Role of dopamine in the therapeutic and reinforcing effects of methylphenidate in humans: results from imaging studies

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Abstract

Methylphenidate is the most commonly prescribed drug for the treatment of ADHD. We have used positron emission tomography to assess the role that methylphenidate’s effects in brain dopamine have on its therapeutic and reinforcing effects. We have documented that in the human brain therapeutic doses of methylphenidate block more than 50% of the dopamine transporters and significantly enhance extracellular DA, an effect that appears to be modulated by the rate of DA release. Thus, we postulate that methylphenidate’s therapeutic effects are in part due to amplification of DA signals, that variability in responses is in part due to differences in DA tone and that methylphenidate’s effects are context dependent. Methylphenidate-induced increases in DA are also associated with its reinforcing effects but only when this occurs rapidly, as with intravenous administration. Moreover, abuse of methylphenidate is constrained by its long half-life, which we postulate limits the frequency at which it can be administered.

Introduction

Methylphenidate (MP) is the most commonly prescribed psychotropic medication for children in the United States (Greenhill et al., 2002). It is the drug of choice for the treatment of attention deficit disorder (ADD), which is the most common behavioral disorder of childhood; its prevalence is estimated to be 5–10% of the general population (Swanson et al., 1998). MP is very effective for the treatment of ADHD; it is estimated that 60–70% of ADHD subjects have favorable responses (Swanson et al., 1991). MP is also used for the treatment of narcolepsy (Littner et al., 2001) and has been used as an antidepressant (Challman and Lipsky, 2000; Chiarello and Cole, 1987), particularly in the treatment of medically ill withdrawn elderly patients (Rozans et al., 2001; Kaufman et al., 1984).

Though MP has been used therapeutically for the past 50 years its mechanism(s) of action is poorly understood. MP is a stimulant drug that blocks the dopamine (DA) and the norepinephrine transporter and it is hypothesized that these pharmacological actions are relevant to its therapeutic effects (Solanto, 1998). Particularly relevant are its effects on DA transporters (DAT) in view of the recent findings documenting significant increases in DAT in subjects with ADHD (Dougherty et al., 1999; Krause et al., 2000) and the reported association between expression of the DAT1 allele and scores of hyperactivity–impulsivity in subjects with ADHD (Waldman et al., 1998). MP’s effects on the DAT are also relevant since the reinforcing effects of cocaine have been related to its ability to block DAT (Ritz et al., 1987), which has raised concerns about the abuse liability of MP, which is currently classified as a schedule 2 drug of the Controlled Substance Act (Parran and Jasinski, 1991). Because cocaine and MP have similar affinities for the DAT (Ki for inhibition of DA uptake correspond to 640 and 390 nM, respectively), one might predict similar reinforcing properties for cocaine and for MP if the only variables contributing to reinforcement are affinity for DAT and bioavailability. While MP is self-administered by animals (Bergman et al., 1989; Johanson and Shuster, 1975) and abused by humans (Kollins et al., 2001; Llana and Crismon, 1999), its abuse in humans appears to be much more limited than that of cocaine (Parran and Jasinski, 1991). Although, socioeconomic factors (drug availability in the streets, fashions in the drug culture) could account for the higher rate of cocaine abuse than that of MP, it is possible that pharmacological differences (i.e., pharmacokinetics) are responsible for the differences in abuse liability of these two drugs.

We have used positron emission tomography (PET) with different radiotracers to investigate the effects of MP on the brain DA system in human subjects. Specifically we have used PET to measure the spatial distribution and kinetics of MP and its enantiomers labeled with carbon-11 (positron emitting radioisotope with a 20-min half life), to assess its potency in the human brain in blocking DAT and in increasing DA, to investigate the mechanisms responsible for the variability among subjects in the responses to MP and to assess its dependency to the context of its administration.

Section snippets

Distribution and pharmacokinetics of methylphendiate in the human brain

MP was labeled with carbon-11 to measure its regional distribution and pharmacokinetics in the human brain and to assess the relationship between its pharmacokinetics in brain and the temporal patterns of its behavioral effects (Volkow et al., 1995). The uptake of [11C]methylphenidate in brain was high and corresponded approximately to 10% of the injected dose. The highest uptake of MP occurred in the basal ganglia where it bound to DAT. MP entered the brain rapidly (8–10 min) and had a

Distribution and kinetics of methylphendiate’s enantiomers in human brain

MP is a racemic mixture composed of d-threo and l-threo enantiomers and it is believed that the d-enantiomer is responsible for the therapeutic effects of MP. We used PET to compare the regional brain distribution and binding characteristics of the two enantiomers of MP in the human brain (Ding et al., 1997). The brain distribution of the two enantiomers differed; whereas [11C]d-threo-MP had the highest regional uptake in basal ganglia, [11C]l-threo-MP had an homogeneous distribution throughout

Dopamine transporter blockade by methylphenidate in human brain

We measured the levels of DAT occupancy by different doses of intravenous MP (Volkow et al., 1999a). MP was very effective in blocking DAT and it induced a dose-dependent blockade that corresponded to 35±5% for 0.025 mg/kg; 62±13% for 0.1 mg/kg; 67±3% for 0.25 mg/kg i.v. and 78±11% for 0.5 mg/kg (Fig. 5A). The ED50 (dose required to block 50% of the DAT) for MP corresponded to 0.075 mg/kg). This ED50 was lower than that we had previously obtained for cocaine, which corresponded to 0.13 mg/kg.

Methylphendiate-induced increases in extracellular dopamine in human brain

Though DAT blockade is the initial pharmacological effect of MP or of cocaine, it is the increase in DA and the activation of DA receptors that are responsible for their behavioral effects (Egilmez et al., 1995). Though there are multiple studies documenting the importance of DA receptor activation by DA in the reinforcing effects of psychostimulants in laboratory animals (De Wit and Wise, 1977; Richardson et al., 1994; Self et al., 1996), its relevance in humans had not been investigated. To

Context dependency for methylphenidate’s effects

MP is a DAT blocker (Kuczenski and Segal, 1997) and hence it amplifies DA release resultant from DA cell firing, which in turn is responsive to environmental stimulation (Overton and Clark, 1997). We hypothesize that MP’s therapeutic effects are a result of DA signal amplification (Volkow et al., 2001), which implies that MP-induced DA increases are dependent on DA cell activity and predicts that MP’s effects should be context dependent. If this hypothesis is correct, then MP-induced DA

Intersubject variability in response to methylphenidate

Though MP is very effective for the treatment of ADHD the doses required to achieve clinical responses vary significantly across individuals (0.1–1 mg/kg) (Swanson et al., 1991). Similarly the responses to MP when given in a laboratory setting for research purposes are also quite variable. Though the mechanisms underlying this variability in response to MP are not properly understood here we report on a series of studies that provide some light on some of the mechanisms, other than differences

Summary

Imaging studies have corroborated the relevance that MP induced increases in extracellular DA have on its reinforcing and therapeutic effects and they have also highlighted the importance that the kinetics of the DA changes and of its interaction with DA D2 receptors have on reward. Based on the results from these imagine studies we postulate that:

(1) MP’s therapeutic effects of MP are a result of amplification of weak DA signals, which results in an increase in signal to noise ratio for target

Acknowledgements

This research was supported in part by the US Department of Energy (office of Health and Environmental Research) under Contract DE-ACO2-76CH00016 and the Institute of Drug Abuse under Grants No. DA 06891, DA 09490, and DA 06278.

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