1986). This variability may depend on differential levels of exposure to chronic dopaminergic therapy that might normalize the receptor number and/or sensitivity (i.e., patients with advanced PD would have been more exposed to chronic dopaminergic therapy when compared with patients with intermediate PD stages) (Alexander et al. 1993). However, it is also possible that molecular mechanisms independent

from drug therapy intervene Inhibitors,research,lifescience,medical to reduce the D2 receptor number and/or sensitivity over time. There is indeed evidence that the number and/or sensitivity of D2 SB431542 receptors decreases in Parkinsonian monkeys with chronic nigrostriatal lesion even if they did not receive dopaminergic therapy (Decamp et al. 1999). Nonetheless, differences in treatment duration in our PD patients may have played a role in determining Inhibitors,research,lifescience,medical the sensitivity of D2 receptors and thus the heterogeneity of their brain responses to apomorphine. It is also noteworthy that apomorphine decreased activation of the SFG, a specific PFC region linked to stimulus manipulation during working memory (du Boisgueheneuc Inhibitors,research,lifescience,medical et al. 2006). SFG is linked to basal-ganglia circuits involved in filtering irrelevant information during working memory (Moustafa et al. 2008; Baier et al. 2010); hence, apomorphine might indirectly alter the SFG function via dopaminergic receptors in the striatum. Our finding that DAT striatal levels

modulated BOLD responses to apomorphine in SFG during all working-memory loads support this hypothesis. Alternatively, apomorphine might influence dopaminergic receptors Inhibitors,research,lifescience,medical on cortical neurons within the SFG itself. This possibility is supported by previous research in behaving monkeys showing that excessive levels of D1 receptor stimulation reduce delay-related firing of PFC neurons and erode the tuning of their responses during working memory (Vijayraghavan et al. 2007). In line with a recent staging model

of executive dysfunctions and mental fatigue in PD (de la Fuente-Fernandez 2012), it is also possible that apomorphine stimulation “overdosed” Inhibitors,research,lifescience,medical the direct VTA-PFC dopaminergic pathways via D4 receptors, a D2 receptor family expressed in the neocortex and implicated in the pathophysiology of a range of neuropsychiatric disorders (Oak et al. 2000; Wang et al. 2002). Two other PFC areas (i.e., the found inferior frontal gyrus, IFG, and the dACC) showed a significant modulation by the striatal DAT levels and apomorphine therapy. The IFG has been consistently associated with response inhibition, a key neuropsychological function during working-memory tasks that require response inhibition (Aron and Poldrack 2005, 2006; Aron 2011). In contrast, the dACC has been linked to error and conflict monitoring, two other fundamental processes to execute a wide range of cognitive paradigms (van Veen and Carter 2002; Hester et al.