Attention deficit/hyperactivity disorder (ADHD) is considered to be the most prevalent psychiatric disorder of childhood and its increasingly being recognized in adults too. The disorder is often chronic, with prominent symptoms (inattention, hyperactivity/impulsivity and motivation deficits) and impairment frequently continuing into adulthood. Deficits in dopamine (DA) neurotransmission have been associated with the disorder [1]. In adults, as with youth, stimulant medications (methylphenidate (MPH) or amphetamine), which enhance DA signaling have been used for decades as a first line treatment option [2]. MPH acutely enhances DA signaling by blocking the dopamine transporter (DAT), which is the main mechanism by which DA signals are terminated [1]. However, while the acute DA enhancing effects of MPH have been associated with symptom improvement in children [3] and adults [4] with ADHD very little work has been done to evaluate its chronic effects in brain DA signaling. Inasmuch as DAT appear to adapt to the levels of synaptic DA (downregulating when DA is low and upregulating when DA is high), we hypothesized that chronic MPH treatment would result in upregulation of DAT.

To test this hypothesis, we conducted a Positron Emission Tomography (PET) study using [¹¹C]cocaine in 18 stimulant-naïve adult patients with ADHD whom we scanned before and after 1 year of clinical treatment with MPH. The retest PET scan was conducted 24 hours after the last clinical MPH dose to ensure that the acute occupancy of DAT would have dissipated. In parallel we also measured DAT availability in 11 healthy controls at baseline and 12 months later with no intervening medication treatment. We hypothesized that long-term MPH treatment would upregulate DAT availability in the brain in response to stimulant-induced elevations in synaptic DA whereas there would be no changes in DAT availability in controls tested at a 12-month interval.

The ADHD subjects and control subjects are similar in age and socioeconomic background (Table 1). Prior to MPH treatment, each of the following CAARS subscale scores was higher for ADHD subjects than controls: A. Inattention/memory problems; B. Hyperactivity/Restlessness; C. Impulsivity/Emotional liability; D. problems with self concept; E. DSM-IV Inattentive symptoms; E. DSM-IV Hyperactive-impulsive symptoms, G. DSM-IV ADHD total symptom; H. ADHD index. The scores on inattention from the SWAN scale were higher for ADHD participants than for controls (Table 2). During treatment, all the CAARS subscales and the SWAN scores obtained while on medication within the week prior to the PET scan were significantly improved for the ADHD subjects (Table 1). Moreover, except for impulsivity (p<0.02) and inattention (p<0.04), most of the scores for the ADHD subjects while on medication were not significantly different from that of controls.

Table 3 shows the measures of DAT availability obtained prior to and after 1 year of MPH for the ADHD participants and for the controls for the baseline and follow-up measures. The repeated measures ANOVA showed that DAT availability in caudate and putamen did not differ between scans (baseline vs. follow-up) neither in the controls nor in the ADHD participants. In contrast the repeated measures differed in the ventral striatum in the ADHD participants was on average 24% higher than that at the baseline (the standard error of this relative percentage change is 32%, p<0.01) but the difference was not significant in controls (Figure 1).

The comparison of DAT availability between groups (ADHD vs. Controls) for the baseline scan did not differ (Table 4). It was significantly higher at the 1-year follow-up scan in the caudate (p<0.007) and the putamen (p<0.005) of the ADHD participants than in the controls. There were no differences at follow up on DAT availability between the groups in the ventral striatum.

