (3) 181- 187
PubMed Link to Article
Rosa-Neto  PLou  HCCumming  PPryds  OKarrebaek  HLunding  JGjedde  A Methylphenidate-evoked changes in striatal dopamine correlate with inattention and impulsivity in adolescents with attention deficit hyperactivity disorder. Neuroimage 2005;25 (3) 868- 876
PubMed Link to Article
Dewey  SLSmith  GSLogan  JBrodie  JDFowler  JSWolf  AP Striatal binding of the PET ligand 11C-raclopride is altered by drugs that modify synaptic dopamine levels. Synapse 1993;13 (4) 350- 356
PubMed Link to Article
Volkow  NDWang  GJFowler  JSLogan  JSchlyer  DHitzemann  RLieberman  JAngrist  BPappas  NMacGregor  R Imaging endogenous dopamine competition with [11C]raclopride in the human brain. Synapse 1994;16 (4) 255- 262
PubMed Link to Article
Conners  CK Rating scales in attention-deficit/hyperactivity disorder: use in assessment and treatment monitoring. J Clin Psychiatry 1998;59 ((suppl 7)) 24- 30
PubMed Link to Article
Hamilton  M The assessment of anxiety states by rating. Br J Med Psychol 1959;32 (1) 50- 55
PubMed Link to Article
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;2356- 62
PubMed Link to Article
Wang  GJVolkow  NDHitzemann  RJWong  CAngrist  BBurr  GPascani  KPappas  NLu  ACooper  TLieberman  JA Behavioral and cardiovascular effects of intravenous methylphenidate in normal subjects and cocaine abusers. Eur Addict Res 1997;349- 54
Link to Article
Fischman  MWFoltin  RW Utility of subjective-effects measurements in assessing abuse liability of drugs in humans. Br J Addict 1991;86 (12) 1563- 1570
PubMed Link to Article
Alexoff  DShea  CFowler  JSKing  PGatley  SJSchlyer  DJWolf  AP Plasma input function determination for PET using a commercial laboratory robot. Nucl Med Biol 1995;22 (7) 893- 904
PubMed Link to Article
Logan  JFowler  JSVolkow  NDWolf  APDewey  SLSchlyer  DJMacGregor  RRHitzemann  RBendriem  BGatley  SJ Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(-)-cocaine PET studies in human subjects. J Cereb Blood Flow Metab 1990;10 (5) 740- 747
PubMed Link to Article
Friston  KJHolmes  APWorsley  KJPoline  JBFrith  CDFrackowiak  RSJ Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp 1995;2189- 210
Link to Article
Lancaster  JLWoldorff  MGParsons  LMLiotti  MFreitas  CSRainy  LKochunov  PVNickerson  DMikiten  SAFox  PT Automated Talairach atlas labels for functional brain mapping. Hum Brain Mapp 2000;10 (3) 120- 131
PubMed Link to Article
Efron  BTibshirani  R An Introduction to the Bootstrap.  Boca Raton, FL Chapman & Hall/CRC Press1993;
Casella  GBerger  RL Statistical Inference. 2nd Pacific Grove, CA Duxbury2002;
Volkow  NDWang  GJFowler  JSGatley  SJLogan  JDing  YSHitzemann  RPappas  N Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. Am J Psychiatry 1998;155 (10) 1325- 1331
PubMed
Volkow  NDWang  GJFowler  JSGatley  SJLogan  JDing  YSDewey  SLHitzemann  RGifford  ANPappas  NR Blockade of striatal dopamine transporters by intravenous methylphenidate is not sufficient to induce self-reports of “high.” J Pharmacol Exp Ther 1999;288 (1) 14- 20
PubMed
Bush  GValera  EMSeidman  LJ Functional neuroimaging of attention-deficit/hyperactivity disorder: a review and suggested future directions. Biol Psychiatry 2005;57 (11) 1273- 1284
PubMed Link to Article
Lou  HCAndresen  JSteinberg  BMcLaughlin  TFriberg  L The striatum in a putative cerebral network activated by verbal awareness in normals and in ADHD children. Eur J Neurol 1998;5 (1) 67- 74
PubMed Link to Article
Karreman  MMoghaddam  B The prefrontal cortex regulates the basal release of dopamine in the limbic striatum: an effect mediated by ventral tegmental area. J Neurochem 1996;66 (2) 589- 598
