A significant group × drug challenge interaction was found in the left putamen for the anticipation of reward vs. anticipation of a neutral condition contrast (Fig. 2, panel C). The mean percentage signal change as shown for the striatum in Fig. 3 during reward anticipation

confirms the different effects induced by reward anticipation in both groups, and the effect of MPH there upon: under activation in the dAMPH users at baseline (without MPH) and reduced brain activation after the MPH challenge in the controls. Moreover, in the dAMPH RAD001 in vitro users, the left putamen became more strongly activated during anticipation of reward after the MPH challenge. No interaction effects for the other contrasts (loss versus neutral, reward versus loss, large reward versus small reward) were observed. We observed a different striatal response following MK0683 a monetary incentive delay task in recreational dAMPH users compared to healthy controls. This task has been found to robustly activate the nucleus accumbens and the caudate when anticipating reward, where receiving the actual reward mainly elicits a response

in the medial PFC (Knutson et al., 2001 and Haber and Knutson, 2010). When anticipating reward, dAMPH users showed diminished striatal activation in comparison to control subjects. We also observed a statistically different effect of a DA challenge in which MPH induced a decrease in striatal activation during reward anticipation in healthy controls, whereas no effect in dAMPH users was found. No effects of group or challenge were observed on anticipation of loss and size of the reward. One of the explanations for the lower reward anticipation found in recreational dAMPH users may be an innate hypofunction of the

DAergic system, which, in turn, may reflect increased sensitivity toward dAMPH (ab)use and or addiction. A leading theory about addiction states that reduced sensitivity for natural reinforcers underlies the development of addiction (also referred to as the reward deficiency hypothesis; Comings and Blum, 2000). According to this theory, the dAMPH group may have an innate DAergic hypofunction, which, in turn, old has predisposed them to developing a penchant for stimulant use. Indeed, even after prolonged abstinence, lower D2 receptor availability in a wide variety of addicted individuals has been reported (for review see Volkow et al., 2009). In addition, lower D2 receptor availability has been linked to increased impulsivity measures (Buckholtz et al., 2010), which in itself has been put forward as a component cause for the development of addiction (for review see Hommer et al., 2011). Thus, it is possible that our findings may not relate to dAMPH use, but rather increased impulsivity due to low D2 receptor availability.