This study shows that long-term treatment with MPH up-regulated DAT availability in the ventral striatum, providing the first evidence of DAT neuroplasticity after long-term treatment with a clinically relevant dose of MPH in the human brain. DAT is responsible for recycling DA from the extracellular space into the pre-synaptic terminal [14]. The DAT levels in the membrane are regulated by the concentration of extracellular DA; DAT levels decrease when extracellular DA is low and increase when extracellular DA is high [15]. Repeated administration of a variety of stimulant drugs (e.g., cocaine, amphetamine) has been shown to change DAT expression in preclinical models. These studies show different results for stimulant drugs that are DAT blockers, such as cocaine, from those of stimulant drugs that are DA releasers, such as methamphetamine and amphetamine. Cocaine, which like MPH blocks DAT, temporarily increases the expression of DAT after chronic administration [16]. Indeed humans, postmortem and imaging studies have shown increased DAT (20–50%) in the striatum of chronic cocaine abusers when compared with controls [17], [18]. These increases are positively correlated with the severity of cocaine use and can recover with detoxification. This is consistent with an adaptation response to compensate for chronic increases in extracellular DA secondary to repeated cocaine intoxication.

Similarly, subchronic MPH treatment results in an attenuation of DA release in rodents, which was ascribed to either an upregulation of DAT or enhanced autoreceptor sensitivity [19]. In ADHD adults we also recently showed that long-term treatment with clinical doses of MPH resulted in an attenuation of MPH induced DA increases in the striatum [20]. Similar to treatment with other DAT blockers the increased expression of DAT in the striatum after long term MPH treatment in this study might reflect an accelerated clearance of synaptic DA in response to chronic DA enhancement from long-term exposure to MPH [14]. In this study the clinical measures at follow-up were obtained while subjects were under the influence of the medication (MPH), which explains the significant improvement in all of the clinical symptoms. However it would have been desirable to test them also when they were not under the effects of MPH (i.e. in the morning prior to medication intake) to assess if the upregulation of DAT after chronic MPH was associated with impaired performance.

Few studies have investigated the behavioral consequences of long-term exposure to MPH and the extent to which chronic exposure results in tolerance is still a matter of debate. Indeed, studies on the chronic effects of MPH have reported conflicting results with some documenting sensitization to the locomotor effects of MPH [21], others tolerance [22], and others no changes [23]. The reasons for these discrepancies are likely to reflect differences in doses, conditions of drug administration and age of the animals. The findings on the effects of chronic MPH (using doses that are therapeutically relevant), on the rewarding effects of drugs of abuse are also not consistent. Whereas one study reported that MPH pretreatment in preadolescence or in adulthood decreased the rewarding effects of cocaine (as assessed by conditioned place preference) later in life [24], two others [25], [26] reported that chronic MPH treatment in adolescence or in adulthood enhanced cocaine's reinforcing effects (as assessed by cocaine self-administration and the latency for acquisition of self-administration). These behavioral changes are likely to reflect in part changes in brain DA activity since DA is involved both in locomotor activity as well as the rewarding effects of cocaine. In this study, even though the ADHD subjects did not show more hyperactivity as compared to the controls prior to MPH treatment, the SWAN scores for the hyperactivity/impulsivity dimension in the ADHD subjects were significantly reduced after long-term MPH treatment.

We hypothesize that the increased DAT availability is a compensation for the pharmacologic occupancy of DAT (estimated to be greater than 50%) [27] and the increased elevations in synaptic DA. The results of this prospective treatment study and theory of DAT plasticity suggest that some of the discrepancies in the literature regarding the levels of DAT in ADHD may reflect treatment histories. Note also that in some instances the results are confounded by measuring DAT while the pharmacological effects of MPH are still present [28], which would result in lower measures of DAT availability secondary to DAT occupancy by MPH. Thus we postulate that decreased synaptic levels of DA might drive the changes in DAT levels reported in ADHD (which vary to maintain equilibrium of synaptic DA levels in brain).

Here we report an upregulation of DAT secondary to long-term treatment with stimulant medication, which could result in further decreases in dopaminergic signaling when the individual with ADHD is not medicated (i.e. over weekend holidays). To the extent that reduced DA release in ADHD is associated with inattention [29], this could result in more severe inattention and the need for higher doses of medication. Though there is limited literature on loss of efficacy of stimulant medication with long-term treatment this is an area that merits further investigation. Studies are necessary to test if DAT down-regulate after MPH discontinuation and the time necessary for their recovery.