PubMed Link to Article
Kolachana  BSSaunders  RCWeinberge  DR Augmentation of prefrontal cortical monoaminergic activity inhibits dopamine release in the caudate nucleus: an in vivo neurochemical assessment in the rhesus monkey. Neuroscience 1995;69 (3) 859- 868
PubMed Link to Article
Seamans  JKYang  CR The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol 2004;74 (1) 1- 58
PubMed Link to Article
Gjedde  AWong  DFRosa-Neto  PCumming  P Mapping neuroreceptors at work: on the definition and interpretation of binding potentials after 20 years of progress. Int Rev Neurobiol 2005;631- 20
PubMed
Wong  DFPearlson  GDTune  LEYoung  LTMeltzer  CCDannals  RFRavert  HTReith  JKuhar  MJGjedde  A Quantification of neuroreceptors in the living human brain: IV. Effect of aging and elevations of D2-like receptors in schizophrenia and bipolar illness. J Cereb Blood Flow Metab 1997;17 (3) 331- 342
PubMed Link to Article
Ilgin  NSenol  SGucuyener  KGokcora  NSener  S Is increased D2 receptor availability associated with response to stimulant medication in ADHD. Dev Med Child Neurol 2001;43 (11) 755- 760
PubMed Link to Article
Volkow  NDWang  GJFowler  JSLogan  JGatley  SJMacGregor  RRSchlyer  DJHitzemann  RWolf  AP Measuring age-related changes in dopamine D2 receptors with 11C-raclopride and 18F-N-methylspiroperidol. Psychiatry Res 1996;67 (1) 11- 16
PubMed Link to Article
Vaidya  CJBunge  SADudukovic  NMZalecki  CAElliott  GRGabrieli  JD Altered neural substrates of cognitive control in childhood ADHD: evidence from functional magnetic resonance imaging. Am J Psychiatry 2005;162 (9) 1605- 1613
PubMed Link to Article
Lou  HCRosa  PPryds  OKarrebaek  HLunding  JCumming  PGjedde  A ADHD: increased dopamine receptor availability linked to attention deficit and low neonatal cerebral blood flow. Dev Med Child Neurol 2004;46 (3) 179- 183
PubMed Link to Article
Benke  TDelazer  MBartha  LAuer  A Basal ganglia lesions and the theory of fronto-subcortical loops: neuropsychological findings in two patients with left caudate lesions. Neurocase 2003;9 (1) 70- 85
PubMed Link to Article
Tseng  KYO’Donnell  P Dopamine modulation of prefrontal cortical interneurons changes during adolescence. Cereb Cortex 2007;17 (5) 1235- 1240
PubMed Link to Article
Andersen  SLLeBlanc  CJLyss  PJ Maturational increases in c-fos expression in the ascending dopamine systems. Synapse 2001;41 (4) 345- 350
PubMed Link to Article
Andersen  SL Changes in the second messenger cyclic AMP during development may underlie motoric symptoms in attention deficit/hyperactivity disorder (ADHD). Behav Brain Res 2002;130 (1-2) 197- 201
PubMed Link to Article
Biederman  JMick  EFaraone  SV Age-dependent decline of symptoms of attention deficit hyperactivity disorder: impact of remission definition and symptom type. Am J Psychiatry 2000;157 (5) 816- 818
PubMed Link to Article
Volkow  NDSwanson  JM Variables that affect the clinical use and abuse of methylphenidate in the treatment of ADHD. Am J Psychiatry 2003;160 (11) 1909- 1918
PubMed Link to Article
Kessler  RCAdler  LBarkley  RBiederman  JConners  CKDemler  OFaraone  SVGreenhill  LLHowes  MJSecnik  KSpencer  TUstun  TBWalters  EEZaslavsky  AM The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry 2006;163 (4) 716- 723
PubMed Link to Article
Volkow  NDWang  GJFowler  JSLogan  JGatley  SJHitzemann  RChen  ADDewey  SLPappas  N Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature 1997;386 (6627) 830- 833
PubMed Link to Article
Martinez  DGil  RSlifstein  MHwang  DRHuang  YPerez  AKegeles  LTalbot  PEvans  SKrystal  JLaruelle  MAbi-Dargham  A Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum. Biol Psychiatry 2005;58 (10) 779- 786
