2001, 2002a, 2003, 2010], which are associated with the dorsolateral frontostriatal circuit, whereas it has a beneficial effect on probabilistic reversal learning, associated with the orbital frontostriatal circuit [Cools et al. 2002b, 2006, 2007]. Because the effects of levodopa depend mainly on its ability to elevate dopamine levels in the striatum [Maruyama et al. 1996], the observed different effects on set-shifting and working memory versus reversal learning are most likely due to effects of dopamine in the dorsal and the ventral striatum, respectively, which are known to be connected Inhibitors,research,lifescience,medical to different cortical areas via segregated

frontostriatal circuits [Cools et al. 2006]. This double dissociation is evident

when directly comparing patients ‘on’ and ‘off’ medication and is in line with the ‘dopamine overdose hypothesis’, first formulated by Gotham and colleagues [Gotham et al. 1986], which suggests that the administration of dopaminergic medication to PD patients may replete dopamine-depleted Inhibitors,research,lifescience,medical circuits, but overdose relatively intact ones. Indeed, other recent studies confirmed that in the early stages of PD, the treatment with levodopa has a beneficial effect on DLPFC-related executive functions, including attention, set-shifting, working memory and click here planning [Beato et al. 2008; Fera Inhibitors,research,lifescience,medical et al. 2007; Hanna-Pladdy and Heilman, 2010; Mollion et al. 2003; Molloy et al. 2006; Pascual-Sedano et al. 2008] but has a detrimental effect on OFC-related executive functions, that provide a reward-based control of behavior, as evidenced by poor performances in tasks of decision making under ambiguity Inhibitors,research,lifescience,medical and reversal learning [Jahanshahi et Inhibitors,research,lifescience,medical al. 2010; Rowe et al. 2008]. In advanced PD, when the dopamine depletion affects also the orbital frontostriatal circuit,

levodopa is expected to have beneficial effects also on the executive functions related to this frontostriatal circuit; this prediction is actually not sustained by empirical evidence because no studies assessed OFC-related executive functions in advanced PD patients, probably due to the frequent association with dementia in these later mafosfamide stages, and since severe motor impairment often hampers the neuropsychological assessment and the identification of specific cognitive deficits in these patients [Poletti and Bonuccelli, 2012]. As underlined at the beginning of this section, the majority of studies on the effects of dopaminergic drugs on the cognitive status of PD patients focused on executive prefrontal functions, while very few studies investigated other cognitive functions. The enhancement effect of levodopa involves not only functions that are influenced by executive functions [Martin et al. 2003; Vanderploeg et al. 1994], such as prospective memory and verbal learning [Costa et al. 2008; Mattis et al.