Only a large-scale prospective study, as we previously conducted for MDMA (de Win et al., 2008), will be able to show the causal nature of our findings, and exclude that pre-existing differences (such as low D2 receptor availability) underlie our findings. Addiction has also long been associated with aberrant reward-related Z-VAD-FMK molecular weight responses (for a review see Volkow et al., 2011). It has been demonstrated that alcoholics show reduced ventral striatum activation during the anticipation of monetary gain (Wrase et al., 2007)

and a correlation between this response and impulsivity measures has also been reported (Beck et al., 2009). However, cocaine dependent were not different from healthy controls in the anticipation of reward (Asensio et al., 2010). Therefore addiction alone cannot be held exclusively responsible for the changes in reward-related behavior. Although we cannot exclude that the participants in our study were addicted, they clearly stated that they were recreational dAMPH users and not diagnosed with addiction or substance abuse in the past. Moreover, they used dAMPH “only” 28 times per year, which is about once every two weeks and this can

hardly be called addictive use of dAMPH with loss of control. Therefore, it is unlikely that addiction-related changes in the mesolimbic DA pathway involved in drug-reward selleck inhibitor are the predominant mechanism underlying our results. Another explanation for the reduced sensitivity for reward in the recreational dAMPH users is that this is caused by neurotoxic changes induced by chronic dAMPH use. This interpretation

is based on a large body of preclinical studies, such as that from Ricaurte et al. (2005) who observed a reduction in the number of both DAT and vesicular science monoamine transporter (VMAT) in non-human primates treated with a dAMPH in a regimen similar to the one used in the treatment of patients with ADHD (Ricaurte et al., 2005). In addition, PET studies in amphetamine treated vervet monkeys have shown reductions in striatal [18F]fluoro-l-dopa uptake (Melega et al., 1996 and Melega et al., 1997) and reductions in DAT have been observed in combined dAMPH and MDMA users using [123I]β-CIT SPECT (Reneman et al., 2002). Furthermore, studies on the striatal DAergic system in rats have shown that chronic dAMPH exposure results in neurotoxicity characterized by decreases in DA levels and DAT densities, swollen nerve terminals and degenerated axons (Ricaurte et al., 1984). Given the large body of evidence directly documenting the DAergic neurotoxic potential of dAMPH in rodents and nonhuman primates, and because reward functions are strongly connected to the DA system, our data provide further evidence that recreational use of dAMPH is associated with DAergic dysfunction, as evidenced by a reduced activation during reward anticipation.