PubMed Link to Article
Wilens  TEFaraone  SVBiederman  JGunawardene  S Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? a meta-analytic review of the literature. Pediatrics 2003;111 (1) 179- 185
PubMed Link to Article
Plessen  KJBansal  RZhu  HWhiteman  RAmat  JQuackenbush  GAMartin  LDurkin  KBlair  CRoyal  JHugdahl  KPeterson  BS Hippocampus and amygdala morphology in attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 2006;63 (7) 795- 807
PubMed Link to Article
Ernst  MKimes  ASLondon  EDMatochik  JAEldreth  DTata  SContoreggi  CLeff  MBolla  K Neural substrates of decision making in adults with attention deficit hyperactivity disorder. Am J Psychiatry 2003;160 (6) 1061- 1070
PubMed Link to Article
Aalto  SBruck  ALaine  MNagren  KRinne  JO Frontal and temporal dopamine release during working memory and attention tasks in healthy humans: a positron emission tomography study using the high-affinity dopamine D2 receptor ligand [11C]FLB 457. J Neurosci 2005;25 (10) 2471- 2477
PubMed Link to Article
Dowson  JHMcLean  ABazanis  EToone  BYoung  SRobbins  TWSahakian  BJ Impaired spatial working memory in adults with attention-deficit/hyperactivity disorder: comparisons with performance in adults with borderline personality disorder and in control subjects. Acta Psychiatr Scand 2004;110 (1) 45- 54
PubMed Link to Article
Breier  ASu  TPSaunders  RCarson  REKolachana  BSde Bartolomeis  AWeinberger  DRWeisenfeld  NMalhotra  AKEckelman  WCPickar  D Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci U S A 1997;94 (6) 2569- 2574
PubMed Link to Article
Castellanos  FXGiedd  JNMarsh  WLHamburger  SDVaituzis  ACDickstein  DPSarfatti  SEVauss  YCSnell  JWLange  NKaysen  DKrain  ALRitchie  GFRajapakse  JCRapoport  JL Quantitative brain magnetic resonance imaging in attention-deficit hyperactivity disorder. Arch Gen Psychiatry 1996;53 (7) 607- 616
PubMed Link to Article
Castellanos  FXGiedd  JNBerquin  PCWalter  JMSharp  WTran  TVaituzis  ACBlumenthal  JDNelson  JBastain  TMZijdenbos  AEvans  ACRapoport  JL Quantitative brain magnetic resonance imaging in girls with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 2001;58 (3) 289- 295
PubMed Link to Article
Filipek  PASemrud-Clikeman  MSteingard  RJRenshaw  PFKennedy  DNBiederman  J Volumetric MRI analysis comparing subjects having attention-deficit hyperactivity disorder with normal controls. Neurology 1997;48 (3) 589- 601
PubMed Link to Article
Rousset  OGMa  YEvans  AC Correction for partial volume effects in PET: principle and validation. J Nucl Med 1998;39 (5) 904- 911
PubMed
Wang  GJVolkow  NDLevy  AVFowler  JSLogan  JAlexoff  DHitzemann  RJSchyler  DJ MR-PET image coregistration for quantitation of striatal dopamine D2 receptors. J Comput Assist Tomogr 1996;20 (3) 423- 428
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Effects of methylphenidate hydrochloride on brain dopamine. A, Distribution volume ratio images for raclopride labeled with carbon 11 at the level of striatum and the cerebellum in a control and a subject with attention-deficit/hyperactivity disorder (ADHD) after placebo and after methylphenidate. Note the decrease in specific binding (distribution volume ratios) with methylphenidate and the attenuated response to methylphenidate in the subject with ADHD when compared with the control. B, Histogram for percentage change in Bmax′/Kd′ (D2 receptor availability) between placebo and methylphenidate for the caudate (average of left and right) and putamen (average of left and right) for controls and subjects with ADHD. * Indicates repeated factorial analysis of variance significant interaction effect (P < .05).