Preclinical studies have shown that even relatively low doses of dAMPH (equivalent to the doses used in clinical practice) can lead to striatal DA neurotoxicity in rodents and non-human primates (Ricaurte et al., 2005), as evidenced for instance by reductions in striatal DA concentrations and DA transporter (DAT) binding sites. PET studies in dAMPH treated monkeys have shown reductions in striatal [18F]fluoro-l-dopa uptake in vervet monkeys

(Melega et al., BMS-907351 ic50 1996 and Melega et al., 1997). In line with this, in humans, a study by Reneman et al. (2002) has shown that recreational dAMPH use is linked to lower striatal DAT availability. Because the DAT is a structural component of the DA-axon, loss in DAT has been used as a marker for DAergic damage (Reneman et al., 2002). Because dAMPH is frequently prescribed in the treatment of ADHD it is a drug that is relatively easy to obtain for illicit purposes and in fact is misused by subjects both with and without ADHD (Wilens et al., 2008). Therefore it is important to further investigate

DA dysfunction in recreational users of dAMPH. Recreational users, i.e., subjects not being treated for substance abuse, tend to use less frequently and lower dosages than subjects with a substance use disorder. To the best of our knowledge, no other studies have yet investigated the DA system in recreational users of this drug. Studies in abstinent selleck chemicals dAMPH users have demonstrated sustained deficits in several behavioral paradigms, including decision-making (Ersche et al., 2005), memory (Rapeli et al., 2005) and set-shifting (Ornstein et al., 2000). Although functional MRI (fMRI) measures changes in blood oxygenation rather than neurochemistry, it has been suggested that striatal activation during anticipation of reward as measured with fMRI might partially index DAergic function (Schultz, 2002). In addition, fMRI can give region-specific neurovascular responses to a DAergic challenge (Knutson et al., 2004); Willson et al., 2004). In view of this, it is of interest

to investigate anticipation of reward in recreational old users of dAMPH and their reaction to a DA challenge. The combination of a DA challenge with fMRI (pharmacological MRI; phMRI) enables a more direct assessment of DA functions, because brain activity during striatal activation is investigated in addition to the modulating effect of a DA agent (Honey and Bullmore, 2004). A drug that is well known to activate the DA system is methylphenidate (MPH), commonly used in the treatment of ADHD. MPH acts by blocking the DAT, which prevents the reuptake of DA by the presynaptic neuron and thus increases DA concentration in the synaptic cleft. Oral MPH challenges have been used in fMRI investigations involving both healthy and ADHD populations (Shafritz et al., 2004, Bush et al., 2008, Schlosser et al., 2009 and Rubia et al., 2009), but not dAMPH users.