Knutson et al. (2004) investigated
the effects of 0.25 mg/kg oral dAMPH in healthy volunteers, using a similar monetary incentive delay task to the one used here, and found that dAMPH blunted the response in the ventral striatum during reward anticipation. However, since dAMPH not only blocks the DAT (similar to MPH), but also enhances DA release, it is expected that higher synaptic DA concentrations were obtained in the study by Knutson than in the current study. It is thought that the magnitude of phasic DA release in the ventral striatum is reduced by a challenge with a DA agent such selleck chemicals as dAMPH or MPH during anticipation of reward (Knutson et al., 2004), thereby diminishing brain activation. Selleck AUY-922 In dAMPH users we did not observe such a response, providing further evidence for striatal dysfunction. This dysfunction may also be linked to the phenomenon of drug tolerance. It has been shown that repeated dosing with dAMPH leads to a greater behavioral response and can cause an increased DA release in response to a subsequent
challenge which can still be observed one year later (Boileau et al., 2006 and Strakowski et al., 1996). After continued exposure this increased sensitivity disappears and DA release is smaller in response to a similar dose (Jacobs et al., 1981 and Segal and Kuczenski, 1997). One theory states that this is due to depleted DA stores or alterations in D2 auto-receptor function (Kuczenski and Segal, 1997). Using D1 or D2 receptor specific Endonuclease agonists or antagonists, phMRI studies in rats, combined with microdialysis have demonstrated that specific receptor types are responsible for different aspects of the hemodynamic response to a DAergic challenge (Chen et al., 2005, Chen et al., 2010 and Dixon et al., 2005). Where the D1 receptor is only present post-synaptically, the D2 receptor is expressed both pre- and post-synaptically and can inhibit DA release when located on the pre-synaptic neuron (for review see Missale et al., 1998). A lower level of D2 expression may lead to a larger relative percentage of D2 occupation by DA following a challenge,
leading to a blunted hemodynamic response to the MPH administration. This mechanism could be responsible for the blunted response we observed in individuals that used dAMPH on a regular basis. In line with this, a reduction in D2 receptors has been found in non-human primates following chronic dAMPH treatment (Ginovart et al., 1999). Reduced levels of D2 expression may therefore also explain the blunted hemodynamic response observed and this may also be a result of the dAMPH use in our group of dAMPH users. However, a lower D2 expression (linked to increased impulsivity as stated above) could also have been pre-existent to the dAMPH use and causative for the start of psychostimulant use in these subjects.