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Brain areas where methylphenidate hydrochloride increased dopamine. A, Location of the regions where statistical parametric mapping analysis revealed significant decrements (P < .001) in distribution volume ratio (measure for dopamine increases) after methylphenidate in controls and in subjects with attention-deficit/hyperactivity disorder (ADHD). Note that methylphenidate not only reduced binding in striatum but also in amygdala and hippocampus and that the volume of decrements is larger for controls than for subjects with ADHD. * Highlights planes where decrements were smaller in subjects with ADHD than controls. B, Histogram showing the percentage volume of a given region where methylphenidate significantly decreased the distribution volume ratio in controls and in subjects with ADHD. † Indicates bootstrap comparisons where values differed significantly between groups (P < .001). Note that the volume of decrements is larger for controls than for subjects with ADHD.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Regression slopes between changes in dopamine (DA) in caudate and in putamen and scores on Conners Adult ADHD Rating Scales (CAARS) section E (DSM-IV symptoms of inattention) in subjects with attention-deficit/hyperactivity disorder (ADHD). Correlations correspond for left caudate (r = −0.49, P < .04), right caudate (r = −0.56, P < .02), left putamen (r = −0.61, P < .008), and right putamen (r = −0.71, P < .001).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Measures for K1, Distribution Volume, and Bmax′/Kd′ for Controls and Subjects With ADHD a
Table Graphic Jump LocationTable 2. Behavioral Effects of Intravenous Methylphenidate in Controls and Subjects With ADHD

References

 National Institutes of Health Consensus Development Conference Statement: diagnosis and treatment of attention-deficit/hyperactivity disorder (ADHD). J Am Acad Child Adolesc Psychiatry 2000;39 (2) 182- 193
PubMed Link to Article
Sagvolden  TJohansen  EBAase  HRussell  VA A dynamic developmental theory of attention-deficit/hyperactivity disorder (ADHD) predominantly hyperactive/impulsive and combined subtypes. Behav Brain Sci 2005;28 (3) 397- 419
PubMed Link to Article
Kuczenski  RSegal  DS Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: comparison with amphetamine. J Neurochem 1997;68 (5) 2032- 2037
PubMed Link to Article
Zahniser  NRDoolen  S Chronic and acute regulation of Na+/Cl− -dependent neurotransmitter transporters: drugs, substrates, presynaptic receptors, and signaling systems. Pharmacol Ther 2001;92 (1) 21- 55
PubMed Link to Article
Spencer  TJBiederman  JMadras  BKFaraone  SVDougherty  DDBonab  AAFischman  AJ In vivo neuroreceptor imaging in attention-deficit/hyperactivity disorder: a focus on the dopamine transporter. Biol Psychiatry 2005;57 (11) 1293- 1300
PubMed Link to Article
van Dyck  CHQuinlan  DMCretella  LMStaley  JKMalison  RTBaldwin  RMSeibyl  JPInnis  RB Unaltered dopamine transporter availability in adult attention deficit hyperactivity disorder. Am J Psychiatry 2002;159 (2) 309- 312
PubMed Link to Article
Volkow  NDWang  GJNewcorn  JFowler  JSTelang  FSolanto  MVLogan  JWong  CMa  YSwanson  JMSchultz  KPradhan  K Brain dopamine transporter levels in treatment and drug naive adults with ADHD. Neuroimage 2007;34 (3) 1182- 1190
PubMed Link to Article
Hesse  SBallaschkle  OBarthel  Hvon Cramon  DSabri  O The striatal dopamine transporter availability is reduced in adults with attention-deficit/hyperactivity disorder [abstract]. J Nucl Med 2006;47142
Ernst  MZametkin  AJMatochik  JAJons  PHCohen  RM DOPA decarboxylase activity in attention deficit hyperactivity disorder adults: a [fluorine-18]fluorodopa positron emission tomographic study. J Neurosci 1998;18 (15) 5901- 5907
PubMed
Ernst  MZametkin  AJMatochik  JAPascualvaca  DJons  PHCohen  RM High midbrain [18F]DOPA accumulation in children with attention deficit hyperactivity disorder. Am J Psychiatry 1999;156 (8) 1209- 1215
PubMed
Volkow  NDWang  GJFowler  JSLogan  JFranceschi  DMaynard  LDing  YSGatley  SJGifford  AZhu  WSwanson  JM Relationship between blockade of dopamine transporters by oral methylphenidate and the increases in extracellular dopamine: therapeutic implications. Synapse 2002;43 (3) 181- 187
PubMed Link to Article
Rosa-Neto  PLou  HCCumming  PPryds  OKarrebaek  HLunding  JGjedde  A Methylphenidate-evoked changes in striatal dopamine correlate with inattention and impulsivity in adolescents with attention deficit hyperactivity disorder. Neuroimage 2005;25 (3) 868- 876
PubMed Link to Article
Dewey  SLSmith  GSLogan  JBrodie  JDFowler  JSWolf  AP Striatal binding of the PET ligand 11C-raclopride is altered by drugs that modify synaptic dopamine levels. Synapse 1993;13 (4) 350- 356
PubMed Link to Article
Volkow  NDWang  GJFowler  JSLogan  JSchlyer  DHitzemann  RLieberman  JAngrist  BPappas  NMacGregor  R Imaging endogenous dopamine competition with [11C]raclopride in the human brain. Synapse 1994;16 (4) 255- 262
PubMed Link to Article
Conners  CK Rating scales in attention-deficit/hyperactivity disorder: use in assessment and treatment monitoring. J Clin Psychiatry 1998;59 ((suppl 7)) 24- 30
PubMed Link to Article
Hamilton  M The assessment of anxiety states by rating. Br J Med Psychol 1959;32 (1) 50- 55
PubMed Link to Article
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;2356- 62
PubMed Link to Article
Wang  GJVolkow  NDHitzemann  RJWong  CAngrist  BBurr  GPascani  KPappas  NLu  ACooper  TLieberman  JA Behavioral and cardiovascular effects of intravenous methylphenidate in normal subjects and cocaine abusers. Eur Addict Res 1997;349- 54
Link to Article
Fischman  MWFoltin  RW Utility of subjective-effects measurements in assessing abuse liability of drugs in humans. Br J Addict 1991;86 (12) 1563- 1570
PubMed Link to Article
Alexoff  DShea  CFowler  JSKing  PGatley  SJSchlyer  DJWolf  AP Plasma input function determination for PET using a commercial laboratory robot. Nucl Med Biol 1995;22 (7) 893- 904
PubMed Link to Article
Logan  JFowler  JSVolkow  NDWolf  APDewey  SLSchlyer  DJMacGregor  RRHitzemann  RBendriem  BGatley  SJ Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(-)-cocaine PET studies in human subjects. J Cereb Blood Flow Metab 1990;10 (5) 740- 747
PubMed Link to Article
Friston  KJHolmes  APWorsley  KJPoline  JBFrith  CDFrackowiak  RSJ Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp 1995;2189- 210
Link to Article
Lancaster  JLWoldorff  MGParsons  LMLiotti  MFreitas  CSRainy  LKochunov  PVNickerson  DMikiten  SAFox  PT Automated Talairach atlas labels for functional brain mapping. Hum Brain Mapp 2000;10 (3) 120- 131
PubMed Link to Article
Efron  BTibshirani  R An Introduction to the Bootstrap.  Boca Raton, FL Chapman & Hall/CRC Press1993;
Casella  GBerger  RL Statistical Inference. 2nd Pacific Grove, CA Duxbury2002;
Volkow  NDWang  GJFowler  JSGatley  SJLogan  JDing  YSHitzemann  RPappas  N Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. Am J Psychiatry 1998;155 (10) 1325- 1331
PubMed
Volkow  NDWang  GJFowler  JSGatley  SJLogan  JDing  YSDewey  SLHitzemann  RGifford  ANPappas  NR Blockade of striatal dopamine transporters by intravenous methylphenidate is not sufficient to induce self-reports of “high.” J Pharmacol Exp Ther 1999;288 (1) 14- 20
PubMed
Bush  GValera  EMSeidman  LJ Functional neuroimaging of attention-deficit/hyperactivity disorder: a review and suggested future directions. Biol Psychiatry 2005;57 (11) 1273- 1284
PubMed Link to Article
Lou  HCAndresen  JSteinberg  BMcLaughlin  TFriberg  L The striatum in a putative cerebral network activated by verbal awareness in normals and in ADHD children. Eur J Neurol 1998;5 (1) 67- 74
PubMed Link to Article
Karreman  MMoghaddam  B The prefrontal cortex regulates the basal release of dopamine in the limbic striatum: an effect mediated by ventral tegmental area. J Neurochem 1996;66 (2) 589- 598
PubMed Link to Article
Kolachana  BSSaunders  RCWeinberge  DR Augmentation of prefrontal cortical monoaminergic activity inhibits dopamine release in the caudate nucleus: an in vivo neurochemical assessment in the rhesus monkey. Neuroscience 1995;69 (3) 859- 868
PubMed Link to Article
Seamans  JKYang  CR The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol 2004;74 (1) 1- 58
PubMed Link to Article
Gjedde  AWong  DFRosa-Neto  PCumming  P Mapping neuroreceptors at work: on the definition and interpretation of binding potentials after 20 years of progress. Int Rev Neurobiol 2005;631- 20
PubMed
Wong  DFPearlson  GDTune  LEYoung  LTMeltzer  CCDannals  RFRavert  HTReith  JKuhar  MJGjedde  A Quantification of neuroreceptors in the living human brain: IV. Effect of aging and elevations of D2-like receptors in schizophrenia and bipolar illness. J Cereb Blood Flow Metab 1997;17 (3) 331- 342
PubMed Link to Article
Ilgin  NSenol  SGucuyener  KGokcora  NSener  S Is increased D2 receptor availability associated with response to stimulant medication in ADHD. Dev Med Child Neurol 2001;43 (11) 755- 760
PubMed Link to Article
Volkow  NDWang  GJFowler  JSLogan  JGatley  SJMacGregor  RRSchlyer  DJHitzemann  RWolf  AP Measuring age-related changes in dopamine D2 receptors with 11C-raclopride and 18F-N-methylspiroperidol. Psychiatry Res 1996;67 (1) 11- 16
PubMed Link to Article
Vaidya  CJBunge  SADudukovic  NMZalecki  CAElliott  GRGabrieli  JD Altered neural substrates of cognitive control in childhood ADHD: evidence from functional magnetic resonance imaging. Am J Psychiatry 2005;162 (9) 1605- 1613
PubMed Link to Article
Lou  HCRosa  PPryds  OKarrebaek  HLunding  JCumming  PGjedde  A ADHD: increased dopamine receptor availability linked to attention deficit and low neonatal cerebral blood flow. Dev Med Child Neurol 2004;46 (3) 179- 183
PubMed Link to Article
Benke  TDelazer  MBartha  LAuer  A Basal ganglia lesions and the theory of fronto-subcortical loops: neuropsychological findings in two patients with left caudate lesions. Neurocase 2003;9 (1) 70- 85
PubMed Link to Article
Tseng  KYO’Donnell  P Dopamine modulation of prefrontal cortical interneurons changes during adolescence. Cereb Cortex 2007;17 (5) 1235- 1240
PubMed Link to Article
Andersen  SLLeBlanc  CJLyss  PJ Maturational increases in c-fos expression in the ascending dopamine systems. Synapse 2001;41 (4) 345- 350
PubMed Link to Article
Andersen  SL Changes in the second messenger cyclic AMP during development may underlie motoric symptoms in attention deficit/hyperactivity disorder (ADHD). Behav Brain Res 2002;130 (1-2) 197- 201
PubMed Link to Article
Biederman  JMick  EFaraone  SV Age-dependent decline of symptoms of attention deficit hyperactivity disorder: impact of remission definition and symptom type. Am J Psychiatry 2000;157 (5) 816- 818
PubMed Link to Article
Volkow  NDSwanson  JM Variables that affect the clinical use and abuse of methylphenidate in the treatment of ADHD. Am J Psychiatry 2003;160 (11) 1909- 1918
PubMed Link to Article
Kessler  RCAdler  LBarkley  RBiederman  JConners  CKDemler  OFaraone  SVGreenhill  LLHowes  MJSecnik  KSpencer  TUstun  TBWalters  EEZaslavsky  AM The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry 2006;163 (4) 716- 723
PubMed Link to Article
Volkow  NDWang  GJFowler  JSLogan  JGatley  SJHitzemann  RChen  ADDewey  SLPappas  N Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature 1997;386 (6627) 830- 833
PubMed Link to Article
Martinez  DGil  RSlifstein  MHwang  DRHuang  YPerez  AKegeles  LTalbot  PEvans  SKrystal  JLaruelle  MAbi-Dargham  A Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum. Biol Psychiatry 2005;58 (10) 779- 786
PubMed Link to Article
Wilens  TEFaraone  SVBiederman  JGunawardene  S Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? a meta-analytic review of the literature. Pediatrics 2003;111 (1) 179- 185
PubMed Link to Article
Plessen  KJBansal  RZhu  HWhiteman  RAmat  JQuackenbush  GAMartin  LDurkin  KBlair  CRoyal  JHugdahl  KPeterson  BS Hippocampus and amygdala morphology in attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 2006;63 (7) 795- 807
PubMed Link to Article
Ernst  MKimes  ASLondon  EDMatochik  JAEldreth  DTata  SContoreggi  CLeff  MBolla  K Neural substrates of decision making in adults with attention deficit hyperactivity disorder. Am J Psychiatry 2003;160 (6) 1061- 1070
PubMed Link to Article
Aalto  SBruck  ALaine  MNagren  KRinne  JO Frontal and temporal dopamine release during working memory and attention tasks in healthy humans: a positron emission tomography study using the high-affinity dopamine D2 receptor ligand [11C]FLB 457. J Neurosci 2005;25 (10) 2471- 2477
PubMed Link to Article
Dowson  JHMcLean  ABazanis  EToone  BYoung  SRobbins  TWSahakian  BJ Impaired spatial working memory in adults with attention-deficit/hyperactivity disorder: comparisons with performance in adults with borderline personality disorder and in control subjects. Acta Psychiatr Scand 2004;110 (1) 45- 54
PubMed Link to Article
Breier  ASu  TPSaunders  RCarson  REKolachana  BSde Bartolomeis  AWeinberger  DRWeisenfeld  NMalhotra  AKEckelman  WCPickar  D Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci U S A 1997;94 (6) 2569- 2574
PubMed Link to Article
Castellanos  FXGiedd  JNMarsh  WLHamburger  SDVaituzis  ACDickstein  DPSarfatti  SEVauss  YCSnell  JWLange  NKaysen  DKrain  ALRitchie  GFRajapakse  JCRapoport  JL Quantitative brain magnetic resonance imaging in attention-deficit hyperactivity disorder. Arch Gen Psychiatry 1996;53 (7) 607- 616
PubMed Link to Article
Castellanos  FXGiedd  JNBerquin  PCWalter  JMSharp  WTran  TVaituzis  ACBlumenthal  JDNelson  JBastain  TMZijdenbos  AEvans  ACRapoport  JL Quantitative brain magnetic resonance imaging in girls with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 2001;58 (3) 289- 295
PubMed Link to Article
Filipek  PASemrud-Clikeman  MSteingard  RJRenshaw  PFKennedy  DNBiederman  J Volumetric MRI analysis comparing subjects having attention-deficit hyperactivity disorder with normal controls. Neurology 1997;48 (3) 589- 601
PubMed Link to Article
Rousset  OGMa  YEvans  AC Correction for partial volume effects in PET: principle and validation. J Nucl Med 1998;39 (5) 904- 911
PubMed
Wang  GJVolkow  NDLevy  AVFowler  JSLogan  JAlexoff  DHitzemann  RJSchyler  DJ MR-PET image coregistration for quantitation of striatal dopamine D2 receptors. J Comput Assist Tomogr 1996;20 (3) 423- 428
PubMed Link to Article

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